Intranasal Administration of PACAP: Uptake by Brain and Brain Region Targeting with Cyclodextrins

PubMed Central

Nonaka, Naoko; Farr, Susan A.; Nakamachi, Tomoya; Morley, John E.; Nakamura, Masanori; Shioda, Seiji; Banks, William A.

2012-01-01

Pituitary adenylate cyclase activating polypeptide (PACAP) is a potent neurotrophic and neuroprotectant that is transported across the blood-brain barrier in amounts sufficient to affect brain function. However, its short half-life in blood makes it difficult to administer peripherally. Here, we determined whether the radioactively labeled 38 amino acid form of PACAP can enter the brain after intranasal (i.n.) administration. Occipital cortex and striatum were the regions with the highest uptake, peaking at levels of about 2-4 percent of the injected dose per g of brain region. Inclusion of unlabeled PACAP greatly increased retention of I-PACAP by brain probably because of inhibition of the brain-to-blood efflux transporter for PACAP located at the blood-brain barrier. Sufficient amounts of PACAP could be delivered to the brain to affect function as shown by improvement of memory in aged SAMP8 mice, a model of Alzheimer’s disease. We found that each of three cyclodextrins when included in the i.n. injection produced a unique distribution pattern of I-PACAP among brain regions. As examples, β-cyclodextrin greatly increased uptake by the occipital cortex and hypothalamus, α-cyclodextrin increased uptake by the olfactory bulb and decreased uptake by the occipital cortex and striatum, and (2-hydropropyl)-β-cyclodextrin increased uptake by the thalamus and decreased uptake by the striatum. These results show that therapeutic amounts of PACAP can be delivered to the brain by intranasal administration and that cyclodextrins may be useful in the therapeutic targeting of peptides to specific brain regions. PMID:22687366

Metabolism of Cryptic Peptides Derived from Neuropeptide FF Precursors: The Involvement of Insulin-Degrading Enzyme

PubMed Central

Grasso, Giuseppe; Mielczarek, Przemyslaw; Niedziolka, Magdalena; Silberring, Jerzy

2014-01-01

The term “cryptome” refers to the subset of cryptic peptides with bioactivities that are often unpredictable and very different from the parent protein. These cryptic peptides are generated by proteolytic cleavage of proteases, whose identification in vivo can be very challenging. In this work, we show that insulin-degrading enzyme (IDE) is able to degrade specific amino acid sequences present in the neuropeptide pro-NPFFA (NPFF precursor), generating some cryptic peptides that are also observed after incubation with rat brain cortex homogenate. The reported experimental findings support the increasingly accredited hypothesis, according to which, due to its wide substrate selectivity, IDE is involved in a wide variety of physiopathological processes. PMID:25247577

Platelets are responsible for the accumulation of β-amyloid in blood clots inside and around blood vessels in mouse brain after thrombosis.

PubMed

Kucheryavykh, Lilia Y; Dávila-Rodríguez, Josué; Rivera-Aponte, David E; Zueva, Lidia V; Washington, A Valance; Sanabria, Priscilla; Inyushin, Mikhail Y

2017-01-01

Platelets contain beta-amyloid precursor protein (APP) as well as Aβ peptide (Aβ) that can be released upon activation. During thrombosis, platelets are concentrated in clots and activated. We used in vivo fluorescent analysis and electron microscopy in mice to determine to what degree platelets are concentrated in clots. We used immunostaining to visualize Aβ after photothrombosis in mouse brains. Both in vivo results and electron microscopy revealed that platelets were 300-500 times more concentrated in clots than in non-clotted blood. After thrombosis in control mice, but not in thrombocytopenic animals, Aβ immunofluorescence was present inside blood vessels in the visual cortex and around capillaries in the entorhinal cortex. The increased concentration of platelets allows enhanced release of Aβ during thrombosis, suggesting an additional source of Aβ in the brains of Alzheimer's patients that may arise if frequent micro-thrombosis events occur in their brains. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS Aβ Reduction

PubMed Central

2012-01-01

Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer’s disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats. PMID:23412139

Markers of Alzheimer's Disease in Primary Visual Cortex in Normal Aging in Mice

PubMed Central

Perez-Hernández, Montserrat; Torres-Romero, Abigail; Gorostieta-Salas, Elisa; Gulias-Cañizo, Rosario; Quiroz-Mercado, Hugo

2017-01-01

Aging is the principal risk factor for the development of Alzheimer's disease (AD). The hallmarks of AD are accumulation of the amyloid-β peptide 1–42 (Aβ42) and abnormal hyperphosphorylation of Tau (p-Tau) protein in different areas of the brain and, more recently reported, in the visual cortex. Recently, Aβ42 peptide overproduction has been involved in visual loss. Similar to AD, in normal aging, there is a significant amyloid deposition related to the overactivation of the aforementioned mechanisms. However, the mechanisms associated with visual loss secondary to age-induced visual cortex affectation are not completely understood. Young and aged mice were used as model to analyze the presence of Aβ42, p-Tau, glial-acidic fibrillary protein (GFAP), and presenilin-2, one of the main enzymes involved in Aβ42 production. Our results show a significant increase of Aβ42 deposition in aged mice in the following cells and/or tissues: endothelial cells and blood vessels and neurons of the visual cortex; they also show an increase of the expression of GFAP and presenilin-2 in this region. These results provide a comprehensive framework for the role of Aβ42 in visual loss due to inflammation present with aging and offer some clues for fruitful avenues for the study of healthy aging. PMID:29138750

[Proteolytic events in the maturation of pro-neuropeptides. The somatostatin model].

PubMed

Morel, A; Gluschankof, P; Gomez, S; Cohen, P

1986-01-01

The post-translational processing (maturation) of the precursors was studied on the model of the prosomatostatin. We have shown the presence of a single and common precursor to both somatostatin -28 and -14 in mouse hypothalamus, in contrast with the situation in the Teleostean fish, Lophius piscatorius. The search for a maturation activity was carried out using a synthetic undecapeptide substrate including in its sequence the cleavage site for somatostatin-14 release. Using this peptide, we characterized in rat brain cortex extracts a specific enzyme activity of 90 kD. This "maturase", colocalized in the neurosecretory granules with the somatostatin products, generates both the N-terminal peptide S-28, and the tetradecapeptide hormone (S-14) from the somatostatin-28, acting as a "S-28 convertase" producing free Arg and Lys residues present at the pair of basic amino acids signal. We propose a model where three peptide bonds are cleaved by this enzymatic activity. In the teleostean fish: Lophius piscatorius, two precursors coding for two different somatostatin were predicted by the determination of cDNA sequence. In this system, we observed the presence of a unique form of the tetradecapeptide hormone. We show that the final maturation product of the second precursor is a new 28 amino acid hormone called Somatostatin-28 II. Moreover, the product of this second gene after the action of the Somatostatin-28 convertase from rat brain cortex is the (Tyr7, Gly 10)S-14 derivative predicted by the clone.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional metabolism of Met-enkephalin and cholecystokinin on intact ratbrain slices: characterization of specific peptidases.

PubMed

Konkoy, C S; Davis, T P

1995-12-01

The metabolism of Met-enkephalin and cholecystokinin (CCK) 8-(sulfated) by intact microslices was studied in rat brain regions. Incubation of brain slices with Met-enkephalin (400 microM) resulted in a linear rate of disappearance of parent peptide and appearance of metabolic fragments whose rate of accumulation was specific to brain region. The degradative rate (pmol/min/mg of protein) of Met-enkephalin was high in caudate-putamen (5,160 +/- 120) and lower in nucleus accumbens (3,630 +/- 110) and frontal cortex (3,180 +/- 120). Inhibition of aminopeptidases decreased Met-enkephalin degradation (50-97% vs. control) in frontal cortex but was less effective in caudate-putamen (20-34%). Tyr-Gly-Gly and Phe-Met were recovered in caudate-putamen and nucleus accumbens, whereas negligible quantities of these fragments were recovered from frontal cortex. Phosphoramidon, an inhibitor of neutral endopeptidase 24.11, decreased Met-enkephalin degradation in caudate-putamen (14%) but had no effect on that in frontal cortex. A cocktail of bestatin or leuhistin (inhibitors of aminopeptidases), phosphoramidon, and captopril (an inhibitor of angiotensin converting enzyme) protected Met-enkephalin from degradation (recovery > 95%) in caudate-putamen. CCK 8-(sulfated) degradation on slices from caudate-putamen, nucleus accumbens, and frontal cortex was not altered by inhibitors of neutral endopeptidase 24.11, metalloendopeptidase 24.15, angiotensin converting enzyme, or thiol proteases. Inhibitors of either aminopeptidases or serine proteases produced small reductions (13-30%) in CCK degradation in each region. These data provide evidence for regional and structural specificity in terminating the actions of neuropeptides.

Pediatric respiratory and systemic effects of chronic air pollution exposure: nose, lung, heart, and brain pathology.

PubMed

Calderón-Garcidueñas, Lilian; Franco-Lira, Maricela; Torres-Jardón, Ricardo; Henriquez-Roldán, Carlos; Barragán-Mejía, Gerardo; Valencia-Salazar, Gildardo; González-Maciel, Angelica; Reynoso-Robles, Rafael; Villarreal-Calderón, Rafael; Reed, William

2007-01-01

Exposures to particulate matter and gaseous air pollutants have been associated with respiratory tract inflammation, disruption of the nasal respiratory and olfactory barriers, systemic inflammation, production of mediators of inflammation capable of reaching the brain and systemic circulation of particulate matter. Mexico City (MC) residents are exposed to significant amounts of ozone, particulate matter and associated lipopolysaccharides. MC dogs exhibit brain inflammation and an acceleration of Alzheimer's-like pathology, suggesting that the brain is adversely affected by air pollutants. MC children, adolescents and adults have a significant upregulation of cyclooxygenase-2 (COX2) and interleukin-1beta (IL-1beta) in olfactory bulb and frontal cortex, as well as neuronal and astrocytic accumulation of the 42 amino acid form of beta -amyloid peptide (Abeta 42), including diffuse amyloid plaques in frontal cortex. The pathogenesis of Alzheimer's disease (AD) is characterized by brain inflammation and the accumulation of Abeta 42, which precede the appearance of neuritic plaques and neurofibrillary tangles, the pathological hallmarks of AD. Our findings of nasal barrier disruption, systemic inflammation, and the upregulation of COX2 and IL-1beta expression and Abeta 42 accumulation in brain suggests that sustained exposures to significant concentrations of air pollutants such as particulate matter could be a risk factor for AD and other neurodegenerative diseases.

Mitochondrial accumulation of APP and Aβ: significance for Alzheimer disease pathogenesis

PubMed Central

Pavlov, Pavel F; Petersen, Camilla Hansson; Glaser, Elzbieta; Ankarcrona, Maria

2009-01-01

Accumulating evidence suggest that alterations in energy metabolism are among the earliest events that occur in the Alzheimer disease (AD) affected brain. Energy consumption is drastically decreased in the AD-affected regions of cerebral cortex and hippocampus pointing towards compromised mitochondrial function of neurons within specific brain regions. This is accompanied by an elevated production of reactive oxygen species contributing to increased rates of neuronal loss in the AD-affected brain regions. In this review, we will discuss the role of mitochondrial function and dysfunction in AD. We will focus on the consequences of amyloid precursor protein and amyloid-β peptide accumulation in mitochondria and their involvement in AD pathogenesis. PMID:19725915

[Intranasal epitalon infusion modulates neuronal activity in the rat neocortex].

PubMed

Sibarov, D A; Vol'nova, A B; Frolov, D S; Nosdrachev, A D

2006-08-01

Properties of tetrapeptide epitalon (Ala-Glu-Asp-Gly) constructed on the basis of pineal peptide extract, have been studied. The intranasal infusions: a noninvasive way to deliver this peptide to CNS hypassing the blood-brain barrier, was used. The aim of the study is to estimate epitalon action on rat motor cortex spontaneous activity. Wistar male rats were anesthetized with urethane (1 g/kg). Extracellular unit recording was made using glass microelectrodes (1-2 MOhm). After recording of spontaneous activity (10-15 min), epitalon intranasal infusion (2 ng) was followed by 30-minute recording. Within a few minutes after the infusion, significant activation of neural activity was observed (2-2.5-fold higher frequency of neuronal spikes). Complex response consisting of several phases was identified in some recordings. The spikes frequency growth during 5 to 7 min (first phase) after the infusion was followed by the second (11-12 min) and the third (17-18 min) phases. An increase of neuronal spontaneous activity was conditioned by the higher frequency of already active units and by the involvement of previously silent cells. At least the first phase of epitalon action can be explained by direct action of the peptide on the cells of the motor cortex.

Cerebral Apolipoprotein-D Is Hypoglycosylated Compared to Peripheral Tissues and Is Variably Expressed in Mouse and Human Brain Regions.

PubMed

Li, Hongyun; Ruberu, Kalani; Karl, Tim; Garner, Brett

2016-01-01

Recent studies have shown that cerebral apoD levels increase with age and in Alzheimer's disease (AD). In addition, loss of cerebral apoD in the mouse increases sensitivity to lipid peroxidation and accelerates AD pathology. Very little data are available, however, regarding the expression of apoD protein levels in different brain regions. This is important as both brain lipid peroxidation and neurodegeneration occur in a region-specific manner. Here we addressed this using western blotting of seven different regions (olfactory bulb, hippocampus, frontal cortex, striatum, cerebellum, thalamus and brain stem) of the mouse brain. Our data indicate that compared to most brain regions, the hippocampus is deficient in apoD. In comparison to other major organs and tissues (liver, spleen, kidney, adrenal gland, heart and skeletal muscle), brain apoD was approximately 10-fold higher (corrected for total protein levels). Our analysis also revealed that brain apoD was present at a lower apparent molecular weight than tissue and plasma apoD. Utilising peptide N-glycosidase-F and neuraminidase to remove N-glycans and sialic acids, respectively, we found that N-glycan composition (but not sialylation alone) were responsible for this reduction in molecular weight. We extended the studies to an analysis of human brain regions (hippocampus, frontal cortex, temporal cortex and cerebellum) where we found that the hippocampus had the lowest levels of apoD. We also confirmed that human brain apoD was present at a lower molecular weight than in plasma. In conclusion, we demonstrate apoD protein levels are variable across different brain regions, that apoD levels are much higher in the brain compared to other tissues and organs, and that cerebral apoD has a lower molecular weight than peripheral apoD; a phenomenon that is due to the N-glycan content of the protein.

C-type natriuretic peptide and atrial natriuretic peptide receptors of rat brain.

PubMed

Brown, J; Zuo, Z

1993-03-01

Natriuretic peptide receptors in rat brain were mapped by in vitro autoradiography using 125I-labeled [Tyr0]CNP-(1-22) to bind atrial natriuretic peptide receptor (ANPR)-B and ANPR-C receptors selectively, and 125I-labeled alpha-ANP to select ANPR-A and ANPR-C receptors. Des-[Gln18,Ser19,Gly20,Leu21,Gly22]ANP-(4- 23)-amide (C-ANP) was used for its selectivity for ANPR-C over ANPR-A. Specific binding of 125I-[Tyr0]CNP-(1-22) with a dissociation constant (Kd) approximately 1 nM occurred in olfactory bulb, cerebral cortex, lateral septal nucleus, choroid plexus, and arachnoid mater. This binding was abolished by C-type natriuretic peptide [CNP-(1-22)], alpha-ANP and C-ANP, and conformed to ANPR-C. 125I-alpha-ANP bound to all structures that bound 125I-[Tyr0]CNP-(1-22). This binding was also inhibited by both CNP-(1-22) and C-ANP, confirming the presence of ANPR-C-like binding sites. However, ANPR-C-like binding sites were heterogenous because only some had high affinities for 125I-[Tyr0]CNP-(1-22) and CNP-(1-22). 125I-alpha-ANP also bound sites without affinities for C-ANP or CNP-(1-22). These sites were consistent with ANPR-A. They occurred mainly on the olfactory bulb, the choroid plexus, and the subfornical organ. Guanosine 3',5'-cyclic monophosphate production was strongly stimulated by alpha-ANP but not by CNP-(1-22) in olfactory bulb. Neither ligand stimulated it in cortical tissue. Thus the natriuretic peptide binding sites of rat brain conformed to ANPR-A and to heterogenous ANPR-C-like sites. No ANPR-B were detected.

Markers of Alzheimer's Disease in Primary Visual Cortex in Normal Aging in Mice.

PubMed

Hernández-Zimbrón, Luis Fernando; Perez-Hernández, Montserrat; Torres-Romero, Abigail; Gorostieta-Salas, Elisa; Gonzalez-Salinas, Roberto; Gulias-Cañizo, Rosario; Quiroz-Mercado, Hugo; Zenteno, Edgar

2017-01-01

Aging is the principal risk factor for the development of Alzheimer's disease (AD). The hallmarks of AD are accumulation of the amyloid- β peptide 1-42 (A β 42) and abnormal hyperphosphorylation of Tau (p-Tau) protein in different areas of the brain and, more recently reported, in the visual cortex. Recently, A β 42 peptide overproduction has been involved in visual loss. Similar to AD, in normal aging, there is a significant amyloid deposition related to the overactivation of the aforementioned mechanisms. However, the mechanisms associated with visual loss secondary to age-induced visual cortex affectation are not completely understood. Young and aged mice were used as model to analyze the presence of A β 42, p-Tau, glial-acidic fibrillary protein (GFAP), and presenilin-2, one of the main enzymes involved in A β 42 production. Our results show a significant increase of A β 42 deposition in aged mice in the following cells and/or tissues: endothelial cells and blood vessels and neurons of the visual cortex; they also show an increase of the expression of GFAP and presenilin-2 in this region. These results provide a comprehensive framework for the role of A β 42 in visual loss due to inflammation present with aging and offer some clues for fruitful avenues for the study of healthy aging.

Rosuvastatin ameliorates cognitive impairment in rats fed with high-salt and cholesterol diet via inhibiting acetylcholinesterase activity and amyloid beta peptide aggregation.

PubMed

Husain, I; Akhtar, M; Abdin, M Zainul; Islamuddin, M; Shaharyar, M; Najmi, A K

2018-04-01

Amyloid beta (Aβ) peptide aggregation and cholinergic neurodegeneration are involved in the development of cognitive impairment. Therefore, in this article, we examined rosuvastatin (RSV), an oral hypolipidemic drug, to determine its potential as a dual inhibitor of acetylcholinesterase (AChE) and Aβ peptide aggregation for the treatment of cognitive impairment. Molecular docking study was done to examine the affinity of RSV with Aβ 1-42 and AChE in silico. We also employed neurobehavioral activity tests, biochemical estimation, and histopathology to study the anti-Aβ 1-42 aggregation capability of RSV in vivo. Molecular docking study provided evidence that RSV has the best binding conformer at its receptor site or active site of an enzyme. The cognitive impairment in female Wistar rats was induced by high-salt and cholesterol diet (HSCD) ad libitum for 8 weeks. RSV ameliorated serum cholesterol level, AChE activity, and Aβ 1-42 peptide aggregations in HSCD induced cognitive impairment. In addition, RSV-treated rats showed greater scores in the open field (locomotor activity) test. Moreover, the histopathological studies in the hippocampus and cortex of rat brain also supported that RSV markedly reduced the cognitive impairment and preserved the normal histoarchitectural pattern of the hippocampus and cortex. Taken together, these data indicate that RSV may act as a dual inhibitor of AChE and Aβ 1-42 peptide aggregation, therefore suggesting a therapeutic strategy for cognitive impairment treatment.

Ghrelin mimics fasting to enhance human hedonic, orbitofrontal cortex, and hippocampal responses to food.

PubMed

Goldstone, Anthony P; Prechtl, Christina G; Scholtz, Samantha; Miras, Alexander D; Chhina, Navpreet; Durighel, Giuliana; Deliran, Seyedeh S; Beckmann, Christian; Ghatei, Mohammad A; Ashby, Damien R; Waldman, Adam D; Gaylinn, Bruce D; Thorner, Michael O; Frost, Gary S; Bloom, Stephen R; Bell, Jimmy D

2014-06-01

Ghrelin, which is a stomach-derived hormone, increases with fasting and energy restriction and may influence eating behaviors through brain hedonic reward-cognitive systems. Therefore, changes in plasma ghrelin might mediate counter-regulatory responses to a negative energy balance through changes in food hedonics. We investigated whether ghrelin administration (exogenous hyperghrelinemia) mimics effects of fasting (endogenous hyperghrelinemia) on the hedonic response and activation of brain-reward systems to food. In a crossover design, 22 healthy, nonobese adults (17 men) underwent a functional magnetic resonance imaging (fMRI) food-picture evaluation task after a 16-h overnight fast (Fasted-Saline) or after eating breakfast 95 min before scanning (730 kcal, 14% protein, 31% fat, and 55% carbohydrate) and receiving a saline (Fed-Saline) or acyl ghrelin (Fed-Ghrelin) subcutaneous injection before scanning. One male subject was excluded from the fMRI analysis because of excess head motion, which left 21 subjects with brain-activation data. Compared with the Fed-Saline visit, both ghrelin administration to fed subjects (Fed-Ghrelin) and fasting (Fasted-Saline) significantly increased the appeal of high-energy foods and associated orbitofrontal cortex activation. Both fasting and ghrelin administration also increased hippocampus activation to high-energy- and low-energy-food pictures. These similar effects of endogenous and exogenous hyperghrelinemia were not explicable by consistent changes in glucose, insulin, peptide YY, and glucagon-like peptide-1. Neither ghrelin administration nor fasting had any significant effect on nucleus accumbens, caudate, anterior insula, or amygdala activation during the food-evaluation task or on auditory, motor, or visual cortex activation during a control task. Ghrelin administration and fasting have similar acute stimulatory effects on hedonic responses and the activation of corticolimbic reward-cognitive systems during food evaluations. Similar effects of recurrent or chronic hyperghrelinemia on an anticipatory food reward may contribute to the negative impact of skipping breakfast on dietary habits and body weight and the long-term failure of energy restriction for weight loss. © 2014 American Society for Nutrition.

Effects of female sex hormones on expression of the Ang-(1-7)/Mas-R/nNOS pathways in rat brain.

PubMed

Cheng, Yuan; Li, Qiaoying; Zhang, Yidan; Wen, Quan; Zhao, Jianjun

2015-11-01

Female sex hormones are considered to reduce the risk of ischemic stroke. As a part of the renin-angiotensin system, angiotensin-(1-7) [Ang-(1-7)] has recently been reported to play a role in protecting neuronal tissues from ischemic stroke. Thus, we examined the effects of female sex hormones on the levels of Ang-(1-7) and its downstream pathways in the brain. Female rats were ovariectomized and 17β-estradiol (17β-EST), progesterone (PGR), or a combination of 17β-EST plus PGR were administered. Our data demonstrated that lack of female sex hormones significantly decreased the levels of Ang-(1-7) in the cerebral cortex and hippocampal CA1 area. Also, we observed a linear relationship between cortex levels of Ang-(1-7) and plasma brain natriuretic peptide levels (as an indicator for risk of ischemic stroke). We further showed that lack of female sex hormones decreased the expression of Ang-(1-7), Mas-receptor (Mas-R), and neuronal nitric oxide synthase (nNOS). Overall, our findings show for the first time that Ang-(1-7) and Mas-R/nNOS in the cortex are influenced by circulating 17β-EST and (or) PGR, whereas Ang-(1-7) and its pathways in the hippocampal CA1 area are primarily altered by 17β-EST. This suggests that female sex hormones play a role in regulating the expression of Ang-(1-7) and its pathways during ischemic brain injuries.

[Pinealon and Cortexin influence on behavior and neurochemical processes in 18-month aged rats within hypoxia and hypothermia].

PubMed

Mendzheritsky, A M; Karantysh, G V; Ryzhak, G A; Prokofiev, V N

The research of Cortexin and Pinealon within two models of stress, acute hypobaric hypoxia and mild hypothermia, within 18-month aged rats has been held. The peculiarities of peptide preparations' influence on behavior and neurochemical indeces have been identified. Cortexin shows a more pronounced effect on free radical processes and caspase 3 activity in brain than Pinealon. Both preparations forward an accumulation of adrenergic mediator within rats' brains in the model of acute hypobaric hypoxia, as well as serotonin within cerebrum cortex in the model of mild hypothermia, which may underlie their geroprotective effects.

Spatially Directed Proteomics of the Human Lens Outer Cortex Reveals an Intermediate Filament Switch Associated With the Remodeling Zone

PubMed Central

Wenke, Jamie L.; McDonald, W. Hayes; Schey, Kevin L.

2016-01-01

Purpose To quantify protein changes in the morphologically distinct remodeling zone (RZ) and adjacent regions of the human lens outer cortex using spatially directed quantitative proteomics. Methods Lightly fixed human lens sections were deparaffinized and membranes labeled with fluorescent wheat germ agglutinin (WGA-TRITC). Morphology directed laser capture microdissection (LCM) was used to isolate tissue from four distinct regions of human lens outer cortex: differentiating zone (DF), RZ, transition zone (TZ), and inner cortex (IC). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) of the plasma membrane fraction from three lenses (21-, 22-, and 27-year) revealed changes in major cytoskeletal proteins including vimentin, filensin, and phakinin. Peptides from proteins of interest were quantified using multiple reaction monitoring (MRM) mass spectrometry and isotopically-labeled internal peptide standards. Results Results revealed an intermediate filament switch from vimentin to beaded filament proteins filensin and phakinin that occurred at the RZ. Several other cytoskeletal proteins showed significant changes between regions, while most crystallins remained unchanged. Targeted proteomics provided accurate, absolute quantification of these proteins and confirmed vimentin, periplakin, and periaxin decrease from the DF to the IC, while filensin, phakinin, and brain acid soluble protein 1 (BASP1) increase significantly at the RZ. Conclusions Mass spectrometry-compatible fixation and morphology directed laser capture enabled proteomic analysis of narrow regions in the human lens outer cortex. Results reveal dramatic cytoskeletal protein changes associated with the RZ, suggesting that one role of these proteins is in membrane deformation and/or the establishment of ball and socket joints in the human RZ. PMID:27537260

Transcriptomic Modification in the Cerebral Cortex following Noninvasive Brain Stimulation: RNA-Sequencing Approach

PubMed Central

Holmes, Ben; Jung, Seung Ho; Lu, Jing; Wagner, Jessica A.; Rubbi, Liudmilla; Pellegrini, Matteo

2016-01-01

Transcranial direct current stimulation (tDCS) has been shown to modulate neuroplasticity. Beneficial effects are observed in patients with psychiatric disorders and enhancement of brain performance in healthy individuals has been observed following tDCS. However, few studies have attempted to elucidate the underlying molecular mechanisms of tDCS in the brain. This study was conducted to assess the impact of tDCS on gene expression within the rat cerebral cortex. Anodal tDCS was applied at 3 different intensities followed by RNA-sequencing and analysis. In each current intensity, approximately 1,000 genes demonstrated statistically significant differences compared to the sham group. A variety of functional pathways, biological processes, and molecular categories were found to be modified by tDCS. The impact of tDCS on gene expression was dependent on current intensity. Results show that inflammatory pathways, antidepressant-related pathways (GTP signaling, calcium ion binding, and transmembrane/signal peptide pathways), and receptor signaling pathways (serotonergic, adrenergic, GABAergic, dopaminergic, and glutamate) were most affected. Of the gene expression profiles induced by tDCS, some changes were observed across multiple current intensities while other changes were unique to a single stimulation intensity. This study demonstrates that tDCS can modify the expression profile of various genes in the cerebral cortex and that these tDCS-induced alterations are dependent on the current intensity applied. PMID:28119786

Enzymes processing somatostatin precursors: an Arg-Lys esteropeptidase from the rat brain cortex converting somatostatin-28 into somatostatin-14.

PubMed Central

Gluschankof, P; Morel, A; Gomez, S; Nicolas, P; Fahy, C; Cohen, P

1984-01-01

The post-translational proteolytic conversion of somatostatin-14 precursors was studied to characterize the enzyme system responsible for the production of the tetradecapeptide either from its 15-kDa precursor protein or from its COOH-terminal fragment, somatostatin-28. A synthetic undecapeptide Pro-Arg-Glu-Arg-Lys-Ala-Gly-Ala-Lys-Asn-Tyr(NH2), homologous to the amino acid sequence of the octacosapeptide at the putative Arg-Lys cleavage locus, was used as substrate, after 125I labeling on the COOH-terminal tyrosine residue. A 90-kDa proteolytic activity was detected in rat brain cortex extracts after molecular sieve fractionation followed by ion exchange chromatography. The protease released the peptide 125I-Ala-Gly-Ala-Lys-Asn-Tyr(NH2) from the synthetic undecapeptide substrate and converted somatostatin-28 into somatostatin-14 under similar conditions (pH 7.0). Under these experimental conditions, the product tetradecapeptide was not further degraded by the enzyme. In contrast, the purified 15-kDa hypothalamic precursor remained unaffected when exposed to the proteolytic enzyme under identical conditions. It is concluded that this Arg-Lys esteropeptidase from the brain cortex may be involved in the in vivo processing of the somatostatin-28 fragment of prosomatostatin into somatostatin-14, the former species being an obligatory intermediate in a two-step proteolytic mechanism leading to somatostatin-14. PMID:6149550

A serine peptidase responsible for the inactivation of endogenous cholecystokinin in brain.

PubMed

Rose, C; Camus, A; Schwartz, J C

1988-11-01

A serine endopeptidase was characterized as a major inactivating enzyme for endogenous cholecystokinin (CCK) in brain. CCK-8 released by depolarization of slices of rat cerebral cortex, as measured by its immunoreactivity (CCK-ir), undergoes extensive degradation (approximately 85% of the amount released) before reaching the incubation medium. However, recovery of CCK-ir is enhanced up to 3-fold in the presence of serine-alkylating reagents (i.e., phenylmethylsulfonyl fluoride) as well as selected active site-directed inactivators (i.e., peptide chloromethyl ketones) or transition-state inhibitors (i.e., peptide boronic acids) of serine peptidases. Among these compounds, elastase inhibitors were the most potent protecting agents, whereas trypsin or chymotrypsin inhibitors were ineffective. HPLC analysis of endogenous CCK-ir recovered in media of depolarized slices indicated that endogenous CCK-5 [CCK-(29-33)-pentapeptide] was the most abundant fragment and that its formation was strongly decreased in the presence of an elastase inhibitor. HPLC analysis of fragments formed upon incubation of exogenous CCK-8 [CCK-(26-33)-octapeptide] with brain slices showed CCK-5, Gly-Trp-Met, and Trp-Met to be major metabolites of CCK-8 whose formation was prevented or at least diminished in the presence of the elastase inhibitor. It is concluded that there is an elastase-like serine endopeptidase in brain that cleaves the two peptide bonds of CCK-8 where the carboxyl group is donated by a methionine residue and constitutes a major inactivation ectoenzyme for the neuropeptide.

A serine peptidase responsible for the inactivation of endogenous cholecystokinin in brain.

PubMed Central

Rose, C; Camus, A; Schwartz, J C

1988-01-01

A serine endopeptidase was characterized as a major inactivating enzyme for endogenous cholecystokinin (CCK) in brain. CCK-8 released by depolarization of slices of rat cerebral cortex, as measured by its immunoreactivity (CCK-ir), undergoes extensive degradation (approximately 85% of the amount released) before reaching the incubation medium. However, recovery of CCK-ir is enhanced up to 3-fold in the presence of serine-alkylating reagents (i.e., phenylmethylsulfonyl fluoride) as well as selected active site-directed inactivators (i.e., peptide chloromethyl ketones) or transition-state inhibitors (i.e., peptide boronic acids) of serine peptidases. Among these compounds, elastase inhibitors were the most potent protecting agents, whereas trypsin or chymotrypsin inhibitors were ineffective. HPLC analysis of endogenous CCK-ir recovered in media of depolarized slices indicated that endogenous CCK-5 [CCK-(29-33)-pentapeptide] was the most abundant fragment and that its formation was strongly decreased in the presence of an elastase inhibitor. HPLC analysis of fragments formed upon incubation of exogenous CCK-8 [CCK-(26-33)-octapeptide] with brain slices showed CCK-5, Gly-Trp-Met, and Trp-Met to be major metabolites of CCK-8 whose formation was prevented or at least diminished in the presence of the elastase inhibitor. It is concluded that there is an elastase-like serine endopeptidase in brain that cleaves the two peptide bonds of CCK-8 where the carboxyl group is donated by a methionine residue and constitutes a major inactivation ectoenzyme for the neuropeptide. PMID:3186727

Synaptosomal degradation of substance P and some other neuropeptides.

PubMed

Arzumanyan, A M; Arutunyan, A A; Akopyan, T N

1985-12-01

Synaptosomes purified from spinal cord and from different rat brain areas exhibit peptide hydrolase activity, cleaving substance P (SP), bradykinin, THRH, LHRH, and neurotensin. The lowest activity for all the peptides tested was found in spinal cord, while the region with the highest degrading activity depended on the substrate: for substance P, it was striatum and cortex; for bradykinin, hypothalamus, and medulla oblongata; for THRH, striatum; for LHRH, midbrain; and for neurotensin, hippocampus. Degradation of substance P takes place at the plasma membrane of synaptosomes. Synaptosome ghosts cleave substance P (pH optimum 7-9, Km-2.5 X 10(-5) M, Vmax-130 nmol . hr-1 . mg protein-1) and also a number of its C-terminal fragments. Effects of the inhibitors show that several different classes of peptidases and proteases are involved in the degradation process. Peptide cleavage represents the probable pathway of synaptosomal inactivation of substance P.

Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with γ-secretase and regulates neuronal amyloid β-peptide levels.

PubMed

Schedin-Weiss, Sophia; Inoue, Mitsuhiro; Hromadkova, Lenka; Teranishi, Yasuhiro; Yamamoto, Natsuko Goto; Wiehager, Birgitta; Bogdanovic, Nenad; Winblad, Bengt; Sandebring-Matton, Anna; Frykman, Susanne; Tjernberg, Lars O

2017-08-01

Increased levels of the pathogenic amyloid β-peptide (Aβ), released from its precursor by the transmembrane protease γ-secretase, are found in Alzheimer disease (AD) brains. Interestingly, monoamine oxidase B (MAO-B) activity is also increased in AD brain, but its role in AD pathogenesis is not known. Recent neuroimaging studies have shown that the increased MAO-B expression in AD brain starts several years before the onset of the disease. Here, we show a potential connection between MAO-B, γ-secretase and Aβ in neurons. MAO-B immunohistochemistry was performed on postmortem human brain. Affinity purification of γ-secretase followed by mass spectrometry was used for unbiased identification of γ-secretase-associated proteins. The association of MAO-B with γ-secretase was studied by coimmunoprecipitation from brain homogenate, and by in-situ proximity ligation assay (PLA) in neurons as well as mouse and human brain sections. The effect of MAO-B on Aβ production and Notch processing in cell cultures was analyzed by siRNA silencing or overexpression experiments followed by ELISA, western blot or FRET analysis. Methodology for measuring relative intraneuronal MAO-B and Aβ42 levels in single cells was developed by combining immunocytochemistry and confocal microscopy with quantitative image analysis. Immunohistochemistry revealed MAO-B staining in neurons in the frontal cortex, hippocampus CA1 and entorhinal cortex in postmortem human brain. Interestingly, the neuronal staining intensity was higher in AD brain than in control brain in these regions. Mass spectrometric data from affinity purified γ-secretase suggested that MAO-B is a γ-secretase-associated protein, which was confirmed by immunoprecipitation and PLA, and a neuronal location of the interaction was shown. Strikingly, intraneuronal Aβ42 levels correlated with MAO-B levels, and siRNA silencing of MAO-B resulted in significantly reduced levels of intraneuronal Aβ42. Furthermore, overexpression of MAO-B enhanced Aβ production. This study shows that MAO-B levels are increased not only in astrocytes but also in pyramidal neurons in AD brain. The study also suggests that MAO-B regulates Aβ production in neurons via γ-secretase and thereby provides a key to understanding the relationship between MAO-B and AD pathogenesis. Potentially, the γ-secretase/MAO-B association may be a target for reducing Aβ levels using protein-protein interaction breakers.

Blood-brain barrier dysfunction and amyloid precursor protein accumulation in microvascular compartment following ischemia-reperfusion brain injury with 1-year survival.

PubMed

Pluta, R

2003-01-01

This study examined the late microvascular consequences of brain ischemia due to cardiac arrest in rats. In reacted vibratome sections scattered foci of extravasated horseradish peroxidase were noted throughout the brain and did not appear to be restricted to any specific area of brain. Ultrastructural investigation of leaky sites frequently presented platelets adhering to the endothelium of venules and capillaries. Endothelial cells demonstrated pathological changes with evidence of perivascular astrocytic swelling. At the same time, we noted C-terminal of amyloid precursor protein/beta-amyloid peptide (CAPP/betaA) deposits in cerebral blood vessels, with a halo of CAPP/betaA immunoreactivity in the surrounding parenchyma suggested diffusion of CAPP/betaA out of the vascular compartment. Changes predominated in the hippocampus, cerebral and entorhinal cortex, corpus callosum, thalamus, basal ganglia and around the lateral ventricles. These data implicate delayed abnormal endothelial function of vessels following ischemia-reperfusion brain injury as a primary event in the pathogenesis of the recurrent cerebral infarction.

Complement peptide C3a stimulates neural plasticity after experimental brain ischaemia.

PubMed

Stokowska, Anna; Atkins, Alison L; Morán, Javier; Pekny, Tulen; Bulmer, Linda; Pascoe, Michaela C; Barnum, Scott R; Wetsel, Rick A; Nilsson, Jonas A; Dragunow, Mike; Pekna, Marcela

2017-02-01

Ischaemic stroke induces endogenous repair processes that include proliferation and differentiation of neural stem cells and extensive rewiring of the remaining neural connections, yet about 50% of stroke survivors live with severe long-term disability. There is an unmet need for drug therapies to improve recovery by promoting brain plasticity in the subacute to chronic phase after ischaemic stroke. We previously showed that complement-derived peptide C3a regulates neural progenitor cell migration and differentiation in vitro and that C3a receptor signalling stimulates neurogenesis in unchallenged adult mice. To determine the role of C3a-C3a receptor signalling in ischaemia-induced neural plasticity, we subjected C3a receptor-deficient mice, GFAP-C3a transgenic mice expressing biologically active C3a in the central nervous system, and their respective wild-type controls to photothrombotic stroke. We found that C3a overexpression increased, whereas C3a receptor deficiency decreased post-stroke expression of GAP43 (P < 0.01), a marker of axonal sprouting and plasticity, in the peri-infarct cortex. To verify the translational potential of these findings, we used a pharmacological approach. Daily intranasal treatment of wild-type mice with C3a beginning 7 days after stroke induction robustly increased synaptic density (P < 0.01) and expression of GAP43 in peri-infarct cortex (P < 0.05). Importantly, the C3a treatment led to faster and more complete recovery of forepaw motor function (P < 0.05). We conclude that C3a-C3a receptor signalling stimulates post-ischaemic neural plasticity and intranasal treatment with C3a receptor agonists is an attractive approach to improve functional recovery after ischaemic brain injury. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cathepsin L plays a major role in cholecystokinin production in mouse brain cortex and in pituitary AtT-20 cells: protease gene knockout and inhibitor studies.

PubMed

Beinfeld, Margery C; Funkelstein, Lydiane; Foulon, Thierry; Cadel, Sandrine; Kitagawa, Kouki; Toneff, Thomas; Reinheckel, Thomas; Peters, Christoph; Hook, Vivian

2009-10-01

Cholecystokinin (CCK) is a peptide neurotransmitter whose production requires proteolytic processing of the proCCK precursor to generate active CCK8 neuropeptide in brain. This study demonstrates the significant role of the cysteine protease cathepsin L for CCK8 production. In cathepsin L knockout (KO) mice, CCK8 levels were substantially reduced in brain cortex by an average of 75%. To evaluate the role of cathepsin L in producing CCK in the regulated secretory pathway of neuroendocrine cells, pituitary AtT-20 cells that stably produce CCK were treated with the specific cathepsin L inhibitor, CLIK-148. CLIK-148 inhibitor treatment resulted in decreased amounts of CCK secreted from the regulated secretory pathway of AtT-20 cells. CLIK-148 also reduced cellular levels of CCK9 (Arg-CCK8), consistent with CCK9 as an intermediate product of cathepsin L, shown by the decreased ratio of CCK9/CCK8. The decreased CCK9/CCK8 ratio also suggests a shift in the production to CCK8 over CCK9 during inhibition of cathepsin L. During reduction of the PC1/3 processing enzyme by siRNA, the ratio of CCK9/CCK8 was increased, suggesting a shift to the cathepsin L pathway for the production of CCK9. The changes in ratios of CCK9 compared to CCK8 are consistent with dual roles of the cathepsin L protease pathway that includes aminopeptidase B to remove NH2-terminal Arg or Lys, and the PC1/3 protease pathway. These results suggest that cathepsin L functions as a major protease responsible for CCK8 production in mouse brain cortex, and participates with PC1/3 for CCK8 production in pituitary cells.

Effect of memantine on the levels of glial cells, neuropeptides, and peptide-degrading enzymes in rat brain regions of ibotenic acid-treated alzheimer's disease model.

PubMed

Ahmed, M M; Hoshino, H; Chikuma, T; Yamada, M; Kato, T

2004-01-01

It has been implicated that glia activation plays a critical role in the progression of Alzheimer's disease (AD). However, the precise mechanism of glia activation is not clearly understood yet. In our present studies, we confirmed our previous results where change the levels of neuropeptides and peptidases in ibotenic acid (IBO) infusion into the rat nucleus basalis magnocellularis, an animal model of AD. Furthermore, we extended our study to investigate a possible protection effect of co-administration on the changes of neuropeptides, and neuronal and glial cells in IBO-infused rat brain by memantine treatment. The levels of substance P and somatostatin were decreased in the striatum and frontal cortex 1 week after IBO infusion, and recovered to the control level by memantine treatment, indicating the involvement of neuropeptides in AD pathology. Furthermore, the immunohistochemical and enzymatic studies of GFAP and CD 11b, and peptidylarginine deiminase, markers of glia, in the striatum and frontal cortex showed the increase in IBO-treated rat brain as compared with controls, while co-administration of memantine and IBO no increase of astrocytes and microglia activation was observed. The present biochemical and immunohistochemical results suggest that glia activation might play an important role to the pathology of AD, and correlate with the changes of neuropeptide levels in AD brain that is recovered by memantine treatment.

Irisin Peptide Protects Brain Against Ischemic Injury Through Reducing Apoptosis and Enhancing BDNF in a Rodent Model of Stroke.

PubMed

Asadi, Yasin; Gorjipour, Fazel; Behrouzifar, Sedigheh; Vakili, Abedin

2018-06-07

Evidence has shown therapeutic potential of irisin in cerebral stroke. The present study aimed to assess the effects of recombinant irisin on the infarct size, neurological outcomes, blood-brain barrier (BBB) permeability, apoptosis and brain-derived neurotrophic factor (BDNF) expression in a mouse model of stroke. Transient focal cerebral ischemia was established by middle cerebral artery occlusion (MCAO) for 45 min and followed reperfusion for 23 h in mice. Recombinant irisin was administrated at doses of 0.1, 0.5, 2.5, 7.5, and 15 µg/kg, intracerebroventricularly (ICV), on the MCAO beginning. Neurological outcomes, infarct size, brain edema and BBB permeability were evaluated by modified neurological severity score (mNSS), 2,3,5-triphenyltetrazolium chloride (TTC) staining and Evans blue (EB) extravasation methods, respectively, at 24 h after ischemia. Apoptotic cells and BDNF protein were detected by TUNEL assay and immunohistochemistry techniques. The levels of Bcl-2, Bax and caspase-3 proteins were measured by immunoblotting technique. ICV irisin administration at doses of 0.5, 2.5, 7.5 and 15 µg/kg, significantly reduced infarct size, whereas only in 7.5 and 15 µg/kg improved neurological outcome (P < 0.001). Treatment with irisin (7.5 µg/kg) reduced brain edema (P < 0.001) without changing BBB permeability (P > 0.05). Additionally, irisin (7.5 µg/kg) significantly diminished apoptotic cells and increased BDNF immunoreactivity in the ischemic brain cortex (P < 0.004). Irisin administration significantly downregulated the Bax and caspase-3 expression and upregulated the Bcl-2 protein. The present study indicated that irisin attenuates brain damage via reducing apoptosis and increasing BDNF protein of brain cortex in the experimental model of stroke in mice.

Distribution of cholecystokinin mRNA and peptides in the human brain.

PubMed

Lindefors, N; Brené, S; Kopp, J; Lindén, A; Brodin, E; Sedvall, G; Persson, H

1991-01-01

Expression of preprocholecystokinin mRNA was studied in regions of post mortem human brain using RNA blot analysis (Northern blot) and in situ hybridization. Northern blot analysis using a cDNA probe showed high levels of an approximately 0.8 kb preprocholecystokinin mRNA in all regions of neocortex examined. Lower levels of preprocholecystokinin mRNA were detected in amygdaloid body and thalamus. In situ hybridization analysis using the same cDNA probe revealed numerous weakly labelled neurons in different areas of human neocortex and less numerous neurons in hippocampus and amygdaloid body. High-performance liquid-chromatography and gel-chromatography combined with radioimmunoassay of cholecystokinin-like immunoreactivity from human cerebral cortex and caudate nucleus revealed two major forms, one coeluting with sulphated cholecystokinin-8 and the other coeluting with sulphated cholecystokinin-58. Two minor components coeluting with cholecystokinin-4 and cholecystokinin-5 were also detected. The finding of cholecystokinin-like immunoreactivity corresponding to cholecystokinin-8 and cholecystokinin-58 in caudate nucleus where no preprocholecystokinin mRNA was found, indicates the presence of these peptides in afferent nerve terminals.

Phosphoproteomic analysis reveals compensatory effects in the piriform cortex of VX nerve agent exposed rats.

PubMed

Nirujogi, Raja Sekhar; Wright, James D; Manda, Srikanth S; Zhong, Jun; Na, Chan Hyun; Meyerhoff, James; Benton, Bernard; Jabbour, Rabih; Willis, Kristen; Kim, Min-Sik; Pandey, Akhilesh; Sekowski, Jennifer W

2015-01-01

To gain insights into the toxicity induced by the nerve agent VX, an MS-based phosphoproteomic analysis was carried out on the piriform cortex region of brains from VX-treated rats. Using isobaric tag based TMT labeling followed by titanium dioxide enrichment strategy, we identified 9975 unique phosphosites derived from 3287 phosphoproteins. Temporal changes in the phosphorylation status of peptides were observed over a time period of 24 h in rats exposed to a 1× LD50, intravenous (i.v.) dose with the most notable changes occurring at the 1 h postexposure time point. Five major functional classes of proteins exhibited changes in their phosphorylation status: (i) ion channels/transporters, including ATPases, (ii) kinases/phosphatases, (iii) GTPases, (iv) structural proteins, and (v) transcriptional regulatory proteins. This study is the first quantitative phosphoproteomic analysis of VX toxicity in the brain. Understanding the toxicity and compensatory signaling mechanisms will improve the understanding of the complex toxicity of VX in the brain and aid in the elucidation of novel molecular targets that would be important for development of improved countermeasures. All MS data have been deposited in the ProteomeXchange with identifier PXD001184 (http://proteomecentral.proteomexchange.org/dataset/PXD001184). © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The von Economo neurons in frontoinsular and anterior cingulate cortex in great apes and humans.

PubMed

Allman, John M; Tetreault, Nicole A; Hakeem, Atiya Y; Manaye, Kebreten F; Semendeferi, Katerina; Erwin, Joseph M; Park, Soyoung; Goubert, Virginie; Hof, Patrick R

2010-06-01

The von Economo neurons (VENs) are large bipolar neurons located in frontoinsular (FI) and anterior cingulate cortex in great apes and humans, but not other primates. We performed stereological counts of the VENs in FI and LA (limbic anterior, a component of anterior cingulate cortex) in great apes and in humans. The VENs are more numerous in humans than in apes, although one gorilla approached the lower end of the human range. We also examined the ontological development of the VENs in FI and LA in humans. The VENs first appear in small numbers in the 36th week post-conception, are rare at birth, and increase in number during the first 8 months after birth. There are significantly more VENs in the right hemisphere than in the left in FI and LA in postnatal brains of apes and humans. This asymmetry in VEN numbers may be related to asymmetries in the autonomic nervous system. The activity of the inferior anterior insula, which contains FI, is related to physiological changes in the body, decision-making, error recognition, and awareness. The VENs appear to be projection neurons, although their targets are unknown. We made a preliminary study of the connections of FI cortex based on diffusion tensor imaging in the brain of a gorilla. The VEN-containing regions connect to the frontal pole as well as to other parts of frontal and insular cortex, the septum, and the amygdala. It is likely that the VENs in FI are projecting to some or all of these structures and relaying information related to autonomic control, decision-making, or awareness. The VENs selectively express the bombesin peptides neuromedin B (NMB) and gastrin releasing peptide (GRP) which are also expressed in another population of closely related neurons, the fork cells. NMB and GRP signal satiety. The genes for NMB and GRP are expressed selectively in small populations of neurons in the insular cortex in mice. These populations may be related to the VEN and fork cells and may be involved in the regulation of appetite. The loss of these cells may be related to the loss of satiety signaling in patients with frontotemporal dementia who have damage to FI. The VENs and fork cells may be morphological specializations of an ancient population of neurons involved in the control of appetite present in the insular cortex in all mammals. We found that the protein encoded by the gene DISC1 (disrupted in schizophrenia) is preferentially expressed by the VENs. DISC1 has undergone rapid evolutionary change in the line leading to humans, and since it suppresses dendritic branching it may be involved in the distinctive VEN morphology.

Role of cocaine- and amphetamine-regulated transcript in estradiol-mediated neuroprotection

NASA Astrophysics Data System (ADS)

Xu, Yun; Zhang, Wenri; Klaus, Judith; Young, Jennifer; Koerner, Ines; Sheldahl, Laird C.; Hurn, Patricia D.; Martínez-Murillo, Francisco; Alkayed, Nabil J.

2006-09-01

Estrogen reduces brain injury after experimental cerebral ischemia in part through a genomic mechanism of action. Using DNA microarrays, we analyzed the genomic response of the brain to estradiol, and we identified a transcript, cocaine- and amphetamine-regulated transcript (CART), that is highly induced in the cerebral cortex by estradiol under ischemic conditions. Using in vitro and in vivo models of neural injury, we confirmed and characterized CART mRNA and protein up-regulation by estradiol in surviving neurons, and we demonstrated that i.v. administration of a rat CART peptide is protective against ischemic brain injury in vivo. We further demonstrated binding of cAMP response element (CRE)-binding protein to a CART promoter CRE site in ischemic brain and rapid activation by CART of ERK in primary cultured cortical neurons. The findings suggest that CART is an important player in estrogen-mediated neuroprotection and a potential therapeutic agent for stroke and other neurodegenerative diseases. ischemia | stroke | estrogen

Nicotinamide Forestalls Pathology and Cognitive Decline in Alzheimer Mice: Evidence for Improved Neuronal Bioenergetics and Autophagy Procession

PubMed Central

Liu, Dong; Pitta, Michael; Jiang, Haiyang; Lee, Jong-Hwan; Zhang, Guofeng; Chen, Xinzhi; Kawamoto, Elisa M.; Mattson, Mark P.

2012-01-01

Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline and the pathological accumulations of amyloid β-peptide (Aβ) and hyperphosphorylated Tau (p-Tau) in Alzheimer's disease (AD). To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the NAD+ precursor nicotinamide on brain cell mitochondrial function and macroautophagy, bioenergetics-related signaling and cognitive performance were studied in cultured neurons and in a mouse model of AD. Oxidative stress resulted in decreased mitochondrial mass, mitochondrial degeneration and autophagosome accumulation in neurons. Nicotinamide preserved mitochondrial integrity and autophagy function, and reduced neuronal vulnerability to oxidative/metabolic insults and Aβ toxicity. NAD+ biosynthesis, autophagy and PI3K signaling were required for the neuroprotective action of nicotinamide. Treatment of 3xTgAD mice with nicotinamide for 8 months resulted in improved cognitive performance, and reduced Aβ and p-Tau pathologies in hippocampus and cerebral cortex. Nicotinamide treatment preserved mitochondrial integrity, and improved autophagy-lysosome procession by enhancing lysosome/autolysosome acidification to reduce autophagosome accumulation. Treatment of 3xTgAD mice with nicotinamide resulted in elevated levels of activated neuroplasticity-related kinases (Akt and ERKs) and the transcription factor cyclic AMP response element-binding protein in the hippocampus and cerebral cortex. Thus, nicotinamide suppresses AD pathology and cognitive decline in a mouse model of AD by a mechanism involving improved brain bioenergetics with preserved functionality of mitochondria and the autophagy system. PMID:23273573

[Prevention of the brain neurodegeneration in rats with experimental Alzheimer's disease by adaptation to hypoxia].

PubMed

Manukhina, E B; Goriacheva, A V; Barskov, I V; Viktorov, I V; Guseva, A A; Pshennikova, M G; Khomenko, I P; Mashina, S Iu; Pokidyshev, D A; Malyshev, I Iu

2009-07-01

The study focused on a possibility of preventing brain neurodegeneration by adaptation to intermittent hypoxia (AH) in rats with experimental Alzheimer's disease (AD) modeled by injection of a neurotoxic bert-amyloid peptide fragment (Ab) into n. basalis magnocellularis. AH was produ- ced in an altitude chamber (4.000 m; 4 hours daily; 14 days). The following results were obtained after fifteen days of the Ab injection: (1) AH substantially prevented the memory impairment induced by Ab, which was determined using the conditioned avoidance reflex test; (2) the AH significantly restricted the enhanced oxidative stress, which was determined spectrophotometrically by thiobarbituric acid-reactive substance level in the hippocampus; (3) the AH completely prevented Ab-induced nitric oxide (NO) overproduction in brain, which was measured by tissue level of nitrite and nitrate; (4) pathologically changed and dead neurons (Niessle staining) were absent in the brain cortex of rats exposed to AH before the Ab injection. Therefore AH seems to effectively prevent oxidative and nitrosative stress thereby providing protection of brain against neurodegeneration and preservation of cognitive function in experimental AD.

Peptide pills for brain diseases? Reality and future perspectives.

PubMed

Serrano Lopez, Dolores Remedios; Lalatsa, Aikaterini

2013-04-01

The peptide therapeutic market is one of the fastest growth areas of the pharmaceutical industry. Although few orally administered peptides are marketed and many are in different phases of clinical development, there is no marketed oral peptide therapeutic used for CNS disorders. The major challenges involved in orally delivering peptides to the brain relate to their enzymatic instability and inability to permeate across physiological barriers. The paucity of therapies for the treatment of brain diseases and the presence of the blood-brain barrier excluding 98% of therapeutic molecules necessitates parenteral administration. Various approaches have been applied to enhance oral peptide bioavailability, but only nanoparticulate strategies were able to deliver orally therapeutic peptides to the brain. Although industry may be reluctant to invest in developing oral peptide nanomedicines, the increasingly unmet clinical need and economic burden associated with brain diseases will fuel the development of the first marketed oral-to-brain peptide therapy.

IGF-1 Restores Visual Cortex Plasticity in Adult Life by Reducing Local GABA Levels

PubMed Central

Maya-Vetencourt, José Fernando; Baroncelli, Laura; Viegi, Alessandro; Tiraboschi, Ettore; Castren, Eero; Cattaneo, Antonino; Maffei, Lamberto

2012-01-01

The central nervous system architecture is markedly modified by sensory experience during early life, but a decline of plasticity occurs with age. Recent studies have challenged this dogma providing evidence that both pharmacological treatments and paradigms based on the manipulation of environmental stimulation levels can be successfully employed as strategies for enhancing plasticity in the adult nervous system. Insulin-like growth factor 1 (IGF-1) is a peptide implicated in prenatal and postnatal phases of brain development such as neurogenesis, neuronal differentiation, synaptogenesis, and experience-dependent plasticity. Here, using the visual system as a paradigmatic model, we report that IGF-1 reactivates neural plasticity in the adult brain. Exogenous administration of IGF-1 in the adult visual cortex, indeed, restores the susceptibility of cortical neurons to monocular deprivation and promotes the recovery of normal visual functions in adult amblyopic animals. These effects were accompanied by a marked reduction of intracortical GABA levels. Moreover, we show that a transitory increase of IGF-1 expression is associated to the plasticity reinstatement induced by environmental enrichment (EE) and that blocking IGF-1 action by means of the IGF-1 receptor antagonist JB1 prevents EE effects on plasticity processes. PMID:22720172

The distribution of the orphan bombesin receptor subtype-3 in the rat CNS.

PubMed

Jennings, C A; Harrison, D C; Maycox, P R; Crook, B; Smart, D; Hervieu, G J

2003-01-01

Bombesin receptor subtype 3 (BRS-3) is an orphan G-protein coupled receptor that shares between 47 and 51% homology with other known bombesin receptors. The natural ligand for BRS-3 is currently unknown and little is known about the mechanisms regulating BRS-3 gene expression. Unlike other mammalian bombesin receptors that have been shown to be predominantly expressed in the CNS and gastrointestinal tract, expression of the BRS-3 receptor in the rat brain has previously not been observed. To gain further understanding of the biology of BRS-3, we have studied the distribution of BRS-3 mRNA and protein in the rat CNS. The mRNA expression pattern was studied using reverse transcription followed by quantitative polymerase chain reaction. Using immunohistological techniques, the distribution of BRS-3 protein in the rat brain was investigated using a rabbit affinity-purified polyclonal antiserum raised against an N-terminal peptide. The BRS-3 receptor was found to be widely expressed in the rat brain at both mRNA and protein levels. Particularly strong immunosignals were observed in the cerebral cortex, hippocampal formation, hypothalamus and thalamus. Other regions of the brain such as the basal ganglia, midbrain and reticular formation were also immunopositive for BRS-3. In conclusion, our neuroanatomical data provide evidence that BRS-3 is as widely expressed in the rat brain as other bombesin-like peptide receptors and suggest that this receptor may also have important roles in the CNS, mediating the functions of a so far unidentified ligand.

Mapping glucose-mediated gut-to-brain signalling pathways in humans.

PubMed

Little, Tanya J; McKie, Shane; Jones, Richard B; D'Amato, Massimo; Smith, Craig; Kiss, Orsolya; Thompson, David G; McLaughlin, John T

2014-08-01

Previous fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role. Changes in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250ml) of: 1M glucose+predosing with dexloxiglumide (CCK1 receptor antagonist), 1M glucose+placebo, or 0.9% saline (control)+placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded. Intragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose+dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex. Glucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway. Copyright © 2014. Published by Elsevier Inc.

Pentadecapeptide BPC 157 and its effects on a NSAID toxicity model: diclofenac-induced gastrointestinal, liver, and encephalopathy lesions.

PubMed

Ilic, Spomenko; Drmic, Domagoj; Franjic, Sandra; Kolenc, Danijela; Coric, Marijana; Brcic, Luka; Klicek, Robert; Radic, Bozo; Sever, Marko; Djuzel, Viktor; Filipovic, Marinko; Djakovic, Zeljko; Stambolija, Vasilije; Blagaic, Alenka Boban; Zoricic, Ivan; Gjurasin, Miroslav; Stupnisek, Mirjana; Romic, Zeljko; Zarkovic, Kamelija; Dzidic, Senka; Seiwerth, Sven; Sikiric, Predrag

2011-03-14

We attempted to fully antagonize the extensive toxicity caused by NSAIDs (using diclofenac as a prototype). Herein, we used the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419), an anti-ulcer peptide shown to be efficient in inflammatory bowel disease clinical trials (PL 14736) and various wound treatments with no toxicity reported. This peptide was given to antagonize combined gastrointestinal, liver, and brain toxicity induced by diclofenac (12.5mg/kg intraperitoneally, once daily for 3 days) in rats. Already considered a drug that can reverse the toxic side effects of NSAIDs, BPC 157 (10 μg/kg, 10 ng/kg) was strongly effective throughout the entire experiment when given (i) intraperitoneally immediately after diclofenac or (ii) per-orally in drinking water (0.16 μg/mL, 0.16 ng/mL). Without BPC 157 treatment, at 3h following the last diclofenac challenge, we encountered a complex deleterious circuit of diclofenac toxicity characterized by severe gastric, intestinal and liver lesions, increased bilirubin, aspartate transaminase (AST), alanine transaminase (ALT) serum values, increased liver weight, prolonged sedation/unconsciousness (after any diclofenac challenge) and finally hepatic encephalopathy (brain edema particularly located in the cerebral cortex and cerebellum, more in white than in gray matter, damaged red neurons, particularly in the cerebral cortex and cerebellar nuclei, Purkinje cells and less commonly in the hippocampal neurons). The very extensive antagonization of diclofenac toxicity achieved with BPC 157 (μg-/ng-regimen, intraperitoneally, per-orally) may encourage its further use as a therapy to counteract diclofenac- and other NSAID-induced toxicity. Copyright © 2011 Elsevier Inc. All rights reserved.

Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide

PubMed Central

Barde, Swapnali; Rüegg, Joelle; Prud’homme, Josée; Ekström, Tomas J.; Palkovits, Miklos; Turecki, Gustavo; Bagdy, Gyorgy; Ihnatko, Robert; Theodorsson, Elvar; Juhasz, Gabriella; Diaz-Heijtz, Rochellys; Mechawar, Naguib; Hökfelt, Tomas G. M.

2016-01-01

Major depressive disorder (MDD) is a substantial burden to patients, families, and society, but many patients cannot be treated adequately. Rodent experiments suggest that the neuropeptide galanin (GAL) and its three G protein-coupled receptors, GAL1–3, are involved in mood regulation. To explore the translational potential of these results, we assessed the transcript levels (by quantitative PCR), DNA methylation status (by bisulfite pyrosequencing), and GAL peptide by RIA of the GAL system in postmortem brains from depressed persons who had committed suicide and controls. Transcripts for all four members were detected and showed marked regional variations, GAL and galanin receptor 1 (GALR1) being most abundant. Striking increases in GAL and GALR3 mRNA levels, especially in the noradrenergic locus coeruleus and the dorsal raphe nucleus, in parallel with decreased DNA methylation, were found in both male and female suicide subjects as compared with controls. In contrast, GAL and GALR3 transcript levels were decreased, GALR1 was increased, and DNA methylation was increased in the dorsolateral prefrontal cortex of male suicide subjects, however, there were no changes in the anterior cingulate cortex. Thus, GAL and its receptor GALR3 are differentially methylated and expressed in brains of MDD subjects in a region- and sex-specific manner. Such an epigenetic modification in GALR3, a hyperpolarizing receptor, might contribute to the dysregulation of noradrenergic and serotonergic neurons implicated in the pathogenesis of MDD. Thus, one may speculate that a GAL3 antagonist could have antidepressant properties by disinhibiting the firing of these neurons, resulting in increased release of noradrenaline and serotonin in forebrain areas involved in mood regulation. PMID:27940914

Hemopressins and other hemoglobin-derived peptides in mouse brain: Comparison between brain, blood, and heart peptidome and regulation in Cpefat/fat mice

PubMed Central

Gelman, Julia S.; Sironi, Juan; Castro, Leandro M.; Ferro, Emer S.; Fricker, Lloyd D.

2010-01-01

Many hemoglobin-derived peptides are present in mouse brain, and several of these have bioactive properties including the hemopressins, a related series of peptides that bind to cannabinoid CB1 receptors. Although hemoglobin is a major component of red blood cells, it is also present in neurons and glia. To examine whether the hemoglobin-derived peptides in brain are similar to those present in blood and heart, we used a peptidomics approach involving mass spectrometry. Many hemoglobin-derived peptides are found only in brain and not in blood, whereas all hemoglobin-derived peptides found in heart were also seen in blood. Thus, it is likely that the majority of the hemoglobin-derived peptides detected in brain are produced from brain hemoglobin and not erythrocytes. We also examined if the hemopressins and other major hemoglobin-derived peptides were regulated in the Cpefat/fat mouse; previously these mice were reported to have elevated levels of several hemoglobin-derived peptides. Many, but not all of the hemoglobin-derived peptides were elevated in several brain regions of the Cpefat/fat mouse. Taken together, these findings suggest that the post-translational processing of alpha and beta hemoglobin into the hemopressins, as well as other peptides, is upregulated in some but not all Cpefat/fat mouse brain regions. PMID:20202081

Glio-vascular changes during ageing in wild-type and Alzheimer's disease-like APP/PS1 mice.

PubMed

Janota, C S; Brites, D; Lemere, C A; Brito, M A

2015-09-16

Vascular and glial involvement in the development of neurodegenerative disorders, such as Alzheimer's disease (AD), and age-related brain vulnerabilities have been suggested. Therefore, we sought to: (i) investigate which vascular and glial events are evident in ageing and/or AD, (ii) to establish the temporal evolution of vascular and glial changes in AD-like and wild-type (WT) mice and (iii) to relate them to amyloid-β (Aβ) peptide accumulation. We examined immunohistochemically hippocampi and cortex from APP/PS1dE9 and WT C57BL/6 mice along ageing and disease progression (young-adulthood, middle- and old-age). Ageing resulted in the increase in receptor for advanced glycation endproducts expression, as well as the entrance of thrombin and albumin in hippocampal parenchyma. In contrast, the loss of platelet-derived growth factor receptor-β (PDGFR-β) positive cells, in both regions, was only related to AD pathogenesis. Hypovascularization was affected by both ageing and AD in the hippocampus, but resulted from the interaction between both factors in the cortex. Astrogliosis was a result of AD in hippocampus and of both factors in cortex, while microgliosis was associated with fibrillar amyloid plaques in AD-like mice and with the interaction between both factors in each of the studied regions. In sum, these data show that senile plaques precede vascular and glial alterations only in hippocampus, whereas in cortex, vascular and glial alterations, namely the loss of PDGFR-β-positive cells and astrogliosis, accompanied the first senile plaques. Hence, this study points to vascular and glial events that co-exist in AD pathogenesis and age-related brain vulnerabilities. Copyright © 2015 Elsevier B.V. All rights reserved.

GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial

PubMed Central

Farr, Olivia M.; Sofopoulos, Michail; Tsoukas, Michael A.; Dincer, Fadime; Thakkar, Bindiya; Sahin-Efe, Ayse; Filippaios, Andreas; Bowers, Jennifer; Srnka, Alexandra; Gavrieli, Anna; Ko, Byung-Joon; Liakou, Chrysoula; Kanyuch, Nickole; Tseleni-Balafouta, Sofia; Mantzoros, Christos S.

2016-01-01

Aims/hypothesis Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome). Methods In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrollment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (fMRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center. Results Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide −0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation. Conclusions/interpretation For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity. PMID:26831302

Peptides and the blood–brain barrier

PubMed Central

Banks, William A.

2016-01-01

The demonstration that peptides and regulatory proteins can cross the blood–brain barrier (BBB) is one of the major contributions of Dr. Abba J. Kastin. He was the first to propose that peptides could cross the BBB, the first to show that an endogenous peptide did so, and the first to describe a saturable transport system at the BBB for peptides. His work shows that in crossing the BBB, peptides and regulatory proteins act as informational molecules, informing the brain of peripheral events. Brain-to-blood passage helps to control levels of peptides with the brain and can deliver information in the brain-to-blood direction. He showed that the transporters for peptides and proteins are not static, but respond to developmental and physiological changes and are affected by disease states. As such, the BBB is adaptive to the needs of the CNS, but when that adaption goes awry, the BBB can be a cause of disease. The mechanisms by which peptides and proteins cross the BBB offer opportunities for drug delivery of these substances or their analogs to the brain in the treatment of diseases of the central nervous system. PMID:25805003

Regulation of the neurotensin NT1 receptor in the developing rat brain following chronic treatment with the antagonist SR 48692

PubMed Central

Lépée-Lorgeoux, Isabelle; Betancur, Catalina; Souazé, Frédérique; Rostène, William; Bérod, Anne; Pélaprat, Didier

2000-01-01

The aim of the present study was to investigate the role of neurotensin in the regulation of NT1 receptors during postnatal development in the rat brain. Characterization of the ontogeny of neurotensin concentration and [125I]neurotensin binding to NT1 receptors in the brain at different embryonic and postnatal stages showed that neurotensin was highly expressed at birth, reaching peak levels at postnatal day 5 (P5), and decreasing thereafter. The transient rise in neurotensin levels preceded the maximal expression of NT1 receptors, observed at P10, suggesting that neurotensin may influence the developmental profile of NT1 receptors. Using primary cultures of cerebral cortex neurons from fetal rats, we showed that exposure to the neurotensin agonist JMV 449 (1 nM) decreased (−43%) the amount of NT1 receptor mRNA measured by reverse transcription-PCR, an effect that was abolished by the non-peptide NT1 receptor antagonist SR 48692 (1 μM). However, daily injection of SR 48692 to rat pups from birth for 5, 9 or 15 days, did not modify [125I]neurotensin binding in brain membrane homogenates. Moreover, postnatal blockade of neurotensin transmission did not alter the density and distribution of NT1 receptors assessed by quantitative autoradiography nor NT1 receptor mRNA expression measured by in situ hybridization in the cerebral cortex, caudate-putamen and midbrain. These results suggest that although NT1 receptor expression can be regulated in vitro by the agonist at an early developmental stage, neurotensin is not a major factor in the establishment of the ontogenetic pattern of these receptors in the rat brain. PMID:10797539

Rhenium and technetium complexes that bind to amyloid-β plaques.

PubMed

Hayne, David J; North, Andrea J; Fodero-Tavoletti, Michelle; White, Jonathan M; Hung, Lin W; Rigopoulos, Angela; McLean, Catriona A; Adlard, Paul A; Ackermann, Uwe; Tochon-Danguy, Henri; Villemagne, Victor L; Barnham, Kevin J; Donnelly, Paul S

2015-03-21

Alzheimer's disease is associated with the presence of insoluble protein deposits in the brain called amyloid plaques. The major constituent of these deposits is aggregated amyloid-β peptide. Technetium-99m complexes that bind to amyloid-β plaques could provide important diagnostic information on amyloid-β plaque burden using Single Photon Emission Computed Tomography (SPECT). Tridentate ligands with a stilbene functional group were used to form complexes with the fac-[M(I)(CO)3](+) (M = Re or (99m)Tc) core. The rhenium carbonyl complexes with tridentate co-ligands that included a stilbene functional group and a dimethylamino substituent bound to amyloid-β present in human frontal cortex brain tissue from subjects with Alzheimer's disease. This chemistry was extended to make the analogous [(99m)Tc(I)(CO)3](+) complexes and the complexes were sufficiently stable in human serum. Whilst the lipophilicity (log D7.4) of the technetium complexes appeared ideally suited for penetration of the blood-brain barrier, preliminary biodistribution studies in an AD mouse model (APP/PS1) revealed relatively low brain uptake (0.24% ID g(-1) at 2 min post injection).

Alzheimer's disease-like impaired cognition in endothelial-specific megalin-null mice.

PubMed

Dietrich, Marcelo; Antequera, Desiree; Pascual, Consuelo; Castro, Nerea; Bolos, Marta; Carro, Eva

2014-01-01

Megalin has been suggested to be involved in Alzheimer's disease (AD), mediating blood-brain barrier (BBB) transport of multiple ligands, including amyloid-β peptide (Aβ), but also neuroprotective factors. Because no transgenic model is currently available to study this concept, we have obtained transgenic mice blocking megalin expression at the BBB. These endothelial megalin deficient (EMD) mice developed increased anxiety behavior and impaired learning ability and recognition memory, similar to symptoms described in AD. Degenerating neurons were also observed in the cerebral cortex of EMD mice. In view of our findings we suggest that, in mice, megalin deficiency at the BBB leads to neurodegeneration.

Mu-Opioid (MOP) receptor mediated G-protein signaling is impaired in specific brain regions in a rat model of schizophrenia.

PubMed

Szűcs, Edina; Büki, Alexandra; Kékesi, Gabriella; Horváth, Gyöngyi; Benyhe, Sándor

2016-04-21

Schizophrenia is a complex mental health disorder. Clinical reports suggest that many patients with schizophrenia are less sensitive to pain than other individuals. Animal models do not interpret schizophrenia completely, but they can model a number of symptoms of the disease, including decreased pain sensitivities and increased pain thresholds of various modalities. Opioid receptors and endogenous opioid peptides have a substantial role in analgesia. In this biochemical study we investigated changes in the signaling properties of the mu-opioid (MOP) receptor in different brain regions, which are involved in the pain transmission, i.e., thalamus, olfactory bulb, prefrontal cortex and hippocampus. Our goal was to compare the transmembrane signaling mediated by MOP receptors in control rats and in a recently developed rat model of schizophrenia. Regulatory G-protein activation via MOP receptors were measured in [(35)S]GTPγS binding assays in the presence of a highly selective MOP receptor peptide agonist, DAMGO. It was found that the MOP receptor mediated activation of G-proteins was substantially lower in membranes prepared from the 'schizophrenic' model rats than in control animals. The potency of DAMGO to activate MOP receptor was also decreased in all brain regions studied. Taken together in our rat model of schizophrenia, MOP receptor mediated G-proteins have a reduced stimulatory activity compared to membrane preparations taken from control animals. The observed distinct changes of opioid receptor functions in different areas of the brain do not explain the augmented nociceptive threshold described in these animals. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Peptides and the blood-brain barrier.

PubMed

Banks, William A

2015-10-01

The demonstration that peptides and regulatory proteins can cross the blood-brain barrier (BBB) is one of the major contributions of Dr. Abba J. Kastin. He was the first to propose that peptides could cross the BBB, the first to show that an endogenous peptide did so, and the first to describe a saturable transport system at the BBB for peptides. His work shows that in crossing the BBB, peptides and regulatory proteins act as informational molecules, informing the brain of peripheral events. Brain-to-blood passage helps to control levels of peptides with the brain and can deliver information in the brain-to-blood direction. He showed that the transporters for peptides and proteins are not static, but respond to developmental and physiological changes and are affected by disease states. As such, the BBB is adaptive to the needs of the CNS, but when that adaption goes awry, the BBB can be a cause of disease. The mechanisms by which peptides and proteins cross the BBB offer opportunities for drug delivery of these substances or their analogs to the brain in the treatment of diseases of the central nervous system. Published by Elsevier Inc.

Protective Effects of Forskolin on Behavioral Deficits and Neuropathological Changes in a Mouse Model of Cerebral Amyloidosis

PubMed Central

Zug, Caroline; Schluesener, Hermann J.; Zhang, Zhi-Yuan

2016-01-01

The production of amyloid-β peptides in the brains of patients with Alzheimer disease (AD) may contribute to memory loss and impairments in social behavior. Here, an efficient adenylate cyclase activator, forskolin, was orally administered by gavage (100 mg/kg body weight) to 5-month-old transgenic APP/PS1 mice, which serve as an animal model of cerebral amyloidosis. Analyses of nest construction, sociability, and immunohistochemical features were used to determine the effects of forskolin treatment. After a relatively short term of treatment (10 days), forskolin-treated transgenic mice showed restored nest construction ability (p < 0.05) and their sociability (p < 0.01). There was a reduction of Aβ plaque deposition in the cortex and in the hippocampus. Furthermore, expression of transforming growth factor β, glial fibrillary acidic protein, and Iba-1 in the cortex was reduced in the forskolin-treated group, suggesting regulation of the inflammatory response mediated by activated microglia and astrocytes in the brains of the APP/PS1 mice (p < 0.01). Taken together, these findings suggest that forskolin shows neuroprotective effects in APP/PS1 Tg mice and may be a promising drug in the treatment of patients with AD. PMID:27251043

Protective Effects of Forskolin on Behavioral Deficits and Neuropathological Changes in a Mouse Model of Cerebral Amyloidosis.

PubMed

Owona, Brice Ayissi; Zug, Caroline; Schluesener, Hermann J; Zhang, Zhi-Yuan

2016-07-01

The production of amyloid-β peptides in the brains of patients with Alzheimer disease (AD) may contribute to memory loss and impairments in social behavior. Here, an efficient adenylate cyclase activator, forskolin, was orally administered by gavage (100 mg/kg body weight) to 5-month-old transgenic APP/PS1 mice, which serve as an animal model of cerebral amyloidosis. Analyses of nest construction, sociability, and immunohistochemical features were used to determine the effects of forskolin treatment. After a relatively short term of treatment (10 days), forskolin-treated transgenic mice showed restored nest construction ability (p < 0.05) and their sociability (p < 0.01). There was a reduction of Aβ plaque deposition in the cortex and in the hippocampus. Furthermore, expression of transforming growth factor β, glial fibrillary acidic protein, and Iba-1 in the cortex was reduced in the forskolin-treated group, suggesting regulation of the inflammatory response mediated by activated microglia and astrocytes in the brains of the APP/PS1 mice (p < 0.01). Taken together, these findings suggest that forskolin shows neuroprotective effects in APP/PS1 Tg mice and may be a promising drug in the treatment of patients with AD. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Region-Specific Protein Abundance Changes in the Brain of MPTP-induced Parkinson’s Disease Mouse Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Xu; Zhou, Jianying; Chin, Mark H

2010-02-15

Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration in the nigrostriatal region of the brain; however, the neurodegeneration extends well beyond dopaminergic neurons. To gain a better understanding of the molecular changes relevant to PD, we applied two-dimensional LC-MS/MS to comparatively analyze the proteome changes in four brain regions (striatum, cerebellum, cortex, and the rest of brain) using a MPTP-induced PD mouse model with the objective to identify nigrostriatal-specific and other region-specific protein abundance changes. The combined analyses resulted in the identification of 4,895 non-redundant proteins with at least two unique peptides per protein. The relative abundance changes in eachmore » analyzed brain region were estimated based on the spectral count information. A total of 518 proteins were observed with significant MPTP-induced changes across different brain regions. 270 of these proteins were observed with specific changes occurring either only in the striatum and/or in the rest of the brain region that contains substantia nigra, suggesting that these proteins are associated with the underlying nigrostriatal pathways. Many of the proteins that exhibit significant abundance changes were associated with dopamine signaling, mitochondrial dysfunction, the ubiquitin system, calcium signaling, the oxidative stress response, and apoptosis. A set of proteins with either consistent change across all brain regions or with changes specific to the cortex and cerebellum regions were also detected. One of the interesting proteins is ubiquitin specific protease (USP9X), a deubiquination enzyme involved in the protection of proteins from degradation and promotion of the TGF-β pathway, which exhibited altered abundances in all brain regions. Western blot validation showed similar spatial changes, suggesting that USP9X is potentially associated with neurodegeneration. Together, this study for the first time presents an overall picture of proteome changes underlying both nigrostriatal pathways and other brain regions potentially involved in MPTP-induced neurodegeneration. The observed molecular changes provide a valuable reference resource for future hypothesis-driven functional studies of PD.« less

Differential effects of hunger and satiety on insular cortex and hypothalamic functional connectivity.

PubMed

Wright, Hazel; Li, Xiaoyun; Fallon, Nicholas B; Crookall, Rebecca; Giesbrecht, Timo; Thomas, Anna; Halford, Jason C G; Harrold, Joanne; Stancak, Andrej

2016-05-01

The insula cortex and hypothalamus are implicated in eating behaviour, and contain receptor sites for peptides and hormones controlling energy balance. The insula encompasses multi-functional subregions, which display differential anatomical and functional connectivities with the rest of the brain. This study aimed to analyse the effect of fasting and satiation on the functional connectivity profiles of left and right anterior, middle, and posterior insula, and left and right hypothalamus. It was hypothesized that the profiles would be altered alongside changes in homeostatic energy balance. Nineteen healthy participants underwent two 7-min resting state functional magnetic resonance imaging scans, one when fasted and one when satiated. Functional connectivity between the left posterior insula and cerebellum/superior frontal gyrus, and between left hypothalamus and inferior frontal gyrus was stronger during fasting. Functional connectivity between the right middle insula and default mode structures (left and right posterior parietal cortex, cingulate cortex), and between right hypothalamus and superior parietal cortex was stronger during satiation. Differences in blood glucose levels between the scans accounted for several of the altered functional connectivities. The insula and hypothalamus appear to form a homeostatic energy balance network related to cognitive control of eating; prompting eating and preventing overeating when energy is depleted, and ending feeding or transferring attention away from food upon satiation. This study provides evidence of a lateralized dissociation of neural responses to energy modulations. © 2016 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Joint Pairing and Structured Mapping of Convolutional Brain Morphological Multiplexes for Early Dementia Diagnosis.

PubMed

Lisowska, Anna; Rekik, Islem

2018-06-21

Diagnosis of brain dementia, particularly early mild cognitive impairment (eMCI), is critical for early intervention to prevent the onset of Alzheimer's Disease (AD), where cognitive decline is severe and irreversible. There is a large body of machine-learning based research investigating how dementia alters brain connectivity, mainly using structural (derived from diffusion MRI) and functional (derived from resting-state functional MRI) brain connectomic data. However, how early dementia affects cortical brain connections in morphology remains largely unexplored. To fill this gap, we propose a joint morphological brain multiplexes pairing and mapping strategy for early MCI detection, where a brain multiplex not only encodes the similarity in morphology between pairs of brain regions, but also a pair of brain morphological networks. Experimental results confirm that the proposed framework outperforms in classification accuracy several state-of-the-art methods. More importantly, we unprecedentedly identified most discriminative brain morphological networks between eMCI and NC, which included the paired views derived from maximum principal curvature and the sulcal depth for the left hemisphere and sulcal depth and the average curvature for the right hemisphere. We also identified the most highly correlated morphological brain connections in our cohort, which included the (pericalcarine cortex, insula cortex) on the maximum principal curvature view, (entorhinal cortex, insula cortex) on the mean sulcal depth view, and (entorhinal cortex, pericalcarine cortex) on the mean average curvature view, for both hemispheres. These highly correlated morphological connections might serve as biomarkers for early MCI diagnosis.

Anxiety, Depression, and the Microbiome: A Role for Gut Peptides.

PubMed

Lach, Gilliard; Schellekens, Harriet; Dinan, Timothy G; Cryan, John F

2018-01-01

The complex bidirectional communication between the gut and the brain is finely orchestrated by different systems, including the endocrine, immune, autonomic, and enteric nervous systems. Moreover, increasing evidence supports the role of the microbiome and microbiota-derived molecules in regulating such interactions; however, the mechanisms underpinning such effects are only beginning to be resolved. Microbiota-gut peptide interactions are poised to be of great significance in the regulation of gut-brain signaling. Given the emerging role of the gut-brain axis in a variety of brain disorders, such as anxiety and depression, it is important to understand the contribution of bidirectional interactions between peptide hormones released from the gut and intestinal bacteria in the context of this axis. Indeed, the gastrointestinal tract is the largest endocrine organ in mammals, secreting dozens of different signaling molecules, including peptides. Gut peptides in the systemic circulation can bind cognate receptors on immune cells and vagus nerve terminals thereby enabling indirect gut-brain communication. Gut peptide concentrations are not only modulated by enteric microbiota signals, but also vary according to the composition of the intestinal microbiota. In this review, we will discuss the gut microbiota as a regulator of anxiety and depression, and explore the role of gut-derived peptides as signaling molecules in microbiome-gut-brain communication. Here, we summarize the potential interactions of the microbiota with gut hormones and endocrine peptides, including neuropeptide Y, peptide YY, pancreatic polypeptide, cholecystokinin, glucagon-like peptide, corticotropin-releasing factor, oxytocin, and ghrelin in microbiome-to-brain signaling. Together, gut peptides are important regulators of microbiota-gut-brain signaling in health and stress-related psychiatric illnesses.

Exposure to GSM 900 MHz electromagnetic fields affects cerebral cytochrome c oxidase activity.

PubMed

Ammari, Mohamed; Lecomte, Anthony; Sakly, Mohsen; Abdelmelek, Hafedh; de-Seze, René

2008-08-19

The world-wide and rapidly growing use of mobile phones has raised serious concerns about the biological and health-related effects of radio frequency (RF) radiation, particularly concerns about the effects of RFs upon the nervous system. The goal of this study was conducted to measure cytochrome oxidase (CO) levels using histochemical methods in order to evaluate regional brain metabolic activity in rat brain after exposure to a GSM 900 MHz signal for 45 min/day at a brain-averaged specific absorption rate (SAR) of 1.5 W/Kg or for 15 min/day at a SAR of 6 W/Kg over seven days. Compared to the sham and control cage groups, rats exposed to a GSM signal at 6 W/Kg showed decreased CO activity in some areas of the prefrontal and frontal cortex (infralimbic cortex, prelimbic cortex, primary motor cortex, secondary motor cortex, anterior cingulate cortex areas 1 and 2 (Cg1 and Cg2)), the septum (dorsal and ventral parts of the lateral septal nucleus), the hippocampus (dorsal field CA1, CA2 and CA3 of the hippocampus and dental gyrus) and the posterior cortex (retrosplenial agranular cortex, primary and secondary visual cortex, perirhinal cortex and lateral entorhinal cortex). However, the exposure to GSM at 1.5 W/Kg did not affect brain activity. Our results indicate that 6 W/Kg GSM 900 MHz microwaves may affect brain metabolism and neuronal activity in rats.

Neonatal injury rapidly alters markers of pain and stress in rat pups.

PubMed

Victoria, Nicole C; Karom, Mary C; Eichenbaum, Hila; Murphy, Anne Z

2014-01-01

Less than 60% of infants undergoing invasive procedures in the neonatal intensive care unit receive analgesic therapy. These infants show long-term decreases in pain sensitivity and cortisol reactivity. In rats, we have previously shown that inflammatory pain experienced on the day of birth significantly decreases adult somatosensory thresholds and responses to anxiety- and stress-provoking stimuli. These long-term changes in pain and stress responsiveness are accompanied by two-fold increases in central met-enkephalin and β-endorphin expression. However, the time course over which these changes in central opioid peptide expression occur, relative to the time of injury, are not known. The present studies were conducted to determine whether the observed changes in adult opioid peptide expression were present within the first postnatal week following injury. The impact of neonatal inflammation on plasma corticosterone, a marker for stress reactivity, was also determined. Brain, spinal cord, and trunk blood were harvested at 24 h, 48 h, and 7 d following intraplantar administration of the inflammatory agent carrageenan on the day of birth. Radioimmunoassay was used to determine plasma corticosterone and met-enkephalin and β-endorphin levels within the forebrain, cortex, midbrain, and spinal cord. Within 24 h of injury, met-enkephalin levels were significantly increased in the midbrain, but decreased in the spinal cord and cortex; forebrain β-endorphin levels were significantly increased as a result of early life pain. Corticosterone levels were also significantly increased. At 7 d post-injury, opioid peptides remained elevated relative to controls, suggesting a time point by which injury-induced changes become programmed and permanent. Copyright © 2013 Wiley Periodicals, Inc.

Tapered-Tip Capillary Electrophoresis Nano-Electrospray Ionization Mass Spectrometry for Ultrasensitive Proteomics: the Mouse Cortex

NASA Astrophysics Data System (ADS)

Choi, Sam B.; Zamarbide, Marta; Manzini, M. Chiara; Nemes, Peter

2017-04-01

Ultrasensitive characterization of the proteome raises the potential to understand how differential gene expression orchestrates cell heterogeneity in the brain. Here, we report a microanalytical capillary electrophoresis nano-flow electrospray ionization (CE-nanoESI) interface for mass spectrometry to enable the measurement of limited amounts of proteins in the mouse cortex. Our design integrates a custom-built CE system to a tapered-tip metal emitter in a co-axial sheath-flow configuration. This interface can be constructed in <15 min using readily available components, facilitating broad adaptation. Tapered-tip CE-nanoESI generates stable electrospray by reproducibly anchoring the Taylor cone, minimizes sample dilution in the ion source, and ensures efficient ion generation by sustaining the cone-jet spraying regime. Parallel reaction monitoring provided a 260-zmol lower limit of detection for angiotensin II (156,000 copies). CE was able to resolve a complex mixture of peptides in 330,000 theoretical plates and identify 15 amol ( 1 pg) of BSA or cytochrome c. Over 30 min of separation, 1 ng protein digest from the mouse cortex yielded 217 nonredundant proteins encompassing a 3-log-order concentration range using a quadrupole time-of-flight mass spectrometer. Identified proteins included many products from genes that are traditionally used to mark oligodendrocytes, astrocytes, and microglia. Finally, key proteins involved in neurodegenerative disorders were detected (e.g., parkinsonism and spastic paraplegia). CE-nanoESI-HRMS delivers sufficient sensitivity to detect proteins in limited amounts of tissues and cell populations to help understand how gene expression differences maintain cell heterogeneity in the brain.

Pharmacologic Effects in vivo in Brain by Vector-Mediated Peptide Drug Delivery

NASA Astrophysics Data System (ADS)

Bickel, Ulrich; Yoshikawa, Takayoshi; Landaw, Elliot M.; Faull, Kym F.; Pardridge, William M.

1993-04-01

Pharmacologic effects in brain caused by systemic administration of neuropeptides are prevented by poor transport of the peptide through the brain vascular endothelium, which comprises the blood-brain barrier in vivo. In the present study, successful application of a chimeric peptide approach to enhance drug delivery through the blood-brain barrier for the purpose of achieving a central nervous system pharmacologic effect is described. The chimeric peptide was formed by linkage of a potent vasoactive intestinal peptide (VIP) analogue, which had been monobiotinylated, to a drug transport vector. The vector consisted of a covalent conjugate of avidin and the OX26 monoclonal antibody to the transferrin receptor. Owing to the high concentration of transferrin receptors on brain capillary endothelia, OX26 targets brain and undergoes receptor-mediated transcytosis through the blood-brain barrier. Systemic infusion of low doses (12 μg/kg) of the VIP chimeric peptide in rats resulted in an in vivo central nervous system pharmacologic effect: a 65% increase in cerebral blood flow. Biotinylated VIP analogue without the brain transport vector was ineffective.

Resting-state Functional Magnetic Resonance Imaging Analysis of Brain Functional Activity in Rats with Ischemic Stroke Treated by Electro-acupuncture.

PubMed

Liang, Shengxiang; Lin, Yunjiao; Lin, Bingbing; Li, Jianhong; Liu, Weilin; Chen, Lidian; Zhao, Shujun; Tao, Jing

2017-09-01

To evaluate whether electro-acupuncture (EA) treatment at acupoints of Zusanli (ST 36) and Quchi (LI 11) could reduce motor impairments and enhance brain functional recovery in rats with ischemic stroke. A rat model of middle cerebral artery occlusion (MCAO) was established. EA at ST 36 and LI 11was started at 24 hours (MCAO + EA group) after ischemic stroke. The nontreatment (MCAO) and sham-operated control (SC) groups were included as controls. The neurologic deficits of all groups were assessed by Zea Longa scores and the modified neurologic severity scores on 24 hours and 8 days after MCAO. To further investigate the effect of EA on infract volume and brain function, magnetic resonance imaging was used to estimate the brain lesion and brain neural activities of each group at 8 days after ischemic stroke. Within 1 week after EA treatment, the neurologic deficits were significantly alleviated, and the cerebral infarctions were improved, including visual cortex, motor cortex, striatum, dorsal thalamus, and hippocampus. Furthermore, whole brain neural activities of auditory cortex, lateral nucleus group of dorsal thalamus, hippocampus, motor cortex, orbital cortex, sensory cortex, and striatum were decreased in MCAO group, whereas that of brain neural activities were increased after EA treatment, suggesting these brain regions are in accordance with the brain structure analysis. EA at ST 36 and LI 11 could enhance the neural activity of motor function-related brain regions, including motor cortex, dorsal thalamus, and striatum in rats, which is a potential treatment for ischemia stroke. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Bioavailability and transport of peptides and peptide drugs into the brain.

PubMed

Egleton, R D; Davis, T P

1997-01-01

Rational drug design and the targeting of specific organs has become a reality in modern drug development, with the emergence of molecular biology and receptor chemistry as powerful tools for the pharmacologist. A greater understanding of peptide function as one of the major extracellular message systems has made neuropeptides an important target in neuropharmaceutical drug design. The major obstacle to targeting the brain with therapeutics is the presence of the blood-brain barrier (BBB), which controls the concentration and entry of solutes into the central nervous system. Peptides are generally polar in nature, do not easily cross the blood-brain barrier by diffusion, and except for a small number do not have specific transport systems. Peptides can also undergo metabolic deactivation by peptidases of the blood, brain and the endothelial cells that comprise the BBB. In this review, we discuss a number of the recent strategies which have been used to promote peptide stability and peptide entry into the brain. In addition, we approach the subject of targeting specific transport systems that can be found on the brain endothelial cells, and describe the limitations of the methodologies that are currently used to study brain entry of neuropharmaceuticals.

β-Amyloid Deposition Is Associated with Decreased Right Prefrontal Activation during Task Switching among Cognitively Normal Elderly

PubMed Central

Steffener, Jason; Razlighi, Qolamreza R.; Habeck, Christian; Stern, Yaakov

2016-01-01

The accumulation of β-amyloid (Aβ) peptides, a pathological hallmark of Alzheimer's disease (AD), has been associated with functional alterations, often in an episodic memory system with a particular emphasis on medial temporal lobe function. The topography of Aβ deposition, however, largely overlaps with frontoparietal control (FPC) regions implicated in cognitive control that has been shown to be impaired in early mild AD. To understand the neural mechanism underlying early changes in cognitive control with AD, we examined the impact of Aβ deposition on task-evoked FPC activation using functional magnetic resonance imaging (fMRI) in humans. Forty-three young and 62 cognitively normal older adults underwent an fMRI session during an executive contextual task in which task difficulty varied: single (either letter case or vowel/consonant judgment task) vs dual (switching between letter case and vowel/consonant decisions) task. Older subjects additionally completed 18F-florbetaben positron emission tomography scans and were classified as either amyloid positive (Aβ+) or negative (Aβ−). Consistent with previous reports, age-related increases in brain activity were found in FPC regions commonly identified across groups. For both task conditions, Aβ-related increases in brain activity were found compared with baseline activity. For higher cognitive control load, however, Aβ+ elderly showed reduced task-switching activation in the right inferior frontal cortex. Our findings suggest that with Aβ deposition, brain activation in the cognitive control region reaches a maximum with lower control demand and decreases with higher control demand, which may underlie early impairment in cognitive control with AD progression. SIGNIFICANCE STATEMENT The accumulation of β-amyloid (Aβ) peptides, a pathological hallmark of Alzheimer's disease, spatially overlaps with frontoparietal control (FPC) regions implicated in cognitive control, but the impact of Aβ deposition on FPC regions is largely unknown. Using functional magnetic resonance imaging with a task-switching task, we found Aβ-related increases in FPC regions compared with baseline activity. For higher cognitive control load, however, Aβ-related hypoactivity was found in the right inferior frontal cortex, a region highly implicated in cognitive control. The findings suggest that with Aβ deposition, task-related brain activity may reach a plateau early and undergo downstream pathways of neural dysfunction, which may relate to the early impairment of cognitive control seen in the progression of Aβ pathology. PMID:26865619

GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial.

PubMed

Farr, Olivia M; Sofopoulos, Michail; Tsoukas, Michael A; Dincer, Fadime; Thakkar, Bindiya; Sahin-Efe, Ayse; Filippaios, Andreas; Bowers, Jennifer; Srnka, Alexandra; Gavrieli, Anna; Ko, Byung-Joon; Liakou, Chrysoula; Kanyuch, Nickole; Tseleni-Balafouta, Sofia; Mantzoros, Christos S

2016-05-01

Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome). In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days, and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center. Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide -0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation. For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity. ClinicalTrials.gov NCT01562678 FUNDING : The study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961.

Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism?

PubMed

Whitaker-Azmitia, Patricia M

2005-02-01

The hypothesis explored in this review is that the high levels of serotonin in the blood seen in some autistic children (the so-called hyperserotonemia of autism) may lead to some of the behavioral and cellular changes also observed in the disorder. At early stages of development, when the blood-brain Barrier is not yet fully formed, the high levels of serotonin in the blood can enter the brain of a developing fetus and cause loss of serotonin terminals through a known negative feedback function of serotonin during development. The loss of serotonin innervation persists throughout subsequent development and the symptoms of autism appear. A review of the basic scientific literature on prenatal treatments affecting serotonin is given, in support of this hypothesis, with an emphasis on studies using the serotonin agonist, 5-methoxytryptamine (5-MT). In work using 5-MT to mimic hyperserotonemia, Sprague-Dawley rats are treated from gestational day 12 until postnatal 20. In published reports, these animals have been found to have a significant loss of serotonin terminals, decreased metabolic activity in cortex, changes in columnar development in cortex, changes in serotonin receptors, and "autistic-like" behaviors. In preliminary cellular findings given in this review, the animals have also been found to have cellular changes in two relevant brain regions: 1. Central nucleus of the amygdala, a brain region involved in fear-responding, where an increase in calcitonin gene related peptide (CGRP) was found 2. Paraventricular nucleus of the hypothalamus, a brain region involved in social memory and bonding, where a decrease in oxytocin was found. Both of these cellular changes could result from loss of serotonin innervation, possibly due to loss of terminal outgrowth from the same cells of the raphe nuclei. Thus, increased serotonergic activity during development could damage neurocircuitry involved in emotional responding to social stressors and may have relevance to the symptoms of autism.

Triiodothyronine and brain natriuretic peptide: similar long-term prognostic values for chronic heart failure.

PubMed

Kozdag, Guliz; Ertas, Gokhan; Kilic, Teoman; Acar, Eser; Sahin, Tayfun; Ural, Dilek

2010-01-01

Although low levels of free triiodothyronine and high levels of brain natriuretic peptide have been shown as independent predictors of death in chronic heart failure patients, few studies have compared their prognostic values. The aim of this prospective study was to measure free triiodothyronine and brain natriuretic peptide levels and to compare their prognostic values among such patients.A total of 334 patients (mean age, 62 ± 13 yr; 218 men) with ischemic and nonischemic dilated cardiomyopathy were included in the study. The primary endpoint was a major cardiac event.During the follow-up period, 92 patients (28%) experienced a major cardiac event. Mean free triiodothyronine levels were lower and median brain natriuretic peptide levels were higher in patients with major cardiac events than in those without. A significant negative correlation was found between free triiodothyronine and brain natriuretic peptide levels. Receiver operating characteristic curve analysis showed that the predictive cutoff values were < 2.12 pg/mL for free triiodothyronine and > 686 pg/mL for brain natriuretic peptide. Cumulative survival was significantly lower among patients with free triiodothyronine < 2.12 pg/mL and among patients with brain natriuretic peptide > 686 pg/mL. In multivariate analysis, the significant independent predictors of major cardiac events were age, free triiodothyronine, and brain natriuretic peptide.In the present study, free triiodothyronine and brain natriuretic peptide had similar prognostic values for predicting long-term prognosis in chronic heart failure patients. These results also suggested that combining these biomarkers may provide an important risk indicator for patients with heart failure.

Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics.

PubMed

Bazov, Igor; Sarkisyan, Daniil; Kononenko, Olga; Watanabe, Hiroyuki; Karpyak, Victor M; Yakovleva, Tatiana; Bakalkin, Georgy

2018-06-20

Molecular changes in cortical areas of addicted brain may underlie cognitive impairment and loss of control over intake of addictive substances and alcohol. Prodynorphin (PDYN) gives rise to dynorphin (DYNs) opioid peptides which target kappa-opioid receptor (KOR). DYNs mediate alcohol-induced impairment of learning and memory, while KOR antagonists block excessive, compulsive-like drug and alcohol self-administration in animal models. In human brain, the DYN/KOR system may undergo adaptive changes, which along with neuronal loss, may contribute to alcohol-associated cognitive deficit. We addressed this hypothesis by comparing the expression levels and co-expression (transcriptionally coordinated) patterns of PDYN and KOR (OPRK1) genes in dorsolateral prefrontal cortex (dlPFC) between human alcoholics and controls. Postmortem brain specimens of 53 alcoholics and 55 controls were analyzed. PDYN was found to be downregulated in dlPFC of alcoholics, while OPRK1 transcription was not altered. PDYN downregulation was confined to subgroup of subjects carrying C, a high-risk allele of PDYN promoter SNP rs1997794 associated with alcoholism. Changes in PDYN expression did not depend on the decline in neuronal proportion in alcoholics, and thereby may be attributed to transcriptional adaptations in alcoholic brain. Absolute expression levels of PDYN were lower compared to those of OPRK1, suggesting that PDYN expression is a limiting factor in the DYN/KOR signaling, and that the PDYN downregulation diminishes efficacy of DYN/KOR signaling in dlPFC of human alcoholics. The overall outcome of the DYN/KOR downregulation may be disinhibition of neurotransmission, which when overactivated could contribute to formation of alcohol-related behavior.

Traumatic brain injury and recovery mechanisms: peptide modulation of periventricular neurogenic regions by the choroid plexus–CSF nexus

PubMed Central

Stopa, Edward; Baird, Andrew; Sharma, Hari

2010-01-01

In traumatic brain injury (TBI), severe disruptions occur in the choroid plexus (CP)–cerebrospinal fluid (CSF) nexus that destabilize the nearby hippocampal and subventricular neurogenic regions. Following invasive and non-invasive injuries to cortex, several adverse sequelae harm the brain interior: (i) structural damage to CP epithelium that opens the blood–CSF barrier (BCSFB) to protein, (ii) altered CSF dynamics and intracranial pressure (ICP), (iii) augmentation of leukocyte traffic across CP into the CSF–brain, (iv) reduction in CSF sink action and clearance of debris from ventricles, and (v) less efficient provision of micronutritional and hormonal support for the CNS. However, gradual post-TBI restitution of the injured CP epithelium and ependyma, and CSF homeostatic mechanisms, help to restore subventricular/subgranular neurogenesis and the cognitive abilities diminished by CNS damage. Recovery from TBI is faciltated by upregulated choroidal/ependymal growth factors and neurotrophins, and their secretion into ventricular CSF. There, by an endocrine-like mechanism, CSF bulk flow convects the neuropeptides to target cells in injured cortex for aiding repair processes; and to neurogenic niches for enhancing conversion of stem cells to new neurons. In the recovery from TBI and associated ischemia, the modulating neuropeptides include FGF2, EGF, VEGF, NGF, IGF, GDNF, BDNF, and PACAP. Homeostatic correction of TBI-induced neuropathology can be accelerated or amplified by exogenously boosting the CSF concentration of these growth factors and neurotrophins. Such intraventricular supplementation via the CSF route promotes neural restoration through enhanced neurogenesis, angiogenesis, and neuroprotective effects. CSF translational research presents opportunities that involve CP and ependymal manipulations to expedite recovery from TBI. PMID:20936524

Identification of peptide sequences that target to the brain using in vivo phage display.

PubMed

Li, Jingwei; Zhang, Qizhi; Pang, Zhiqing; Wang, Yuchen; Liu, Qingfeng; Guo, Liangran; Jiang, Xinguo

2012-06-01

Phage display technology could provide a rapid means for the discovery of novel peptides. To find peptide ligands specific for the brain vascular receptors, we performed a modified phage display method. Phages were recovered from mice brain parenchyma after administrated with a random 7-mer peptide library intravenously. A longer circulation time was arranged according to the biodistributive brain/blood ratios of phage particles. Following sequential rounds of isolation, a number of phages were sequenced and a peptide sequence (CTSTSAPYC, denoted as PepC7) was identified. Clone 7-1, which encodes PepC7, exhibited translocation efficiency about 41-fold higher than the random library phage. Immunofluorescence analysis revealed that Clone 7-1 had a significant superiority on transport efficiency into the brain compared with native M13 phage. Clone 7-1 was inhibited from homing to the brain in a dose-dependent fashion when cyclic peptides of the same sequence were present in a competition assay. Interestingly, the linear peptide (ATSTSAPYA, Pep7) and a scrambled control peptide PepSC7 (CSPATSYTC) did not compete with the phage at the same tested concentration (0.2-200 pg). Labeled by Cy5.5, PepC7 exhibited significant brain-targeting capability in in vivo optical imaging analysis. The cyclic conformation of PepC7 formed by disulfide bond, and the correct structure itself play a critical role in maintaining the selectivity and affinity for the brain. In conclusion, PepC7 is a promising brain-target motif never been reported before and it could be applied to targeted drug delivery into the brain.

Mapping glucose-mediated gut-to-brain signalling pathways in humans☆

PubMed Central

Little, Tanya J.; McKie, Shane; Jones, Richard B.; D'Amato, Massimo; Smith, Craig; Kiss, Orsolya; Thompson, David G.; McLaughlin, John T.

2014-01-01

Objectives Previous fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role. Experimental design Changes in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250 ml) of: 1 M glucose + predosing with dexloxiglumide (CCK1 receptor antagonist), 1 M glucose + placebo, or 0.9% saline (control) + placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded. Principal observations Intragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose + dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex. Conclusions Glucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway. PMID:24685436

Investigation of the cortical activation by touching fabric actively using fingers.

PubMed

Wang, Q; Yu, W; He, N; Chen, K

2015-11-01

Human subjects can tactually estimate the perception of touching fabric. Although many psychophysical and neurophysiological experiments have elucidated the peripheral neural mechanisms that underlie fabric hand estimation, the associated cortical mechanisms are not well understood. To identify the brain regions responsible for the tactile stimulation of fabric against human skin, we used the technology of functional magnetic resonance imaging (fMRI), to observe brain activation when the subjects touched silk fabric actively using fingers. Consistent with previous research about brain cognition on sensory stimulation, large activation in the primary somatosensory cortex (SI), the secondary somatosensory cortex (SII) and moto cortex, and little activation in the posterior insula cortex and Broca's Area were observed when the subjects touched silk fabric. The technology of fMRI is a promising tool to observe and characterize the brain cognition on the tactile stimulation of fabric quantitatively. The intensity and extent of activation in the brain regions, especially the primary somatosensory cortex (SI) and the secondary somatosensory cortex (SII), can represent the perception of stimulation of fabric quantitatively. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The elephant brain in numbers

PubMed Central

Herculano-Houzel, Suzana; Avelino-de-Souza, Kamilla; Neves, Kleber; Porfírio, Jairo; Messeder, Débora; Mattos Feijó, Larissa; Maldonado, José; Manger, Paul R.

2014-01-01

What explains the superior cognitive abilities of the human brain compared to other, larger brains? Here we investigate the possibility that the human brain has a larger number of neurons than even larger brains by determining the cellular composition of the brain of the African elephant. We find that the African elephant brain, which is about three times larger than the human brain, contains 257 billion (109) neurons, three times more than the average human brain; however, 97.5% of the neurons in the elephant brain (251 billion) are found in the cerebellum. This makes the elephant an outlier in regard to the number of cerebellar neurons compared to other mammals, which might be related to sensorimotor specializations. In contrast, the elephant cerebral cortex, which has twice the mass of the human cerebral cortex, holds only 5.6 billion neurons, about one third of the number of neurons found in the human cerebral cortex. This finding supports the hypothesis that the larger absolute number of neurons in the human cerebral cortex (but not in the whole brain) is correlated with the superior cognitive abilities of humans compared to elephants and other large-brained mammals. PMID:24971054

Large-Scale Mass Spectrometry Imaging Investigation of Consequences of Cortical Spreading Depression in a Transgenic Mouse Model of Migraine

NASA Astrophysics Data System (ADS)

Carreira, Ricardo J.; Shyti, Reinald; Balluff, Benjamin; Abdelmoula, Walid M.; van Heiningen, Sandra H.; van Zeijl, Rene J.; Dijkstra, Jouke; Ferrari, Michel D.; Tolner, Else A.; McDonnell, Liam A.; van den Maagdenberg, Arn M. J. M.

2015-06-01

Cortical spreading depression (CSD) is the electrophysiological correlate of migraine aura. Transgenic mice carrying the R192Q missense mutation in the Cacna1a gene, which in patients causes familial hemiplegic migraine type 1 (FHM1), exhibit increased propensity to CSD. Herein, mass spectrometry imaging (MSI) was applied for the first time to an animal cohort of transgenic and wild type mice to study the biomolecular changes following CSD in the brain. Ninety-six coronal brain sections from 32 mice were analyzed by MALDI-MSI. All MSI datasets were registered to the Allen Brain Atlas reference atlas of the mouse brain so that the molecular signatures of distinct brain regions could be compared. A number of metabolites and peptides showed substantial changes in the brain associated with CSD. Among those, different mass spectral features showed significant ( t-test, P < 0.05) changes in the cortex, 146 and 377 Da, and in the thalamus, 1820 and 1834 Da, of the CSD-affected hemisphere of FHM1 R192Q mice. Our findings reveal CSD- and genotype-specific molecular changes in the brain of FHM1 transgenic mice that may further our understanding about the role of CSD in migraine pathophysiology. The results also demonstrate the utility of aligning MSI datasets to a common reference atlas for large-scale MSI investigations.

Targeted transport of nanocarriers into brain for theranosis with rabies virus glycoprotein-derived peptide.

PubMed

Fu, Chen; Xiang, Yonggang; Li, Xiaorong; Fu, Ailing

2018-06-01

For successful theranosis of brain diseases, limited access of therapeutic molecules across blood-brain barrier (BBB) needs be overcome in brain delivery. Currently, peptide derivatives of rabies virus glycoprotein (RVG) have been exploited as delivery ligands to transport nanocarriers across BBB and specifically into the brain. The targeting peptides usually conjugate to the nanocarrier surface, and the cargoes, including siRNA, miRNA, DNA, proteins and small molecular chemicals, are complexed or encapsulated in the nanocarriers. The peptide ligand of the RVG-modified nanocarriers introduces the conjugated targeted-delivery into the brain, and the cargoes are involved in disease theranosis. The peptide-modified nanocarriers have been applied to diagnose and treat various brain diseases, such as glioma, Alzheimer's disease, ischemic injury, protein misfolding diseases etc. Since the targeting delivery system has displayed good biocompatibility and desirable therapeutic effect, it will raise a potential application in treating brain diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

A physical multifield model predicts the development of volume and structure in the human brain

NASA Astrophysics Data System (ADS)

Rooij, Rijk de; Kuhl, Ellen

2018-03-01

The prenatal development of the human brain is characterized by a rapid increase in brain volume and a development of a highly folded cortex. At the cellular level, these events are enabled by symmetric and asymmetric cell division in the ventricular regions of the brain followed by an outwards cell migration towards the peripheral regions. The role of mechanics during brain development has been suggested and acknowledged in past decades, but remains insufficiently understood. Here we propose a mechanistic model that couples cell division, cell migration, and brain volume growth to accurately model the developing brain between weeks 10 and 29 of gestation. Our model accurately predicts a 160-fold volume increase from 1.5 cm3 at week 10 to 235 cm3 at week 29 of gestation. In agreement with human brain development, the cortex begins to form around week 22 and accounts for about 30% of the total brain volume at week 29. Our results show that cell division and coupling between cell density and volume growth are essential to accurately model brain volume development, whereas cell migration and diffusion contribute mainly to the development of the cortex. We demonstrate that complex folding patterns, including sinusoidal folds and creases, emerge naturally as the cortex develops, even for low stiffness contrasts between the cortex and subcortex.

Neurotensin effect on Na+, K+-ATPase is CNS area- and membrane-dependent and involves high affinity NT1 receptor.

PubMed

López Ordieres, María Graciela; Rodríguez de Lores Arnaiz, Georgina

2002-11-01

We have previously shown that peptide neurotensin inhibits cerebral cortex synaptosomal membrane Na+, K+-ATPase, an effect fully prevented by blockade of neurotensin NT1 receptor by antagonist SR 48692. The work was extended to analyze neurotensin effect on Na+, K+-ATPase activity present in other synaptosomal membranes and in CNS myelin and mitochondrial fractions. Results indicated that, besides inhibiting cerebral cortex synaptosomal membrane Na+, K+-ATPase, neurotensin likewise decreased enzyme activity in homologous striatal membranes as well as in a commercial preparation obtained from porcine cerebral cortex. However, the peptide failed to alter either Na+, K+-ATPase activity in cerebellar synaptosomal and myelin membranes or ATPase activity in mitochondrial preparations. Whenever an effect was recorded with the peptide, it was blocked by antagonist SR 48692, indicating the involvement of the high affinity neurotensin receptor (NT1), as well as supporting the contention that, through inhibition of ion transport at synaptic membrane level, neurotensin plays a regulatory role in neurotransmission.

Cross-language differences in the brain network subserving intelligible speech.

PubMed

Ge, Jianqiao; Peng, Gang; Lyu, Bingjiang; Wang, Yi; Zhuo, Yan; Niu, Zhendong; Tan, Li Hai; Leff, Alexander P; Gao, Jia-Hong

2015-03-10

How is language processed in the brain by native speakers of different languages? Is there one brain system for all languages or are different languages subserved by different brain systems? The first view emphasizes commonality, whereas the second emphasizes specificity. We investigated the cortical dynamics involved in processing two very diverse languages: a tonal language (Chinese) and a nontonal language (English). We used functional MRI and dynamic causal modeling analysis to compute and compare brain network models exhaustively with all possible connections among nodes of language regions in temporal and frontal cortex and found that the information flow from the posterior to anterior portions of the temporal cortex was commonly shared by Chinese and English speakers during speech comprehension, whereas the inferior frontal gyrus received neural signals from the left posterior portion of the temporal cortex in English speakers and from the bilateral anterior portion of the temporal cortex in Chinese speakers. Our results revealed that, although speech processing is largely carried out in the common left hemisphere classical language areas (Broca's and Wernicke's areas) and anterior temporal cortex, speech comprehension across different language groups depends on how these brain regions interact with each other. Moreover, the right anterior temporal cortex, which is crucial for tone processing, is equally important as its left homolog, the left anterior temporal cortex, in modulating the cortical dynamics in tone language comprehension. The current study pinpoints the importance of the bilateral anterior temporal cortex in language comprehension that is downplayed or even ignored by popular contemporary models of speech comprehension.

Cross-language differences in the brain network subserving intelligible speech

PubMed Central

Ge, Jianqiao; Peng, Gang; Lyu, Bingjiang; Wang, Yi; Zhuo, Yan; Niu, Zhendong; Tan, Li Hai; Leff, Alexander P.; Gao, Jia-Hong

2015-01-01

How is language processed in the brain by native speakers of different languages? Is there one brain system for all languages or are different languages subserved by different brain systems? The first view emphasizes commonality, whereas the second emphasizes specificity. We investigated the cortical dynamics involved in processing two very diverse languages: a tonal language (Chinese) and a nontonal language (English). We used functional MRI and dynamic causal modeling analysis to compute and compare brain network models exhaustively with all possible connections among nodes of language regions in temporal and frontal cortex and found that the information flow from the posterior to anterior portions of the temporal cortex was commonly shared by Chinese and English speakers during speech comprehension, whereas the inferior frontal gyrus received neural signals from the left posterior portion of the temporal cortex in English speakers and from the bilateral anterior portion of the temporal cortex in Chinese speakers. Our results revealed that, although speech processing is largely carried out in the common left hemisphere classical language areas (Broca’s and Wernicke’s areas) and anterior temporal cortex, speech comprehension across different language groups depends on how these brain regions interact with each other. Moreover, the right anterior temporal cortex, which is crucial for tone processing, is equally important as its left homolog, the left anterior temporal cortex, in modulating the cortical dynamics in tone language comprehension. The current study pinpoints the importance of the bilateral anterior temporal cortex in language comprehension that is downplayed or even ignored by popular contemporary models of speech comprehension. PMID:25713366

Peptides and Ageing.

PubMed

Khavinson, Vladimir Kh

2002-01-01

A technology has been developed for manufacturing of biologically active complex peptide preparations from extracts of different tissues. In particular, the pineal preparation (Epithalamin) augments the in vitro outgrowth of explants from the pineal gland but not from other tissues, the latter being stimulated by peptide preparations from respective tissues. Epithalamin increases melatonin production by the pineal gland of rats, improves immunological parameters in rats and mice, produces anticarcinogenic effects in different experimental models, stimulates antioxidant defenses, and restores the reproductive function in old rats. These effects are combined in the ability of Epithalamin to increase the lifespan in rats, mice, and fruit flies. Many of these effects are reproduced in clinical trials, which have demonstrated the geroprotector activity of Epithalamin in humans. Among the effects of the thymic preparation Thymalin, those related to its ability to stimulate immunity are the most prominent. This ability is associated with anticarcinogenic and geroprotector activities. Clinical trials of the peptide preparations obtained from other organs including the prostate, the cerebral cortex, and the eye retina, have demonstrated beneficial effects reflected by the improvement of the conditions of respective organs. Based on the data about the amino acid compositions of the peptide preparations, novel principles of the design of biologically active short peptides possessing tissue-specific activities has been developed. Dipeptides specific for the thymus and tetrapeptides specific for the heart, liver, brain cortex, and pineal glands stimulate the in vitro outgrowth of explants of respective organs. Interestingly, for eye retina and the pineal gland, a common tetrapeptide Ala-Glu-Asp-Gly (Epitalon) has been designed, probably reflecting the common embryonal origin of these two organs. Epitalon reproduces the effects of Epithalamin including those related to its geroprotector activity. In particular, Epitalon increases the lifespan of mice and fruit flies and restores the circadian rhythms of melatonin and cortisol production in old rhesus monkeys. At the same time, Epitalon prolongs the functional integrity of the eye retina in Campbell rats with hereditary Retinitis Pigmentosa and improves the visual functions in patients with pigmental retinal degeneration. Changes in gene expression were observed to be produced by the short peptide preparations. Therefore, the effects of Epitalon are suggested to be mediated by transcriptional machinery common for the pineal gland and the retina and, probably, for regulation of melatonin production in fruit flies. Based on three decades of studies of the peptide preparations, the peptide theory of ageing has been put forward. According this theory, ageing is an evolutionary determined biological process of changes in gene expression resulting in impaired synthesis of regulatory and tissue-specific peptides in organs and tissues, which provokes their structural and functional changes and the development of diseases. Correspondingly, correction of such disorders by means of stimulation of peptide production in the organism or through their delivery can promote the normalisation of disturbed body functions.

Genome-wide alteration of 5-hydroxymenthylcytosine in a mouse model of Alzheimer's disease.

PubMed

Shu, Liqi; Sun, Wenjia; Li, Liping; Xu, Zihui; Lin, Li; Xie, Pei; Shen, Hui; Huang, Luoxiu; Xu, Qi; Jin, Peng; Li, Xuekun

2016-05-20

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder that leads to a decline in cognitive function. In AD, aggregates of amyloid β peptide precede the accumulation of neurofibrillary tangles, both of which are hallmarks of the disease. The great majority (>90 %) of the AD cases are not originated from genetic defects, therefore supporting the central roles of epigenetic modifications that are acquired progressively during the life span. Strong evidences have indicated the implication of epigenetic modifications, including histone modification and DNA methylation, in AD. Recent studies revealed that 5-hydroxymethylcytosine (5hmC) is dynamically regulated during neurodevelopment and aging. We show that amyloid peptide 1-42 (Aβ1-42) could significantly reduce the overall level of 5hmC in vitro. We found that the level of 5hmC displayed differential response to the pathogenesis in different brain regions, including the cortex, cerebellum, and hippocampus of APP-PSEN1 double transgenic (DTg) mice. We observed a significant decrease of overall 5hmC in hippocampus, but not in cortex and cerebellum, as the DTg mice aged. Genome-wide profiling identified differential hydroxymethylation regions (DhMRs) in DTg mice, which are highly enriched in introns, exons and intergenic regions. Gene ontology analyses indicated that DhMR-associated genes are highly enriched in multiple signaling pathways involving neuronal development/differentiation and neuronal function/survival. 5hmC-mediated epigenetic regulation could potentially be involved in the pathogenesis of AD.

Secretin and autism: a basic morphological study about the distribution of secretin in the nervous system.

PubMed

Köves, Katalin; Kausz, Mária; Reser, Diana; Illyés, György; Takács, József; Heinzlmann, Andrea; Gyenge, Eszter; Horváth, Károly

2004-12-15

For the first time, the relationship between secretin and autism has been demonstrated by one of us. Intravenous administration of secretin in autistic children caused a fivefold higher pancreaticobiliary fluid secretion than in healthy ones and, at least in some of the patients, better mental functions were reported after the secretin test. Because the precise localization of secretin in the brain is still not completely known, the abovementioned observation led us to map secretin immunoreactivity in the nervous system of several mammalian species. In the present work, the distribution of secretin immunoreactivity in cat and human nervous systems was compared with that of rats using an immunohistochemical approach. Secretin immunoreactivity was observed in the following brain structures of both humans and in colchicine-treated rats: (1) Purkinje cells in the cerebellar cortex; (2) central cerebellar nuclei; (3) pyramidal cells in the motor cortex; and (4) primary sensory neurons. Additionally, secretin immnoreactive cells were observed in the human hippocampus and amygdala and in third-order sensory neurons of the rat auditory system. In cats, secretin was only observed in the spinal ganglia. Our findings support the view that secretin is not only a gastrointestinal peptide but that it is also a neuropeptide. Its presence or the lack of its presence may have a role in the development of behavioral disorders.

Immunohistochemical expression and colocalization of somatostatin, carboxypeptidase-E and prohormone convertases 1 and 2 in rat brain.

PubMed

Billova, S; Galanopoulou, A S; Seidah, N G; Qiu, X; Kumar, U

2007-06-29

The processing of many peptides for their maturation in target tissue depends upon the presence of sorting receptor. Several previous studies have predicted that carboxypeptidase-E (CPE), prohormone convertase 1 (PC1) and prohormone convertase 2 (PC2) may function as sorting elements for somatostatin (SST) for its maturation and processing to appropriate targets. However, nothing is currently known about whether brain, neuronal culture or even endocrine cells express SST, CPE, PC1 and PC2 and exhibit colocalization. Accordingly, in the present study using peroxidase immunohistochemistry, double-labeled indirect immunofluorescence immunohistochemistry and Western blot analysis, we mapped the distributional pattern of SST, CPE, PC1 and PC2 in different rat brain regions. Additionally, we also determined the colocalization of SST with CPE, PC1 and PC2 as well as colocalization of CPE with PC1 and PC2. The localization of SST, CPE, PC1 and PC2 reveals a distinct and region specific distribution pattern in the rat brain. Using an indirect double-label immunofluorescence method we observed selective neuron specific colocalization in a region specific manner in cortex, striatum and hippocampus. These studies provide the first evidence for colocalization between SST, CPE, PC1 and PC2 as well as CPE with PC1 and PC2. SST in cerebral cortex colocalized in pyramidal and non-pyramidal neurons with CPE, PC1 and PC2. Most importantly, in striatum and hippocampus colocalization was mostly observed selectively and preferentially in interneurons. CPE is also colocalized with PC1 and PC2 in a region specific manner. The data presented here provide a new insight into the distribution and colocalization of SST, CPE, PC1 and PC2 in rat brain. Taken together, our data anticipate the possibility that CPE, PC1 and PC2 might be potential target for the maturation of SST.

Altered structural connectivity of pain-related brain network in burning mouth syndrome-investigation by graph analysis of probabilistic tractography.

PubMed

Wada, Akihiko; Shizukuishi, Takashi; Kikuta, Junko; Yamada, Haruyasu; Watanabe, Yusuke; Imamura, Yoshiki; Shinozaki, Takahiro; Dezawa, Ko; Haradome, Hiroki; Abe, Osamu

2017-05-01

Burning mouth syndrome (BMS) is a chronic intraoral pain syndrome featuring idiopathic oral pain and burning discomfort despite clinically normal oral mucosa. The etiology of chronic pain syndrome is unclear, but preliminary neuroimaging research has suggested the alteration of volume, metabolism, blood flow, and diffusion at multiple brain regions. According to the neuromatrix theory of Melzack, pain sense is generated in the brain by the network of multiple pain-related brain regions. Therefore, the alteration of pain-related network is also assumed as an etiology of chronic pain. In this study, we investigated the brain network of BMS brain by using probabilistic tractography and graph analysis. Fourteen BMS patients and 14 age-matched healthy controls underwent 1.5T MRI. Structural connectivity was calculated in 83 anatomically defined regions with probabilistic tractography of 60-axis diffusion tensor imaging and 3D T1-weighted imaging. Graph theory network analysis was used to evaluate the brain network at local and global connectivity. In BMS brain, a significant difference of local brain connectivity was recognized at the bilateral rostral anterior cingulate cortex, right medial orbitofrontal cortex, and left pars orbitalis which belong to the medial pain system; however, no significant difference was recognized at the lateral system including the somatic sensory cortex. A strengthened connection of the anterior cingulate cortex and medial prefrontal cortex with the basal ganglia, thalamus, and brain stem was revealed. Structural brain network analysis revealed the alteration of the medial system of the pain-related brain network in chronic pain syndrome.

Mapping Prefrontal Cortex Functions in Human Infancy

ERIC Educational Resources Information Center

Grossmann, Tobias

2013-01-01

It has long been thought that the prefrontal cortex, as the seat of most higher brain functions, is functionally silent during most of infancy. This review highlights recent work concerned with the precise mapping (localization) of brain activation in human infants, providing evidence that prefrontal cortex exhibits functional activation much…

N-terminal pro-brain natriuretic peptide in acute Kawasaki disease correlates with coronary artery involvement.

PubMed

Adjagba, Philippe M; Desjardins, Laurent; Fournier, Anne; Spigelblatt, Linda; Montigny, Martine; Dahdah, Nagib

2015-10-01

We have lately documented the importance of N-terminal pro-brain natriuretic peptide in aiding the diagnosis of Kawasaki disease. We sought to investigate the potential value of N-terminal pro-brain natriuretic peptide pertaining to the prediction of coronary artery dilatation (Z-score>2.5) and/or of resistance to intravenous immunoglobulin therapy. We hypothesised that increased serum N-terminal pro-brain natriuretic peptide level correlates with increased coronary artery dilatation and/or resistance to intravenous immunoglobulin. We carried out a prospective study involving newly diagnosed patients treated with 2 g/kg intravenous immunoglobulin within 5-10 days of onset of fever. Echocardiography was performed in all patients at onset, then weekly for 3 weeks, then at month 2, and month 3. Coronary arteries were measured at each visit, and coronary artery Z-score was calculated. All the patients had N-terminal pro-brain natriuretic peptide serum level measured at onset, and the Z-score calculated. There were 109 patients enrolled at 6.58±2.82 days of fever, age 3.79±2.92 years. High N-terminal pro-brain natriuretic peptide level was associated with coronary artery dilatation at onset in 22.2 versus 5.6% for normal N-terminal pro-brain natriuretic peptide levels (odds ratio 4.8 [95% confidence interval 1.05-22.4]; p=0.031). This was predictive of cumulative coronary artery dilatation for the first 3 months (p=0.04-0.02), but not during convalescence at 2-3 months (odds ratio 1.28 [95% confidence interval 0.23-7.3]; p=non-significant). Elevated N-terminal pro-brain natriuretic peptide levels did not predict intravenous immunoglobulin resistance, 15.3 versus 13.5% (p=1). Elevated N-terminal pro-brain natriuretic peptide level correlates with acute coronary artery dilatation in treated Kawasaki disease, but not with intravenous immunoglobulin resistance.

Alterations of motor performance and brain cortex mitochondrial function during ethanol hangover.

PubMed

Bustamante, Juanita; Karadayian, Analia G; Lores-Arnaiz, Silvia; Cutrera, Rodolfo A

2012-08-01

Ethanol has been known to affect various behavioral parameters in experimental animals, even several hours after ethanol (EtOH) is absent from blood circulation, in the period known as hangover. The aim of this study was to assess the effects of acute ethanol hangover on motor performance in association with the brain cortex energetic metabolism. Evaluation of motor performance and brain cortex mitochondrial function during alcohol hangover was performed in mice 6 hours after a high ethanol dose (hangover onset). Animals were injected i.p. either with saline (control group) or with ethanol (3.8 g/kg BW) (hangover group). Ethanol hangover group showed a bad motor performance compared with control animals (p < .05). Oxygen uptake in brain cortex mitochondria from hangover animals showed a 34% decrease in the respiratory control rate as compared with the control group. Mitochondrial complex activities were decreased being the complex I-III the less affected by the hangover condition; complex II-III was markedly decreased by ethanol hangover showing 50% less activity than controls. Complex IV was 42% decreased as compared with control animals. Hydrogen peroxide production was 51% increased in brain cortex mitochondria from the hangover group, as compared with the control animals. Quantification of the mitochondrial transmembrane potential indicated that ethanol injected animals presented 17% less ability to maintain the polarized condition as compared with controls. These results indicate that a clear decrease in proton motive force occurs in brain cortex mitochondria during hangover conditions. We can conclude that a decreased motor performance observed in the hangover group of animals could be associated with brain cortex mitochondrial dysfunction and the resulting impairment of its energetic metabolism. Copyright © 2012 Elsevier Inc. All rights reserved.

Rat immunoreactive cholecystokinin (CCK): characterization using two chromatographic techniques.

PubMed

Bacarese-Hamilton, A J; Adrian, T E; Chohan, P; Bloom, S R

1985-06-01

Acid and neutral extracts of rat cerebral cortex and upper small intestine were prepared and the endogenous concentrations of cholecystokinin-like immunoreactivity (CCK-LI) measured by three new CCK-specific radioimmunoassays. The characterization of the immunoreactive CCK molecular forms was undertaken using gel permeation chromatography in the presence of 6 M urea to minimise problems relating to peptide adsorption or aggregation. Reverse-phase high-performance liquid chromatography (HPLC) was also performed on the rat tissue extracts. Rat cortex contained 268 +/- 12 pmol/g CCK-LI, and over 90% resembled the sulphated CCK-8, which was preferentially extracted at neutral pH. In contrast, the rat upper small intestine (97 +/- 8 pmol/g of CCK-LI) contained less than 20% CCK-8, the majority of immunoreactive CCK being of larger molecular size and being preferentially extracted at acid pH. In the small intestine the predominant molecular form(s) was intermediate in size between CCK-33 and CCK-8. Large amounts of CCK-33 and of a molecular form larger than CCK-33 were also detected. It is concluded that post-translational cleavage of CCK differs in rat brain and gut.

Comparative peptidomics analysis of neural adaptations in rats repeatedly exposed to amphetamine.

PubMed

Romanova, Elena V; Lee, Ji Eun; Kelleher, Neil L; Sweedler, Jonathan V; Gulley, Joshua M

2012-10-01

Repeated exposure to amphetamine (AMPH) induces long-lasting behavioral changes, referred to as sensitization, that are accompanied by various neuroadaptations in the brain. To investigate the chemical changes that occur during behavioral sensitization, we applied a comparative proteomics approach to screen for neuropeptide changes in a rodent model of AMPH-induced sensitization. By measuring peptide profiles with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and comparing signal intensities using principal component analysis and variance statistics, subsets of peptides are found with significant differences in the dorsal striatum, nucleus accumbens, and medial prefrontal cortex of AMPH-sensitized male Sprague-Dawley rats. These biomarker peptides, identified in follow-up analyses using liquid chromatography and tandem mass spectrometry, suggest that behavioral sensitization to AMPH is associated with complex chemical adaptations that regulate energy/metabolism, neurotransmission, apoptosis, neuroprotection, and neuritogenesis, as well as cytoskeleton integrity and neuronal morphology. Our data contribute to a growing number of reports showing that in addition to the mesolimbic dopamine system, which is the best known signaling pathway involved with reinforcing the effect of psychostimulants, concomitant chemical changes in other pathways and in neuronal organization may play a part in the overall effect of chronic AMPH exposure on behavior. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Docosahexaenoic acid provides protection from impairment of learning ability in Alzheimer's disease model rats.

PubMed

Hashimoto, Michio; Hossain, Shahdat; Shimada, Toshio; Sugioka, Kozo; Yamasaki, Hiroshi; Fujii, Yoshimi; Ishibashi, Yutaka; Oka, Jun-Ichiro; Shido, Osamu

2002-06-01

Docosahexaenoic acid (C22:6, n-3), a major n-3 fatty acid of the brain, has been implicated in restoration and enhancement of memory-related functions. Because Alzheimer's disease impairs memory, and infusion of amyloid-beta (Abeta) peptide (1-40) into the rat cerebral ventricle reduces learning ability, we investigated the effect of dietary pre-administration of docosahexaenoic acid on avoidance learning ability in Abeta peptide-produced Alzheimer's disease model rats. After a mini-osmotic pump filled with Abeta peptide or vehicle was implanted in docosahexaenoic acid-fed and control rats, they were subjected to an active avoidance task in a shuttle avoidance system apparatus. Pre-administration of docosahexaenoic acid had a profoundly beneficial effect on the decline in avoidance learning ability in the Alzheimer's disease model rats, associated with an increase in the cortico-hippocampal docosahexaenoic acid/arachidonic acid molar ratio, and a decrease in neuronal apoptotic products. Docosahexaenoic acid pre-administration furthermore increased cortico-hippocampal reduced glutathione levels and glutathione reductase activity, and suppressed the increase in lipid peroxide and reactive oxygen species levels in the cerebral cortex and hippocampus of the Alzheimer's disease model rats, suggesting an increase in antioxidative defence. Docosahexaenoic acid is thus a possible prophylactic means for preventing the learning deficiencies of Alzheimer's disease.

The auditory and non-auditory brain areas involved in tinnitus. An emergent property of multiple parallel overlapping subnetworks

PubMed Central

Vanneste, Sven; De Ridder, Dirk

2012-01-01

Tinnitus is the perception of a sound in the absence of an external sound source. It is characterized by sensory components such as the perceived loudness, the lateralization, the tinnitus type (pure tone, noise-like) and associated emotional components, such as distress and mood changes. Source localization of quantitative electroencephalography (qEEG) data demonstrate the involvement of auditory brain areas as well as several non-auditory brain areas such as the anterior cingulate cortex (dorsal and subgenual), auditory cortex (primary and secondary), dorsal lateral prefrontal cortex, insula, supplementary motor area, orbitofrontal cortex (including the inferior frontal gyrus), parahippocampus, posterior cingulate cortex and the precuneus, in different aspects of tinnitus. Explaining these non-auditory brain areas as constituents of separable subnetworks, each reflecting a specific aspect of the tinnitus percept increases the explanatory power of the non-auditory brain areas involvement in tinnitus. Thus, the unified percept of tinnitus can be considered an emergent property of multiple parallel dynamically changing and partially overlapping subnetworks, each with a specific spontaneous oscillatory pattern and functional connectivity signature. PMID:22586375

Age related rise in lactate and its correlation with lactate dehydrogenase (LDH) status in post-mitochondrial fractions isolated from different regions of brain in mice.

PubMed

Datta, Siddhartha; Chakrabarti, Nilkanta

2018-04-18

Rise in brain lactate is the hallmark of ageing. Separate studies report that ageing is associated with elevation of lactate level and alterations of lactate dehydrogenase (LDH)-A/B mRNA-expression-ratio in cerebral cortex and hippocampus. However, age related lactate rise in brain and its association with LDH status and their brain regional variations are still elusive. In the present study, level of lactate, LDH (A and B) activity and LDH-A expression were evaluated in post-mitochondrial fraction of tissues isolated from four different brain regions (cerebral cortex, hippocampus, substantia nigra and cerebellum) of young and aged mice. Lactate levels elevated in four brain regions with maximum rise in substantia nigra of aged mice. LDH-A protein expression and its activity decreased in cerebral cortex, hippocampus and substantia nigra without any changes of these parameters in cerebellum of aged mice. LDH-B activity decreased in hippocampus, substantia nigra and cerebellum whereas its activity remains unaltered in cerebral cortex of aged mice. Accordingly, the ratio of LDH-A/LDH-B-activity remains unaltered in hippocampus and substantia nigra, decreased in cerebral cortex and increased in cerebellum. Therefore, rise of lactate in three brain regions (cerebral cortex, hippocampus, substantia nigra) appeared to be not correlated with the alterations of its regulatory enzymes activities in these three brain regions, rather it supports the fact of involvement of other mechanisms, like lactate transport and/or aerobic/anaerobic metabolism as the possible cause(s) of lactate rise in these three brain regions. The increase in LDH-A/LDH-B-activity-ratio appeared to be positively correlated with elevated lactate level in cerebellum of aged mice. Overall, the present study indicates that the mechanism of rise in lactate in brain varies with brain regions where LDH status plays an important role during ageing. Copyright © 2018 Elsevier Ltd. All rights reserved.

Brain fMRI study of crave induced by cue pictures in online game addicts (male adolescents).

PubMed

Sun, Yueji; Ying, Huang; Seetohul, Ravi M; Xuemei, Wang; Ya, Zheng; Qian, Li; Guoqing, Xu; Ye, Sun

2012-08-01

To study crave-related cerebral regions induced by game figure cues in online game addicts. fMRI brain imaging was done when the subjects were shown picture cues of the WoW (World of Warcraft, Version: 4.1.014250) game. 10 male addicts of WoW were selected as addicts' group, and 10 other healthy male non-addicts who were matched by age, were used as non-game addicts' group. All volunteers participated in fMRI paradigms. WoW associated cue pictures and neutral pictures were shown. We examined functional cerebral regions activated by the pictures with 3.0 T Philips MRI. The imaging signals' database was analyzed by SPM5. The correlation between game craving scores and different image results were assessed. When the game addicts watch the pictures, some brain areas show increased signal activity namely: dorsolateral prefrontal cortex, bilateral temporal cortex, cerebellum, right inferior parietal lobule, right cuneus, right hippocampus, parahippocampal gyrus, left caudate nucleus. But in these same brain regions we did not observe remarkable activities in the control group. Differential image signal densities of the addict group were subtracted from the health control group, results of which were expressed in the bilateral dorsolateral prefrontal cortex, anterior cingulate cortex, inferior parietal lobe and inferior temporal gyrus, cerebellum, right insular and the right angular gyrus. The increased imaging signal densities were significant and positively correlated with the craving scale scores in the bilateral prefrontal cortex, anterior cingulate cortex and right inferior parietal lobe. Craving of online game addicts was successfully induced by game cue pictures. Crave related brain areas are: dorsolateral prefrontal cortex, anterior cingulate cortex, and right inferior parietal lobe. The brain regions are overlapped with cognitive and emotion related processing brain areas. Copyright © 2012 Elsevier B.V. All rights reserved.

Brain Region–Specific Alterations in the Gene Expression of Cytokines, Immune Cell Markers and Cholinergic System Components during Peripheral Endotoxin–Induced Inflammation

PubMed Central

Silverman, Harold A; Dancho, Meghan; Regnier-Golanov, Angelique; Nasim, Mansoor; Ochani, Mahendar; Olofsson, Peder S; Ahmed, Mohamed; Miller, Edmund J; Chavan, Sangeeta S; Golanov, Eugene; Metz, Christine N; Tracey, Kevin J; Pavlov, Valentin A

2014-01-01

Inflammatory conditions characterized by excessive peripheral immune responses are associated with diverse alterations in brain function, and brain-derived neural pathways regulate peripheral inflammation. Important aspects of this bidirectional peripheral immune–brain communication, including the impact of peripheral inflammation on brain region–specific cytokine responses, and brain cholinergic signaling (which plays a role in controlling peripheral cytokine levels), remain unclear. To provide insight, we studied gene expression of cytokines, immune cell markers and brain cholinergic system components in the cortex, cerebellum, brainstem, hippocampus, hypothalamus, striatum and thalamus in mice after an intraperitoneal lipopolysaccharide injection. Endotoxemia was accompanied by elevated serum levels of interleukin (IL)-1β, IL-6 and other cytokines and brain region–specific increases in Il1b (the highest increase, relative to basal level, was in cortex; the lowest increase was in cerebellum) and Il6 (highest increase in cerebellum; lowest increase in striatum) mRNA expression. Gene expression of brain Gfap (astrocyte marker) was also differentially increased. However, Iba1 (microglia marker) mRNA expression was decreased in the cortex, hippocampus and other brain regions in parallel with morphological changes, indicating microglia activation. Brain choline acetyltransferase (Chat ) mRNA expression was decreased in the striatum, acetylcholinesterase (Ache) mRNA expression was decreased in the cortex and increased in the hippocampus, and M1 muscarinic acetylcholine receptor (Chrm1) mRNA expression was decreased in the cortex and the brainstem. These results reveal a previously unrecognized regional specificity in brain immunoregulatory and cholinergic system gene expression in the context of peripheral inflammation and are of interest for designing future antiinflammatory approaches. PMID:25299421

Activation of sensory cortex by imagined genital stimulation: an fMRI analysis.

PubMed

Wise, Nan J; Frangos, Eleni; Komisaruk, Barry R

2016-01-01

During the course of a previous study, our laboratory made a serendipitous finding that just thinking about genital stimulation resulted in brain activations that overlapped with, and differed from, those generated by physical genital stimulation. This study extends our previous findings by further characterizing how the brain differentially processes physical 'touch' stimulation and 'imagined' stimulation. Eleven healthy women (age range 29-74) participated in an fMRI study of the brain response to imagined or actual tactile stimulation of the nipple and clitoris. Two additional conditions - imagined dildo self-stimulation and imagined speculum stimulation - were included to characterize the effects of erotic versus non-erotic imagery. Imagined and tactile self-stimulation of the nipple and clitoris each activated the paracentral lobule (the genital region of the primary sensory cortex) and the secondary somatosensory cortex. Imagined self-stimulation of the clitoris and nipple resulted in greater activation of the frontal pole and orbital frontal cortex compared to tactile self-stimulation of these two bodily regions. Tactile self-stimulation of the clitoris and nipple activated the cerebellum, primary somatosensory cortex (hand region), and premotor cortex more than the imagined stimulation of these body regions. Imagining dildo stimulation generated extensive brain activation in the genital sensory cortex, secondary somatosensory cortex, hippocampus, amygdala, insula, nucleus accumbens, and medial prefrontal cortex, whereas imagining speculum stimulation generated only minimal activation. The present findings provide evidence of the potency of imagined stimulation of the genitals and that the following brain regions may participate in erogenous experience: primary and secondary sensory cortices, sensory-motor integration areas, limbic structures, and components of the 'reward system'. In addition, these results suggest a mechanism by which some individuals may be able to generate orgasm by imagery in the absence of physical stimulation.

Minimizing Postsampling Degradation of Peptides by a Thermal Benchtop Tissue Stabilization Method

PubMed Central

Segerström, Lova; Gustavsson, Jenny

2016-01-01

Enzymatic degradation is a major concern in peptide analysis. Postmortem metabolism in biological samples entails considerable risk for measurements misrepresentative of true in vivo concentrations. It is therefore vital to find reliable, reproducible, and easy-to-use procedures to inhibit enzymatic activity in fresh tissues before subjecting them to qualitative and quantitative analyses. The aim of this study was to test a benchtop thermal stabilization method to optimize measurement of endogenous opioids in brain tissue. Endogenous opioid peptides are generated from precursor proteins through multiple enzymatic steps that include conversion of one bioactive peptide to another, often with a different function. Ex vivo metabolism may, therefore, lead to erroneous functional interpretations. The efficacy of heat stabilization was systematically evaluated in a number of postmortem handling procedures. Dynorphin B (DYNB), Leu-enkephalin-Arg6 (LARG), and Met-enkephalin-Arg6-Phe7 (MEAP) were measured by radioimmunoassay in rat hypothalamus, striatum (STR), and cingulate cortex (CCX). Also, simplified extraction protocols for stabilized tissue were tested. Stabilization affected all peptide levels to varying degrees compared to those prepared by standard dissection and tissue handling procedures. Stabilization increased DYNB in hypothalamus, but not STR or CCX, whereas LARG generally decreased. MEAP increased in hypothalamus after all stabilization procedures, whereas for STR and CCX, the effect was dependent on the time point for stabilization. The efficacy of stabilization allowed samples to be left for 2 hours in room temperature (20°C) without changes in peptide levels. This study shows that conductive heat transfer is an easy-to-use and efficient procedure for the preservation of the molecular composition in biological samples. Region- and peptide-specific critical steps were identified and stabilization enabled the optimization of tissue handling and opioid peptide analysis. The result is improved diagnostic and research value of the samples with great benefits for basic research and clinical work. PMID:27007059

The gravitational field and brain function.

PubMed

Mei, L; Zhou, C D; Lan, J Q; Wang, Z G; Wu, W C; Xue, X M

1983-01-01

The frontal cortex is recognized as the highest adaptive control center of the human brain. The principle of the "frontalization" of human brain function offers new possibilities for brain research in space. There is evolutionary and experimental evidence indicating the validity of the principle, including it's role in nervous response to gravitational stimulation. The gravitational field is considered here as one of the more constant and comprehensive factors acting on brain evolution, which has undergone some successive crucial steps: "encephalization", "corticalization", "lateralization" and "frontalization". The dominating effects of electrical responses from the frontal cortex have been discovered 1) in experiments under gravitational stimulus; and 2) in processes potentially relating to gravitational adaptation, such as memory and learning, sensory information processing, motor programing, and brain state control. A brain research experiment during space flight is suggested to test the role of the frontal cortex in space adaptation and it's potentiality in brain control.

Neuropeptide Y and sleep.

PubMed

Dyzma, Michal; Boudjeltia, Karim Z; Faraut, Brice; Kerkhofs, Myriam

2010-06-01

Neuropeptide Y (NPY), a 36-amino-acid peptide from the pancreatic polypeptide family, is one of the more abundant peptides in the central nervous system. It acts as a neurohormone and as a neuromodulator. NPY is widely distributed in the brain, particularly the hypothalamus, the amygdala, the locus coeruleus and the cerebral cortex. At least six NPY receptors subtypes have been identified. NPY is involved in the regulation of several physiological functions such as food intake, hormonal release, circadian rhythms, cardiovascular disease, thermoregulation, stress response, anxiety and sleep. Sleep promoting effects of NPY as well as wakefulness effects of NPY were found in animals, depending on the site of injection as well as on the functional state of the structure. In humans, NPY was found to have hypnotic properties, possibly acting as a physiological antagonist of corticotropin-releasing hormone (CRH). In conclusion, NPY participates in sleep regulation in humans, particularly in the timing of sleep onset and may as such play a role in the integration of sleep regulation, food intake and metabolism. Copyright 2009 Elsevier Ltd. All rights reserved.

Enhanced brain distribution and pharmacodynamics of rivastigmine by liposomes following intranasal administration.

PubMed

Yang, Zhen-Zhen; Zhang, Yan-Qing; Wang, Zhan-Zhang; Wu, Kai; Lou, Jin-Ning; Qi, Xian-Rong

2013-08-16

Alzheimer's disease (AD) is a common progressive neurodegenerative disorder associated with cholinergic neurons degeneration. The blood-brain barrier (BBB) not only provides protection for the brain but also hinders the treatment and diagnosis of this neurological disease, because the drugs must cross BBB to reach the lesions. The present work was aimed at formulating rivastigmine liposomes (Lp) and cell-penetrating peptide (CPP) modified liposomes (CPP-Lp) to improve rivastigmine distribution in brain and proceed to enhance pharmacodynamics by intranasal (IN) administration and minimize side effects. The results revealed that Lp especially the CPP-Lp can enhance the permeability across the BBB by murine brain microvascular endothelial cells model in vitro. IN administration of rivastigmine solution and rivastigmine liposomes demonstrated the capacity to improve rivastigmine distribution and adequate retention in CNS regions especially in hippocampus and cortex, which were the regions most affected by AD, than that of IV administration. Importantly, the lagging but intense inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities were relative to the extended release, absorption and retention. In addition, there was very mild nasal toxicity of liposomal formulations. The data suggest that rivastigmine liposomes especially CPP-Lp improve the brain delivery and enhance pharmacodynamics which respect to BBB penetration and nasal olfactory pathway into brain after IN administration, and simultaneously decrease the hepatic first pass metabolism and gastrointestinal adverse effects. Copyright © 2013 Elsevier B.V. All rights reserved.

Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis

PubMed Central

Ishiuji, Y.; Coghill, R.C.; Patel, T.S.; Oshiro, Y.; Kraft, R.A.; Yosipovitch, G.

2009-01-01

Summary Background Little is known about brain mechanisms supporting the experience of chronic puritus in disease states. Objectives To examine the difference in brain processing of histamine-induced itch in patients with active atopic dermatitis (AD) vs. healthy controls with the emerging technique of functional magnetic resonance imaging (fMRI) using arterial spin labelling (ASL). Methods Itch was induced with histamine iontophoresis in eight patients with AD and seven healthy subjects. Results We found significant differences in brain processing of histamine-induced itch between patients with AD and healthy subjects. Patients with AD exhibited bilateral activation of the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), retrosplenial cingulate cortex and dorsolateral prefrontal cortex (DLPFC) as well as contralateral activation of the caudate nucleus and putamen. In contrast, healthy subjects activated the primary motor cortex, primary somatosensory cortex and superior parietal lobe. The PCC and precuneus exhibited significantly greater activity in patients vs. healthy subjects. A significant correlation between percentage changes of brain activation was noted in the activation of the ACC and contralateral insula and histamine-induced itch intensity as well as disease severity in patients with AD. In addition, an association was noted between DLPFC activity and disease severity. Conclusions Our results demonstrate that ASL fMRI is a promising technique to assess brain activity in chronic itch. Brain activity of acute itch in AD seems to differ from that in healthy subjects. Moreover, the activity in cortical areas involved in affect and emotion correlated to measures of disease severity. PMID:19663870

State of the Art: Novel Applications for Cortical Stimulation.

PubMed

De Ridder, Dirk; Perera, Sanjaya; Vanneste, Sven

2017-04-01

Electrical stimulation via implanted electrodes that overlie the cortex of the brain is an upcoming neurosurgical technique that was hindered for a long time by insufficient knowledge of how the brain functions in a dynamic, physiological, and pathological way, as well as by technological limitations of the implantable stimulation devices. This paper provides an overview of cortex stimulation via implantable devices and introduces future possibilities to improve cortex stimulation. Cortex stimulation was initially used preoperatively as a technique to localize functions in the brain and only later evolved into a treatment technique. It was first used for pain, but more recently a multitude of pathologies are being targeted by cortex stimulation. These disorders are being treated by stimulating different cortical areas of the brain. Risks and complications are essentially similar to those related to deep brain stimulation and predominantly include haemorrhage, seizures, infection, and hardware failures. For cortex stimulation to fully mature, further technological development is required to predict its outcomes and improve stimulation designs. This includes the development of network science-based functional connectivity approaches, genetic analyses, development of navigated high definition transcranial alternating current stimulation, and development of pseudorandom stimulation designs for preventing habituation. In conclusion, cortex stimulation is a nascent but very promising approach to treating a variety of diseases, but requires further technological development for predicting outcomes, such as network science based functional connectivity approaches, genetic analyses, development of navigated transcranial electrical stimulation, and development of pseudorandom stimulation designs for preventing habituation. © 2017 International Neuromodulation Society.

[Relationship between the Expression of α-syn and Neuronal Apoptosis in Brain Cortex of Acute Alcoholism Rats].

PubMed

Li, F; Zhang, Y; Ma, S L

2016-12-01

To observe the changes of expression of α-synuclein （α-syn） and neuronal apoptosis in brain cortex of acute alcoholism rats and to explore the mechanism of the damage caused by ethanol to the neurons. The model of acute alcoholism rat was established by 50% alcohol gavage. The α-syn and caspase-3 were detected by immunohistochemical staining and imaging analysis at 1 h, 3 h, 6 h and 12 h after acute alcoholism. The number of positive cell and mean of optical density were detected and the trend change was analyzed. The variance analysis and t -test were also performed. The number of α-syn positive cell and average optical density in brain cortex of acute alcoholism rat increased significantly and peaked at 6 hour with a following slight decrease at 12 h, but still higher than the groups at 1 h and 3 h. Within 12 hours after poisoning, the number of caspase-3 positive cell and average optical density in brain cortex of rats gradually increased. The abnormal aggregation of α-syn caused by brain edema and hypoxia may participate the early stage of neuronal apoptosis in brain cortex after acute alcoholism. Copyright© by the Editorial Department of Journal of Forensic Medicine

Connectivity-based neurofeedback: Dynamic causal modeling for real-time fMRI☆

PubMed Central

Koush, Yury; Rosa, Maria Joao; Robineau, Fabien; Heinen, Klaartje; W. Rieger, Sebastian; Weiskopf, Nikolaus; Vuilleumier, Patrik; Van De Ville, Dimitri; Scharnowski, Frank

2013-01-01

Neurofeedback based on real-time fMRI is an emerging technique that can be used to train voluntary control of brain activity. Such brain training has been shown to lead to behavioral effects that are specific to the functional role of the targeted brain area. However, real-time fMRI-based neurofeedback so far was limited to mainly training localized brain activity within a region of interest. Here, we overcome this limitation by presenting near real-time dynamic causal modeling in order to provide feedback information based on connectivity between brain areas rather than activity within a single brain area. Using a visual–spatial attention paradigm, we show that participants can voluntarily control a feedback signal that is based on the Bayesian model comparison between two predefined model alternatives, i.e. the connectivity between left visual cortex and left parietal cortex vs. the connectivity between right visual cortex and right parietal cortex. Our new approach thus allows for training voluntary control over specific functional brain networks. Because most mental functions and most neurological disorders are associated with network activity rather than with activity in a single brain region, this novel approach is an important methodological innovation in order to more directly target functionally relevant brain networks. PMID:23668967

Visual hallucinations of autobiographic memory and asomatognosia: a case of epilepsy due to brain cysticercosis.

PubMed

Orjuela-Rojas, Juan Manuel; Ramírez-Bermúdez, Jesús; Martínez-Juárez, Iris E; Kerik, Nora Estela; Diaz Meneses, Iván; Pérez-Gay, Fernanda Juárez

2015-01-01

The current study describes the case of a woman with symptomatic epilepsy due to brain cysticercosis acquired during childhood. During her adolescence, she developed seizures characterized by metamorphopsia, hallucinations of autobiographic memory and, finally, asomatognosia. Magnetic brain imaging showed a calcified lesion in the right occipitotemporal cortex, and positron emission tomography imaging confirmed the presence of interictal hypometabolism in two regions: the right parietal cortex and the right lateral and posterior temporal cortex. We discuss the link between these brain areas and the symptoms described under the concepts of epileptogenic lesion, epileptogenic zone, functional deficit zone, and symptomatogenic zone.

Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer's disease.

PubMed

Boche, Delphine; Donald, Jane; Love, Seth; Harris, Scott; Neal, James W; Holmes, Clive; Nicoll, James A R

2010-07-01

Alzheimer's disease (AD) pathology is characterised by aggregation in the brain of amyloid-beta (Abeta) peptide and hyperphosphorylated tau (phospho-tau), although how these proteins interact in disease pathogenesis is unclear. Abeta immunisation results in removal of Abeta from the brain but cognitive decline continues to progress, possibly due to persistent phospho-tau. We quantified phospho-tau and Abeta42 in the brains of 10 AD patients (iAD) who were actively immunised with Abeta42 (AN1792, Elan Pharmaceuticals) compared with 28 unimmunised AD cases (cAD). The phospho-tau load was lower in the iAD than the cAD group in the cerebral cortex (cAD 1.08% vs. iAD 0.72%, P = 0.048), CA1 hippocampus (cAD 2.26% vs. iAD 1.05%; P = 0.001), subiculum (cAD 1.60% vs. iAD 0.31%; P = 0.001) and entorhinal cortex (cAD 1.10% vs. iAD 0.18%; P < 0.001). Assessment of the localisation within neurons of phospho-tau indicated that the Abeta immunotherapy-associated reduction was confined to neuronal processes, i.e. neuropil threads and dystrophic neurites. However, the phospho-tau accumulation in the neuronal cell bodies, contributing to neurofibrillary tangles, appeared not to be affected. In showing that Abeta immunisation can influence phospho-tau pathology, we confirm the position of Abeta as a target for modifying tau accumulation in AD and demonstrate a link between these proteins. However, the continuing progression of cognitive decline in AD patients after Abeta immunisation may be explained by its lack of apparent effect on tangles.

Magnetic resonance imaging for monitoring therapeutic response in a transgenic mouse model of Alzheimer's disease using voxel-based analysis of amyloid plaques.

PubMed

Kim, Jae-Hun; Ha, Tae Lin; Im, Geun Ho; Yang, Jehoon; Seo, Sang Won; Chung, Julius Juhyun; Chae, Sun Young; Lee, In Su; Lee, Jung Hee

2014-03-05

In this study, we have shown the potential of a voxel-based analysis for imaging amyloid plaques and its utility in monitoring therapeutic response in Alzheimer's disease (AD) mice using manganese oxide nanoparticles conjugated with an antibody of Aβ1-40 peptide (HMON-abAβ40). T1-weighted MR brain images of a drug-treated AD group (n=7), a nontreated AD group (n=7), and a wild-type group (n=7) were acquired using a 7.0 T MRI system before (D-1), 24-h (D+1) after, and 72-h (D+3) after injection with an HMON-abAβ40 contrast agent. For the treatment of AD mice, DAPT was injected intramuscularly into AD transgenic mice (50 mg/kg of body weight). For voxel-based analysis, the skull-stripped mouse brain images were spatially normalized, and these voxels' intensities were corrected to reduce voxel intensity differences across scans in different mice. Statistical analysis showed higher normalized MR signal intensity in the frontal cortex and hippocampus of AD mice over wild-type mice on D+1 and D+3 (P<0.01, uncorrected for multiple comparisons). After the treatment of AD mice, the normalized MR signal intensity in the frontal cortex and hippocampus decreased significantly in comparison with nontreated AD mice on D+1 and D+3 (P<0.01, uncorrected for multiple comparisons). These results were confirmed by histological analysis using a thioflavin staining. This unique strategy allows us to detect brain regions that are subjected to amyloid plaque deposition and has the potential for human applications in monitoring therapeutic response for drug development in AD.

Characterization of a neurokinin B receptor site in rat brain using a highly selective radioligand.

PubMed

Laufer, R; Gilon, C; Chorev, M; Selinger, Z

1986-08-05

We have recently characterized a tachykinin receptor subtype (SP-N) whose preferred ligand is the mammalian neuropeptide, neurokinin B (Laufer, R., Wormser, U., Friedman, Z. Y., Gilon, C., Chorev, M., and Selinger, Z. (1985) Proc. Natl. Acad. Sci. U.S.A. 82, 7444-7448). To investigate this novel tachykinin receptor, we have now prepared a radiolabeled peptide, N alpha-[( 125I]desamino-3-iodotyrosyl)-[Asp5,6, N-methyl-Phe8]substance P (5-11) heptapeptide (125I-BH-NH-Senktide), which selectively interacts with the SP-N receptor subtype. The binding of 125I-BH-NH-Senktide to rat cerebral cortex membranes was studied under conditions that minimized nonspecific binding. Unlike other tachykinin receptor probes, this radioligand is not degraded during the binding experiment. Binding of 125I-BH-NH-Senktide is reversible, saturable, and of high affinity (KD = 0.9 nM). The radioligand labels a single class of binding site (122 fmol binding sites/mg of protein), as indicated by a linear Scatchard plot and a Hill coefficient close to unity (nH = 1.05). The pharmacological specificity of this binding site corresponds to that of the neuronal SP-N receptor in guinea pig ileum myenteric plexus, which was determined by a functional bioassay. Among various rat brain regions, the highest binding was observed in the cerebral cortex, olfactory bulb, hypothalamus, and hippocampus. These results suggest the existence and specific distribution of a neurokinin B receptor site of the SP-N type in rat brain. 125I-BH-NH-Senktide is the first selective and potent probe for this receptor and is thus an important tool for further studies of its distribution, regulation, and functional role.

Spatial association of prolyl oligopeptidase, inositol 1,4,5-triphosphate type 1 receptor, substance P and its neurokinin-1 receptor in the rat brain: an immunohistochemical colocalization study.

PubMed

Myöhänen, T T; Venäläinen, J I; Garcia-Horsman, J A; Männistö, P T

2008-06-02

Prolyl oligopeptidase (POP) is a serine endopeptidase which hydrolyzes proline-containing peptides shorter than 30 amino acids. It has been suggested that POP is associated with cognitive functions, possibly via the cleavage of neuropeptides such as substance P (SP). Recently, several studies have also linked POP to the inositol 1,4,5-triphosphate (IP(3)) signaling. However, the neuroanatomical interactions between these substances are not known. We used double-labeled immunofluorescence to determine the POP colocalization with SP, SP receptor (neurokinin-1 receptor, NK-1R) and IP(3) type 1 receptor (IP(3)R1) in the rat brain. Furthermore, since striatal and cortical GABAergic neurons are involved in SP neurotransmission, we studied the coexpression of POP, SP and GABA by triple-labeled immunofluorescence. POP was moderately present in IP(3)R1-containing cells in cortex; the colocalization was particularly high in the thalamus, hippocampal CA1 field and cerebellar Purkinje cells. Colocalization of POP with SP and NK1-receptor was infrequent throughout the brain, though some POP and SP coexpression was observed in cerebellar Purkinje cells. We also found that POP partially colocalized with SP-containing GABAergic neurons in striatum and cortex. Our findings support the view that POP is at least spatially associated with the IP(3)-signaling in the thalamus, hippocampus and cerebellar Purkinje cells. This might point to a role for POP in the regulation of long-term potentiation and/or depression. Moreover, the low degree of colocalization of POP, SP and its NK-1R suggests that a transport system is needed either for POP or SP to make hydrolysis possible and that POP may act both intra- and extracellularly.

Frontal top-down signals increase coupling of auditory low-frequency oscillations to continuous speech in human listeners.

PubMed

Park, Hyojin; Ince, Robin A A; Schyns, Philippe G; Thut, Gregor; Gross, Joachim

2015-06-15

Humans show a remarkable ability to understand continuous speech even under adverse listening conditions. This ability critically relies on dynamically updated predictions of incoming sensory information, but exactly how top-down predictions improve speech processing is still unclear. Brain oscillations are a likely mechanism for these top-down predictions [1, 2]. Quasi-rhythmic components in speech are known to entrain low-frequency oscillations in auditory areas [3, 4], and this entrainment increases with intelligibility [5]. We hypothesize that top-down signals from frontal brain areas causally modulate the phase of brain oscillations in auditory cortex. We use magnetoencephalography (MEG) to monitor brain oscillations in 22 participants during continuous speech perception. We characterize prominent spectral components of speech-brain coupling in auditory cortex and use causal connectivity analysis (transfer entropy) to identify the top-down signals driving this coupling more strongly during intelligible speech than during unintelligible speech. We report three main findings. First, frontal and motor cortices significantly modulate the phase of speech-coupled low-frequency oscillations in auditory cortex, and this effect depends on intelligibility of speech. Second, top-down signals are significantly stronger for left auditory cortex than for right auditory cortex. Third, speech-auditory cortex coupling is enhanced as a function of stronger top-down signals. Together, our results suggest that low-frequency brain oscillations play a role in implementing predictive top-down control during continuous speech perception and that top-down control is largely directed at left auditory cortex. This suggests a close relationship between (left-lateralized) speech production areas and the implementation of top-down control in continuous speech perception. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Frontal Top-Down Signals Increase Coupling of Auditory Low-Frequency Oscillations to Continuous Speech in Human Listeners

PubMed Central

Park, Hyojin; Ince, Robin A.A.; Schyns, Philippe G.; Thut, Gregor; Gross, Joachim

2015-01-01

Summary Humans show a remarkable ability to understand continuous speech even under adverse listening conditions. This ability critically relies on dynamically updated predictions of incoming sensory information, but exactly how top-down predictions improve speech processing is still unclear. Brain oscillations are a likely mechanism for these top-down predictions [1, 2]. Quasi-rhythmic components in speech are known to entrain low-frequency oscillations in auditory areas [3, 4], and this entrainment increases with intelligibility [5]. We hypothesize that top-down signals from frontal brain areas causally modulate the phase of brain oscillations in auditory cortex. We use magnetoencephalography (MEG) to monitor brain oscillations in 22 participants during continuous speech perception. We characterize prominent spectral components of speech-brain coupling in auditory cortex and use causal connectivity analysis (transfer entropy) to identify the top-down signals driving this coupling more strongly during intelligible speech than during unintelligible speech. We report three main findings. First, frontal and motor cortices significantly modulate the phase of speech-coupled low-frequency oscillations in auditory cortex, and this effect depends on intelligibility of speech. Second, top-down signals are significantly stronger for left auditory cortex than for right auditory cortex. Third, speech-auditory cortex coupling is enhanced as a function of stronger top-down signals. Together, our results suggest that low-frequency brain oscillations play a role in implementing predictive top-down control during continuous speech perception and that top-down control is largely directed at left auditory cortex. This suggests a close relationship between (left-lateralized) speech production areas and the implementation of top-down control in continuous speech perception. PMID:26028433

Brain activation during dual-task processing is associated with cardiorespiratory fitness and performance in older adults

PubMed Central

Wong, Chelsea N.; Chaddock-Heyman, Laura; Voss, Michelle W.; Burzynska, Agnieszka Z.; Basak, Chandramallika; Erickson, Kirk I.; Prakash, Ruchika S.; Szabo-Reed, Amanda N.; Phillips, Siobhan M.; Wojcicki, Thomas; Mailey, Emily L.; McAuley, Edward; Kramer, Arthur F.

2015-01-01

Higher cardiorespiratory fitness is associated with better cognitive performance and enhanced brain activation. Yet, the extent to which cardiorespiratory fitness-related brain activation is associated with better cognitive performance is not well understood. In this cross-sectional study, we examined whether the association between cardiorespiratory fitness and executive function was mediated by greater prefrontal cortex activation in healthy older adults. Brain activation was measured during dual-task performance with functional magnetic resonance imaging in a sample of 128 healthy older adults (59–80 years). Higher cardiorespiratory fitness was associated with greater activation during dual-task processing in several brain areas including the anterior cingulate and supplementary motor cortex (ACC/SMA), thalamus and basal ganglia, right motor/somatosensory cortex and middle frontal gyrus, and left somatosensory cortex, controlling for age, sex, education, and gray matter volume. Of these regions, greater ACC/SMA activation mediated the association between cardiorespiratory fitness and dual-task performance. We provide novel evidence that cardiorespiratory fitness may support cognitive performance by facilitating brain activation in a core region critical for executive function. PMID:26321949

Two Alzheimer’s disease risk genes increase entorhinal cortex volume in young adults

PubMed Central

DiBattista, Amanda Marie; Stevens, Benson W.; Rebeck, G. William; Green, Adam E.

2014-01-01

Alzheimer’s disease (AD) risk genes alter brain structure and function decades before disease onset. Apolipoprotein E (APOE) is the strongest known genetic risk factor for AD, and a related gene, apolipoprotein J (APOJ), also affects disease risk. However, the extent to which these genes affect brain structure in young adults remains unclear. Here, we report that AD risk alleles of these two genes, APOE-ε4 and APOJ-C, cumulatively alter brain volume in young adults. Using voxel-based morphometry (VBM) in 57 individuals, we examined the entorhinal cortex, one of the earliest brain regions affected in AD pathogenesis. Apolipoprotein E-ε4 carriers exhibited higher right entorhinal cortex volume compared to non-carriers. Interestingly, APOJ-C risk genotype was associated with higher bilateral entorhinal cortex volume in non-APOE-ε4 carriers. To determine the combined disease risk of APOE and APOJ status per subject, we used cumulative odds ratios as regressors for volumetric measurements. Higher disease risk corresponded to greater right entorhinal cortex volume. These results suggest that, years before disease onset, two key AD genetic risk factors may exert influence on the structure of a brain region where AD pathogenesis takes root. PMID:25339884

Brain Activity During the Encoding, Retention, and Retrieval of Stimulus Representations

PubMed Central

de Zubicaray, Greig I.; McMahon, Katie; Wilson, Stephen J.; Muthiah, Santhi

2001-01-01

Studies of delayed nonmatching-to-sample (DNMS) performance following lesions of the monkey cortex have revealed a critical circuit of brain regions involved in forming memories and retaining and retrieving stimulus representations. Using event-related functional magnetic resonance imaging (fMRI), we measured brain activity in 10 healthy human participants during performance of a trial-unique visual DNMS task using novel barcode stimuli. The event-related design enabled the identification of activity during the different phases of the task (encoding, retention, and retrieval). Several brain regions identified by monkey studies as being important for successful DNMS performance showed selective activity during the different phases, including the mediodorsal thalamic nucleus (encoding), ventrolateral prefrontal cortex (retention), and perirhinal cortex (retrieval). Regions showing sustained activity within trials included the ventromedial and dorsal prefrontal cortices and occipital cortex. The present study shows the utility of investigating performance on tasks derived from animal models to assist in the identification of brain regions involved in human recognition memory. PMID:11584070

How cortical neurons help us see: visual recognition in the human brain

PubMed Central

Blumberg, Julie; Kreiman, Gabriel

2010-01-01

Through a series of complex transformations, the pixel-like input to the retina is converted into rich visual perceptions that constitute an integral part of visual recognition. Multiple visual problems arise due to damage or developmental abnormalities in the cortex of the brain. Here, we provide an overview of how visual information is processed along the ventral visual cortex in the human brain. We discuss how neurophysiological recordings in macaque monkeys and in humans can help us understand the computations performed by visual cortex. PMID:20811161

Susceptibility of Primary Sensory Cortex to Spreading Depolarizations.

PubMed

Bogdanov, Volodymyr B; Middleton, Natalie A; Theriot, Jeremy J; Parker, Patrick D; Abdullah, Osama M; Ju, Y Sungtaek; Hartings, Jed A; Brennan, K C

2016-04-27

Spreading depolarizations (SDs) are recognized as actors in neurological disorders as diverse as migraine and traumatic brain injury (TBI). Migraine aura involves sensory percepts, suggesting that sensory cortices might be intrinsically susceptible to SDs. We used optical imaging, MRI, and field potential and potassium electrode recordings in mice and electrocorticographic recordings in humans to determine the susceptibility of different brain regions to SDs. Optical imaging experiments in mice under isoflurane anesthesia showed that both cortical spreading depression and terminal anoxic depolarization arose preferentially in the whisker barrel region of parietal sensory cortex. MRI recordings under isoflurane, ketamine/xylazine, ketamine/isoflurane, and urethane anesthesia demonstrated that the depolarizations did not propagate from a subcortical source. Potassium concentrations showed larger increases in sensory cortex, suggesting a mechanism of susceptibility. Sensory stimulation biased the timing but not the location of depolarization onset. In humans with TBI, there was a trend toward increased incidence of SDs in parietal/temporal sensory cortex compared with other regions. In conclusion, SDs are inducible preferentially in primary sensory cortex in mice and most likely in humans. This tropism can explain the predominant sensory phenomenology of migraine aura. It also demonstrates that sensory cortices are vulnerable in brain injury. Spreading depolarizations (SDs) are involved in neurologic disorders as diverse as migraine and traumatic brain injury. In migraine, the nature of aura symptoms suggests that sensory cortex may be preferentially susceptible. In brain injury, SDs occur at a vulnerable time, during which the issue of sensory stimulation is much debated. We show, in mouse and human, that sensory cortex is more susceptible to SDs. We find that sensory stimulation biases the timing but not the location of the depolarizations. Finally, we show a relative impairment of potassium clearance in sensory cortex, providing a potential mechanism for the susceptibility. Our data help to explain the sensory nature of the migraine aura and reveal that sensory cortices are vulnerable in brain injury. Copyright © 2016 the authors 0270-6474/16/364733-11$15.00/0.

Susceptibility of Primary Sensory Cortex to Spreading Depolarizations

PubMed Central

Bogdanov, Volodymyr B.; Middleton, Natalie A.; Theriot, Jeremy J.; Parker, Patrick D.; Abdullah, Osama M.; Ju, Y. Sungtaek; Hartings, Jed A.

2016-01-01

Spreading depolarizations (SDs) are recognized as actors in neurological disorders as diverse as migraine and traumatic brain injury (TBI). Migraine aura involves sensory percepts, suggesting that sensory cortices might be intrinsically susceptible to SDs. We used optical imaging, MRI, and field potential and potassium electrode recordings in mice and electrocorticographic recordings in humans to determine the susceptibility of different brain regions to SDs. Optical imaging experiments in mice under isoflurane anesthesia showed that both cortical spreading depression and terminal anoxic depolarization arose preferentially in the whisker barrel region of parietal sensory cortex. MRI recordings under isoflurane, ketamine/xylazine, ketamine/isoflurane, and urethane anesthesia demonstrated that the depolarizations did not propagate from a subcortical source. Potassium concentrations showed larger increases in sensory cortex, suggesting a mechanism of susceptibility. Sensory stimulation biased the timing but not the location of depolarization onset. In humans with TBI, there was a trend toward increased incidence of SDs in parietal/temporal sensory cortex compared with other regions. In conclusion, SDs are inducible preferentially in primary sensory cortex in mice and most likely in humans. This tropism can explain the predominant sensory phenomenology of migraine aura. It also demonstrates that sensory cortices are vulnerable in brain injury. SIGNIFICANCE STATEMENT Spreading depolarizations (SDs) are involved in neurologic disorders as diverse as migraine and traumatic brain injury. In migraine, the nature of aura symptoms suggests that sensory cortex may be preferentially susceptible. In brain injury, SDs occur at a vulnerable time, during which the issue of sensory stimulation is much debated. We show, in mouse and human, that sensory cortex is more susceptible to SDs. We find that sensory stimulation biases the timing but not the location of the depolarizations. Finally, we show a relative impairment of potassium clearance in sensory cortex, providing a potential mechanism for the susceptibility. Our data help to explain the sensory nature of the migraine aura and reveal that sensory cortices are vulnerable in brain injury. PMID:27122032

Retest imaging of [11C]NOP-1A binding to nociceptin/orphanin FQ peptide (NOP) receptors in the brain of healthy humans.

PubMed

Lohith, Talakad G; Zoghbi, Sami S; Morse, Cheryl L; Araneta, Maria D Ferraris; Barth, Vanessa N; Goebl, Nancy A; Tauscher, Johannes T; Pike, Victor W; Innis, Robert B; Fujita, Masahiro

2014-02-15

[(11)C]NOP-1A is a novel high-affinity PET ligand for imaging nociceptin/orphanin FQ peptide (NOP) receptors. Here, we report reproducibility and reliability measures of binding parameter estimates for [(11)C]NOP-1A binding in the brain of healthy humans. After intravenous injection of [(11)C]NOP-1A, PET scans were conducted twice on eleven healthy volunteers on the same (10/11 subjects) or different (1/11 subjects) days. Subjects underwent serial sampling of radial arterial blood to measure parent radioligand concentrations. Distribution volume (VT; a measure of receptor density) was determined by compartmental (one- and two-tissue) modeling in large regions and by simpler regression methods (graphical Logan and bilinear MA1) in both large regions and voxel data. Retest variability and intraclass correlation coefficient (ICC) of VT were determined as measures of reproducibility and reliability respectively. Regional [(11)C]NOP-1A uptake in the brain was high, with a peak radioactivity concentration of 4-7 SUV (standardized uptake value) and a rank order of putamen>cingulate cortex>cerebellum. Brain time-activity curves fitted well in 10 of 11 subjects by unconstrained two-tissue compartmental model. The retest variability of VT was moderately good across brain regions except cerebellum, and was similar across different modeling methods, averaging 12% for large regions and 14% for voxel-based methods. The retest reliability of VT was also moderately good in most brain regions, except thalamus and cerebellum, and was similar across different modeling methods averaging 0.46 for large regions and 0.48 for voxels having gray matter probability >20%. The lowest retest variability and highest retest reliability of VT were achieved by compartmental modeling for large regions, and by the parametric Logan method for voxel-based methods. Moderately good reproducibility and reliability measures of VT for [(11)C]NOP-1A make it a useful PET ligand for comparing NOP receptor binding between different subject groups or under different conditions in the same subject. Copyright © 2013. Published by Elsevier Inc.

Diagnostics and therapy of Alzheimer's disease.

PubMed

Mikiciuk-Olasik, Elzbieta; Szymański, Paweł; Zurek, Elzbieta

2007-04-01

Alzheimer's Disease (AD) is described as a degenerative disease of the central nervous system characterized by a noticeable cognitive decline defined by a loss of memory and learning ability, together with a reduced ability to perform basic activities of daily living. In the brain of an AD patients is the dramatic decrease in cholinergic innervation in the cortex and hippocampus due to the loss of neurons in the basal forebrain. The above findings led to the development of the cholinergic hypothesis, which proposes that the cognitive loss associated with AD is related to decreased cortical cholinergic neurotransmission. In brain of Alzheimer's patient's one ascertained presence of neuritic plaques containing the beta-amyloid peptide and protein tau. Biochemical and genetics studies implicated a central role for beta-amyloid in the pathological cascade of events in AD. The most therapeutic strategies in AD have been directed to two main targets: the beta-amyloid peptide and the cholinergic neurotransmission. The first approach is to act on the amyloid precursor protein (APP) processing. The second main approach is to slow of decline of neuronal degeneration or increasing cholinergic transmission. Diagnosis of AD is very difficult and to date no specific diagnostic tests of the disease are available. Intellectual function testing to determine the degree of cognitive status during routine medical examination is a useful supplementary method of diagnosing dementia. The permissible result, come down from radiopharmacy, which is an integral part of a nuclear medicine. A radiopharmaceutical may be defined as a pharmaceutical substance containing radioactive atoms. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are capable of mapping the distribution of radionuclides in three dimensions, producing maps of brain biochemical and physiological processes. The techniques are reasonably sensitive and specific in differentiating AD from other dementias.

Endogenous ghrelin-O-acyltransferase (GOAT) acylates local ghrelin in the hippocampus.

PubMed

Murtuza, Mohammad I; Isokawa, Masako

2018-01-01

Ghrelin is an appetite-stimulating peptide. Serine 3 on ghrelin must be acylated by octanoate via the enzyme ghrelin-O-acyltransferase (GOAT) for the peptide to bind and activate the cognate receptor, growth hormone secretagogue receptor type 1a (GHSR1a). Interest in GHSR1a increased dramatically when GHSR1a mRNA was demonstrated to be widespread in the brain, including the cortex and hippocampus, indicating that it has multifaceted functions beyond the regulation of metabolism. However, the source of octanoylated ghrelin for GHSR1a in the brain, outside of the hypothalamus, is not well understood. Here, we report the presence of GOAT and its ability to acylate non-octanoylated ghrelin in the hippocampus. GOAT immunoreactivity is aggregated at the base of the dentate granule cell layer in the rat and wild-type mouse. This immunoreactivity was not affected by the pharmacological inhibition of GHSR1a or the metabolic state-dependent fluctuation of systemic ghrelin levels. However, it was absent in the GHSR1a knockout mouse hippocampus, pointing the possibility that the expression of GHSR1a may be a prerequisite for the production of GOAT. Application of fluorescein isothiocyanate (FITC)-conjugated non-octanoylated ghrelin in live hippocampal slice culture (but not in fixed culture or in the presence of GOAT inhibitors) mimicked the binding profile of FITC-conjugated octanoylated ghrelin, suggesting that extracellularly applied non-octanoylated ghrelin was acylated by endogenous GOAT in the live hippocampus while GOAT being mobilized out of neurons. Our results will advance the understanding for the role of endogenous GOAT in the hippocampus and facilitate the search for the source of ghrelin that is intrinsic to the brain. © 2017 International Society for Neurochemistry.

Blood-brain barrier shuttle peptides enhance AAV transduction in the brain after systemic administration.

PubMed

Zhang, Xintao; He, Ting; Chai, Zheng; Samulski, R Jude; Li, Chengwen

2018-09-01

The adeno-associated virus (AAV) vector has been used in preclinical and clinical trials of gene therapy for central nervous system (CNS) diseases. One of the biggest challenges of effectively delivering AAV to the brain is to surmount the blood-brain barrier (BBB). Herein, we identified several potential BBB shuttle peptides that significantly enhanced AAV8 transduction in the brain after a systemic administration, the best of which was the THR peptide. The enhancement of AAV8 brain transduction by THR is dose-dependent, and neurons are the primary THR targets. Mechanism studies revealed that THR directly bound to the AAV8 virion, increasing its ability to cross the endothelial cell barrier. Further experiments showed that binding of THR to the AAV virion did not interfere with AAV8 infection biology, and that THR competitively blocked transferrin from binding to AAV8. Taken together, our results demonstrate, for the first time, that BBB shuttle peptides are able to directly interact with AAV and increase the ability of the AAV vectors to cross the BBB for transduction enhancement in the brain. These results will shed important light on the potential applications of BBB shuttle peptides for enhancing brain transduction with systemic administration of AAV vectors. Copyright © 2018 Elsevier Ltd. All rights reserved.

Decoding brain responses to pixelized images in the primary visual cortex: implications for visual cortical prostheses

PubMed Central

Guo, Bing-bing; Zheng, Xiao-lin; Lu, Zhen-gang; Wang, Xing; Yin, Zheng-qin; Hou, Wen-sheng; Meng, Ming

2015-01-01

Visual cortical prostheses have the potential to restore partial vision. Still limited by the low-resolution visual percepts provided by visual cortical prostheses, implant wearers can currently only “see” pixelized images, and how to obtain the specific brain responses to different pixelized images in the primary visual cortex (the implant area) is still unknown. We conducted a functional magnetic resonance imaging experiment on normal human participants to investigate the brain activation patterns in response to 18 different pixelized images. There were 100 voxels in the brain activation pattern that were selected from the primary visual cortex, and voxel size was 4 mm × 4 mm × 4 mm. Multi-voxel pattern analysis was used to test if these 18 different brain activation patterns were specific. We chose a Linear Support Vector Machine (LSVM) as the classifier in this study. The results showed that the classification accuracies of different brain activation patterns were significantly above chance level, which suggests that the classifier can successfully distinguish the brain activation patterns. Our results suggest that the specific brain activation patterns to different pixelized images can be obtained in the primary visual cortex using a 4 mm × 4 mm × 4 mm voxel size and a 100-voxel pattern. PMID:26692860

Analyzing pitch chroma and pitch height in the human brain.

PubMed

Warren, Jason D; Uppenkamp, Stefan; Patterson, Roy D; Griffiths, Timothy D

2003-11-01

The perceptual pitch dimensions of chroma and height have distinct representations in the human brain: chroma is represented in cortical areas anterior to primary auditory cortex, whereas height is represented posterior to primary auditory cortex.

Connectivity-based parcellation of human cingulate cortex and its relation to functional specialization.

PubMed

Beckmann, Matthias; Johansen-Berg, Heidi; Rushworth, Matthew F S

2009-01-28

Whole-brain neuroimaging studies have demonstrated regional variations in function within human cingulate cortex. At the same time, regional variations in cingulate anatomical connections have been found in animal models. It has, however, been difficult to estimate the relationship between connectivity and function throughout the whole cingulate cortex within the human brain. In this study, magnetic resonance diffusion tractography was used to investigate cingulate probabilistic connectivity in the human brain with two approaches. First, an algorithm was used to search for regional variations in the probabilistic connectivity profiles of all cingulate cortex voxels with the whole of the rest of the brain. Nine subregions with distinctive connectivity profiles were identified. It was possible to characterize several distinct areas in the dorsal cingulate sulcal region. Several distinct regions were also found in subgenual and perigenual cortex. Second, the probabilities of connection between cingulate cortex and 11 predefined target regions of interest were calculated. Cingulate voxels with a high probability of connection with the different targets formed separate clusters within cingulate cortex. Distinct connectivity fingerprints characterized the likelihood of connections between the extracingulate target regions and the nine cingulate subregions. Last, a meta-analysis of 171 functional studies reporting cingulate activation was performed. Seven different cognitive conditions were selected and peak activation coordinates were plotted to create maps of functional localization within the cingulate cortex. Regional functional specialization was found to be related to regional differences in probabilistic anatomical connectivity.

Neural stem cells encapsulated in a functionalized self-assembling peptide hydrogel for brain tissue engineering.

PubMed

Cheng, Tzu-Yun; Chen, Ming-Hong; Chang, Wen-Han; Huang, Ming-Yuan; Wang, Tzu-Wei

2013-03-01

Brain injury is almost irreparable due to the poor regenerative capability of neural tissue. Nowadays, new therapeutic strategies have been focused on stem cell therapy and supplying an appropriate three dimensional (3D) matrix for the repair of injured brain tissue. In this study, we specifically linked laminin-derived IKVAV motif on the C-terminal to enrich self-assembling peptide RADA(16) as a functional peptide-based scaffold. Our purpose is providing a functional self-assembling peptide 3D hydrogel with encapsulated neural stem cells to enhance the reconstruction of the injured brain. The physiochemical properties reported that RADA(16)-IKVAV can self-assemble into nanofibrous morphology with bilayer β-sheet structure and become gelationed hydrogel with mechanical stiffness similar to brain tissue. The in vitro results showed that the extended IKVAV sequence can serve as a signal or guiding cue to direct the encapsulated neural stem cells (NSCs) adhesion and then towards neuronal differentiation. Animal study was conducted in a rat brain surgery model to demonstrate the damage in cerebral neocortex/neopallium loss. The results showed that the injected peptide solution immediately in situ formed the 3D hydrogel filling up the cavity and bridging the gaps. The histological analyses revealed the RADA(16)-IKVAV self-assembling peptide hydrogel not only enhanced survival of encapsulated NSCs but also reduced the formation of glial astrocytes. The peptide hydrogel with IKVAV extended motifs also showed the support of encapsulated NSCs in neuronal differentiation and the improvement in brain tissue regeneration after 6 weeks post-transplantation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Receptors for VIP and PACAP in guinea pig cerebral cortex: effects on cyclic AMP synthesis and characterization by 125I-VIP binding.

PubMed

Zawilska, Jolanta B; Dejda, Agnieszka; Niewiadomski, Pawel; Gozes, Illana; Nowak, Jerzy Z

2005-01-01

Receptors for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in guinea pig cerebral cortex were characterized by (1) radioreceptor binding of 125I-labeled VIP (human/rat/porcine), and (2) cyclic AMP (cAMP) formation. Saturation analysis of 125I-VIP binding to membranes of guinea pig cerebral cortex resulted in a linear Scatchard plot, suggesting the presence of a single class of high-affinity receptor-binding sites, with a Kd of 0.63 nM and a B(max) of 77 fmol/mg protein. Various peptides from the PACAP/VIP/secretin family displaced the specific binding of 125I-VIP to guinea pig cerebrum with the relative rank order of potency: chicken VIP (cVIP) > or = PACAP38 approximately PACAP27 approximately guinea pig VIP (gpVIP) > or = mammalian (human/rat/porcine) VIP (mVIP) > peptide histidine-methionine (PHM) > peptide histidine-isoleucine (PHI) > secretin. Analysis of the competition curves revealed displacement of 125I-VIP from high- and lower-affinity binding sites, with IC50 values in the picomolar and the nanomolar range, respectively. About 70% of the specific 125I-VIP-binding sites in guinea pig cerebral cortex were sensitive to Gpp(NH)p, a nonhydrolyzable analog of GTP. Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38), PACAP27, cVIP, gpVIP, mVIP, PHM, and PHI stimulated cAMP production in [3H]adenine-prelabeled slices of guinea pig cerebral cortex in a concentration-dependent manner. Of the tested peptides, the most effective were PACAP38 and PACAP27, which at a 1 microM concentration produced a 17- to 19-fold rise in cAMP synthesis, increasing the nucleotide production to approx 11% conversion above the control value. The three forms of VIP (cVIP, mVIP, and gpVIP) at the highest concentration used, i.e., 3 microM, produced net increases in cAMP production in the range of 8-9% conversion, whereas 5 microM PHM and PHI, by, respectively, 6.7% and 4.9% conversion. It is concluded that cerebral cortex of guinea pig contains VPAC- type receptors positively linked to cAMP formation. In addition, the observed stronger action of PACAP (both PACAP38 and PACAP27), when compared to any form of VIP, on cAMP production in this tissue, suggests its interaction with both PAC1 and VPAC receptors.

The Role of Medial Frontal Cortex in Action Anticipation in Professional Badminton Players.

PubMed

Xu, Huan; Wang, Pin; Ye, Zhuo'er; Di, Xin; Xu, Guiping; Mo, Lei; Lin, Huiyan; Rao, Hengyi; Jin, Hua

2016-01-01

Some studies show that the medial frontal cortex is associated with more skilled action anticipation, while similar findings are not observed in some other studies, possibly due to the stimuli employed and the participants used as the control group. In addition, no studies have investigated whether there is any functional connectivity between the medial frontal cortex and other brain regions in more skilled action anticipation. Therefore, the present study aimed to re-investigate how the medial frontal cortex is involved in more skilled action anticipation by circumventing the limitations of previous research and to investigate that the medial frontal cortex functionally connected with other brain regions involved in action processing in more skilled action anticipation. To this end, professional badminton players and novices were asked to anticipate the landing position of the shuttlecock while watching badminton match videos or to judge the gender of the players in the matches. The video clips ended right at the point that the shuttlecock and the racket came into contact to reduce the effect of information about the trajectory of the shuttlecock. Novices who lacked training and watching experience were recruited for the control group to reduce the effect of sport-related experience on the medial frontal cortex. Blood oxygenation level-dependent activation was assessed by means of functional magnetic resonance imaging. Compared to novices, badminton players exhibited stronger activation in the left medial frontal cortex during action anticipation and greater functional connectivity between left medial frontal cortex and some other brain regions (e.g., right posterior cingulate cortex). Therefore, the present study supports the position that the medial frontal cortex plays a role in more skilled action anticipation and that there is a specific brain network for more skilled action anticipation that involves right posterior cingulate cortex, right fusiform gyrus, right inferior parietal lobule, left insula and particularly, and left medial frontal cortex.

The Role of Medial Frontal Cortex in Action Anticipation in Professional Badminton Players

PubMed Central

Xu, Huan; Wang, Pin; Ye, Zhuo’er; Di, Xin; Xu, Guiping; Mo, Lei; Lin, Huiyan; Rao, Hengyi; Jin, Hua

2016-01-01

Some studies show that the medial frontal cortex is associated with more skilled action anticipation, while similar findings are not observed in some other studies, possibly due to the stimuli employed and the participants used as the control group. In addition, no studies have investigated whether there is any functional connectivity between the medial frontal cortex and other brain regions in more skilled action anticipation. Therefore, the present study aimed to re-investigate how the medial frontal cortex is involved in more skilled action anticipation by circumventing the limitations of previous research and to investigate that the medial frontal cortex functionally connected with other brain regions involved in action processing in more skilled action anticipation. To this end, professional badminton players and novices were asked to anticipate the landing position of the shuttlecock while watching badminton match videos or to judge the gender of the players in the matches. The video clips ended right at the point that the shuttlecock and the racket came into contact to reduce the effect of information about the trajectory of the shuttlecock. Novices who lacked training and watching experience were recruited for the control group to reduce the effect of sport-related experience on the medial frontal cortex. Blood oxygenation level-dependent activation was assessed by means of functional magnetic resonance imaging. Compared to novices, badminton players exhibited stronger activation in the left medial frontal cortex during action anticipation and greater functional connectivity between left medial frontal cortex and some other brain regions (e.g., right posterior cingulate cortex). Therefore, the present study supports the position that the medial frontal cortex plays a role in more skilled action anticipation and that there is a specific brain network for more skilled action anticipation that involves right posterior cingulate cortex, right fusiform gyrus, right inferior parietal lobule, left insula and particularly, and left medial frontal cortex. PMID:27909422

Spinal Cord Injury Disrupts Resting-State Networks in the Human Brain.

PubMed

Hawasli, Ammar H; Rutlin, Jerrel; Roland, Jarod L; Murphy, Rory K J; Song, Sheng-Kwei; Leuthardt, Eric C; Shimony, Joshua S; Ray, Wilson Z

2018-03-15

Despite 253,000 spinal cord injury (SCI) patients in the United States, little is known about how SCI affects brain networks. Spinal MRI provides only structural information with no insight into functional connectivity. Resting-state functional MRI (RS-fMRI) quantifies network connectivity through the identification of resting-state networks (RSNs) and allows detection of functionally relevant changes during disease. Given the robust network of spinal cord afferents to the brain, we hypothesized that SCI produces meaningful changes in brain RSNs. RS-fMRIs and functional assessments were performed on 10 SCI subjects. Blood oxygen-dependent RS-fMRI sequences were acquired. Seed-based correlation mapping was performed using five RSNs: default-mode (DMN), dorsal-attention (DAN), salience (SAL), control (CON), and somatomotor (SMN). RSNs were compared with normal control subjects using false-discovery rate-corrected two way t tests. SCI reduced brain network connectivity within the SAL, SMN, and DMN and disrupted anti-correlated connectivity between CON and SMN. When divided into separate cohorts, complete but not incomplete SCI disrupted connectivity within SAL, DAN, SMN and DMN and between CON and SMN. Finally, connectivity changed over time after SCI: the primary motor cortex decreased connectivity with the primary somatosensory cortex, the visual cortex decreased connectivity with the primary motor cortex, and the visual cortex decreased connectivity with the sensory parietal cortex. These unique findings demonstrate the functional network plasticity that occurs in the brain as a result of injury to the spinal cord. Connectivity changes after SCI may serve as biomarkers to predict functional recovery following an SCI and guide future therapy.

[Asperger syndrome with highly exceptional calendar memory: a case report].

PubMed

Sevik, Ali Emre; Cengel Kültür, Ebru; Demirel, Hilal; Karlı Oğuz, Kader; Akça, Onur; Lay Ergün, Eser; Demir, Başaran

2010-01-01

Some patients with pervasive developmental disorders develop unusual talents, which are characterized as savant syndrome. Herein we present neuropsychological examination and brain imaging (fMRI and brain SPECT) findings of an 18-year-old male with Asperger syndrome and highly unusual calendar memory. Neuropsychological evaluation of the case indicated mild attention, memory, and problem solving deficits, and severe executive function deficits that included conceptualization, category formation, and abstraction. Functional MRI findings showed activation above the baseline level (P<0.05) in the bilateral inferior parietal lobule, precuneus, superior and middle frontal gyri, and medial frontal cortex. Brain SPECT findings, in comparison to rest-SPECT findings, showed that there was hypoperfusion in some brain regions, including the right frontal cortex and right parietal cortex. Baseline blood perfusion in the left frontal cortex was also observed, as well as hypoperfusion in the right parietal-occipital cortex and in the right basal ganglion (compared to the left side). The results of the present study and further research will contribute to our understanding of calendar memory and savant syndrome.

Fasting mediated increase in p-BAD(ser155) and p-AKT(ser473) in the prefrontal cortex of mice.

PubMed

Pitchaimani, Vigneshwaran; Arumugam, Somasundaram; Thandavarayan, Rajarajan Amirthalingam; Karuppagounder, Vengadeshprabhu; Sreedhar, Remya; Afrin, Rejina; Harima, Meilei; Suzuki, Hiroshi; Miyashita, Shizuka; Nomoto, Mayumi; Sone, Hirohito; Suzuki, Kenji; Watanabe, Kenichi

2014-09-05

BAD-deficient mice and fasting have several common functional roles in seizures, beta-hydroxybutyrate (BHB) uptake in brain and alteration in counterregulatory hormonal regulation during hypoglycemia. Neuronal specific insulin receptor knockout (NIRKO) mice display impaired counterregulatory hormonal responses during hypoglycemia. In this study we investigated the fasting mediated expression of p-BAD(ser155) and p-AKT(ser473) in different regions of brain (prefrontal cortex, hippocampus, midbrain and hypothalamus). Fasting specifically increases p-BAD(ser155) and p-AKT(ser473) in prefrontal cortex and decreases in other regions of brain. Our results suggest that fasting may increase the uptake BHB by decreasing p-BAD(ser155) in the brain during hypoglycemia except prefrontal cortex and it uncovers specific functional area of p-BAD(ser155) and p-AKT(ser473) that may regulates counter regulatory hormonal response. Overall in support with previous findings, fasting mediated hypoglycemia activates prefrontal cortex insulin signaling which influences the hypothalamic paraventricular nucleus mediated activation of sympathoadrenal hormonal responses. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Resting state electrical brain activity and connectivity in fibromyalgia

PubMed Central

Vanneste, Sven; Ost, Jan; Van Havenbergh, Tony; De Ridder, Dirk

2017-01-01

The exact mechanism underlying fibromyalgia is unknown, but increased facilitatory modulation and/or dysfunctional descending inhibitory pathway activity are posited as possible mechanisms contributing to sensitization of the central nervous system. The primary goal of this study is to identify a fibromyalgia neural circuit that can account for these abnormalities in central pain. The second goal is to gain a better understanding of the functional connectivity between the default and the executive attention network (salience network plus dorsal lateral prefrontal cortex) in fibromyalgia. We examine neural activity associated with fibromyalgia (N = 44) and compare these with healthy controls (N = 44) using resting state source localized EEG. Our data support an important role of the pregenual anterior cingulate cortex but also suggest that the degree of activation and the degree of integration between different brain areas is important. The inhibition of the connectivity between the dorsal lateral prefrontal cortex and the posterior cingulate cortex on the pain inhibitory pathway seems to be limited by decreased functional connectivity with the pregenual anterior cingulate cortex. Our data highlight the functional dynamics of brain regions integrated in brain networks in fibromyalgia patients. PMID:28650974

Neural plasticity in amplitude of low frequency fluctuation, cortical hub construction, regional homogeneity resulting from working memory training.

PubMed

Takeuchi, Hikaru; Taki, Yasuyuki; Nouchi, Rui; Sekiguchi, Atsushi; Kotozaki, Yuka; Nakagawa, Seishu; Makoto Miyauchi, Carlos; Sassa, Yuko; Kawashima, Ryuta

2017-05-03

Working memory training (WMT) induces changes in cognitive function and various neurological systems. Here, we investigated changes in recently developed resting state functional magnetic resonance imaging measures of global information processing [degree of the cortical hub, which may have a central role in information integration in the brain, degree centrality (DC)], the magnitude of intrinsic brain activity [fractional amplitude of low frequency fluctuation (fALFF)], and local connectivity (regional homogeneity) in young adults, who either underwent WMT or received no intervention for 4 weeks. Compared with no intervention, WMT increased DC in the anatomical cluster, including anterior cingulate cortex (ACC), to the medial prefrontal cortex (mPFC). Furthermore, WMT increased fALFF in the anatomical cluster including the right dorsolateral prefrontal cortex (DLPFC), frontopolar area and mPFC. WMT increased regional homogeneity in the anatomical cluster that spread from the precuneus to posterior cingulate cortex and posterior parietal cortex. These results suggest WMT-induced plasticity in spontaneous brain activity and global and local information processing in areas of the major networks of the brain during rest.

Transport of cargo from periphery to brain by circulating monocytes.

PubMed

Cintron, Amarallys F; Dalal, Nirjari V; Dooyema, Jeromy; Betarbet, Ranjita; Walker, Lary C

2015-10-05

The misfolding and aggregation of the Aβ peptide - a fundamental event in the pathogenesis of Alzheimer׳s disease - can be instigated in the brains of experimental animals by the intracranial infusion of brain extracts that are rich in aggregated Aβ. Recent experiments have found that the peripheral (intraperitoneal) injection of Aβ seeds induces Aβ deposition in the brains of APP-transgenic mice, largely in the form of cerebral amyloid angiopathy. Macrophage-type cells normally are involved in pathogen neutralization and antigen presentation, but under some circumstances, circulating monocytes have been found to act as vectors for the transport of pathogenic agents such as viruses and prions. The present study assessed the ability of peripheral monocytes to transport Aβ aggregates from the peritoneal cavity to the brain. Our initial experiments showed that intravenously delivered macrophages that had previously ingested fluorescent nanobeads as tracers migrate primarily to peripheral organs such as spleen and liver, but that a small number also reach the brain parenchyma. We next injected CD45.1-expressing monocytes from donor mice intravenously into CD45.2-expressing host mice; after 24h, analysis by fluorescence-activated cell sorting (FACS) and histology confirmed that some CD45.1 monocytes enter the brain, particularly in the superficial cortex and around blood vessels. When the donor monocytes are first exposed to Aβ-rich brain extracts from human AD cases, a subset of intravenously delivered Aβ-containing cells migrate to the brain. These experiments indicate that, in mouse models, circulating monocytes are potential vectors by which exogenously delivered, aggregated Aβ travels from periphery to brain, and more generally support the hypothesis that macrophage-type cells can participate in the dissemination of proteopathic seeds. Copyright © 2015 Elsevier B.V. All rights reserved.

Activation of sensory cortex by imagined genital stimulation: an fMRI analysis

PubMed Central

Wise, Nan J.; Frangos, Eleni; Komisaruk, Barry R.

2016-01-01

Background During the course of a previous study, our laboratory made a serendipitous finding that just thinking about genital stimulation resulted in brain activations that overlapped with, and differed from, those generated by physical genital stimulation. Objective This study extends our previous findings by further characterizing how the brain differentially processes physical ‘touch’ stimulation and ‘imagined’ stimulation. Design Eleven healthy women (age range 29–74) participated in an fMRI study of the brain response to imagined or actual tactile stimulation of the nipple and clitoris. Two additional conditions – imagined dildo self-stimulation and imagined speculum stimulation – were included to characterize the effects of erotic versus non-erotic imagery. Results Imagined and tactile self-stimulation of the nipple and clitoris each activated the paracentral lobule (the genital region of the primary sensory cortex) and the secondary somatosensory cortex. Imagined self-stimulation of the clitoris and nipple resulted in greater activation of the frontal pole and orbital frontal cortex compared to tactile self-stimulation of these two bodily regions. Tactile self-stimulation of the clitoris and nipple activated the cerebellum, primary somatosensory cortex (hand region), and premotor cortex more than the imagined stimulation of these body regions. Imagining dildo stimulation generated extensive brain activation in the genital sensory cortex, secondary somatosensory cortex, hippocampus, amygdala, insula, nucleus accumbens, and medial prefrontal cortex, whereas imagining speculum stimulation generated only minimal activation. Conclusion The present findings provide evidence of the potency of imagined stimulation of the genitals and that the following brain regions may participate in erogenous experience: primary and secondary sensory cortices, sensory-motor integration areas, limbic structures, and components of the ‘reward system’. In addition, these results suggest a mechanism by which some individuals may be able to generate orgasm by imagery in the absence of physical stimulation. PMID:27791966

Substance P receptors: localization by light microscopic autoradiography in rat brain using [3H]SP as the radioligand.

PubMed

Mantyh, P W; Hunt, S P; Maggio, J E

1984-07-30

Substance P (SP) is a putative neurotransmitter in both the peripheral and central nervous systems. In the present report we have used a modification of the Young and Kuhar technique to investigate some of the SP receptors binding properties and the distribution of SP receptors in rat brain. Tritiated SP [( 3H]SP) absorbed extensively to glass but this adsorbtion was greatly reduced by preincubating the slide-mounted tissue sections in a solution containing the cationic polymer polyethylenimine. [3H]SP was found to bind to rat tissue in a saturable fashion with a Bmax of 14.7 fmol/mg tissue wet weight and a Kd of 1.1 nM. The rank order of potencies for displacing [3H]SP binding from rat tissue sections was SP greater than SP sulphoxide greater than DiMeC7 greater than Eledoisin greater than SP(5-11) greater than SP(COOH) greater than SP(1-9) amide. Using autoradiography coupled with LKB tritium-sensitive Ultrofilm or the dry emulsion-coated coverslip technique the distribution of [3H]SP binding sites was found to be very dense within olfactory bulb, amygdalo-hippocampal area and the nucleus of the solitary tract. Heavy concentrations of receptors were observed in the septum, diagonal band of Broca, striatum subiculum, hypothalamus, locus coeruleus, parabrachial nucleus and lobule 9 and 10 of the cerebellum. Moderate to low concentrations of receptors were observed in the cerebral cortex, globus pallidus, raphe nuclei and the trigeminal nucleus. Very low densities were observed in most aspects of the dorsal thalamus, substantia nigra and cerebellum (other than lobule 9 and 10). Comparisons of the present data with SP peptide levels indicate that in some areas of the brain there is a rough correlation between peptide and receptor levels. However, in other brain areas (olfactory bulb, globus pallidus and substantia nigra) there is little obvious correlation between the two.

Antiviral Peptides Targeting the West Nile Virus Envelope Protein▿

PubMed Central

Bai, Fengwei; Town, Terrence; Pradhan, Deepti; Cox, Jonathan; Ashish; Ledizet, Michel; Anderson, John F.; Flavell, Richard A.; Krueger, Joanna K.; Koski, Raymond A.; Fikrig, Erol

2007-01-01

West Nile virus (WNV) can cause fatal murine and human encephalitis. The viral envelope protein interacts with host cells. A murine brain cDNA phage display library was therefore probed with WNV envelope protein, resulting in the identification of several adherent peptides. Of these, peptide 1 prevented WNV infection in vitro with a 50% inhibition concentration of 67 μM and also inhibited infection of a related flavivirus, dengue virus. Peptide 9, a derivative of peptide 1, was a particularly potent inhibitor of WNV in vitro, with a 50% inhibition concentration of 2.6 μM. Moreover, mice challenged with WNV that had been incubated with peptide 9 had reduced viremia and fatality compared with control animals. Peptide 9 penetrated the murine blood-brain barrier and was found in the brain parenchyma, implying that it may have antiviral activity in the central nervous system. These short peptides serve as the basis for developing new therapeutics for West Nile encephalitis and, potentially, other flaviviruses. PMID:17151121

The Peptide Vaccine Combined with Prior Immunization of a Conventional Diphtheria-Tetanus Toxoid Vaccine Induced Amyloid β Binding Antibodies on Cynomolgus Monkeys and Guinea Pigs.

PubMed

Yano, Akira; Ito, Kaori; Miwa, Yoshikatsu; Kanazawa, Yoshito; Chiba, Akiko; Iigo, Yutaka; Kashimoto, Yoshinori; Kanda, Akira; Murata, Shinji; Makino, Mitsuhiro

2015-01-01

The reduction of brain amyloid beta (Aβ) peptides by anti-Aβ antibodies is one of the possible therapies for Alzheimer's disease. We previously reported that the Aβ peptide vaccine including the T-cell epitope of diphtheria-tetanus combined toxoid (DT) induced anti-Aβ antibodies, and the prior immunization with conventional DT vaccine enhanced the immunogenicity of the peptide. Cynomolgus monkeys were given the peptide vaccine subcutaneously in combination with the prior DT vaccination. Vaccination with a similar regimen was also performed on guinea pigs. The peptide vaccine induced anti-Aβ antibodies in cynomolgus monkeys and guinea pigs without chemical adjuvants, and excessive immune responses were not observed. Those antibodies could preferentially recognize Aβ 40, and Aβ 42 compared to Aβ fibrils. The levels of serum anti-Aβ antibodies and plasma Aβ peptides increased in both animals and decreased the brain Aβ 40 level of guinea pigs. The peptide vaccine could induce a similar binding profile of anti-Aβ antibodies in cynomolgus monkeys and guinea pigs. The peptide vaccination could be expected to reduce the brain Aβ peptides and their toxic effects via clearance of Aβ peptides by generated antibodies.

Acute hepatic encephalopathy presenting as cortical laminar necrosis: case report.

PubMed

Choi, Jong Mun; Kim, Yoon Hee; Roh, Sook Young

2013-01-01

We report on a 55-year-old man with alcoholic liver cirrhosis who presented with status epilepticus. Laboratory analysis showed markedly elevated blood ammonia. Brain magnetic resonance imaging (MRI) showed widespread cortical signal changes with restricted diffusion, involving both temporo-fronto-parietal cortex, while the perirolandic regions and occipital cortex were uniquely spared. A follow-up brain MRI demonstrated diffuse cortical atrophy with increased signals on T1-weighted images in both the basal ganglia and temporal lobe cortex, representing cortical laminar necrosis. We suggest that the brain lesions, in our case, represent a consequence of toxic effect of ammonia.

Alterations of brain activity in fibromyalgia patients.

PubMed

Sawaddiruk, Passakorn; Paiboonworachat, Sahattaya; Chattipakorn, Nipon; Chattipakorn, Siriporn C

2017-04-01

Fibromyalgia is a chronic pain syndrome, characterized by widespread musculoskeletal pain with diffuse tenderness at multiple tender points. Despite intense investigations, the pathophysiology of fibromyalgia remains elusive. Evidence shows that it could be due to changes in either the peripheral or central nervous system (CNS). For the CNS changes, alterations in the high brain area of fibromyalgia patients have been investigated but the definite mechanisms are still unclear. Magnetic Resonance Imaging (MRI) and Functional Magnetic Resonance (fMRI) have been used to gather evidence regarding the changes of brain morphologies and activities in fibromyalgia patients. Nevertheless, due to few studies, limited knowledge for alterations in brain activities in fibromyalgia is currently available. In this review, the changes in brain activity in various brain areas obtained from reports in fibromyalgia patients are comprehensively summarized. Changes of the grey matter in multiple regions such as the superior temporal gyrus, posterior thalamus, amygdala, basal ganglia, cerebellum, cingulate cortex, SII, caudate and putamen from the MRI as well as the increase of brain activities in the cerebellum, prefrontal cortex, anterior cingulate cortex, thalamus, somatosensory cortex, insula in fMRI studies are presented and discussed. Moreover, evidence from pharmacological interventions offering benefits for fibromyalgia patients by reducing brain activity is presented. Because of limited knowledge regarding the roles of brain activity alterations in fibromyalgia, this summarized review will encourage more future studies to elucidate the underlying mechanisms involved in the brains of these patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Fetal brain hypometabolism during prolonged hypoxaemia in the llama

PubMed Central

Ebensperger, Germán; Ebensperger, Renato; Herrera, Emilio A; Riquelme, Raquel A; Sanhueza, Emilia M; Lesage, Florian; Marengo, Juan J; Tejo, Rodrigo I; Llanos, Aníbal J; Reyes, Roberto V

2005-01-01

In this study we looked for additional evidence to support the hypothesis that fetal llama reacts to hypoxaemia with adaptive brain hypometabolism. We determined fetal llama brain temperature, Na+ and K+ channel density and Na+–K+-ATPase activity. Additionally, we looked to see whether there were signs of cell death in the brain cortex of llama fetuses submitted to prolonged hypoxaemia. Ten fetal llamas were instrumented under general anaesthesia to measure pH, arterial blood gases, mean arterial pressure, heart rate, and brain and core temperatures. Measurements were made 1 h before and every hour during 24 h of hypoxaemia (n = 5), which was imposed by reducing maternal inspired oxygen fraction to reach a fetal arterial partial pressure of oxygen (Pa,O2) of about 12 mmHg. A normoxaemic group was the control (n = 5). After 24 h of hypoxaemia, we determined brain cortex Na+–K+-ATPase activity, ouabain binding, and the expression of NaV1.1, NaV1.2, NaV1.3, NaV1.6, TREK1, TRAAK and KATP channels. The lack of brain cortex damage was assessed as poly ADP-ribose polymerase (PARP) proteolysis. We found a mean decrease of 0.56°C in brain cortex temperature during prolonged hypoxaemia, which was accompanied by a 51% decrease in brain cortex Na+–K+-ATPase activity, and by a 44% decrease in protein content of NaV1.1, a voltage-gated Na+ channel. These changes occurred in absence of changes in PARP protein degradation, suggesting that the cell death of the brain was not enhanced in the fetal llama during hypoxaemia. Taken together, these results provide further evidence to support the hypothesis that the fetal llama responds to prolonged hypoxaemia with adaptive brain hypometabolism, partly mediated by decreases in Na+–K+-ATPase activity and expression of NaV channels. PMID:16037083

The effect of electromagnetic radiation on the rat brain: an experimental study.

PubMed

Eser, Olcay; Songur, Ahmet; Aktas, Cevat; Karavelioglu, Ergun; Caglar, Veli; Aylak, Firdevs; Ozguner, Fehmi; Kanter, Mehmet

2013-01-01

The aim of this study is to determine the structural changes of electromagnetic waves in the frontal cortex, brain stem and cerebellum. 24 Wistar Albino adult male rats were randomly divided into four groups: group I consisted of control rats, and groups II-IV comprised electromagnetically irradiated (EMR) with 900, 1800 and 2450 MHz. The heads of the rats were exposed to 900, 1800 and 2450 MHz microwaves irradiation for 1h per day for 2 months. While the histopathological changes in the frontal cortex and brain stem were normal in the control group, there were severe degenerative changes, shrunken cytoplasm and extensively dark pyknotic nuclei in the EMR groups. Biochemical analysis demonstrated that the Total Antioxidative Capacity level was significantly decreased in the EMR groups and also Total Oxidative Capacity and Oxidative Stress Index levels were significantly increased in the frontal cortex, brain stem and cerebellum. IL-1β level was significantly increased in the EMR groups in the brain stem. EMR causes to structural changes in the frontal cortex, brain stem and cerebellum and impair the oxidative stress and inflammatory cytokine system. This deterioration can cause to disease including loss of these areas function and cancer development.

Cellular scaling rules for the brain of Artiodactyla include a highly folded cortex with few neurons

PubMed Central

Kazu, Rodrigo S.; Maldonado, José; Mota, Bruno; Manger, Paul R.; Herculano-Houzel, Suzana

2014-01-01

Quantitative analysis of the cellular composition of rodent, primate, insectivore, and afrotherian brains has shown that non-neuronal scaling rules are similar across these mammalian orders that diverged about 95 million years ago, and therefore appear to be conserved in evolution, while neuronal scaling rules appear to be free to vary in a clade-specific manner. Here we analyze the cellular scaling rules that apply to the brain of artiodactyls, a group within the order Cetartiodactyla, believed to be a relatively recent radiation from the common Eutherian ancestor. We find that artiodactyls share non-neuronal scaling rules with all groups analyzed previously. Artiodactyls share with afrotherians and rodents, but not with primates, the neuronal scaling rules that apply to the cerebral cortex and cerebellum. The neuronal scaling rules that apply to the remaining brain areas are, however, distinct in artiodactyls. Importantly, we show that the folding index of the cerebral cortex scales with the number of neurons in the cerebral cortex in distinct fashions across artiodactyls, afrotherians, rodents, and primates, such that the artiodactyl cerebral cortex is more convoluted than primate cortices of similar numbers of neurons. Our findings suggest that the scaling rules found to be shared across modern afrotherians, glires, and artiodactyls applied to the common Eutherian ancestor, such as the relationship between the mass of the cerebral cortex as a whole and its number of neurons. In turn, the distribution of neurons along the surface of the cerebral cortex, which is related to its degree of gyrification, appears to be a clade-specific characteristic. If the neuronal scaling rules for artiodactyls extend to all cetartiodactyls, we predict that the large cerebral cortex of cetaceans will still have fewer neurons than the human cerebral cortex. PMID:25429261

Enhanced peripheral visual processing in congenitally deaf humans is supported by multiple brain regions, including primary auditory cortex.

PubMed

Scott, Gregory D; Karns, Christina M; Dow, Mark W; Stevens, Courtney; Neville, Helen J

2014-01-01

Brain reorganization associated with altered sensory experience clarifies the critical role of neuroplasticity in development. An example is enhanced peripheral visual processing associated with congenital deafness, but the neural systems supporting this have not been fully characterized. A gap in our understanding of deafness-enhanced peripheral vision is the contribution of primary auditory cortex. Previous studies of auditory cortex that use anatomical normalization across participants were limited by inter-subject variability of Heschl's gyrus. In addition to reorganized auditory cortex (cross-modal plasticity), a second gap in our understanding is the contribution of altered modality-specific cortices (visual intramodal plasticity in this case), as well as supramodal and multisensory cortices, especially when target detection is required across contrasts. Here we address these gaps by comparing fMRI signal change for peripheral vs. perifoveal visual stimulation (11-15° vs. 2-7°) in congenitally deaf and hearing participants in a blocked experimental design with two analytical approaches: a Heschl's gyrus region of interest analysis and a whole brain analysis. Our results using individually-defined primary auditory cortex (Heschl's gyrus) indicate that fMRI signal change for more peripheral stimuli was greater than perifoveal in deaf but not in hearing participants. Whole-brain analyses revealed differences between deaf and hearing participants for peripheral vs. perifoveal visual processing in extrastriate visual cortex including primary auditory cortex, MT+/V5, superior-temporal auditory, and multisensory and/or supramodal regions, such as posterior parietal cortex (PPC), frontal eye fields, anterior cingulate, and supplementary eye fields. Overall, these data demonstrate the contribution of neuroplasticity in multiple systems including primary auditory cortex, supramodal, and multisensory regions, to altered visual processing in congenitally deaf adults.

Identification, localisation and functional implication of 26RFa orthologue peptide in the brain of zebra finch (Taeniopygia guttata).

PubMed

Tobari, Y; Iijima, N; Tsunekawa, K; Osugi, T; Haraguchi, S; Ubuka, T; Ukena, K; Okanoya, K; Tsutsui, K; Ozawa, H

2011-09-01

Several neuropeptides with the C-terminal Arg-Phe-NH(2) (RFa) sequence have been identified in the hypothalamus of a variety of vertebrates. The present study was conducted to isolate novel RFa peptides from the zebra finch brain. Peptides were isolated by immunoaffinity purification using an antibody that recognises avian RFa peptides. The isolated peptide consisted of 25 amino acids with RFa at its C-terminus. The sequence was SGTLGNLAEEINGYNRRKGGFTFRFa. Alignment of the peptide with vertebrate 26RFa has revealed that the identified peptide is the zebra finch 26RFa. We also cloned the precursor cDNA encoding this peptide. Synteny analysis of the gene showed a high conservation of this gene among vertebrates. In addition, we cloned the cDNA encoding a putative 26RFa receptor, G protein-coupled receptor 103 (GPR103) in the zebra finch brain. GPR103 cDNA encoded a 432 amino acid protein that has seven transmembrane domains. In situ hybridisation analysis in the brain showed that the expression of 26RFa mRNA is confined to the anterior-medial hypothalamic area, ventromedial nucleus of the hypothalamus and the lateral hypothalamic area, the brain regions that are involved in the regulation of feeding behaviour, whereas GPR103 mRNA is distributed throughout the brain in addition to the hypothalamic nuclei. When administered centrally in free-feeding male zebra finches, 26RFa increased food intake 24 h after injection without body mass change. Diencephalic GPR103 mRNA expression was up-regulated by fasting for 10 h. Our data suggest that the hypothalamic 26RFa-its receptor system plays an important role in the central control of food intake and energy homeostasis in the zebra finch. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.

Oxysterols decrease apical-to-basolateral transport of Aß peptides via an ABCB1-mediated process in an in vitro Blood-brain barrier model constituted of bovine brain capillary endothelial cells.

PubMed

Saint-Pol, Julien; Candela, Pietra; Boucau, Marie-Christine; Fenart, Laurence; Gosselet, Fabien

2013-06-23

It is known that activation of the liver X receptors (LXRs) by natural or synthetic agonists decreases the amyloid burden and enhances cognitive function in transgenic murine models of Alzheimer's disease (AD). Recent evidence suggests that LXR activation may affect the transport of amyloid ß (Aß) peptides across the blood-brain barrier (the BBB, which isolates the brain from the peripheral circulation). By using a well-characterized in vitro BBB model, we demonstrated that LXR agonists (24S-hydroxycholesterol, 27-hydroxycholesterol and T0901317) modulated the expression of target genes involved in cholesterol homeostasis (such as ATP-binding cassette sub-family A member 1 (ABCA1)) and promoted cellular cholesterol efflux to apolipoprotein A-I and high density lipoproteins. Interestingly, we also observed a decrease in Aß peptide influx across brain capillary endothelial cells, although ABCA1 did not appear to be directly involved in this process. By focusing on others receptors and transporters that are thought to have major roles in Aß peptide entry into the brain, we then demonstrated that LXR stimulation provoked an increase in expression of the ABCB1 transporter (also named P-glycoprotein (P-gp)). Further investigations confirmed ABCB1's involvement in the restriction of Aß peptide influx. Taken as a whole, our results not only reinforce the BBB's key role in cerebral cholesterol homeostasis but also demonstrate the importance of the LXR/ABCB1 axis in Aß peptide influx-highlighting an attractive new therapeutic approach whereby the brain could be protected from peripheral Aß peptide entry. Copyright © 2013 Elsevier B.V. All rights reserved.

An in vitro and in vivo study of peptide-functionalized nanoparticles for brain targeting: The importance of selective blood-brain barrier uptake.

PubMed

Bode, Gerard H; Coué, Gregory; Freese, Christian; Pickl, Karin E; Sanchez-Purrà, Maria; Albaiges, Berta; Borrós, Salvador; van Winden, Ewoud C; Tziveleka, Leto-Aikaterini; Sideratou, Zili; Engbersen, Johan F J; Singh, Smriti; Albrecht, Krystyna; Groll, Jürgen; Möller, Martin; Pötgens, Andy J G; Schmitz, Christoph; Fröhlich, Eleonore; Grandfils, Christian; Sinner, Frank M; Kirkpatrick, C James; Steinbusch, Harry W M; Frank, Hans-Georg; Unger, Ronald E; Martinez-Martinez, Pilar

2017-04-01

Targeted delivery of drugs across endothelial barriers remains a formidable challenge, especially in the case of the brain, where the blood-brain barrier severely limits entry of drugs into the central nervous system. Nanoparticle-mediated transport of peptide/protein-based drugs across endothelial barriers shows great potential as a therapeutic strategy in a wide variety of diseases. Functionalizing nanoparticles with peptides allows for more efficient targeting to specific organs. We have evaluated the hemocompatibilty, cytotoxicity, endothelial uptake, efficacy of delivery and safety of liposome, hyperbranched polyester, poly(glycidol) and acrylamide-based nanoparticles functionalized with peptides targeting brain endothelial receptors, in vitro and in vivo. We used an ELISA-based method for the detection of nanoparticles in biological fluids, investigating the blood clearance rate and in vivo biodistribution of labeled nanoparticles in the brain after intravenous injection in Wistar rats. Herein, we provide a detailed report of in vitro and in vivo observations. Copyright © 2016 Elsevier Inc. All rights reserved.

Rivastigmine is Associated with Restoration of Left Frontal Brain Activity in Parkinson’s Disease

PubMed Central

Possin, Katherine L.; Kang, Gail A.; Guo, Christine; Fine, Eric M.; Trujillo, Andrew J.; Racine, Caroline A.; Wilheim, Reva; Johnson, Erica T.; Witt, Jennifer L.; Seeley, William W.; Miller, Bruce L.; Kramer, Joel H.

2013-01-01

Objective To investigate how acetylcholinesterase inhibitor (ChEI) treatment impacts brain function in Parkinson’s disease (PD). Methods Twelve patients with PD and either dementia or mild cognitive impairment underwent task-free functional magnetic resonance imaging before and after three months of ChEI treatment and were compared to 15 age and sex matched neurologically healthy controls. Regional spontaneous brain activity was measured using the fractional amplitude of low frequency fluctuations. Results At baseline, patients showed reduced spontaneous brain activity in regions important for motor control (e.g., caudate, supplementary motor area, precentral gyrus, thalamus), attention and executive functions (e.g., lateral prefrontal cortex), and episodic memory (e.g., precuneus, angular gyrus, hippocampus). After treatment, the patients showed a similar but less extensive pattern of reduced spontaneous brain activity relative to controls. Spontaneous brain activity deficits in the left premotor cortex, inferior frontal gyrus, and supplementary motor area were restored such that the activity was increased post-treatment compared to baseline and was no longer different from controls. Treatment-related increases in left premotor and inferior frontal cortex spontaneous brain activity correlated with parallel reaction time improvement on a test of controlled attention. Conclusions PD patients with cognitive impairment show numerous regions of decreased spontaneous brain function compared to controls, and rivastigmine is associated with performance-related normalization in left frontal cortex function. PMID:23847120

Peptides: important tools for the treatment of central nervous system disorders.

PubMed

Malavolta, Luciana; Cabral, Francisco Romero

2011-10-01

This review shows some classical applications of peptides and suggests there is great promise for the treatment of various central nervous system diseases. Actually, peptides are considered the new generation of biologically active tools because they are key regulators in cellular and intercellular physiological responses, which possess enormous potential for the treatment of various diseases. In spite of their clinical potential, native peptides have seen limited use due to their poor bioavailability and low stability in physiological conditions. Moreover, most peptide or protein pharmaceuticals currently in use are delivered by invasive routes such as via subcutaneous injection. Considerable efforts have been made to design new drugs based on peptides and recent developments in technology and science have provided the means and opportunity to produce a stable as well as controlled-release form of peptide and protein drugs to combat poorly controlled diseases and to increase patients' quality of life. A major challenge in this regard, however, is the delivery of peptides over the blood-brain barrier. This review gives an overview of some strategies used to improve both bioavailability and uptake of peptide drugs for delivery into the brain. Indeed, recent findings suggest that the use of peptides by conjugation to a polymer such as nanoparticles can offer tremendous hope in the treatment of brain disorders. The polymer conjugation improves pharmacokinetics by increasing the molecular mass of proteins and peptides and shielding them from proteolytic enzymes. These new strategies will create new opportunities for the future development of neurotherapeutic drugs. In the present review we have focused our attention on the peptide controlled delivery, summarizing literature reports on the use of peptides and nanotechnology for the treatment and diagnosis of brain disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

Female adolescents with severe substance and conduct problems have substantially less brain gray matter volume.

PubMed

Dalwani, Manish S; McMahon, Mary Agnes; Mikulich-Gilbertson, Susan K; Young, Susan E; Regner, Michael F; Raymond, Kristen M; McWilliams, Shannon K; Banich, Marie T; Tanabe, Jody L; Crowley, Thomas J; Sakai, Joseph T

2015-01-01

Structural neuroimaging studies have demonstrated lower regional gray matter volume in adolescents with severe substance and conduct problems. These research studies, including ours, have generally focused on male-only or mixed-sex samples of adolescents with conduct and/or substance problems. Here we compare gray matter volume between female adolescents with severe substance and conduct problems and female healthy controls of similar ages. Female adolescents with severe substance and conduct problems will show significantly less gray matter volume in frontal regions critical to inhibition (i.e. dorsolateral prefrontal cortex and ventrolateral prefrontal cortex), conflict processing (i.e., anterior cingulate), valuation of expected outcomes (i.e., medial orbitofrontal cortex) and the dopamine reward system (i.e. striatum). We conducted whole-brain voxel-based morphometric comparison of structural MR images of 22 patients (14-18 years) with severe substance and conduct problems and 21 controls of similar age using statistical parametric mapping (SPM) and voxel-based morphometric (VBM8) toolbox. We tested group differences in regional gray matter volume with analyses of covariance, adjusting for age and IQ at p<0.05, corrected for multiple comparisons at whole-brain cluster-level threshold. Female adolescents with severe substance and conduct problems compared to controls showed significantly less gray matter volume in right dorsolateral prefrontal cortex, left ventrolateral prefrontal cortex, medial orbitofrontal cortex, anterior cingulate, bilateral somatosensory cortex, left supramarginal gyrus, and bilateral angular gyrus. Considering the entire brain, patients had 9.5% less overall gray matter volume compared to controls. Female adolescents with severe substance and conduct problems in comparison to similarly aged female healthy controls showed substantially lower gray matter volume in brain regions involved in inhibition, conflict processing, valuation of outcomes, decision-making, reward, risk-taking, and rule-breaking antisocial behavior.

Environmental Enrichment Alters Neurotrophin Levels After Fetal Alcohol Exposure in Rats

PubMed Central

Parks, Elizabeth A.; McMechan, Andrew P.; Hannigan, John H.; Berman, Robert F.

2014-01-01

Background Prenatal alcohol exposure causes abnormal brain development, leading to behavioral deficits, some of which can be ameliorated by environmental enrichment. As both environmental enrichment and prenatal alcohol exposure can individually alter neurotrophin expression, we studied the interaction of prenatal alcohol and postweaning environmental enrichment on brain neurotrophin levels in rats. Methods Pregnant rats received alcohol by gavage, 0, 4, or 6 g / kg / d (Zero, Low, or High groups), or no treatment (Naïve group), on gestational days 8 to 20. After weaning on postnatal day 21, offspring were housed for 6 weeks in Isolated, Social, or Enriched conditions. Levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) were then measured in frontal cortex, occipital cortex, hippocampus, and cerebellar vermis. Results Prenatal alcohol exposure increased NGF levels in frontal cortex (High-dose group) and cerebellar vermis (High- and Low-dose groups); increased BDNF in frontal cortex, occipital cortex and hippocampus (Low-dose groups), and increased NT-3 in hippocampus and cerebellar vermis (High-dose). Environmental enrichment resulted in lower NGF, BDNF, and NT-3 levels in occipital cortex and lower NGF in frontal cortex. The only significant interaction between prenatal alcohol treatment and environment was in cerebellar vermis where NT-3 levels were higher for enriched animals after prenatal alcohol exposure, but not for animals housed under Isolated or Social conditions. Conclusions Both prenatal alcohol exposure and postweaning housing conditions alter brain neurotrophin levels, but the effects appear to be largely independent. Although environmental enrichment can improve functional outcomes, these results do not provide strong support for the hypothesis that rearing in a complex environment ameliorates prenatal alcohol effects on brain neurotrophin levels in rats. PMID:18652597

Brain Delivery of Drug and MRI Contrast Agent: Detection and Quantitative Determination of Brain Deposition of CPT-Glu Using LC-MS/MS and Gd-DTPA Using Magnetic Resonance Imaging.

PubMed

Tabanor, Kayann; Lee, Phil; Kiptoo, Paul; Choi, In-Young; Sherry, Erica B; Eagle, Cheyenne Sun; Williams, Todd D; Siahaan, Teruna J

2016-02-01

Successful treatment and diagnosis of neurological diseases depend on reliable delivery of molecules across the blood-brain barrier (BBB), which restricts penetration of pharmaceutical drugs and diagnostic agents into the brain. Thus, developing new noninvasive strategies to improve drug delivery across the BBB is critically needed. This study was aimed at evaluating the activity of HAV6 peptide (Ac-SHAVSS-NH2) in improving brain delivery of camptothecin-glutamate (CPT-Glu) conjugate and gadolinium-diethylenetriaminepentaacetate (Gd-DTPA) contrast agent in Sprague-Dawley rats. Brain delivery of both CPT-Glu and Gd-DTPA was evaluated in an in situ rat brain perfusion model in the presence and absence of HAV6 peptide (1.0 mM). Gd-DTPA (0.6 mmol/kg) was intravenously (iv) administered with and without HAV6 peptide (0.019 mmol/kg) in rats. The detection and quantification of CPT-Glu and Gd-DTPA in the brain were carried out by LC-MS/MS and quantitative magnetic resonance imaging (MRI), respectively. Rats perfused with CPT-Glu in combination with HAV6 had significantly higher deposition of drug in the brain compared to CPT-Glu alone. MRI results also showed that administration of Gd-DTPA in the presence of HAV6 peptide led to significant accumulation of Gd-DTPA in various regions of the brain in both the in situ rat brain perfusion and in vivo studies. All observations taken together indicate that HAV6 peptide can disrupt the BBB and enhance delivery of small molecules into the brain.

Brain Delivery of Drug and MRI Contrast Agent: Detection and Quantitative Determination of Brain Deposition of CPT-Glu Using LC-MS/MS and Gd-DTPA Using Magnetic Resonance Imaging

PubMed Central

Tabanor, Kayann; Lee, Phil; Kiptoo, Paul; Choi, In-Young; Sherry, Erica B.; Eagle, Cheyenne Sun; Williams, Todd D.; Siahaan, Teruna J.

2015-01-01

Successful treatment and diagnosis of neurological diseases depend on reliable delivery of molecules across the blood-brain barrier (BBB), which restricts penetration of pharmaceutical drugs and diagnostic agents into the brain. Thus, developing new non-invasive strategies to improve drug delivery across the BBB is critically needed. This study was aimed at evaluating the activity of HAV6 peptide (Ac-SHAVSS-NH2) in improving brain delivery of camptothecin-glutamate (CPT-Glu) conjugate and gadolinium-diethylenetriaminepentaacetate (Gd-DTPA) contrast agent in Sprague-Dawley rats. Brain delivery of both CPT-Glu and Gd-DTPA was evaluated in an in situ rat brain perfusion model in the presence and absence of HAV6 peptide (1.0 mM). Gd-DTPA (0.6 mmol/kg) was intravenously (i.v.) administered with and without HAV6 peptide (0.019 mmol/kg) in rats. The detection and quantification of CPT-Glu and Gd-DTPA in the brain were carried out by LC-MS/MS and quantitative magnetic resonance imaging (MRI), respectively. Rats perfused with CPT-Glu in combination with HAV6 had significantly higher deposition of drug in the brain compared to CPT-Glu alone. MRI results also showed that administration of Gd-DTPA in the presence of HAV6 peptide led to significant accumulation of Gd-DTPA in various regions of the brain in both the in situ rat brain perfusion and in vivo studies. All observations taken together indicate that HAV6 peptide can disrupt the BBB and enhance delivery of small molecules into the brain. PMID:26705088

Detoxification depot for beta-amyloid peptides.

PubMed

Sundaram, Ranjini K; Kasinathan, Chinnaswamy; Stein, Stanley; Sundaram, Pazhani

2008-02-01

Alzheimer's Disease (AD) is caused by the deposition of insoluble and toxic amyloid peptides (Abeta) in the brain leading to memory loss and other associated neurodegenerative symptoms. To date there is limited treatment options and strategies for treating AD. Studies have shown that clearance of the amyloid plaques from the brain and thus from the blood could be effective in stopping and or delaying the progression of the disease. Small peptides derived from the Abeta-42 sequence, in particular KLVFF, have shown to be effective binders of Abeta peptides and thus could be useful in delaying progression of the disease. We have taken advantage of this property by generating the retro-inverso (RI) version of this peptide, ffvlk, in different formats. We are presenting a new detox gel system using poly ethylene glycol (PEG), polymerized and cross linked with the RI peptides. We hypothesize that detox gel incorporating RI peptides will act like a 'sink' to capture the Abeta peptides from the surrounding environment. We tested these detox gels for their ability to capture biotinylated Abeta-42 peptides in vitro. The results showed that the detox gels bound Abeta-42 peptides effectively and irreversibly. Gels incorporating the tetramer RI peptide exhibited maximum binding capacity. The detox gel could be a potential candidate for treatment strategies to deplete the brain of toxic amyloid peptides.

Acute exercise increases brain region-specific expression of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins.

PubMed

Takimoto, Masaki; Hamada, Taku

2014-05-01

The brain is capable of oxidizing lactate and ketone bodies through monocarboxylate transporters (MCTs). We examined the protein expression of MCT1, MCT2, MCT4, glucose transporter 1 (GLUT1), and cytochrome-c oxidase subunit IV (COX IV) in the rat brain within 24 h after a single exercise session. Brain samples were obtained from sedentary controls and treadmill-exercised rats (20 m/min, 8% grade). Acute exercise resulted in an increase in lactate in the cortex, hippocampus, and hypothalamus, but not the brainstem, and an increase in β-hydroxybutyrate in the cortex alone. After a 2-h exercise session MCT1 increased in the cortex and hippocampus 5 h postexercise, and the effect lasted in the cortex for 24 h postexercise. MCT2 increased in the cortex and hypothalamus 5-24 h postexercise, whereas MCT2 increased in the hippocampus immediately after exercise, and remained elevated for 10 h postexercise. Regional upregulation of MCT2 after exercise was associated with increases in brain-derived neurotrophic factor and tyrosine-related kinase B proteins, but not insulin-like growth factor 1. MCT4 increased 5-10 h postexercise only in the hypothalamus, and was associated with increased hypoxia-inducible factor-1α expression. However, none of the MCT isoforms in the brainstem was affected by exercise. Whereas GLUT 1 in the cortex increased only at 18 h postexercise, COX IV in the hippocampus increased 10 h after exercise and remained elevated for 24 h postexercise. These results suggest that acute prolonged exercise induces the brain region-specific upregulation of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins.

Retrograde Cerebral Perfusion Results in Better Perfusion to the Striatum Than the Cerebral Cortex During Deep Hypothermic Circulatory Arrest: A Microdialysis Study.

PubMed

Liang, Meng-Ya; Chen, Guang-Xian; Tang, Zhi-Xian; Rong, Jian; Yao, Jian-ping; Wu, Zhong-Kai

2016-03-01

It remains controversial whether contemporary cerebral perfusion techniques, utilized during deep hypothermic circulatory arrest (DHCA), establish adequate perfusion to deep structures in the brain. This study aimed to investigate whether selective antegrade cerebral perfusion (SACP) or retrograde cerebral perfusion (RCP) can provide perfusion equally to various anatomical positions in the brain using metabolic evidence obtained from microdialysis. Eighteen piglets were randomly assigned to 40 min of circulatory arrest (CA) at 18°C without cerebral perfusion (DHCA group, n = 6) or with SACP (SACP group, n = 6) or RCP (RCP group, n = 6). Microdialysis parameters (glucose, lactate, pyruvate, and glutamate) were measured every 30 min in cortex and striatum. After 3 h of reperfusion, brain tissue was harvested for Western blot measurement of α-spectrin. After 40 min of CA, the DHCA group showed marked elevations of lactate and glycerol and a reduction in glucose in the microdialysis perfusate (all P < 0.05). The changes in glucose, lactate, and glycerol in the perfusate and α-spectrin expression in brain tissue were similar between cortex and striatum in the SACP group (all P > 0.05). In the RCP group, the cortex exhibited lower glucose, higher lactate, and higher glycerol in the perfusate and higher α-spectrin expression in brain tissue compared with the striatum (all P < 0.05). Glutamate showed no difference between cortex and striatum in all groups (all P > 0.05). In summary, SACP provided uniform and continuous cerebral perfusion to most anatomical sites in the brain, whereas RCP resulted in less sufficient perfusion to the cortex but better perfusion to the striatum. Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Lithium ameliorates lipopolysaccharide-induced neurotoxicity in the cortex and hippocampus of the adult rat brain.

PubMed

Khan, Muhammad Sohail; Ali, Tahir; Abid, Muhammad Noman; Jo, Myeung Hoon; Khan, Amjad; Kim, Min Woo; Yoon, Gwang Ho; Cheon, Eun Woo; Rehman, Shafiq Ur; Kim, Myeong Ok

2017-09-01

Lithium an effective mood stabilizer, primary used in the treatment of bipolar disorders, has been reported as a protective agent in various neurological disorders. In this study, we examined the neuroprotective role of lithium chloride (LiCl) against lipopolysaccharide (LPS) in the cortex and hippocampus of the adult rat brain. We determined that LiCl -attenuated LPS-induced activated toll-like receptor 4 (TLR4) signalling and significantly reduced the nuclear factor- k B (NF- K B) translation factor and various other inflammatory mediators such as interleukin-1 beta (IL-1β) and tumour necrosis factor alpha (TNF-α). We also analyzed that LiCl significantly abrogated activated gliosis via attenuation of specific markers for activated microglia, ionized calcium-binding adaptor molecule (Iba-1) and astrocytes, glial fibrillary acidic protein (GFAP) in both the cortex and hippocampus of the adult rat brain. Furthermore, we also observed that LiCl treatment significantly ameliorated the increase expression level of apoptotic neurodegeneration protein markers Bax/Bcl2, activated caspase-3 and poly (ADP-ribose) polymerase-1 (PARP-1) in the cortex and hippocampus regions of the LPS-treated adult rat brain. In addition, the morphological results of the fluoro-jade B (FJB) and Nissl staining showed that LiCl attenuated the neuronal degeneration in the cortex and hippocampus regions of the LPS-treated adult rat brain. Taken together, our Western blot and morphological results indicated that LiCl significantly prevents the LPS-induced neurotoxicity via attenuation of neuroinflammation and apoptotic neurodegeneration in the cortex and hippocampus of the adult rat brain. Copyright © 2017 Elsevier Ltd. All rights reserved.

[The predictive value of plasma B-type natriuretic peptide levels on outcome in children with pulmonary hypertension undergoing congenital heart surgery].

PubMed

Baysal, Ayse; Saşmazel, Ahmet; Yildirim, Ayse; Ozyaprak, Buket; Gundogus, Narin; Kocak, Tuncer

2014-01-01

In children undergoing congenital heart surgery, plasma brain natriuretic peptide levels may have a role in development of low cardiac output syndrome that is defined as a combination of clinical findings and interventions to augment cardiac output in children with pulmonary hypertension. In a prospective observational study, fifty-one children undergoing congenital heart surgery with preoperative echocardiographic study showing pulmonary hypertension were enrolled. The plasma brain natriuretic peptide levels were collected before operation, 12, 24 and 48h after operation. The patients enrolled into the study were divided into two groups depending on: (1) Development of LCOS which is defined as a combination of clinical findings or interventions to augment cardiac output postoperatively; (2) Determination of preoperative brain natriuretic peptide cut-off value by receiver operating curve analysis for low cardiac output syndrome. The secondary end points were: (1) duration of mechanical ventilation ≥72h, (2) intensive care unit stay >7days, and (3) mortality. The differences in preoperative and postoperative brain natriuretic peptide levels of patients with or without low cardiac output syndrome (n=35, n=16, respectively) showed significant differences in repeated measurement time points (p=0.0001). The preoperative brain natriuretic peptide cut-off value of 125.5pgmL-1 was found to have the highest sensitivity of 88.9% and specificity of 96.9% in predicting low cardiac output syndrome in patients with pulmonary hypertension. A good correlation was found between preoperative plasma brain natriuretic peptide level and duration of mechanical ventilation (r=0.67, p=0.0001). In patients with pulmonary hypertension undergoing congenital heart surgery, 91% of patients with preoperative plasma brain natriuretic peptide levels above 125.5pgmL-1 are at risk of developing low cardiac output syndrome which is an important postoperative outcome. Copyright © 2013 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

Peptides released by ameboid microglia regulate astroglial proliferation

PubMed Central

1985-01-01

Peptides that stimulate astroglial proliferation are produced in traumatized adult rat brain by 10 d after injury. These same peptides are released by ameboid microglia activated in vitro. Our findings suggest that astroglial scarring is regulated in part by the release of factors from ameboid microglia near the site of brain injury. PMID:4066764

Carnosine reverses the aging-induced down regulation of brain regional serotonergic system.

PubMed

Banerjee, Soumyabrata; Ghosh, Tushar K; Poddar, Mrinal K

2015-12-01

The purpose of the present investigation was to study the role of carnosine, an endogenous dipeptide biomolecule, on brain regional (cerebral cortex, hippocampus, hypothalamus and pons-medulla) serotonergic system during aging. Results showed an aging-induced brain region specific significant (a) increase in Trp (except cerebral cortex) and their 5-HIAA steady state level with an increase in their 5-HIAA accumulation and declination, (b) decrease in their both 5-HT steady state level and 5-HT accumulation (except cerebral cortex). A significant decrease in brain regional 5-HT/Trp ratio (except cerebral cortex) and increase in 5-HIAA/5-HT ratio were also observed during aging. Carnosine at lower dosages (0.5-1.0μg/Kg/day, i.t. for 21 consecutive days) didn't produce any significant response in any of the brain regions, but higher dosages (2.0-2.5μg/Kg/day, i.t. for 21 consecutive days) showed a significant response on those aging-induced brain regional serotonergic parameters. The treatment with carnosine (2.0μg/Kg/day, i.t. for 21 consecutive days), attenuated these brain regional aging-induced serotonergic parameters and restored towards their basal levels that observed in 4 months young control rats. These results suggest that carnosine attenuates and restores the aging-induced brain regional down regulation of serotonergic system towards that observed in young rats' brain regions. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Lipopolysaccharides upregulate hepcidin in neuron via microglia and the IL-6/STAT3 signaling pathway.

PubMed

Qian, Zhong-Ming; He, Xuan; Liang, Tuo; Wu, Ka-Chun; Yan, Yik-Chun; Lu, Li-Na; Yang, Guang; Luo, Qian Qian; Yung, Wing-Ho; Ke, Ya

2014-12-01

Neuroinflammation is closely related to brain iron homeostasis. Our previous study demonstrated that lipopolysaccharides (LPS) can regulate expression of iron-regulatory peptide hepcidin; however, the mechanism is undefined. Here, we demonstrated that intracerebroventricular injection of LPS in rat brain upregulated hepcidin and downregulated ferroportin 1 in the cortex and substantia nigra. LPS increased hepcidin expression in neurons only when they were co-cultured with BV-2 microglia, and the upregulation was suppressed by IL-6 neutralizing antibody in vitro. In addition, IL-6 but not IL-1α, IL-1β, or tumor necrosis factor-alpha increased hepcidin expression and signal transducer and activator of transcription 3 (STAT3) phosphorylation in cortical neurons and MES23.5 dopaminergic neurons. These effects were blocked by the STAT3 inhibitor, stattic. Our results show that neurons are the major source of increased hepcidin expression in response to LPS challenge but microglia play a key mediator role by releasing IL-6 and recruiting the STAT3 pathway. We conclude that LPS upregulates hepcidin expression in neurons via microglia and the IL-6/STAT3 signaling pathway.

Neurobiology of the aging dog.

PubMed

Head, Elizabeth

2011-09-01

Aged canines naturally accumulate several types of neuropathology that may have links to cognitive decline. On a gross level, significant cortical atrophy occurs with age along with an increase in ventricular volume based on magnetic resonance imaging studies. Microscopically, there is evidence of select neuron loss and reduced neurogenesis in the hippocampus of aged dogs, an area critical for intact learning and memory. The cause of neuronal loss and dysfunction may be related to the progressive accumulation of toxic proteins, oxidative damage, cerebrovascular pathology, and changes in gene expression. For example, aged dogs naturally accumulate human-type beta-amyloid peptide, a protein critically involved with the development of Alzheimer's disease in humans. Further, oxidative damage to proteins, DNA/RNA and lipids occurs with age in dogs. Although less well explored in the aged canine brain, neuron loss, and cerebrovascular pathology observed with age are similar to human brain aging and may also be linked to cognitive decline. Interestingly, the prefrontal cortex appears to be particularly vulnerable early in the aging process in dogs and this may be reflected in dysfunction in specific cognitive domains with age.

Developmental synchrony of thalamocortical circuits in the neonatal brain.

PubMed

Poh, Joann S; Li, Yue; Ratnarajah, Nagulan; Fortier, Marielle V; Chong, Yap-Seng; Kwek, Kenneth; Saw, Seang-Mei; Gluckman, Peter D; Meaney, Michael J; Qiu, Anqi

2015-08-01

The thalamus is a deep gray matter structure and consists of axonal fibers projecting to the entire cortex, which provide the anatomical support for its sensorimotor and higher-level cognitive functions. There is limited in vivo evidence on the normal thalamocortical development, especially in early life. In this study, we aimed to investigate the developmental patterns of the cerebral cortex, the thalamic substructures, and their connectivity with the cortex in the first few weeks of the postnatal brain. We hypothesized that there is developmental synchrony of the thalamus, its cortical projections, and corresponding target cortical structures. We employed diffusion tensor imaging (DTI) and divided the thalamus into five substructures respectively connecting to the frontal, precentral, postcentral, temporal, and parietal and occipital cortex. T2-weighted magnetic resonance imaging (MRI) was used to measure cortical thickness. We found age-related increases in cortical thickness of bilateral frontal cortex and left temporal cortex in the early postnatal brain. We also found that the development of the thalamic substructures was synchronized with that of their respective thalamocortical connectivity in the first few weeks of the postnatal life. In particular, the right thalamo-frontal substructure had the fastest growth in the early postnatal brain. Our study suggests that the distinct growth patterns of the thalamic substructures are in synchrony with those of the cortex in early life, which may be critical for the development of the cortical and subcortical functional specialization. Copyright © 2015 Elsevier Inc. All rights reserved.

Dorsomedial prefontal cortex supports spontaneous thinking per se.

PubMed

Raij, T T; Riekki, T J J

2017-06-01

Spontaneous thinking, an action to produce, consider, integrate, and reason through mental representations, is central to our daily experience and has been suggested to serve crucial adaptive purposes. Such thinking occurs among other experiences during mind wandering that is associated with activation of the default mode network among other brain circuitries. Whether and how such brain activation is linked to the experience of spontaneous thinking per se remains poorly known. We studied 51 healthy subjects using a comprehensive experience-sampling paradigm during 3T functional magnetic resonance imaging. In comparison with fixation, the experiences of spontaneous thinking and spontaneous perception were related to activation of wide-spread brain circuitries, including the cortical midline structures, the anterior cingulate cortex and the visual cortex. In direct comparison of the spontaneous thinking versus spontaneous perception, activation was observed in the anterior dorsomedial prefrontal cortex. Modality congruence of spontaneous-experience-related brain activation was suggested by several findings, including association of the lingual gyrus with visual in comparison with non-verbal-non-visual thinking. In the context of current literature, these findings suggest that the cortical midline structures are involved in the integrative core substrate of spontaneous thinking that is coupled with other brain systems depending on the characteristics of thinking. Furthermore, involvement of the anterior dorsomedial prefrontal cortex suggests the control of high-order abstract functions to characterize spontaneous thinking per se. Hum Brain Mapp 38:3277-3288, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Mercury, selenium and neurochemical biomarkers in different brain regions of migrating common loons from Lake Erie, Canada.

PubMed

Hamilton, Melanie; Scheuhammer, Anton; Basu, Niladri

2011-10-01

Common loons (Gavia immer) can be exposed to relatively high levels of dietary methylmercury (MeHg) through fish consumption, and several studies have documented MeHg-associated health effects in this species. To further study the neurological risks of MeHg accumulation, migrating loons dying of Type E botulism were collected opportunistically from the Lake Erie shore at Long Point (Ontario, Canada) and relationships between total mercury (THg), selenium (Se), and selected neurochemical receptors and brain enzymes were investigated. THg concentrations were 1-78 μg/g in liver; and 0.3-4 μg/g in the brain (all concentrations reported on a dry weight basis). A significant (p < 0.05) positive correlation was found between THg in liver and THg in 3 subregions of the brain (cerebral cortex: r = 0.433; cerebellum: r = 0.293; brain stem: r = 0.405). THg varied significantly among different brain regions, with the cortex having the highest concentrations. Se levels in the cortex and cerebellum were 1-29 and 1-10 μg/g, respectively, with no significant differences between regions. Se was not measured in brain stem due to insufficient tissue mass. There were molar excesses of Se over mercury (Hg) in both cortex and cerebellum at all Hg concentrations, and a significant positive relationship between THg and the Hg:Se molar ratio (cortex: r = 0.63; cerebellum: r = 0.47). No significant associations were observed between brain THg and the N-methyl-D-aspartic acid (NMDA) receptor concentration, nor between THg and muscarinic cholinergic (mACh) receptor concentration; however, brain THg levels were lower than in previous studies that reported significant Hg-associated changes in neuroreceptor densities. Together with previous studies, the current findings add to our understanding of Hg distribution in the brain of common loons, and the associations between Hg and sub-lethal neurochemical changes in fish-eating wildlife.

Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide.

PubMed

Youssef, Mariam M; Underwood, Mark D; Huang, Yung-Yu; Hsiung, Shu-Chi; Liu, Yan; Simpson, Norman R; Bakalian, Mihran J; Rosoklija, Gorazd B; Dwork, Andrew J; Arango, Victoria; Mann, J John

2018-06-01

Brain-derived neurotrophic factor is implicated in the pathophysiology of major depressive disorder and suicide. Both are partly caused by early life adversity, which reduces brain-derived neurotrophic factor protein levels. This study examines the association of brain-derived neurotrophic factor Val66Met polymorphism and brain brain-derived neurotrophic factor levels with depression and suicide. We hypothesized that both major depressive disorder and early life adversity would be associated with the Met allele and lower brain brain-derived neurotrophic factor levels. Such an association would be consistent with low brain-derived neurotrophic factor mediating the effect of early life adversity on adulthood suicide and major depressive disorder. Brain-derived neurotrophic factor Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 nonsuicides. Additionally, brain-derived neurotrophic factor protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9), anterior cingulate cortex (Brodmann area 24), caudal brainstem, and rostral brainstem. The relationships between these measures and major depressive disorder, death by suicide, and reported early life adversity were examined. Subjects with the Met allele had an increased risk for depression. Depressed patients also have lower brain-derived neurotrophic factor levels in anterior cingulate cortex and caudal brainstem compared with nondepressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower brain-derived neurotrophic factor levels in the anterior cingulate cortex were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported early life adversity. This study provides further evidence implicating low brain brain-derived neurotrophic factor and the brain-derived neurotrophic factor Met allele in major depression risk. Future studies should seek to determine how altered brain-derived neurotrophic factor expression contributes to depression and suicide.

Upregulation of Neurotrophic Factors Selectively in Frontal Cortex in Response to Olfactory Discrimination Learning

PubMed Central

Naimark, Ari; Barkai, Edi; Matar, Michael A.; Kaplan, Zeev; Kozlovsky, Nitzan; Cohen, Hagit

2007-01-01

We have previously shown that olfactory discrimination learning is accompanied by several forms of long-term enhancement in synaptic connections between layer II pyramidal neurons selectively in the piriform cortex. This study sought to examine whether the previously demonstrated olfactory-learning-task-induced modifications are preceded by suitable changes in the expression of mRNA for neurotrophic factors and in which brain areas this occurs. Rats were trained to discriminate positive cues in pair of odors for a water reward. The relationship between the learning task and local levels of mRNA for brain-derived neurotrophic factor, tyrosine kinase B, nerve growth factor, and neurotrophin-3 in the frontal cortex, hippocampal subregions, and other regions were assessed 24 hours post olfactory learning. The olfactory discrimination learning activated production of endogenous neurotrophic factors and induced their signal transduction in the frontal cortex, but not in other brain areas. These findings suggest that different brain areas may be preferentially involved in different learning/memory tasks. PMID:17710248

The brain map of gait variability in aging, cognitive impairment and dementia. A systematic review

PubMed Central

Tian, Qu; Chastan, Nathalie; Bair, Woei-Nan; Resnick, Susan M.; Ferrucci, Luigi; Studenski, Stephanie A.

2017-01-01

While gait variability may reflect subtle changes due to aging or cognitive impairment (CI), associated brain characteristics remain unclear. We summarize structural and functional neuroimaging findings associated with gait variability in older adults with and without CI and dementia. We identified 17 eligible studies; all were cross-sectional; few examined multiple brain areas. In older adults, temporal gait variability was associated with structural differences in medial areas important for lower limb coordination and balance. Both temporal and spatial gait variability were associated with structural and functional differences in hippocampus and primary sensorimotor cortex and structural differences in anterior cingulate cortex, basal ganglia, association tracts, and posterior thalamic radiation. In CI or dementia, some associations were found in primary motor cortex, hippocampus, prefrontal cortex and basal ganglia. In older adults, gait variability may be associated with areas important for sensorimotor integration and coordination. To comprehend the neural basis of gait variability with aging and CI, longitudinal studies of multiple brain areas are needed. PMID:28115194

Neurobiological actions of cysteamine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, M.; Fisher, L.; Mason, R.T.

1985-06-01

Somatostatin (SS)-related peptides act within discrete brain regions to inhibit adrenal epinephrine (E) secretion, to prevent hypothermia, and to produce hyperthermia. Depletion of brain concentrations of these SS-related peptides using cysteamine (CSH) or central administration of an SS receptor antagonist increases adrenal E secretion and impairs thermoregulation. These actions of CSH and the SS receptor antagonist are reversed by administration of SS into the central nervous system. These results support the hypothesis that endogenous brain SS-related peptides are involved in the regulation of adrenal E secretion and thermoregulation.

Cancer 'survivor-care': II. Disruption of prefrontal brain activation top-down control of working memory capacity as possible mechanism for chemo-fog/brain (chemotherapy-associated cognitive impairment).

PubMed

Raffa, R B

2013-08-01

Cancer chemotherapy-associated cognitive impairments (termed 'chemo-fog' or 'chemo-brain'), particularly in memory, have been self-reported or identified in cancer survivors previously treated with chemotherapy. Although a variety of deficits have been detected, a consistent theme is a detriment in visuospatial working memory. The parietal cortex, a major site of storage of such memory, is implicated in chemotherapy-induced damage. However, if the findings of two recent publications are combined, the (pre)frontal cortex might be an equally viable target. Two recent studies, one postulating a mechanism for 'top-down control' of working memory capacity and another visualizing chemotherapy-induced alterations in brain activation during working memory processing, are reviewed and integrated. A computational model and the proposal that the prefrontal cortex plays a role in working memory via top-down control of parietal working memory capacity is consistent with a recent demonstration of decreased frontal hyperactivation following chemotherapy. Chemotherapy-associated impairment of visuospatial working memory might include the (pre)frontal cortex in addition to the parietal cortex. This provides new opportunity for basic science and clinical investigation. © 2013 John Wiley & Sons Ltd.

Structural characterization of osmoregulator peptides from the brain of the leech Theromyzon tessulatum: IPEPYVWD and IPEPYVWD-amide.

PubMed

Salzet, M; Vandenbulcke, F; Verger-Bocquet, M

1996-12-31

Neurons immunoreactive to an antiserum (a-OT) directed specifically against the C-terminal part (prolyl-leucyl-glycinamide) of vertebrate oxytocin (OT) were detected in the brain of the leech Theromyzon tessulatum. With high pressure gel permeation chromatography followed by reversed-phase HPLC on brain extracts, evidence was given of the presence of three peptides (P1, P2, P3) immunoreactive to a-OT. Results of injection experiments in T. tessulatum and of titrations of each peptide at the different physiological stages of the animals which showed a peak in peptide P1 amount at stage 3B, indicated that P1 is the active OT-like peptide. Using three steps of reversed-phase HPLC, Edman degradation and electrospray mass spectrometry, two sequences for P1 (IPEPYVWD and IPEPYVWD-amide) were found. These peptides differ from peptides to the oxytocin/vasopressin family and are unique in the animal kingdom. Confirmation of their action on the hydric balance and their distribution in the CNS were presented.

The hunt for brain Aβ oligomers by peripherally circulating multi-functional nanoparticles: Potential therapeutic approach for Alzheimer disease.

PubMed

Mancini, Simona; Minniti, Stefania; Gregori, Maria; Sancini, Giulio; Cagnotto, Alfredo; Couraud, Pierre-Olivier; Ordóñez-Gutiérrez, Lara; Wandosell, Francisco; Salmona, Mario; Re, Francesca

2016-01-01

We previously showed the ability of liposomes bi-functionalized with phosphatidic acid and an ApoE-derived peptide (mApoE-PA-LIP) to reduce brain Aβ in transgenic Alzheimer mice. Herein we investigated the efficacy of mApoE-PA-LIP to withdraw Aβ peptide in different aggregation forms from the brain, using a transwell cellular model of the blood-brain barrier and APP/PS1 mice. The spontaneous efflux of Aβ oligomers (Aβo), but not of Aβ fibrils, from the 'brain' side of the transwell was strongly enhanced (5-fold) in presence of mApoE-PA-LIP in the 'blood' compartment. This effect is due to a withdrawal of Aβo exerted by peripheral mApoE-PA-LIP by sink effect, because, when present in the brain side, they did not act as Aβo carrier and limit the oligomer efflux. In vivo peripheral administration of mApoE-PA-LIP significantly increased the plasma Aβ level, suggesting that Aβ-binding particles exploiting the sink effect can be used as a therapeutic strategy for Alzheimer disease. From the Clinical Editor: Alzheimer disease (AD) at present is an incurable disease, which is thought to be caused by an accumulation of amyloid-β (Aβ) peptides in the brain. Many strategies in combating this disease have been focused on either the prevention or dissolving these peptides. In this article, the authors showed the ability of liposomes bi-functionalized with phosphatidic acid and with an ApoE- derived peptide to withdraw amyloid peptides from the brain. The data would help the future design of more novel treatment for Alzheimer disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Medial reward and lateral non-reward orbitofrontal cortex circuits change in opposite directions in depression.

PubMed

Cheng, Wei; Rolls, Edmund T; Qiu, Jiang; Liu, Wei; Tang, Yanqing; Huang, Chu-Chung; Wang, XinFa; Zhang, Jie; Lin, Wei; Zheng, Lirong; Pu, JunCai; Tsai, Shih-Jen; Yang, Albert C; Lin, Ching-Po; Wang, Fei; Xie, Peng; Feng, Jianfeng

2016-12-01

The first brain-wide voxel-level resting state functional connectivity neuroimaging analysis of depression is reported, with 421 patients with major depressive disorder and 488 control subjects. Resting state functional connectivity between different voxels reflects correlations of activity between those voxels and is a fundamental tool in helping to understand the brain regions with altered connectivity and function in depression. One major circuit with altered functional connectivity involved the medial orbitofrontal cortex Brodmann area 13, which is implicated in reward, and which had reduced functional connectivity in depression with memory systems in the parahippocampal gyrus and medial temporal lobe, especially involving the perirhinal cortex Brodmann area 36 and entorhinal cortex Brodmann area 28. The Hamilton Depression Rating Scale scores were correlated with weakened functional connectivity of the medial orbitofrontal cortex Brodmann area 13. Thus in depression there is decreased reward-related and memory system functional connectivity, and this is related to the depressed symptoms. The lateral orbitofrontal cortex Brodmann area 47/12, involved in non-reward and punishing events, did not have this reduced functional connectivity with memory systems. Second, the lateral orbitofrontal cortex Brodmann area 47/12 had increased functional connectivity with the precuneus, the angular gyrus, and the temporal visual cortex Brodmann area 21. This enhanced functional connectivity of the non-reward/punishment system (Brodmann area 47/12) with the precuneus (involved in the sense of self and agency), and the angular gyrus (involved in language) is thus related to the explicit affectively negative sense of the self, and of self-esteem, in depression. A comparison of the functional connectivity in 185 depressed patients not receiving medication and 182 patients receiving medication showed that the functional connectivity of the lateral orbitofrontal cortex Brodmann area 47/12 with these three brain areas was lower in the medicated than the unmedicated patients. This is consistent with the hypothesis that the increased functional connectivity of the lateral orbitofrontal cortex Brodmann area 47/12 is related to depression. Relating the changes in cortical connectivity to our understanding of the functions of different parts of the orbitofrontal cortex in emotion helps to provide new insight into the brain changes related to depression. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Screening of quorum sensing peptides for biological effects in neuronal cells.

PubMed

Janssens, Yorick; Wynendaele, Evelien; Verbeke, Frederick; Debunne, Nathan; Gevaert, Bert; Audenaert, Kurt; Van DeWiele, Christophe; De Spiegeleer, Bart

2018-03-01

Quorum sensing peptides (QSP) are an important class of bacterial peptides which can have an effect on human host cells. These peptides are used by bacteria to communicate with each other. Some QSP are able to cross the blood-brain barrier and reach the brain parenchyma. However, nothing is known about the effects of these peptides in the brain. Therefore, 85 quorum sensing peptides were screened on six different neuronal cell lines using MTT toxicity, neurite differentiation, cytokine production and morphology as biological outcomes. This primary screening resulted in 22 peptides with effects observed on neuronal cell lines, indicating a possible role in the gut-brain axis. Four peptides (Q138, Q143, Q180 and Q212) showed induction of neurite outgrowth while two peptides (Q162 and Q208) inhibited NGF-induced neurite outgrowth in PC12 cells. Eight peptides (Q25, Q135, Q137, Q146, Q151, Q165, Q208 and Q298) induced neurite outgrowth in human SH-SY5Y neuroblastoma cells. Two peptides (Q13 and Q52) were toxic for SH-SY5Y cells and one (Q123) for BV-2 microglia cells based on the MTT assay. Six peptides had an effect on BV-2 microglia, Q180, Q184 and Q191 were able to induce IL-6 expression and Q164, Q192 and Q208 induced NO production. Finally, Q75 and Q147 treated C8D1A astrocytes demonstrated a higher fraction of round cells. Overall, these in vitro screening study results indicate for the first time possible effects of QSP on neuronal cells. Copyright © 2018 Elsevier Inc. All rights reserved.

Structural brain correlates of unconstrained motor activity in people with schizophrenia.

PubMed

Farrow, Tom F D; Hunter, Michael D; Wilkinson, Iain D; Green, Russell D J; Spence, Sean A

2005-11-01

Avolition affects quality of life in chronic schizophrenia. We investigated the relationship between unconstrained motor activity and the volume of key executive brain regions in 16 male patients with schizophrenia. Wristworn actigraphy monitors were used to record motor activity over a 20 h period. Structural magnetic resonance imaging brain scans were parcellated and individual volumes for anterior cingulate cortex and dorsolateral prefrontal cortex extracted. Patients'total activity was positively correlated with volume of left anterior cingulate cortex. These data suggest that the volume of specific executive structures may affect (quantifiable) motor behaviours, having further implications for models of the 'will' and avolition.

Self-assembled cationic peptide nanoparticles as an efficient antimicrobial agent

NASA Astrophysics Data System (ADS)

Liu, Lihong; Xu, Kaijin; Wang, Huaying; Jeremy Tan, P. K.; Fan, Weimin; Venkatraman, Subbu S.; Li, Lanjuan; Yang, Yi-Yan

2009-07-01

Antimicrobial cationic peptides are of interest because they can combat multi-drug-resistant microbes. Most peptides form α-helices or β-sheet-like structures that can insert into and subsequently disintegrate negatively charged bacterial cell surfaces. Here, we show that a novel class of core-shell nanoparticles formed by self-assembly of an amphiphilic peptide have strong antimicrobial properties against a range of bacteria, yeasts and fungi. The nanoparticles show a high therapeutic index against Staphylococcus aureus infection in mice and are more potent than their unassembled peptide counterparts. Using Staphylococcus aureus-infected meningitis rabbits, we show that the nanoparticles can cross the blood-brain barrier and suppress bacterial growth in infected brains. Taken together, these nanoparticles are promising antimicrobial agents that can be used to treat brain infections and other infectious diseases.

Different forms of effective connectivity in primate frontotemporal pathways.

PubMed

Petkov, Christopher I; Kikuchi, Yukiko; Milne, Alice E; Mishkin, Mortimer; Rauschecker, Josef P; Logothetis, Nikos K

2015-01-23

It is generally held that non-primary sensory regions of the brain have a strong impact on frontal cortex. However, the effective connectivity of pathways to frontal cortex is poorly understood. Here we microstimulate sites in the superior temporal and ventral frontal cortex of monkeys and use functional magnetic resonance imaging to evaluate the functional activity resulting from the stimulation of interconnected regions. Surprisingly, we find that, although certain earlier stages of auditory cortical processing can strongly activate frontal cortex, downstream auditory regions, such as voice-sensitive cortex, appear to functionally engage primarily an ipsilateral temporal lobe network. Stimulating other sites within this activated temporal lobe network shows strong activation of frontal cortex. The results indicate that the relative stage of sensory processing does not predict the level of functional access to the frontal lobes. Rather, certain brain regions engage local networks, only parts of which have a strong functional impact on frontal cortex.

Different forms of effective connectivity in primate frontotemporal pathways

PubMed Central

Petkov, Christopher I.; Kikuchi, Yukiko; Milne, Alice E.; Mishkin, Mortimer; Rauschecker, Josef P.; Logothetis, Nikos K.

2015-01-01

It is generally held that non-primary sensory regions of the brain have a strong impact on frontal cortex. However, the effective connectivity of pathways to frontal cortex is poorly understood. Here we microstimulate sites in the superior temporal and ventral frontal cortex of monkeys and use functional magnetic resonance imaging to evaluate the functional activity resulting from the stimulation of interconnected regions. Surprisingly, we find that, although certain earlier stages of auditory cortical processing can strongly activate frontal cortex, downstream auditory regions, such as voice-sensitive cortex, appear to functionally engage primarily an ipsilateral temporal lobe network. Stimulating other sites within this activated temporal lobe network shows strong activation of frontal cortex. The results indicate that the relative stage of sensory processing does not predict the level of functional access to the frontal lobes. Rather, certain brain regions engage local networks, only parts of which have a strong functional impact on frontal cortex. PMID:25613079

The Peptide Vaccine Combined with Prior Immunization of a Conventional Diphtheria-Tetanus Toxoid Vaccine Induced Amyloid β Binding Antibodies on Cynomolgus Monkeys and Guinea Pigs

PubMed Central

Yano, Akira; Ito, Kaori; Miwa, Yoshikatsu; Kanazawa, Yoshito; Chiba, Akiko; Iigo, Yutaka; Kashimoto, Yoshinori; Kanda, Akira; Murata, Shinji; Makino, Mitsuhiro

2015-01-01

The reduction of brain amyloid beta (Aβ) peptides by anti-Aβ antibodies is one of the possible therapies for Alzheimer's disease. We previously reported that the Aβ peptide vaccine including the T-cell epitope of diphtheria-tetanus combined toxoid (DT) induced anti-Aβ antibodies, and the prior immunization with conventional DT vaccine enhanced the immunogenicity of the peptide. Cynomolgus monkeys were given the peptide vaccine subcutaneously in combination with the prior DT vaccination. Vaccination with a similar regimen was also performed on guinea pigs. The peptide vaccine induced anti-Aβ antibodies in cynomolgus monkeys and guinea pigs without chemical adjuvants, and excessive immune responses were not observed. Those antibodies could preferentially recognize Aβ 40, and Aβ 42 compared to Aβ fibrils. The levels of serum anti-Aβ antibodies and plasma Aβ peptides increased in both animals and decreased the brain Aβ 40 level of guinea pigs. The peptide vaccine could induce a similar binding profile of anti-Aβ antibodies in cynomolgus monkeys and guinea pigs. The peptide vaccination could be expected to reduce the brain Aβ peptides and their toxic effects via clearance of Aβ peptides by generated antibodies. PMID:26539559

Glucagon-related peptides and the regulation of food intake in chickens.

PubMed

Honda, Kazuhisa

2016-09-01

The regulatory mechanisms underlying food intake in chickens have been a focus of research in recent decades to improve production efficiency when raising chickens. Lines of evidence have revealed that a number of brain-gut peptides function as a neurotransmitter or peripheral satiety hormone in the regulation of food intake both in mammals and chickens. Glucagon, a 29 amino acid peptide hormone, has long been known to play important roles in maintaining glucose homeostasis in mammals and birds. However, the glucagon gene encodes various peptides that are produced by tissue-specific proglucagon processing: glucagon is produced in the pancreas, whereas oxyntomodulin (OXM), glucagon-like peptide (GLP)-1 and GLP-2 are produced in the intestine and brain. Better understanding of the roles of these peptides in the regulation of energy homeostasis has led to various physiological roles being proposed in mammals. For example, GLP-1 functions as an anorexigenic neurotransmitter in the brain and as a postprandial satiety hormone in the peripheral circulation. There is evidence that OXM and GLP-2 also induce anorexia in mammals. Therefore, it is possible that the brain-gut peptides OXM, GLP-1 and GLP-2 play physiological roles in the regulation of food intake in chickens. More recently, a novel GLP and its specific receptor were identified in the chicken brain. This review summarizes current knowledge about the role of glucagon-related peptides in the regulation of food intake in chickens. © 2016 The Authors. Animal Science Journal published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Animal Science.

Brain abnormalities in antisocial individuals: implications for the law.

PubMed

Yang, Yaling; Glenn, Andrea L; Raine, Adrian

2008-01-01

With the increasing popularity in the use of brain imaging on antisocial individuals, an increasing number of brain imaging studies have revealed structural and functional impairments in antisocial, psychopathic, and violent individuals. This review summarizes key findings from brain imaging studies on antisocial/aggressive behavior. Key regions commonly found to be impaired in antisocial populations include the prefrontal cortex (particularly orbitofrontal and dorsolateral prefrontal cortex), superior temporal gyrus, amygdala-hippocampal complex, and anterior cingulate cortex. Key functions of these regions are reviewed to provide a better understanding on how deficits in these regions may predispose to antisocial behavior. Objections to the use of imaging findings in a legal context are outlined, and alternative perspectives raised. It is argued that brain dysfunction is a risk factor for antisocial behavior and that it is likely that imaging will play an increasing (albeit limited) role in legal decision-making. (c) 2008 John Wiley & Sons, Ltd.

Neural connectivity of the lateral geniculate body in the human brain: diffusion tensor imaging study.

PubMed

Kwon, Hyeok Gyu; Jang, Sung Ho

2014-08-22

A few studies have reported on the neural connectivity of some neural structures of the visual system in the human brain. However, little is known about the neural connectivity of the lateral geniculate body (LGB). In the current study, using diffusion tensor tractography (DTT), we attempted to investigate the neural connectivity of the LGB in normal subjects. A total of 52 healthy subjects were recruited for this study. A seed region of interest was placed on the LGB using the FMRIB Software Library which is a probabilistic tractography method based on a multi-fiber model. Connectivity was defined as the incidence of connection between the LGB and target brain areas at the threshold of 5, 25, and 50 streamlines. In addition, connectivity represented the percentage of connection in all hemispheres of 52 subjects. We found the following characteristics of connectivity of the LGB at the threshold of 5 streamline: (1) high connectivity to the corpus callosum (91.3%) and the contralateral temporal cortex (56.7%) via the corpus callosum, (2) high connectivity to the ipsilateral cerebral cortex: the temporal lobe (100%), primary visual cortex (95.2%), and visual association cortex (77.9%). The LGB appeared to have high connectivity to the corpus callosum and both temporal cortexes as well as the ipsilateral occipital cortex. We believe that the results of this study would be helpful in investigation of the neural network associated with the visual system and brain plasticity of the visual system after brain injury. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

From motor cortex to visual cortex: the application of noninvasive brain stimulation to amblyopia.

PubMed

Thompson, Benjamin; Mansouri, Behzad; Koski, Lisa; Hess, Robert F

2012-04-01

Noninvasive brain stimulation is a technique for inducing changes in the excitability of discrete neural populations in the human brain. A current model of the underlying pathological processes contributing to the loss of motor function after stroke has motivated a number of research groups to investigate the potential therapeutic application of brain stimulation to stroke rehabilitation. The loss of motor function is modeled as resulting from a combination of reduced excitability in the lesioned motor cortex and an increased inhibitory drive from the nonlesioned hemisphere over the lesioned hemisphere. This combination of impaired neural function and pathological suppression resonates with current views on the cause of the visual impairment in amblyopia. Here, we discuss how the rationale for using noninvasive brain stimulation in stroke rehabilitation can be applied to amblyopia, review a proof-of-principle study demonstrating that brain stimulation can temporarily improve amblyopic eye function, and propose future research avenues. Copyright © 2010 Wiley Periodicals, Inc.

Laterality patterns of brain functional connectivity: gender effects.

PubMed

Tomasi, Dardo; Volkow, Nora D

2012-06-01

Lateralization of brain connectivity may be essential for normal brain function and may be sexually dimorphic. Here, we study the laterality patterns of short-range (implicated in functional specialization) and long-range (implicated in functional integration) connectivity and the gender effects on these laterality patterns. Parallel computing was used to quantify short- and long-range functional connectivity densities in 913 healthy subjects. Short-range connectivity was rightward lateralized and most asymmetrical in areas around the lateral sulcus, whereas long-range connectivity was rightward lateralized in lateral sulcus and leftward lateralizated in inferior prefrontal cortex and angular gyrus. The posterior inferior occipital cortex was leftward lateralized (short- and long-range connectivity). Males had greater rightward lateralization of brain connectivity in superior temporal (short- and long-range), inferior frontal, and inferior occipital cortices (short-range), whereas females had greater leftward lateralization of long-range connectivity in the inferior frontal cortex. The greater lateralization of the male's brain (rightward and predominantly short-range) may underlie their greater vulnerability to disorders with disrupted brain asymmetries (schizophrenia, autism).

Laterality Patterns of Brain Functional Connectivity: Gender Effects

PubMed Central

Tomasi, Dardo; Volkow, Nora D.

2012-01-01

Lateralization of brain connectivity may be essential for normal brain function and may be sexually dimorphic. Here, we study the laterality patterns of short-range (implicated in functional specialization) and long-range (implicated in functional integration) connectivity and the gender effects on these laterality patterns. Parallel computing was used to quantify short- and long-range functional connectivity densities in 913 healthy subjects. Short-range connectivity was rightward lateralized and most asymmetrical in areas around the lateral sulcus, whereas long-range connectivity was rightward lateralized in lateral sulcus and leftward lateralizated in inferior prefrontal cortex and angular gyrus. The posterior inferior occipital cortex was leftward lateralized (short- and long-range connectivity). Males had greater rightward lateralization of brain connectivity in superior temporal (short- and long-range), inferior frontal, and inferior occipital cortices (short-range), whereas females had greater leftward lateralization of long-range connectivity in the inferior frontal cortex. The greater lateralization of the male's brain (rightward and predominantly short-range) may underlie their greater vulnerability to disorders with disrupted brain asymmetries (schizophrenia, autism). PMID:21878483

The timing of language learning shapes brain structure associated with articulation.

PubMed

Berken, Jonathan A; Gracco, Vincent L; Chen, Jen-Kai; Klein, Denise

2016-09-01

We compared the brain structure of highly proficient simultaneous (two languages from birth) and sequential (second language after age 5) bilinguals, who differed only in their degree of native-like accent, to determine how the brain develops when a skill is acquired from birth versus later in life. For the simultaneous bilinguals, gray matter density was increased in the left putamen, as well as in the left posterior insula, right dorsolateral prefrontal cortex, and left and right occipital cortex. For the sequential bilinguals, gray matter density was increased in the bilateral premotor cortex. Sequential bilinguals with better accents also showed greater gray matter density in the left putamen, and in several additional brain regions important for sensorimotor integration and speech-motor control. Our findings suggest that second language learning results in enhanced brain structure of specific brain areas, which depends on whether two languages are learned simultaneously or sequentially, and on the extent to which native-like proficiency is acquired.

Hemispherical map for the human brain cortex

NASA Astrophysics Data System (ADS)

Tosun, Duygu; Prince, Jerry L.

2001-07-01

Understanding the function of the human brain cortex is a primary goal in human brain mapping. Methods to unfold and flatten the cortical surface for visualization and measurement have been described in previous literature; but comparison across multiple subjects is still difficult because of the lack of a standard mapping technique. We describe a new approach that maps each hemisphere of the cortex to a portion of a sphere in a standard way, making comparison of anatomy and function across different subjects possible. Starting with a three-dimensional magnetic resonance image of the brain, the cortex is segmented and represented as a triangle mesh. Defining a cut around the corpus collosum identifies the left and right hemispheres. Together, the two hemispheres are mapped to the complex plane using a conformal mapping technique. A Mobius transformation, which is conformal, is used to transform the points on the complex plane so that a projective transformation maps each brain hemisphere onto a spherical segment comprising a sphere with a cap removed. We determined the best size of the spherical cap by minimizing the relative area distortion between hemispherical maps and original cortical surfaces. The relative area distortion between the hemispherical maps and the original cortical surfaces for fifteen human brains is analyzed.

Interpreting sulci on hominin endocasts: old hypotheses and new findings

PubMed Central

Falk, Dean

2014-01-01

Paleoneurologists analyze internal casts (endocasts) of fossilized braincases, which provide information about the size, shape and, to a limited degree, sulcal patterns reproduced from impressions left by the surface of the brain. When interpreted in light of comparative data from the brains of living apes and humans, sulcal patterns reproduced on hominin endocasts provide important information for studying the evolution of the cerebral cortex and cognition in human ancestors. Here, new evidence is discussed for the evolution of sulcal patterns associated with cortical reorganization in three parts of the hominin brain: (1) the parietotemporo-occipital association cortex, (2) Broca's speech area, and (3) dorsolateral prefrontal association cortex. Of the three regions, the evidence regarding the last is the clearest. Compared to great apes, Australopithecus endocasts reproduce a clear middle frontal sulcus in the dorsolateral prefrontal cortex that is derived toward the human condition. This finding is consistent with data from comparative cytoarchitectural studies of ape and human brains as well as shape analyses of australopithecine endocasts. The comparative and direct evidence for all three regions suggests that hominin brain reorganization was underway by at least the time of Australopithecus africanus (~2.5 to 3.0 mya), despite the ape-sized brains of these hominins, and that it entailed expansion of both rostral and caudal association cortices. PMID:24822043

Nose-to-Brain Delivery of Peptide Drugs Enhanced by Coadministration of Cell-penetrating Peptides: Therapeutic Potential for Dementia.

PubMed

Kamei, Noriyasu

2017-01-01

Recent reports suggest that peptide drugs such as insulin have the potential to serve as therapeutics in neurodegenerative diseases such as Alzheimer's disease. However, the transport of these drugs to the therapeutic target, the brain, is significantly hindered by the blood-brain barrier (BBB). Intranasal administration appears to be an ideal solution for drug delivery to the brain, bypassing the BBB, however the entry of peptide drugs into neuronal and epithelial cells in the olfactory mucosa remains low. In this study, we therefore examined whether intranasal coadministration of cell-penetrating peptides (CPPs) could improve nose-to-brain drug transport. In both mice and rats, we found that direct transport of insulin into the brain was significantly facilitated when coadministered with amphipathic CPP penetratin, and eventually insulin reached the deeper regions of the brain such as the hippocampus. In the mouse line senescence-accelerated mouse prone-8 (SAMP8), spatial learning tests demonstrated that long-term intranasal coadministration of insulin with penetratin improved mild memory loss in the early stages of dementia. In contrast, the severe cognitive dysfunction in the aged SAMP8 mice was preserved despite intranasal coadministration of insulin with penetratin. The immunohistological examination of the hippocampus suggested that enhanced nose-to-brain delivery of insulin had a partial neuroprotective effect but unexpectedly increased amyloid β plaque deposition. In conclusion, intranasal coadministration of insulin with CPPs has the potential to serve as a therapeutic for mild cognitive dysfunction. To identify suitable pharmacotherapy for dementia with severe pathology, further studies of nose-to-brain delivery of molecularly appropriate biopharmaceuticals are necessary.

Reduced Global Functional Connectivity of the Medial Prefrontal Cortex in Major Depressive Disorder

PubMed Central

Murrough, James W.; Abdallah, Chadi G.; Anticevic, Alan; Collins, Katherine A.; Geha, Paul; Averill, Lynnette A.; Schwartz, Jaclyn; DeWilde, Kaitlin E.; Averill, Christopher; Yang, Genevieve Jia-wei; Wong, Edmund; Tang, Cheuk Y.; Krystal, John H.; Iosifescu, Dan V.; Charney, Dennis S.

2016-01-01

Background Major depressive disorder is a disabling neuropsychiatric condition that is associated with disrupted functional connectivity across brain networks. The precise nature of altered connectivity, however, remains incompletely understood. The current study was designed to examine the coherence of large-scale connectivity in depression using a recently developed technique termed global brain connectivity. Methods A total of 82 subjects, including medication-free patients with major depression (n=57) and healthy volunteers (n=25) underwent functional magnetic resonance imaging with resting data acquisition for functional connectivity analysis. Global brain connectivity was computed as the mean of each voxel’s time series correlation with every other voxel and compared between study groups. Relationships between global connectivity and depressive symptom severity measured using the Montgomery-Åsberg Depression Rating Scale were examined by means of linear correlation. Results Relative to the healthy group, patients with depression evidenced reduced global connectivity bilaterally within multiple regions of medial and lateral prefrontal cortex. The largest between-group difference was observed within the right subgenual anterior cingulate cortex, extending into ventromedial prefrontal cortex bilaterally (Hedges’ g = −1.48, p<0.000001). Within the depressed group, patients with the lowest connectivity evidenced the highest symptom severity within ventromedial prefrontal cortex (r = −0.47, p=0.0005). Conclusions Patients with major depressive evidenced abnormal large-scale functional coherence in the brain that was centered within the subgenual cingulate cortex, and medial prefrontal cortex more broadly. These data extend prior studies of connectivity in depression and demonstrate that functional disconnection of the medial prefrontal cortex is a key pathological feature of the disorder. PMID:27144347

Focal stimulation of the brain by entirely extracranial means. An example of radiation controlled focal pharmacology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Remler, M.P.

A method for focal stimulation of the brain by entirely extracranial means is presented. A focal x ray lesion of cortex was made that reduces the blood-brain barrier in that area. Then parenteral penicillin was administered. Penicillin is primarily confined to the vascular space by the blood-brain barrier in all parts of the brain except for some leakage into the brain at higher doses. An increased concentration of penicillin is created in the irradiated cortex. The penicillin creates a focal epileptic lesion in the irradiated area. This is an example of radiation-controlled focal pharmacology in the central nervous system. (auth)

Effects of valerian consumption during pregnancy on cortical volume and the levels of zinc and copper in the brain tissue of mouse fetus.

PubMed

Mahmoudian, Alireza; Rajaei, Ziba; Haghir, Hossein; Banihashemian, Shahaboldin; Hami, Javad

2012-04-01

The aim of the present study was to determine the effects of valerian (Valeriana officinalis) consumption in pregnancy on cortical volume and the levels of zinc and copper, two essential elements that affect brain development and function, in the brain tissues of mouse fetuses. Pregnant female mice were treated with either saline or 1.2 g/kg body weight valerian extract intraperitoneally daily on gestation days (GD) 7 to 17. On GD 20, mice were sacrificed and their fetuses were collected. Fetal brains were dissected, weighed and processed for histological analysis. The volume of cerebral cortex was estimated by the Cavalieri principle. The levels of zinc and copper in the brain tissues were measured by atomic absorption spectroscopy. The results indicated that valerian consumption in pregnancy had no significant effect on brain weight, cerebral cortex volume and copper level in fetal brain. However,it significantly decreased the level of zinc in the brain (P<0.05). Using valerian during midgestation do not have an adverse effect on cerebral cortex; however,it caused a significant decrease in zinc level in the fetal brain. This suggests that valerian use should be limited during pregnancy.

Expression of Tau Pathology-Related Proteins in Different Brain Regions: A Molecular Basis of Tau Pathogenesis.

PubMed

Hu, Wen; Wu, Feng; Zhang, Yanchong; Gong, Cheng-Xin; Iqbal, Khalid; Liu, Fei

2017-01-01

Microtubule-associated protein tau is hyperphosphorylated and aggregated in affected neurons in Alzheimer disease (AD) brains. The tau pathology starts from the entorhinal cortex (EC), spreads to the hippocampus and frontal and temporal cortices, and finally to all isocortex areas, but the cerebellum is spared from tau lesions. The molecular basis of differential vulnerability of different brain regions to tau pathology is not understood. In the present study, we analyzed brain regional expressions of tau and tau pathology-related proteins. We found that tau was hyperphosphorylated at multiple sites in the frontal cortex (FC), but not in the cerebellum, from AD brain. The level of tau expression in the cerebellum was about 1/4 of that seen in the frontal and temporal cortices in human brain. In the rat brain, the expression level of tau with three microtubule-binding repeats (3R-tau) was comparable in the hippocampus, EC, FC, parietal-temporal cortex (PTC), occipital-temporal cortex (OTC), striatum, thalamus, olfactory bulb (OB) and cerebellum. However, the expression level of 4R-tau was the highest in the EC and the lowest in the cerebellum. Tau phosphatases, kinases, microtubule-related proteins and other tau pathology-related proteins were also expressed in a region-specific manner in the rat brain. These results suggest that higher levels of tau and tau kinases in the EC and low levels of these proteins in the cerebellum may accounts for the vulnerability and resistance of these representative brain regions to the development of tau pathology, respectively. The present study provides the regional expression profiles of tau and tau pathology-related proteins in the brain, which may help understand the brain regional vulnerability to tau pathology in neurodegenerative tauopathies.

Analysis of Time-Dependent Brain Network on Active and MI Tasks for Chronic Stroke Patients

PubMed Central

Chang, Won Hyuk; Kim, Yun-Hee; Lee, Seong-Whan; Kwon, Gyu Hyun

2015-01-01

Several researchers have analyzed brain activities by investigating brain networks. However, there is a lack of the research on the temporal characteristics of the brain network during a stroke by EEG and the comparative studies between motor execution and imagery, which became known to have similar motor functions and pathways. In this study, we proposed the possibility of temporal characteristics on the brain networks of a stroke. We analyzed the temporal properties of the brain networks for nine chronic stroke patients by the active and motor imagery tasks by EEG. High beta band has a specific role in the brain network during motor tasks. In the high beta band, for the active task, there were significant characteristics of centrality and small-worldness on bilateral primary motor cortices at the initial motor execution. The degree centrality significantly increased on the contralateral primary motor cortex, and local efficiency increased on the ipsilateral primary motor cortex. These results indicate that the ipsilateral primary motor cortex constructed a powerful subnetwork by influencing the linked channels as compensatory effect, although the contralateral primary motor cortex organized an inefficient network by using the connected channels due to lesions. For the MI task, degree centrality and local efficiency significantly decreased on the somatosensory area at the initial motor imagery. Then, there were significant correlations between the properties of brain networks and motor function on the contralateral primary motor cortex and somatosensory area for each motor execution/imagery task. Our results represented that the active and MI tasks have different mechanisms of motor acts. Based on these results, we indicated the possibility of customized rehabilitation according to different motor tasks. We expect these results to help in the construction of the customized rehabilitation system depending on motor tasks by understanding temporal functional characteristics on brain network for a stroke. PMID:26656269

Emotion Regulation in the Brain: Conceptual Issues and Directions for Developmental Research

ERIC Educational Resources Information Center

Lewis, Marc D.; Stieben, Jim

2004-01-01

Emotion regulation cannot be temporally distinguished from emotion in the brain, but activation patterns in prefrontal cortex appear to mediate cognitive control during emotion episodes. Frontal event-related potentials (ERPs) can tap cognitive control hypothetically mediated by the anterior cingulate cortex, and developmentalists have used these…

Compensatory brain activation in children with attention deficit/hyperactivity disorder during a simplified Go/No-go task.

PubMed

Ma, Jun; Lei, Du; Jin, Xingming; Du, Xiaoxia; Jiang, Fan; Li, Fei; Zhang, Yiwen; Shen, Xiaoming

2012-05-01

Given that a number of recent studies have shown attenuated brain activation in prefrontal regions in children with ADHD, it has been recognized as a disorder in executive function. However, fewer studies have focused exclusively on the compensatory brain activation in ADHD. The present study objective was to investigate the compensatory brain activation patterns during response inhibition (RI) processing in ADHD children. In this study, 15 ADHD children and 15 sex-, age-, and IQ-matched control children were scanned with a 3-T MRI equipment while performing a simplified letter Go/No-go task. The results showed more brain activation in the ADHD group compared with the control group, whereas the accuracy and reaction time of behavioral performance were the same. Children with ADHD did not activate the normal RI brain circuits, which are thought to be predominantly located in the right middle/inferior frontal gyrus (BA46/44), right inferior parietal regions (BA40), and pre-SMA(BA6), but instead, activated brain regions, such as the left inferior frontal cortex, the right inferior temporal cortex, the right precentral gyrus, the left postcentral gyrus, the inferior occipital cortex, the middle occipital cortex, the right calcarine, the right hippocampus, the right midbrain, and the cerebellum. Our conclusion is that children with ADHD tend to compensatorily use more posterior and diffusive brain regions to sustain normal RI function. © Springer-Verlag 2011

Aging increases amyloid beta-peptide-induced 8-iso-prostaglandin F2alpha release from rat brain.

PubMed

Brunetti, Luigi; Michelotto, Barbara; Orlando, Giustino; Recinella, Lucia; Di Nisio, Chiara; Ciabattoni, Giovanni; Vacca, Michele

2004-01-01

In order to investigate whether amyloid beta-peptide-induced oxidative damage in the brain could be related to aging, we studied the release of 8-iso-prostaglandin (PG)F2alpha, a stable marker of cellular oxidative stress, in brain synaptosomes from Wistar rats of different ages (3, 6, 12, 18 months old), both basally and after amyloid beta-peptide (1-40) perfusion. We found that basal release of 8-iso-PGF2alpha was not significantly different among all age groups of rats. Either phospholipase A2 activation induced by calcium ionophore A23187 (10 nM) or amyloid beta-peptide (5 microM) did not modify isoprostane release, when these substances were used alone. In contrast, amyloid beta-peptide (1-5 microM) preincubation caused a dose-dependent increase of A23187-stimulated 8-iso-PGF2alpha release in each age group, which was also strikingly correlated to aging of rats. Furthermore, ferric ammonium sulfate stimulates isoprostane production to levels comparable to those induced by amyloid beta-peptide. In conclusion, although 8-iso-PGF2alpha production from rat brain synaptosomes is independent from aging in the basal state, aging renders neurons more vulnerable to amyloid beta-peptide-induced oxidative toxicity.

Dendrobium alkaloids prevent Aβ25–35-induced neuronal and synaptic loss via promoting neurotrophic factors expression in mice

PubMed Central

Nie, Jing; Tian, Yong; Zhang, Yu; Lu, Yan-Liu; Li, Li-Sheng

2016-01-01

Background Neuronal and synaptic loss is the most important risk factor for cognitive impairment. Inhibiting neuronal apoptosis and preventing synaptic loss are promising therapeutic approaches for Alzheimer’s disease (AD). In this study, we investigate the protective effects of Dendrobium alkaloids (DNLA), a Chinese medicinal herb extract, on β-amyloid peptide segment 25–35 (Aβ25-35)-induced neuron and synaptic loss in mice. Method Aβ25–35(10 µg) was injected into the bilateral ventricles of male mice followed by an oral administration of DNLA (40 mg/kg) for 19 days. The Morris water maze was used for evaluating the ability of spatial learning and memory function of mice. The morphological changes were examined via H&E staining and Nissl staining. TUNEL staining was used to check the neuronal apoptosis. The ultrastructure changes of neurons were observed under electron microscope. Western blot was used to evaluate the protein expression levels of ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF) in the hippocampus and cortex. Results DNLA significantly attenuated Aβ25–35-induced spatial learning and memory impairments in mice. DNLA prevented Aβ25–35-induced neuronal loss in the hippocampus and cortex, increased the number of Nissl bodies, improved the ultrastructural injury of neurons and increased the number of synapses in neurons. Furthermore, DNLA increased the protein expression of neurotrophic factors BDNF, CNTF and GDNF in the hippocampus and cortex. Conclusions DNLA can prevent neuronal apoptosis and synaptic loss. This effect is mediated at least in part via increasing the expression of BDNF, GDNF and CNTF in the hippocampus and cortex; improving Aβ-induced spatial learning and memory impairment in mice. PMID:27994964

The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease.

PubMed

Winsky-Sommerer, R; Grouselle, D; Rougeot, C; Laurent, V; David, J-P; Delacourte, A; Dournaud, P; Seidah, N G; Lindberg, I; Trottier, S; Epelbaum, J

2003-01-01

A somatostatin deficit occurs in the cerebral cortex of Alzheimer's disease patients without a major loss in somatostatin-containing neurons. This deficit could be related to a reduction in the rate of proteolytic processing of peptide precursors. Since the two proprotein convertases (PC)1 and PC2 are responsible for the processing of neuropeptide precursors directed to the regulated secretory pathway, we examined whether they are involved first in the proteolytic processing of prosomatostatin in mouse and human brain and secondly in somatostatin defect associated with Alzheimer's disease. By size exclusion chromatography, the cleavage of prosomatostatin to somatostatin-14 is almost totally abolished in the cortex of PC2 null mice, while the proportions of prosomatostatin and somatostatin-28 are increased. By immunohistochemistry, PC1 and PC2 were localized in many neuronal elements in human frontal and temporal cortex. The convertases levels were quantified by Western blot, as well as the protein 7B2 which is required for the production of active PC2. No significant change in PC1 levels was observed in Alzheimer's disease. In contrast, a marked decrease in the ratio of the PC2 precursor to the total enzymatic pool was observed in the frontal cortex of Alzheimer patients. This decrease coincides with an increase in the binding protein 7B2. However, the content and enzymatic activity of the PC2 mature form were similar in Alzheimer patients and controls. Therefore, the cortical somatostatin defect is not due to convertase alteration occuring during Alzheimer's disease. Further studies will be needed to assess the mechanisms involved in somatostatin deficiency in Alzheimer's disease.

Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity.

PubMed

Zunhammer, Matthias; Schweizer, Lauren M; Witte, Vanessa; Harris, Richard E; Bingel, Ulrike; Schmidt-Wilcke, Tobias

2016-10-01

The relationship between glutamate and γ-aminobutyric acid (GABA) levels in the living human brain and pain sensitivity is unknown. Combined glutamine/glutamate (Glx), as well as GABA levels can be measured in vivo with single-voxel proton magnetic resonance spectroscopy. In this cross-sectional study, we aimed at determining whether Glx and/or GABA levels in pain-related brain regions are associated with individual differences in pain sensitivity. Experimental heat, cold, and mechanical pain thresholds were obtained from 39 healthy, drug-free individuals (25 men) according to the quantitative sensory testing protocol and summarized into 1 composite measure of pain sensitivity. The Glx levels were measured using point-resolved spectroscopy at 3 T, within a network of pain-associated brain regions comprising the insula, the anterior cingulate cortex, the mid-cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus. GABA levels were measured using GABA-edited spectroscopy (Mescher-Garwood point-resolved spectroscopy) within the insula, the anterior cingulate cortex, and the mid-cingulate cortex. Glx and/or GABA levels correlated positively across all brain regions. Gender, weekly alcohol consumption, and depressive symptoms were significantly associated with Glx and/or GABA levels. A linear regression analysis including all these factors indicated that Glx levels pooled across pain-related brain regions were positively associated with pain sensitivity, whereas no appreciable relationship with GABA was found. In sum, we show that the levels of the excitatory neurotransmitter glutamate and its precursor glutamine across pain-related brain regions are positively correlated with individual pain sensitivity. Future studies will have to determine whether our findings also apply to clinical populations.

Age-Dependent Brain Gene Expression and Copy Number Anomalies in Autism Suggest Distinct Pathological Processes at Young Versus Mature Ages

PubMed Central

Winn, Mary E.; Barnes, Cynthia Carter; Li, Hai-Ri; Weiss, Lauren; Fan, Jian-Bing; Murray, Sarah; April, Craig; Belinson, Haim; Fu, Xiang-Dong; Wynshaw-Boris, Anthony; Schork, Nicholas J.; Courchesne, Eric

2012-01-01

Autism is a highly heritable neurodevelopmental disorder, yet the genetic underpinnings of the disorder are largely unknown. Aberrant brain overgrowth is a well-replicated observation in the autism literature; but association, linkage, and expression studies have not identified genetic factors that explain this trajectory. Few studies have had sufficient statistical power to investigate whole-genome gene expression and genotypic variation in the autistic brain, especially in regions that display the greatest growth abnormality. Previous functional genomic studies have identified possible alterations in transcript levels of genes related to neurodevelopment and immune function. Thus, there is a need for genetic studies involving key brain regions to replicate these findings and solidify the role of particular functional pathways in autism pathogenesis. We therefore sought to identify abnormal brain gene expression patterns via whole-genome analysis of mRNA levels and copy number variations (CNVs) in autistic and control postmortem brain samples. We focused on prefrontal cortex tissue where excess neuron numbers and cortical overgrowth are pronounced in the majority of autism cases. We found evidence for dysregulation in pathways governing cell number, cortical patterning, and differentiation in young autistic prefrontal cortex. In contrast, adult autistic prefrontal cortex showed dysregulation of signaling and repair pathways. Genes regulating cell cycle also exhibited autism-specific CNVs in DNA derived from prefrontal cortex, and these genes were significantly associated with autism in genome-wide association study datasets. Our results suggest that CNVs and age-dependent gene expression changes in autism may reflect distinct pathological processes in the developing versus the mature autistic prefrontal cortex. Our results raise the hypothesis that genetic dysregulation in the developing brain leads to abnormal regional patterning, excess prefrontal neurons, cortical overgrowth, and neural dysfunction in autism. PMID:22457638

Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages.

PubMed

Chow, Maggie L; Pramparo, Tiziano; Winn, Mary E; Barnes, Cynthia Carter; Li, Hai-Ri; Weiss, Lauren; Fan, Jian-Bing; Murray, Sarah; April, Craig; Belinson, Haim; Fu, Xiang-Dong; Wynshaw-Boris, Anthony; Schork, Nicholas J; Courchesne, Eric

2012-01-01

Autism is a highly heritable neurodevelopmental disorder, yet the genetic underpinnings of the disorder are largely unknown. Aberrant brain overgrowth is a well-replicated observation in the autism literature; but association, linkage, and expression studies have not identified genetic factors that explain this trajectory. Few studies have had sufficient statistical power to investigate whole-genome gene expression and genotypic variation in the autistic brain, especially in regions that display the greatest growth abnormality. Previous functional genomic studies have identified possible alterations in transcript levels of genes related to neurodevelopment and immune function. Thus, there is a need for genetic studies involving key brain regions to replicate these findings and solidify the role of particular functional pathways in autism pathogenesis. We therefore sought to identify abnormal brain gene expression patterns via whole-genome analysis of mRNA levels and copy number variations (CNVs) in autistic and control postmortem brain samples. We focused on prefrontal cortex tissue where excess neuron numbers and cortical overgrowth are pronounced in the majority of autism cases. We found evidence for dysregulation in pathways governing cell number, cortical patterning, and differentiation in young autistic prefrontal cortex. In contrast, adult autistic prefrontal cortex showed dysregulation of signaling and repair pathways. Genes regulating cell cycle also exhibited autism-specific CNVs in DNA derived from prefrontal cortex, and these genes were significantly associated with autism in genome-wide association study datasets. Our results suggest that CNVs and age-dependent gene expression changes in autism may reflect distinct pathological processes in the developing versus the mature autistic prefrontal cortex. Our results raise the hypothesis that genetic dysregulation in the developing brain leads to abnormal regional patterning, excess prefrontal neurons, cortical overgrowth, and neural dysfunction in autism.

[Effects of electromagnetic pulse on blood-brain barrier permeability and tight junction proteins in rats].

PubMed

Qiu, Lian-bo; Ding, Gui-rong; Zhang, Ya-mei; Zhou, Yan; Wang, Xiao-wu; Li, Kang-chu; Xu, Sheng-long; Tan, Juan; Zhou, Jia-xing; Guo, Guo-zhen

2009-09-01

To study the effect of electromagnetic pulse (EMP) on the permeability of blood-brain barrier, tight junction (TJ)-associated protein expression and localization in rats. 66 male SD rats, weighing (200 approximately 250) g, were sham or whole-body exposed to EMP at 200 kV/m for 200 pulses. The repetition rate was 1 Hz. The permeability of the blood-brain barrier in rats was assessed by albumin immunohistochemistry. The expression of typical tight junction protein ZO-1 and occludin in both cerebral cortex homogenate and cerebral cortex microvessel homogenate was analyzed by the Western blotting and the distribution of ZO-1 and occludin was examined by immunofluorescence microscopy. In the sham exposure rats, no brain capillaries showed albumin leakage, at 0.5 h after 200 kV/m EMP exposure for 200 pulses; a few brain capillaries with extravasated serum albumin was found, with the time extended, the number of brain capillaries with extravasated serum albumin increased, and reached the peak at 3 h, then began to recover at 6 h. In addition, no change in the distribution of the occludin was found after EMP exposure. Total occludin expression had no significant change compared with the control. However, the expression level of ZO-1 significantly decreased at 1 h and 3 h after EMP exposure in both cerebral cortex homogenate and cerebral cortex microvessel homogenate. Furthermore, immunofluorescence studies also showed alterations in ZO-1 protein localization in cerebral cortex microvessel. The EMP exposure (200 kV/m, 200 pulses) could increase blood-brain barrier permeability in rat, and this change is associated with specific alterations in tight junction protein ZO-1.

What Do I Want and When Do I Want It: Brain Correlates of Decisions Made for Self and Other

PubMed Central

Albrecht, Konstanze; Volz, Kirsten G.; Sutter, Matthias; von Cramon, D. Yves

2013-01-01

A number of recent functional Magnetic Resonance Imaging (fMRI) studies on intertemporal choice behavior have demonstrated that so-called emotion- and reward-related brain areas are preferentially activated by decisions involving immediately available (but smaller) rewards as compared to (larger) delayed rewards. This pattern of activation was not seen, however, when intertemporal choices were made for another (unknown) individual, which speaks to that activation having been triggered by self-relatedness. In the present fMRI study, we investigated the brain correlates of individuals who passively observed intertemporal choices being made either for themselves or for an unknown person. We found higher activation within the ventral striatum, medial prefrontal and orbitofrontal cortex, pregenual anterior cingulate cortex, and posterior cingulate cortex when an immediate reward was possible for the observer herself, which is in line with findings from studies in which individuals actively chose immediately available rewards. Additionally, activation in the dorsal anterior cingulate cortex, posterior cingulate cortex, and precuneus was higher for choices that included immediate options than for choices that offered only delayed options, irrespective of who was to be the beneficiary. These results indicate that (1) the activations found in active intertemporal decision making are also present when the same decisions are merely observed, thus supporting the assumption that a robust brain network is engaged in immediate gratification; and (2) with immediate rewards, certain brain areas are activated irrespective of whether the observer or another person is the beneficiary of a decision, suggesting that immediacy plays a more general role for neural activation. An explorative analysis of participants’ brain activation corresponding to chosen rewards, further indicates that activation in the aforementioned brain areas depends on the mere presence, availability, or actual reception of immediate rewards. PMID:23991196

Endothelial NOS activation induces the blood-brain barrier disruption via ER stress following status epilepticus.

PubMed

Ko, Ah-Reum; Kim, Ji Yang; Hyun, Hye-Won; Kim, Ji-Eun

2015-10-05

The blood-brain barrier (BBB) maintains the unique brain microenvironment, which is separated from the systemic circulating system. Since the endoplasmic reticulum (ER) is an important cell organelle that is responsible for protein synthesis, the correct folding and sorting of proteins contributing to cell survivals, ER stress is a potential cause of cell damage in various diseases. Therefore, it would be worthy to explore the the relationship between the ER stress and BBB disruption during vasogenic edema formation induced by epileptogenic insults. In the present study, we investigated the roles of ER stress in vasogenic edema and its related events in rat epilepsy models provoked by pilocarpine-induced status epilepticus (SE). SE-induced eNOS activation induces BBB breakdown via up-regulation of GRP78 expression and dysfunction of SMI-71 (an endothelial BBB marker) in the piriform cortex (PC). In addition, caveolin-1 peptide (an eNOS inhibitor) effectively attenuated GRP78 expression and down-regulation of SMI-71. Taken together, our findings suggest that eNOS-mediated ER stress may participate in SE-induced vasogenic edema formation. Therefore, the modulation of ER stress may be a considerable strategy for therapy in impairments of endothelial cell function. Copyright © 2015 Elsevier B.V. All rights reserved.

A Neuroprotective Brain-penetrating Endopeptidase Fusion Protein Ameliorates Alzheimer Disease Pathology and Restores Neurogenesis*

PubMed Central

Spencer, Brian; Verma, Inder; Desplats, Paula; Morvinski, Dinorah; Rockenstein, Ed; Adame, Anthony; Masliah, Eliezer

2014-01-01

Alzheimer disease (AD) is characterized by widespread neurodegeneration throughout the association cortex and limbic system, deposition of amyloid-β peptide (Aβ) in the neuropil and around the blood vessels, and formation of neurofibrillary tangles. The endopeptidase neprilysin has been successfully used to reduce the accumulation of Aβ following intracranial viral vector delivery or ex vivo manipulated intracranial delivery. These therapies have relied on direct injections into the brain, whereas a clinically desirable therapy would involve i.v. infusion of a recombinant enzyme. We previously characterized a recombinant neprilysin that contained a 38-amino acid brain-targeting domain. Recombinant cell lines have been generated expressing this brain-targeted enzyme (ASN12). In this report, we characterize the ASN12 recombinant protein for pharmacology in a mouse as well as efficacy in two APPtg mouse models of AD. The recombinant ASN12 transited to the brain with a t½ of 24 h and accumulated to 1.7% of injected dose at 24 h following i.v. delivery. We examined pharmacodynamics in the tg2576 APPtg mouse with the prion promoter APP695 SWE mutation and in the Line41 mThy1 APP751 mutation mouse. Treatment of either APPtg mouse resulted in reduced Aβ, increased neuronal synapses, and improved learning and memory. In addition, the Line41 APPtg mice showed increased levels of C-terminal neuropeptide Y fragments and increased neurogenesis. These results suggest that the recombinant brain-targeted neprilysin, ASN12, may be an effective treatment for AD and warrant further investigation in clinical trials. PMID:24825898

Sex-dependent alterations in motor and anxiety-like behavior of aged bacterial peptidoglycan sensing molecule 2 knockout mice.

PubMed

Arentsen, Tim; Khalid, Roksana; Qian, Yu; Diaz Heijtz, Rochellys

2018-01-01

Peptidoglycan recognition proteins (PGRPs) are key sensing-molecules of the innate immune system that specifically detect bacterial peptidoglycan (PGN) and its derivates. PGRPs have recently emerged as potential key regulators of normal brain development and behavior. To test the hypothesis that PGRPs play a role in motor control and anxiety-like behavior in later life, we used 15-month old male and female peptidoglycan recognition protein 2 (Pglyrp2) knockout (KO) mice. Pglyrp2 is an N-acetylmuramyl-l-alanine amidase that hydrolyzes PGN between the sugar backbone and the peptide chain (which is unique among the mammalian PGRPs). Using a battery of behavioral tests, we demonstrate that Pglyrp2 KO male mice display decreased levels of anxiety-like behavior compared with wild type (WT) males. In contrast, Pglyrp2 KO female mice show reduced rearing activity and increased anxiety-like behavior compared to WT females. In the accelerated rotarod test, however, Pglyrp2 KO female mice performed better compared to WT females (i.e., they had longer latency to fall off the rotarod). Further, Pglyrp2 KO male mice exhibited decreased expression levels of synaptophysin, gephyrin, and brain-derived neurotrophic factor in the frontal cortex, but not in the amygdala. Pglyrp2 KO female mice exhibited increased expression levels of spinophilin and alpha-synuclein in the frontal cortex, while exhibiting decreased expression levels of synaptophysin, gephyrin and spinophilin in the amygdala. Our findings suggest a novel role for Pglyrp2asa key regulator of motor and anxiety-like behavior in late life. Copyright © 2017. Published by Elsevier Inc.

Variation in orbitofrontal cortex volume: relation to sex, emotion regulation and affect.

PubMed

Welborn, B Locke; Papademetris, Xenophon; Reis, Deidre L; Rajeevan, Nallakkandi; Bloise, Suzanne M; Gray, Jeremy R

2009-12-01

Sex differences in brain structure have been examined extensively but are not completely understood, especially in relation to possible functional correlates. Our two aims in this study were to investigate sex differences in brain structure, and to investigate a possible relation between orbitofrontal cortex subregions and affective individual differences. We used tensor-based morphometry to estimate local brain volume from MPRAGE images in 117 healthy right-handed adults (58 female), age 18-40 years. We entered estimates of local brain volume as the dependent variable in a GLM, controlling for age, intelligence and whole-brain volume. Men had larger left planum temporale. Women had larger ventromedial prefrontal cortex (vmPFC), right lateral orbitofrontal (rlOFC), cerebellum, and bilateral basal ganglia and nearby white matter. vmPFC but not rlOFC volume covaried with self-reported emotion regulation strategies (reappraisal, suppression), expressivity of positive emotions (but not of negative), strength of emotional impulses, and cognitive but not somatic anxiety. vmPFC volume statistically mediated sex differences in emotion suppression. The results confirm prior reports of sex differences in orbitofrontal cortex structure, and are the first to show that normal variation in vmPFC volume is systematically related to emotion regulation and affective individual differences.

Dendrimer D5 is a vector for peptide transport to brain cells.

PubMed

Sarantseva, S V; Bolshakova, O I; Timoshenko, S I; Kolobov, A A; Schwarzman, A L

2011-02-01

Dendrimers are a new class of nonviral vectors for gene or drug transport. Dendrimer capacity to penetrate through the blood-brain barrier remaines little studied. Biotinylated polylysine dendrimer D5, similarly to human growth hormone biotinylated fragment covalently bound to D5 dendrimer, penetrates through the blood-brain barrier and accumulates in Drosophila brain after injection into the abdomen. Hence, D5 dendrimer can serve as a vector for peptide transport to brain cells.

Diurnal alterations of brain electrical activity in healthy adults: a LORETA study.

PubMed

Toth, Marton; Kiss, Attila; Kosztolanyi, Peter; Kondakor, Istvan

2007-01-01

EEG background activity was investigated by low resolution brain electromagnetic tomography (LORETA) to test the diurnal alterations of brain electrical activity in healthy adults. Fourteen right-handed healthy male postgraduate medical students were examined four times (8 a.m., 2 p.m., 8 p.m. and next day 2 p.m.). LORETA was computed to localize generators of EEG frequency components. Comparing the EEG activity between 2 p.m. and 8 a.m., increased activity was seen (1) in theta band (6.5-8 Hz) in the left prefrontal, bilateral mesial frontal and anterior cingulate cortex; (2) in alpha2 band (10.5-12 Hz) in the bilateral precuneus and posterior parietal cortex as well as in the right temporo-occipital cortex; (3) in beta1-2-3 band (12.5-30 Hz) in the right hippocampus and parieto-occipital cortex, left frontal and bilateral cingulate cortex. Comparing the brain activity between 8 p.m. and 8 a.m., (1) midline theta activity disappeared; (2) increased alpha2 band activity was seen in the left hemisphere (including the left hippocampus); and (3) increased beta bands activity was found over almost the whole cortex (including both of hippocampi) with the exception of left temporo-occipital region. There were no significant changes between the background activities of 2 p.m. and next day 2 p.m. Characteristic distribution of increased activity of cortex (no change in delta band, and massive changes in the upper frequency bands) may mirror increasing activation of reticular formation and thus evoked thalamocortical feedback mechanisms as a sign of maintenance of arousal.

Cultural differences in human brain activity: a quantitative meta-analysis.

PubMed

Han, Shihui; Ma, Yina

2014-10-01

Psychologists have been trying to understand differences in cognition and behavior between East Asian and Western cultures within a single cognitive framework such as holistic versus analytic or interdependent versus independent processes. However, it remains unclear whether cultural differences in multiple psychological processes correspond to the same or different neural networks. We conducted a quantitative meta-analysis of 35 functional MRI studies to examine cultural differences in brain activity engaged in social and non-social processes. We showed that social cognitive processes are characterized by stronger activity in the dorsal medial prefrontal cortex, lateral frontal cortex and temporoparietal junction in East Asians but stronger activity in the anterior cingulate, ventral medial prefrontal cortex and bilateral insula in Westerners. Social affective processes are associated with stronger activity in the right dorsal lateral frontal cortex in East Asians but greater activity in the left insula and right temporal pole in Westerners. Non-social processes induce stronger activity in the left inferior parietal cortex, left middle occipital and left superior parietal cortex in East Asians but greater activations in the right lingual gyrus, right inferior parietal cortex and precuneus in Westerners. The results suggest that cultural differences in social and non-social processes are mediated by distinct neural networks. Moreover, East Asian cultures are associated with increased neural activity in the brain regions related to inference of others' mind and emotion regulation whereas Western cultures are associated with enhanced neural activity in the brain areas related to self-relevance encoding and emotional responses during social cognitive/affective processes. Copyright © 2014 Elsevier Inc. All rights reserved.

Changes of the directional brain networks related with brain plasticity in patients with long-term unilateral sensorineural hearing loss.

PubMed

Zhang, G-Y; Yang, M; Liu, B; Huang, Z-C; Li, J; Chen, J-Y; Chen, H; Zhang, P-P; Liu, L-J; Wang, J; Teng, G-J

2016-01-28

Previous studies often report that early auditory deprivation or congenital deafness contributes to cross-modal reorganization in the auditory-deprived cortex, and this cross-modal reorganization limits clinical benefit from cochlear prosthetics. However, there are inconsistencies among study results on cortical reorganization in those subjects with long-term unilateral sensorineural hearing loss (USNHL). It is also unclear whether there exists a similar cross-modal plasticity of the auditory cortex for acquired monaural deafness and early or congenital deafness. To address this issue, we constructed the directional brain functional networks based on entropy connectivity of resting-state functional MRI and researched changes of the networks. Thirty-four long-term USNHL individuals and seventeen normally hearing individuals participated in the test, and all USNHL patients had acquired deafness. We found that certain brain regions of the sensorimotor and visual networks presented enhanced synchronous output entropy connectivity with the left primary auditory cortex in the left long-term USNHL individuals as compared with normally hearing individuals. Especially, the left USNHL showed more significant changes of entropy connectivity than the right USNHL. No significant plastic changes were observed in the right USNHL. Our results indicate that the left primary auditory cortex (non-auditory-deprived cortex) in patients with left USNHL has been reorganized by visual and sensorimotor modalities through cross-modal plasticity. Furthermore, the cross-modal reorganization also alters the directional brain functional networks. The auditory deprivation from the left or right side generates different influences on the human brain. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Role of mechanical factors in cortical folding development

NASA Astrophysics Data System (ADS)

Razavi, Mir Jalil; Zhang, Tuo; Li, Xiao; Liu, Tianming; Wang, Xianqiao

2015-09-01

Deciphering mysteries of the structure-function relationship in cortical folding has emerged as the cynosure of recent research on brain. Understanding the mechanism of convolution patterns can provide useful insight into the normal and pathological brain function. However, despite decades of speculation and endeavors the underlying mechanism of the brain folding process remains poorly understood. This paper focuses on the three-dimensional morphological patterns of a developing brain under different tissue specification assumptions via theoretical analyses, computational modeling, and experiment verifications. The living human brain is modeled with a soft structure having outer cortex and inner core to investigate the brain development. Analytical interpretations of differential growth of the brain model provide preliminary insight into the critical growth ratio for instability and crease formation of the developing brain followed by computational modeling as a way to offer clues for brain's postbuckling morphology. Especially, tissue geometry, growth ratio, and material properties of the cortex are explored as the most determinant parameters to control the morphogenesis of a growing brain model. As indicated in results, compressive residual stresses caused by the sufficient growth trigger instability and the brain forms highly convoluted patterns wherein its gyrification degree is specified with the cortex thickness. Morphological patterns of the developing brain predicted from the computational modeling are consistent with our neuroimaging observations, thereby clarifying, in part, the reason of some classical malformation in a developing brain.

Is orbital volume associated with eyeball and visual cortex volume in humans?

PubMed

Pearce, Eiluned; Bridge, Holly

2013-01-01

In humans orbital volume increases linearly with absolute latitude. Scaling across mammals between visual system components suggests that these larger orbits should translate into larger eyes and visual cortices in high latitude humans. Larger eyes at high latitudes may be required to maintain adequate visual acuity and enhance visual sensitivity under lower light levels. To test the assumption that orbital volume can accurately index eyeball and visual cortex volumes specifically in humans. Structural Magnetic Resonance Imaging (MRI) techniques are employed to measure eye and orbit (n = 88) and brain and visual cortex (n = 99) volumes in living humans. Facial dimensions and foramen magnum area (a proxy for body mass) were also measured. A significant positive linear relationship was found between (i) orbital and eyeball volumes, (ii) eyeball and visual cortex grey matter volumes and (iii) different visual cortical areas, independently of overall brain volume. In humans the components of the visual system scale from orbit to eye to visual cortex volume independently of overall brain size. These findings indicate that orbit volume can index eye and visual cortex volume in humans, suggesting that larger high latitude orbits do translate into larger visual cortices.

Is orbital volume associated with eyeball and visual cortex volume in humans?

PubMed Central

Pearce, Eiluned; Bridge, Holly

2013-01-01

Background In humans orbital volume increases linearly with absolute latitude. Scaling across mammals between visual system components suggests that these larger orbits should translate into larger eyes and visual cortices in high latitude humans. Larger eyes at high latitudes may be required to maintain adequate visual acuity and enhance visual sensitivity under lower light levels. Aim To test the assumption that orbital volume can accurately index eyeball and visual cortex volumes specifically in humans. Subjects & Methods Structural Magnetic Resonance Imaging (MRI) techniques are employed to measure eye and orbit (N=88), and brain and visual cortex (N=99) volumes in living humans. Facial dimensions and foramen magnum area (a proxy for body mass) were also measured. Results A significant positive linear relationship was found between (i) orbital and eyeball volumes, (ii) eyeball and visual cortex grey matter volumes, (iii) different visual cortical areas, independently of overall brain volume. Conclusion In humans the components of the visual system scale from orbit to eye to visual cortex volume independently of overall brain size. These findings indicate that orbit volume can index eye and visual cortex volume in humans, suggesting that larger high latitude orbits do translate into larger visual cortices. PMID:23879766

Semantic strategy training increases memory performance and brain activity in patients with prefrontal cortex lesions.

PubMed

Miotto, Eliane C; Savage, Cary R; Evans, Jonathan J; Wilson, Barbara A; Martin, Maria G M; Balardin, Joana B; Barros, Fabio G; Garrido, Griselda; Teixeira, Manoel J; Amaro Junior, Edson

2013-03-01

Memory deficit is a frequent cognitive disorder following acquired prefrontal cortex lesions. In the present study, we investigated the brain correlates of a short semantic strategy training and memory performance of patients with distinct prefrontal cortex lesions using fMRI and cognitive tests. Twenty-one adult patients with post-acute prefrontal cortex (PFC) lesions, twelve with left dorsolateral PFC (LPFC) and nine with bilateral orbitofrontal cortex (BOFC) were assessed before and after a short cognitive semantic training using a verbal memory encoding paradigm during scanning and neuropsychological tests outside the scanner. After the semantic strategy training both groups of patients showed significant behavioral improvement in verbal memory recall and use of semantic strategies. In the LPFC group, greater activity in left inferior and medial frontal gyrus, precentral gyrus and insula was found after training. For the BOFC group, a greater activation was found in the left parietal cortex, right cingulated and precuneus after training. The activation of these specific areas in the memory and executive networks following cognitive training was associated to compensatory brain mechanisms and application of the semantic strategy. Copyright © 2012 Elsevier B.V. All rights reserved.

Control of Food Intake by Gastrointestinal Peptides: Mechanisms of Action and Possible Modulation in the Treatment of Obesity

PubMed Central

Prinz, Philip; Stengel, Andreas

2017-01-01

This review focuses on the control of appetite by food intake-regulatory peptides secreted from the gastrointestinal tract, namely cholecystokinin, glucagon-like peptide 1, peptide YY, ghrelin, and the recently discovered nesfatin-1 via the gut-brain axis. Additionally, we describe the impact of external factors such as intake of different nutrients or stress on the secretion of gastrointestinal peptides. Finally, we highlight possible conservative—physical activity and pharmacotherapy—treatment strategies for obesity as well as surgical techniques such as deep brain stimulation and bariatric surgery also altering these peptidergic pathways. PMID:28096522

[Effects of the removal of the orbito-frontal cortex on the development of reflex analgesia].

PubMed

Reshetniak, V K; Kukushkin, M L

1989-07-01

The authors studied the effect of electric acupuncture stimulation (EAP) on the changes in pain thresholds prior to and after removal of the orbito-frontal cortex (OFC) of the brain in behavioral experiments on adult cats. Removal of OFC increased the thresholds of pain response at the 4th and the 5th levels of the conventional scale, reflecting emotionally-affective manifestations of pain, and intensified the effect of antinociceptive EAP. The results obtained are analysed in relation to the inhibitory tonic effect of OFC on antinociceptive structures of the brain. Different effects of OFC and somatosensory cortex on the antinociceptive structures of the brain are discussed.

Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain

PubMed Central

Liang, Winnie S.; Dunckley, Travis; Beach, Thomas G.; Grover, Andrew; Mastroeni, Diego; Walker, Douglas G.; Caselli, Richard J.; Kukull, Walter A.; McKeel, Daniel; Morris, John C.; Hulette, Christine; Schmechel, Donald; Alexander, Gene E.; Reiman, Eric M.; Rogers, Joseph; Stephan, Dietrich A.

2008-01-01

In this article, we have characterized and compared gene expression profiles from laser capture microdissected neurons in six functionally and anatomically distinct regions from clinically and histopathologically normal aged human brains. These regions, which are also known to be differentially vulnerable to the histopathological and metabolic features of Alzheimer’s disease (AD), include the entorhinal cortex and hippocampus (limbic and paralimbic areas vulnerable to early neurofibrillary tangle pathology in AD), posterior cingulate cortex (a paralimbic area vulnerable to early metabolic abnormalities in AD), temporal and prefrontal cortex (unimodal and heteromodal sensory association areas vulnerable to early neuritic plaque pathology in AD), and primary visual cortex (a primary sensory area relatively spared in early AD). These neuronal profiles will provide valuable reference information for future studies of the brain, in normal aging, AD and other neurological and psychiatric disorders. PMID:17077275

N-terminal pro-brain natriuretic peptide and high-sensitivity troponin in the evaluation of acute chest pain of uncertain etiology. A PITAGORAS substudy.

PubMed

Sanchis, Juan; Bardají, Alfredo; Bosch, Xavier; Loma-Osorio, Pablo; Marín, Francisco; Sánchez, Pedro L; Calvo, Francisco; Avanzas, Pablo; Hernández, Carolina; Serrano, Silvia; Carratalá, Arturo; Barrabés, José A

2013-07-01

High-sensitivity troponin assays have improved the diagnosis of acute coronary syndrome in patients presenting with chest pain and normal troponin levels as measured by conventional assays. Our aim was to investigate whether N-terminal pro-brain natriuretic peptide provides additional information to troponin determination in these patients. A total of 398 patients, included in the PITAGORAS study, presenting to the emergency department with chest pain and normal troponin levels as measured by conventional assay in 2 serial samples (on arrival and 6 h to 8h later) were studied. The samples were also analyzed in a central laboratory for high-sensitivity troponin T (both samples) and for N-terminal pro-brain natriuretic peptide (second sample). The endpoints were diagnosis of acute coronary syndrome and the composite endpoint of in-hospital revascularization or a 30-day cardiac event. Acute coronary syndrome was adjudicated to 79 patients (20%) and the composite endpoint to 59 (15%). When the N-terminal pro-brain natriuretic peptide quartile increased, the diagnosis of acute coronary syndrome also increased (12%, 16%, 23% and 29%; P=.01), as did the risk of the composite endpoint (6%, 13%, 16% and 24%; P=.004). N-terminal pro-brain natriuretic peptide elevation (>125ng/L) was associated with both endpoints (relative risk= 2.0; 95% confidence interval, 1.2-3.3; P=.02; relative risk=2.4; 95% confidence interval, 1.4-4.2; P=.004). However, in the multivariable models adjusted by clinical and electrocardiographic data, a predictive value was found for high-sensitivity T troponin but not for N-terminal pro-brain natriuretic peptide. In low-risk patients with chest pain of uncertain etiology evaluated using high-sensitivity T troponin, N-terminal pro-brain natriuretic peptide does not contribute additional predictive value to diagnosis or the prediction of short-term outcomes. Copyright © 2012 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

Brain gamma-aminobutyric acid deficiency in dialysis encephalopathy.

PubMed

Sweeney, V P; Perry, T L; Price, J D; Reeve, C E; Godolphin, W J; Kish, S J

1985-02-01

We measured levels of gamma-aminobutyric acid (GABA) in the CSF and in the autopsied brain of patients with dialysis encephalopathy. GABA concentrations were low in the CSF of three of five living patients. Mean GABA content was reduced by 30 to 50% in five brain regions (frontal, occipital, and cerebellar cortex, caudate nucleus, and medial dorsal thalamus) in five fatal cases. GABA content was normal in brain regions where GABA is characteristically reduced in Huntington's disease. Choline acetyltransferase activity was diminished (by 25 to 35%) in cerebral cortex of the dialysis encephalopathy patients.

A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries

NASA Astrophysics Data System (ADS)

Mann, Aman P.; Scodeller, Pablo; Hussain, Sazid; Joo, Jinmyoung; Kwon, Ester; Braun, Gary B.; Mölder, Tarmo; She, Zhi-Gang; Kotamraju, Venkata Ramana; Ranscht, Barbara; Krajewski, Stan; Teesalu, Tambet; Bhatia, Sangeeta; Sailor, Michael J.; Ruoslahti, Erkki

2016-06-01

Traumatic brain injury (TBI) is a major health and socio-economic problem, but no pharmacological agent is currently approved for the treatment of acute TBI. Thus, there is a great need for advances in this field. Here, we describe a short peptide (sequence CAQK) identified by in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brain, and systemically injected CAQK specifically homes to sites of brain injury in mouse models. The CAQK target is a proteoglycan complex upregulated in brain injuries. Coupling to CAQK increased injury site accumulation of systemically administered molecules ranging from a drug-sized molecule to nanoparticles. CAQK-coated nanoparticles containing silencing oligonucleotides provided the first evidence of gene silencing in injured brain parenchyma by systemically administered siRNA. These findings present an effective targeting strategy for the delivery of therapeutics in clinical management of acute brain injuries.

Neuropeptide transmission in brain circuits

PubMed Central

van den Pol, Anthony N.

2014-01-01

Neuropeptides are found in many mammalian CNS neurons where they play key roles in modulating neuronal activity. In contrast to amino acid transmitter release at the synapse, neuropeptide release is not restricted to the synaptic specialization, and after release, a neuropeptide may diffuse some distance to exert its action through a G-protein coupled receptor. Some neuropeptides such as hypocretin/orexin are synthesized only in single regions of the brain, and the neurons releasing these peptides probably have similar functional roles. Other peptides such as neuropeptide Y (NPY) are synthesized throughout the brain, and neurons that synthesize the peptide in one region have no anatomical or functional connection with NPY neurons in other brain regions. Here, I review converging data revealing a complex interaction between slow-acting neuromodulator peptides and fast-acting amino acid transmitters in the control of energy homeostasis, drug addiction, mood and motivation, sleep-wake states, and neuroendocrine regulation. PMID:23040809

Regional distribution of neuropeptide Y mRNA in postmortem human brain.

PubMed

Brené, S; Lindefors, N; Kopp, J; Sedvall, G; Persson, H

1989-12-01

The distribution of messenger RNA encoding neuropeptide Y (NPY) was studied in 11 different postmortem human brain regions using in situ hybridization histochemistry, and RNA blot analysis. In situ hybridization data revealed that the highest numerical density of labeled cells corresponded to neurons in accumbens area, caudate nucleus, putamen, and substantia innominata. Significantly fewer NPY mRNA-containing neurons were found in frontal and parietal cortex, amygdaloid body and dentate gyrus. No NPY mRNA-containing cells were found in substantia nigra. NPY mRNA-positive neurons from all regions studied showed relatively similar labeling, as revealed by computerized image analysis. Blot analysis showed an approximately 0.8 kb NPY mRNA in all brain regions studied, except in substantia nigra and cerebellum. Densitometric scanning of the autoradiograms revealed levels of NPY mRNA in the following order: putamen greater than caudate nucleus greater than frontal cortex (Brodmann areas 4 and 6) greater than temporal cortex (Brodmann area 38) greater than parietal cortex (Brodmann areas 5 and 7) greater than frontal cortex (Brodmann area 11). Hence, although NPY mRNA is widely distributed in neurons of the human brain large regional variation exists, with the highest expression in accumbens area and parts of the basal ganglia.

Altered resting-state functional connectivity of the frontal-striatal reward system in social anxiety disorder.

PubMed

Manning, Joshua; Reynolds, Gretchen; Saygin, Zeynep M; Hofmann, Stefan G; Pollack, Mark; Gabrieli, John D E; Whitfield-Gabrieli, Susan

2015-01-01

We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.

Preserved pontine glucose metabolism in Alzheimer disease: A reference region for functional brain image (PET) analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Minoshima, Satoshi; Frey, K.A.; Foster, N.L.

1995-07-01

Our goal was to examine regional preservation of energy metabolism in Alzheimer disease (AD) and to evaluate effects of PET data normalization to reference regions. Regional metabolic rates in the pons, thalamus, putamen, sensorimotor cortex, visual cortex, and cerebellum (reference regions) were determined stereotaxically and examined in 37 patients with probable AD and 22 normal controls based on quantitative {sup 18}FDG-PET measurements. Following normalization of metabolic rates of the parietotemporal association cortex and whole brain to each reference region, distinctions of the two groups were assessed. The pons showed the best preservation of glucose metabolism in AD. Other reference regionsmore » showed relatively preserved metabolism compared with the parietotemporal association cortex and whole brain, but had significant metabolic reduction. Data normalization to the pons not only enhanced statistical significance of metabolic reduction in the parietotemporal association cortex, but also preserved the presence of global cerebral metabolic reduction indicated in analysis of the quantitative data. Energy metabolism in the pons in probable AD is well preserved. The pons is a reliable reference for data normalization and will enhance diagnostic accuracy and efficiency of quantitative and nonquantitative functional brain imaging. 39 refs., 2 figs., 3 tabs.« less

Preserved Self-Awareness following Extensive Bilateral Brain Damage to the Insula, Anterior Cingulate, and Medial Prefrontal Cortices

PubMed Central

Khalsa, Sahib S.; Damasio, Antonio; Tranel, Daniel; Landini, Gregory; Williford, Kenneth

2012-01-01

It has been proposed that self-awareness (SA), a multifaceted phenomenon central to human consciousness, depends critically on specific brain regions, namely the insular cortex, the anterior cingulate cortex (ACC), and the medial prefrontal cortex (mPFC). Such a proposal predicts that damage to these regions should disrupt or even abolish SA. We tested this prediction in a rare neurological patient with extensive bilateral brain damage encompassing the insula, ACC, mPFC, and the medial temporal lobes. In spite of severe amnesia, which partially affected his “autobiographical self”, the patient's SA remained fundamentally intact. His Core SA, including basic self-recognition and sense of self-agency, was preserved. His Extended SA and Introspective SA were also largely intact, as he has a stable self-concept and intact higher-order metacognitive abilities. The results suggest that the insular cortex, ACC and mPFC are not required for most aspects of SA. Our findings are compatible with the hypothesis that SA is likely to emerge from more distributed interactions among brain networks including those in the brainstem, thalamus, and posteromedial cortices. PMID:22927899

Time course of hyperosmolar opening of the blood-brain and blood-CSF barriers in spontaneously hypertensive rats.

PubMed

Al-Sarraf, Hameed; Ghaaedi, Firuz; Redzic, Zoran

2007-01-01

The time course of blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) responses to hyperosmolar mannitol infusion (HMI; 1.6 M) during chronic hypertension was investigated using (14)C-sucrose as a marker of barrier integrity. (14)C-sucrose entry into CSF of both spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats 2 min after HMI increased approximately 7-fold compared to their respective control. The volume of distribution (V(d)) of (14)C-sucrose into brain cortex of SHR increased 13-fold 2 min after HMI while that in WKY rats increased only 4-fold. After HMI V(d) of (14)C-sucrose into the cortex of WKY, and CSF of both SHR and WKY remained steadily greater than their corresponding control for up to 30 min (p < 0.01), whereas in the cortex of SHR the V(d) of (14)C-sucrose reached control values 20 min after HMI (p > 0.05), indicating that after HMI the increase in paracellular diffusion of (14)C-sucrose into SHR cortex was not persistent, in contrast to WKY rats and CSF of both SHR and WKY rats. Electron microscopy of the brain cortex after HMI showed capillary endothelial cell shrinkage and perivascular swellings in the brain cortex, and in the choroid plexus opening of tight junctions were observed. Our results indicate disruption of both the BBB and the BCSFB after HMI in both SHR and WKY rats. The disruption remained persistent up to 25 min after HMI at the BBB of WKY rats and BCSFB in both animal groups, while in SHR the protective function of the BBB returned to control values 20 min after HMI. Copyright 2007 S. Karger AG, Basel.

Evolutionary combinatorial chemistry, a novel tool for SAR studies on peptide transport across the blood-brain barrier. Part 2. Design, synthesis and evaluation of a first generation of peptides.

PubMed

Teixidó, Meritxell; Belda, Ignasi; Zurita, Esther; Llorà, Xavier; Fabre, Myriam; Vilaró, Senén; Albericio, Fernando; Giralt, Ernest

2005-12-01

The use of high-throughput methods in drug discovery allows the generation and testing of a large number of compounds, but at the price of providing redundant information. Evolutionary combinatorial chemistry combines the selection and synthesis of biologically active compounds with artificial intelligence optimization methods, such as genetic algorithms (GA). Drug candidates for the treatment of central nervous system (CNS) disorders must overcome the blood-brain barrier (BBB). This paper reports a new genetic algorithm that searches for the optimal physicochemical properties for peptide transport across the blood-brain barrier. A first generation of peptides has been generated and synthesized. Due to the high content of N-methyl amino acids present in most of these peptides, their syntheses were especially challenging due to over-incorporations, deletions and DKP formations. Distinct fragmentation patterns during peptide cleavage have been identified. The first generation of peptides has been studied by evaluation techniques such as immobilized artificial membrane chromatography (IAMC), a cell-based assay, log Poctanol/water calculations, etc. Finally, a second generation has been proposed. (c) 2005 European Peptide Society and John Wiley & Sons, Ltd.

MR-Guided Unfocused Ultrasound Disruption of the Rat Blood-Brain Barrier

NASA Astrophysics Data System (ADS)

Townsend, Kelly A.; King, Randy L.; Zaharchuk, Greg; Pauly, Kim Butts

2011-09-01

Therapeutic ultrasound with microbubbles can temporarily disrupt the blood-brain barrier (BBB) for drug delivery. Contrast-enhanced MRI (CE-MRI) can visualize gadolinium passage into the brain, indicating BBB opening. Previous studies used focused ultrasound, which is appropriate for the targeted delivery of drugs. The purpose of this study was to investigate unfocused ultrasound for BBB opening across the whole brain. In 10 rats, gadolinium-based MR contrast agent (Gd; 0.25 ml) was administered concurrent with ultrasound microbubbles (Optison, 0.25 ml) and circulated for 20 sec before sonication. A 753 kHz planar PZT transducer, diameter 1.8 cm, sonicated each rat brain with supplied voltage of 300, 400, or 500 mVpp for 10 sec in continuous wave mode, or at 500 mVpp at 20% duty cycle at 10 Hz for 30-300 sec. After sonication, coronal T1-weighted FSE CE-MRI images were acquired with a 3in surface coil. The imaging protocol was repeated 3-5 times after treatment. One control animal was given Gd and microbubbles, but not sonicated, and the other was given Gd and sonicated without microbubbles. Signal change in ROIs over the muscle, mesencephalon/ventricles, and the cortex/striatum were measured at 3-5 time points up to 36 min after sonication. Signal intensity was converted to % signal change compared to the initial image. In the controls, CE-MRI showed brightening of surrounding structures, but not the brain. In the continuous wave subjects, cortex/striatum signal did not increase, but ventricle/mesenchephalon signal did. Those that received pulsed sonications showed signal increases in both the cortex/striatum and ventricles/mesenchephalon. In conclusion, after pulsed unfocused ultrasound sonication, the BBB is disrupted across the whole brain, including cortex and deep grey matter, while continuous wave sonication affects only the ventricles and possibly deeper structures, without opening the cortex BBB. As time passes, the timeline of Gd passage into the brain can be visualized.

Neurochemical Characterization of PSA-NCAM+ Cells in the Human Brain and Phenotypic Quantification in Alzheimer's Disease Entorhinal Cortex.

PubMed

Murray, Helen C; Swanson, Molly E V; Dieriks, B Victor; Turner, Clinton; Faull, Richard L M; Curtis, Maurice A

2018-02-21

Polysialylated neural cell adhesion molecule (PSA-NCAM) is widely expressed in the adult human brain and facilitates structural remodeling of cells through steric inhibition of intercellular NCAM adhesion. We previously showed that PSA-NCAM immunoreactivity is decreased in the entorhinal cortex in Alzheimer's disease (AD). Based on available evidence, we hypothesized that a loss of PSA-NCAM + interneurons may underlie this reduction. PSA-NCAM expression by interneurons has previously been described in the human medial prefrontal cortex. Here we used postmortem human brain tissue to provide further evidence of PSA-NCAM + interneurons throughout the human hippocampal formation and additional cortical regions. Furthermore, PSA-NCAM + cell populations were assessed in the entorhinal cortex of normal and AD cases using fluorescent double labeling and manual cell counting. We found a significant decrease in the number of PSA-NCAM + cells per mm 2 in layer II and V of the entorhinal cortex, supporting our previous description of reduced PSA-NCAM immunoreactivity. Additionally, we found a significant decrease in the proportion of PSA-NCAM + cells that co-labeled with NeuN and parvalbumin, but no change in the proportion that co-labeled with calbindin or calretinin. These results demonstrate that PSA-NCAM is expressed by a variety of interneuron populations throughout the brain. Furthermore, that loss of PSA-NCAM expression by NeuN + cells predominantly contributes to the reduced PSA-NCAM immunoreactivity in the AD entorhinal cortex. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

The cortical language circuit: from auditory perception to sentence comprehension.

PubMed

Friederici, Angela D

2012-05-01

Over the years, a large body of work on the brain basis of language comprehension has accumulated, paving the way for the formulation of a comprehensive model. The model proposed here describes the functional neuroanatomy of the different processing steps from auditory perception to comprehension as located in different gray matter brain regions. It also specifies the information flow between these regions, taking into account white matter fiber tract connections. Bottom-up, input-driven processes proceeding from the auditory cortex to the anterior superior temporal cortex and from there to the prefrontal cortex, as well as top-down, controlled and predictive processes from the prefrontal cortex back to the temporal cortex are proposed to constitute the cortical language circuit. Copyright © 2012 Elsevier Ltd. All rights reserved.

PET Quantification of the Norepinephrine Transporter in Human Brain with (S,S)-18F-FMeNER-D2.

PubMed

Moriguchi, Sho; Kimura, Yasuyuki; Ichise, Masanori; Arakawa, Ryosuke; Takano, Harumasa; Seki, Chie; Ikoma, Yoko; Takahata, Keisuke; Nagashima, Tomohisa; Yamada, Makiko; Mimura, Masaru; Suhara, Tetsuya

2017-07-01

Norepinephrine transporter (NET) in the brain plays important roles in human cognition and the pathophysiology of psychiatric disorders. Two radioligands, ( S , S )- 11 C-MRB and ( S , S )- 18 F-FMeNER-D 2 , have been used for imaging NETs in the thalamus and midbrain (including locus coeruleus) using PET in humans. However, NET density in the equally important cerebral cortex has not been well quantified because of unfavorable kinetics with ( S , S )- 11 C-MRB and defluorination with ( S , S )- 18 F-FMeNER-D 2 , which can complicate NET quantification in the cerebral cortex adjacent to the skull containing defluorinated 18 F radioactivity. In this study, we have established analysis methods of quantification of NET density in the brain including the cerebral cortex using ( S , S )- 18 F-FMeNER-D 2 PET. Methods: We analyzed our previous ( S , S )- 18 F-FMeNER-D 2 PET data of 10 healthy volunteers dynamically acquired for 240 min with arterial blood sampling. The effects of defluorination on the NET quantification in the superficial cerebral cortex was evaluated by establishing a time stability of NET density estimations with an arterial input 2-tissue-compartment model, which guided the less-invasive reference tissue model and area under the time-activity curve methods to accurately quantify NET density in all brain regions including the cerebral cortex. Results: Defluorination of ( S , S )- 18 F-FMeNER-D 2 became prominent toward the latter half of the 240-min scan. Total distribution volumes in the superficial cerebral cortex increased with the scan duration beyond 120 min. We verified that 90-min dynamic scans provided a sufficient amount of data for quantification of NET density unaffected by defluorination. Reference tissue model binding potential values from the 90-min scan data and area under the time-activity curve ratios of 70- to 90-min data allowed for the accurate quantification of NET density in the cerebral cortex. Conclusion: We have established methods of quantification of NET densities in the brain including the cerebral cortex unaffected by defluorination using ( S , S )- 18 F-FMeNER-D 2 These results suggest that we can accurately quantify NET density with a 90-min ( S , S )- 18 F-FMeNER-D 2 scan in broad brain areas. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Exercise training reinstates cortico-cortical sensorimotor functional connectivity following striatal lesioning: Development and application of a subregional-level analytic toolbox for perfusion autoradiographs of the rat brain

NASA Astrophysics Data System (ADS)

Peng, Yu-Hao; Heintz, Ryan; Wang, Zhuo; Guo, Yumei; Myers, Kalisa; Scremin, Oscar; Maarek, Jean-Michel; Holschneider, Daniel

2014-12-01

Current rodent connectome projects are revealing brain structural connectivity with unprecedented resolution and completeness. How subregional structural connectivity relates to subregional functional interactions is an emerging research topic. We describe a method for standardized, mesoscopic-level data sampling from autoradiographic coronal sections of the rat brain, and for correlation-based analysis and intuitive display of cortico-cortical functional connectivity (FC) on a flattened cortical map. A graphic user interface “Cx-2D” allows for the display of significant correlations of individual regions-of-interest, as well as graph theoretical metrics across the cortex. Cx-2D was tested on an autoradiographic data set of cerebral blood flow (CBF) of rats that had undergone bilateral striatal lesions, followed by 4 weeks of aerobic exercise training or no exercise. Effects of lesioning and exercise on cortico-cortical FC were examined during a locomotor challenge in this rat model of Parkinsonism. Subregional FC analysis revealed a rich functional reorganization of the brain in response to lesioning and exercise that was not apparent in a standard analysis focused on CBF of isolated brain regions. Lesioned rats showed diminished degree centrality of lateral primary motor cortex, as well as neighboring somatosensory cortex--changes that were substantially reversed in lesioned rats following exercise training. Seed analysis revealed that exercise increased positive correlations in motor and somatosensory cortex, with little effect in non-sensorimotor regions such as visual, auditory, and piriform cortex. The current analysis revealed that exercise partially reinstated sensorimotor FC lost following dopaminergic deafferentation. Cx-2D allows for standardized data sampling from images of brain slices, as well as analysis and display of cortico-cortical FC in the rat cerebral cortex with potential applications in a variety of autoradiographic and histologic studies.

Localized cortical chronic traumatic encephalopathy pathology after single, severe axonal injury in human brain.

PubMed

Shively, Sharon B; Edgerton, Sarah L; Iacono, Diego; Purohit, Dushyant P; Qu, Bao-Xi; Haroutunian, Vahram; Davis, Kenneth L; Diaz-Arrastia, Ramon; Perl, Daniel P

2017-03-01

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild impact traumatic brain injury from contact sports. Recently, a consensus panel defined the pathognomonic lesion for CTE as accumulations of abnormally hyperphosphorylated tau (p-tau) in neurons (neurofibrillary tangles), astrocytes and cell processes distributed around small blood vessels at sulcal depths in irregular patterns within the cortex. The pathophysiological mechanism for this lesion is unknown. Moreover, a subset of CTE cases harbors cortical β-amyloid plaques. In this study, we analyzed postmortem brain tissues from five institutionalized patients with schizophrenia and history of surgical leucotomy with subsequent survival of at least another 40 years. Because leucotomy involves severing axons bilaterally in prefrontal cortex, this surgical procedure represents a human model of single traumatic brain injury with severe axonal damage and no external impact. We examined cortical tissues at the leucotomy site and at both prefrontal cortex rostral and frontal cortex caudal to the leucotomy site. For comparison, we analyzed brain tissues at equivalent neuroanatomical sites from non-leucotomized patients with schizophrenia, matched in age and gender. All five leucotomy cases revealed severe white matter damage with dense astrogliosis at the axotomy site and also neurofibrillary tangles and p-tau immunoreactive neurites in the overlying gray matter. Four cases displayed p-tau immunoreactivity in neurons, astrocytes and cell processes encompassing blood vessels at cortical sulcal depths in irregular patterns, similar to CTE. The three cases with apolipoprotein E ε4 haplotype showed scattered β-amyloid plaques in the overlying gray matter, but not the two cases with apolipoprotein E ε3/3 genotype. Brain tissue samples from prefrontal cortex rostral and frontal cortex caudal to the leucotomy site, and all cortical samples from the non-leucotomized patients, showed minimal p-tau and β-amyloid pathology. These findings suggest that chronic axonal damage contributes to the unique pathology of CTE over time.

Isolation, structure, synthesis, and activity of a new member of the calcitonin gene-related peptide family from frog skin and molecular cloning of its precursor.

PubMed

Seon, A A; Pierre, T N; Redeker, V; Lacombe, C; Delfour, A; Nicolas, P; Amiche, M

2000-02-25

Calcitonin gene-related peptide has been extracted from the skin exudate of a single living specimen of the frog Phyllomedusa bicolor and purified to homogeneity by a two-step protocol. A total volume of 250 microl of exudate yielded 380 microg of purified peptide. Mass spectrometric analysis and gas phase sequencing of the purified peptide as well as chemical synthesis and cDNA analysis were consistent with the structure SCDTSTCATQRLADFLSRSGGIGSPDFVPTDVSANSF amide and the presence of a disulfide bridge linking Cys(2) and Cys(7). The skin peptide, named skin calcitonin gene-related peptide, differs significantly from all other members of the calcitonin gene-related peptide family of peptides at nine positions but binds with high affinity to calcitonin gene-related peptide receptors in the rat brain and acts as an agonist in the rat vas deferens bioassay with potencies equal to those of human CGRP. Reverse transcriptase-polymerase chain reaction coupled with cDNA cloning and sequencing demonstrated that skin calcitonin gene-related peptide isolated in the skin is identical to that present in the frog's central and enteric nervous systems. These data, which indicate for the first time the existence of calcitonin gene-related peptide in the frog skin, add further support to the brain-skin-gut triangle hypothesis as a useful tool in the identification and/or isolation of mammalian peptides that are present in the brain and other tissues in only minute quantities.

Neuropeptides, Microbiota, and Behavior.

PubMed

Holzer, P

2016-01-01

The gut microbiota and the brain interact with each other through multiple bidirectional signaling pathways in which neuropeptides and neuroactive peptide messengers play potentially important mediator roles. Currently, six particular modes of a neuropeptide link are emerging. (i) Neuropeptides and neurotransmitters contribute to the mutual microbiota-host interaction. (ii) The synthesis of neuroactive peptides is influenced by microbial control of the availability of amino acids. (iii) The activity of neuropeptides is tempered by microbiota-dependent autoantibodies. (iv) Peptide signaling between periphery and brain is modified by a regulatory action of the gut microbiota on the blood-brain barrier. (v) Within the brain, gut hormones released under the influence of the gut microbiota turn into neuropeptides that regulate multiple aspects of brain activity. (vi) Cerebral neuropeptides participate in the molecular, behavioral, and autonomic alterations which the brain undergoes in response to signals from the gut microbiota. © 2016 Elsevier Inc. All rights reserved.

Brain Cortical Thickness Differences in Adolescent Females with Substance Use Disorders.

PubMed

Boulos, Peter K; Dalwani, Manish S; Tanabe, Jody; Mikulich-Gilbertson, Susan K; Banich, Marie T; Crowley, Thomas J; Sakai, Joseph T

2016-01-01

We recruited right-handed female patients, 14-19 years of age, from a university-based treatment program for youths with substance use disorders and community controls similar for age, race and zip code of residence. We obtained 43 T1-weighted structural brain images (22 patients and 21 controls) to examine group differences in cortical thickness across the entire brain as well as six a priori regions-of-interest: 1) medial orbitofrontal cortex; 2) rostral anterior cingulate cortex; and 3) middle frontal cortex, in each hemisphere. Age and IQ were entered as nuisance factors for all analyses. A priori region-of-interest analyses yielded no significant differences. However, whole-brain group comparisons revealed that the left pregenual rostral anterior cingulate cortex extending into the left medial orbitofrontal region (355.84 mm2 in size), a subset of two of our a priori regions-of-interest, was significantly thinner in patients compared to controls (vertex-level threshold p = 0.005 and cluster-level family wise error corrected threshold p = 0.05). The whole-brain group differences did not survive after adjusting for depression or externalizing scores. Whole-brain within-patient analyses demonstrated a positive association between cortical thickness in the left precuneus and behavioral disinhibition scores (458.23 mm2 in size). Adolescent females with substance use disorders have significant differences in brain cortical thickness in regions engaged by the default mode network and that have been associated with problems of emotional dysregulation, inhibition, and behavioral control in past studies.

Aging and Gene Expression in the Primate Brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fraser, Hunter B.; Khaitovich, Philipp; Plotkin, Joshua B.

2005-02-18

It is well established that gene expression levels in many organisms change during the aging process, and the advent of DNA microarrays has allowed genome-wide patterns of transcriptional changes associated with aging to be studied in both model organisms and various human tissues. Understanding the effects of aging on gene expression in the human brain is of particular interest, because of its relation to both normal and pathological neurodegeneration. Here we show that human cerebral cortex, human cerebellum, and chimpanzee cortex each undergo different patterns of age-related gene expression alterations. In humans, many more genes undergo consistent expression changes inmore » the cortex than in the cerebellum; in chimpanzees, many genes change expression with age in cortex, but the pattern of changes in expression bears almost no resemblance to that of human cortex. These results demonstrate the diversity of aging patterns present within the human brain, as well as how rapidly genome-wide patterns of aging can evolve between species; they may also have implications for the oxidative free radical theory of aging, and help to improve our understanding of human neurodegenerative diseases.« less

Regulation of embryonic neurotransmitter and tyrosine hydroxylase protein levels by ascorbic acid

PubMed Central

Meredith, M. Elizabeth; May, James M.

2013-01-01

Scope: Ascorbic acid (ascorbate) is required to recycle tetrahydrobiopterin, which is necessary for neurotransmitter synthesis by the rate-limiting enzymes tyrosine and tryptophan hydroxylases. We sought to determine whether ascorbate might regulate embryonic brain cortex monoamine synthesis utilizing transgenic mouse models with varying intracellular ascorbate levels. Methods and Results: In embryos lacking the sodium-dependent vitamin C transporter 2 (SVCT2), very low levels of brain ascorbate decreased cortex levels of norepinephrine and dopamine by approximately 33%, but had no effect on cortex serotonin or its metabolite, 5-hydroxyindole acetic acid. This decrease in ascorbate also led to a decrease in protein levels of tyrosine hydroxylase, but not of tryptophan hydroxylase. Increased cortex ascorbate in embryos carrying extra copies of the SVCT2 resulted in increased levels of dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), as well as serotonin and 5-hydroxyindole acetic acid. Conclusion: The dependence of embryonic brain cortex neurotransmitter synthesis and tyrosine hydroxylase expression on intracellular ascorbate emphasizes the importance of receiving adequate ascorbate during development. PMID:24095796

Immunological recognition of different forms of the neurotensin receptor in transfected cells and rat brain.

PubMed Central

Boudin, H; Grauz-Guyon, A; Faure, M P; Forgez, P; Lhiaubet, A M; Dennis, M; Beaudet, A; Rostene, W; Pelaprat, D

1995-01-01

In this work, the molecular forms of the rat neurotensin receptor (NTR) expressed in transfected Chinese hamster ovary (CHO) cells, in infected Sf9 insect cells and in rat cerebral cortex were immunologically detected by means of an anti-peptide antibody raised against a fragment of the third intracellular loop of the receptor. Immunoblot experiments against a fusion protein indicated that the anti-peptide antibody recognized, under denaturing conditions, the corresponding amino acid sequence within the NTR. In immunoblot analysis of membranes from NTR-transfected CHO cells, high levels of immunoreactivity were observed between 60 and 72 kDa, while only a faint labelling was observed at 47 kDa, the molecular mass deduced for the rat NTR cDNA. The bands of high molecular mass were no longer observed after deglycosylation of membrane proteins by peptide N-glycosidase F, indicating that they represented glycosylated forms of the receptor. Extracts of membranes derived from baculovirus-infected Sf9 insect-cells expressing the NTR provided a quite different immunoblot pattern, since the major band detected in that case was at 47 kDa, the molecular size of the non-glycosylated receptor. Taken together, these data show that, while most of the NTR protein was glycosylated in CHO cells, it was unglycosylated in Sf9 insect-cells. In addition, molecular sizes of the receptor proteins observed in these two cell lines differed from those obtained for the NTR endogenously expressed in the rat cerebral cortex of 7 day-old rats, where bands at 56 and 54 kDa were detected. Binding experiments carried out on membrane preparations obtained from baculovirus-infected Sf9 cells demonstrated that the immunogenic sequence was still accessible to the antibody when the receptor was embedded in the cell membrane. Immunohistochemical studies carried out on both transfected CHO cells and infected Sf9 cells confirmed this interpretation and further indicated that the antibody could be applied in the visualization of the receptor. Images Figure 1 Figure 2 Figure 3 Figure 5 PMID:7826341

Interpersonal violence in posttraumatic women: brain networks triggered by trauma-related pictures.

PubMed

Neumeister, Paula; Feldker, Katharina; Heitmann, Carina Y; Helmich, Ruth; Gathmann, Bettina; Becker, Michael P I; Straube, Thomas

2017-04-01

Interpersonal violence (IPV) is one of the most frequent causes for the development of posttraumatic stress disorder (PTSD) in women. Trauma-related triggers have been proposed to evoke automatic emotional responses in PTSD. The present functional magnetic resonance study investigated the neural basis of trauma-related picture processing in women with IPV-PTSD (n = 18) relative to healthy controls (n = 18) using a newly standardized trauma-related picture set and a non-emotional vigilance task. We aimed to identify brain activation and connectivity evoked by trauma-related pictures, and associations with PTSD symptom severity. We found hyperactivation during trauma-related vs neutral picture processing in both subcortical [basolateral amygdala (BLA), thalamus, brainstem] and cortical [anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), insula, occipital cortex] regions in IPV-PTSD. In patients, brain activation in amygdala, ACC, insula, occipital cortex and brainstem correlated positively with symptom severity. Furthermore, connectivity analyses revealed hyperconnectivity between BLA and dorsal ACC/mPFC. Results show symptom severity-dependent brain activation and hyperconnectivity in response to trauma-related pictures in brain regions related to fear and visual processing in women suffering from IPV-PTSD. These brain mechanisms appear to be associated with immediate responses to trauma-related triggers presented in a non-emotional context in this PTSD subgroup. © The Author (2016). Published by Oxford University Press.

Intrinsic Brain Connectivity in Chronic Pain: A Resting-State fMRI Study in Patients with Rheumatoid Arthritis

PubMed Central

Flodin, Pär; Martinsen, Sofia; Altawil, Reem; Waldheim, Eva; Lampa, Jon; Kosek, Eva; Fransson, Peter

2016-01-01

Background: Rheumatoid arthritis (RA) is commonly accompanied by pain that is discordant with the degree of peripheral pathology. Very little is known about the cerebral processes involved in pain processing in RA. Here we investigated resting-state brain connectivity associated with prolonged pain in RA. Methods: 24 RA subjects and 19 matched controls were compared with regard to both behavioral measures of pain perception and resting-resting state fMRI data acquired subsequently to fMRI sessions involving pain stimuli. The resting-state fMRI brain connectivity was investigated using 159 seed regions located in cardinal pain processing brain regions. Additional principal component based multivariate pattern analysis of the whole brain connectivity pattern was carried out in a data driven analysis to localize group differences in functional connectivity. Results: When RA patients were compared to controls, we observed significantly lower pain resilience for pressure on the affected finger joints (i.e., P50-joint) and an overall heightened level of perceived global pain in RA patients. Relative to controls, RA patients displayed increased brain connectivity predominately for the supplementary motor areas, mid-cingulate cortex, and the primary sensorimotor cortex. Additionally, we observed an increase in brain connectivity between the insula and prefrontal cortex as well as between anterior cingulate cortex and occipital areas for RA patients. None of the group differences in brain connectivity were significantly correlated with behavioral parameters. Conclusion: Our study provides experimental evidence of increased connectivity between frontal midline regions that are implicated in affective pain processing and bilateral sensorimotor regions in RA patients. PMID:27014038

[The negative side of emotions: addiction to drugs of abuse].

PubMed

Contreras, M; Ceric, F; Torrealba, F

According to the model of emotions, feelings have their origin in the conscious perception of body changes produced in response to an emotional stimulus. These changes are perceived thanks to the fact that they are represented in the brain by the interoceptive system. During abstinence, addicts experience intense feelings of ill-being that drive them to consume drugs. The purpose of this review is to discuss the role played by the interoceptive system, and more especially the insular cortex, in the perception of the negative feelings that characterise abstinence. The continuous processing of interoceptive signals in the insular cortex is what accounts for the conscious appreciation of the body changes that accompany an emotional state. Temporary inactivation of the insular cortex suppresses the search for drugs in addicted rats. Neuroimaging studies reveal an increase in the neuronal activity in the insular cortex and in other areas of the brain while addicts are experiencing the craving to consume drugs. Likewise, nicotine addicts who suffer a brain injury that affects the insular cortex give up smoking easily because they lose the desire to do it. The temporary suppression of neuronal activity in the insular cortex in human addicts by means of non-invasive techniques could be a new therapy to treat the craving to consume drugs. The insular cortex is essential in the perception of the emotional states and in orienting behaviour to match the needs of the body. New therapies that have the insular cortex as their target could be developed to mitigate craving.

Parahippocampal Cortex Mediates the Relationship between Lutein and Crystallized Intelligence in Healthy, Older Adults

PubMed Central

Zamroziewicz, Marta K.; Paul, Erick J.; Zwilling, Chris E.; Johnson, Elizabeth J.; Kuchan, Matthew J.; Cohen, Neal J.; Barbey, Aron K.

2016-01-01

Introduction: Although, diet has a substantial influence on the aging brain, the relationship between dietary nutrients and aspects of brain health remains unclear. This study examines the neural mechanisms that mediate the relationship between a carotenoid important for brain health across the lifespan, lutein, and crystallized intelligence in cognitively intact older adults. We hypothesized that higher serum levels of lutein are associated with better performance on a task of crystallized intelligence, and that this relationship is mediated by gray matter structure of regions within the temporal cortex. This investigation aims to contribute to a growing line of evidence, which suggests that particular nutrients may slow or prevent aspects of cognitive decline by targeting specific features of brain aging. Methods: We examined 76 cognitively intact adults between the ages of 65 and 75 to investigate the relationship between serum lutein, tests of crystallized intelligence (measured by the Wechsler Abbreviated Scale of Intelligence), and gray matter volume of regions within the temporal cortex. A three-step mediation analysis was implemented using multivariate linear regressions to control for age, sex, education, income, depression status, and body mass index. Results: The mediation analysis revealed that gray matter thickness of one region within the temporal cortex, the right parahippocampal cortex (Brodmann's Area 34), partially mediates the relationship between serum lutein and crystallized intelligence. Conclusion: These results suggest that the parahippocampal cortex acts as a mediator of the relationship between serum lutein and crystallized intelligence in cognitively intact older adults. Prior findings substantiate the individual relationships reported within the mediation, specifically the links between (i) serum lutein and temporal cortex structure, (ii) serum lutein and crystallized intelligence, and (iii) parahippocampal cortex structure and crystallized intelligence. This report demonstrates a novel structural mediation between lutein status and crystallized intelligence, and therefore provides further evidence that specific nutrients may slow or prevent features of cognitive decline by hindering particular aspects of brain aging. Future work should examine the potential mechanisms underlying this mediation, including the antioxidant, anti-inflammatory, and membrane modulating properties of lutein. PMID:27999541

Bayesian estimation inherent in a Mexican-hat-type neural network

NASA Astrophysics Data System (ADS)

Takiyama, Ken

2016-05-01

Brain functions, such as perception, motor control and learning, and decision making, have been explained based on a Bayesian framework, i.e., to decrease the effects of noise inherent in the human nervous system or external environment, our brain integrates sensory and a priori information in a Bayesian optimal manner. However, it remains unclear how Bayesian computations are implemented in the brain. Herein, I address this issue by analyzing a Mexican-hat-type neural network, which was used as a model of the visual cortex, motor cortex, and prefrontal cortex. I analytically demonstrate that the dynamics of an order parameter in the model corresponds exactly to a variational inference of a linear Gaussian state-space model, a Bayesian estimation, when the strength of recurrent synaptic connectivity is appropriately stronger than that of an external stimulus, a plausible condition in the brain. This exact correspondence can reveal the relationship between the parameters in the Bayesian estimation and those in the neural network, providing insight for understanding brain functions.

Lip movements entrain the observers’ low-frequency brain oscillations to facilitate speech intelligibility

PubMed Central

Park, Hyojin; Kayser, Christoph; Thut, Gregor; Gross, Joachim

2016-01-01

During continuous speech, lip movements provide visual temporal signals that facilitate speech processing. Here, using MEG we directly investigated how these visual signals interact with rhythmic brain activity in participants listening to and seeing the speaker. First, we investigated coherence between oscillatory brain activity and speaker’s lip movements and demonstrated significant entrainment in visual cortex. We then used partial coherence to remove contributions of the coherent auditory speech signal from the lip-brain coherence. Comparing this synchronization between different attention conditions revealed that attending visual speech enhances the coherence between activity in visual cortex and the speaker’s lips. Further, we identified a significant partial coherence between left motor cortex and lip movements and this partial coherence directly predicted comprehension accuracy. Our results emphasize the importance of visually entrained and attention-modulated rhythmic brain activity for the enhancement of audiovisual speech processing. DOI: http://dx.doi.org/10.7554/eLife.14521.001 PMID:27146891

Peptidomic analysis of the neurolysin-knockout mouse brain.

PubMed

Castro, Leandro M; Cavalcanti, Diogo M L P; Araujo, Christiane B; Rioli, Vanessa; Icimoto, Marcelo Y; Gozzo, Fábio C; Juliano, Maria; Juliano, Luiz; Oliveira, Vitor; Ferro, Emer S

2014-12-05

A large number of intracellular peptides are constantly produced following protein degradation by the proteasome. A few of these peptides function in cell signaling and regulate protein-protein interactions. Neurolysin (Nln) is a structurally defined and biochemically well-characterized endooligopeptidase, and its subcellular distribution and biological activity in the vertebrate brain have been previously investigated. However, the contribution of Nln to peptide metabolism in vivo is poorly understood. In this study, we used quantitative mass spectrometry to investigate the brain peptidome of Nln-knockout mice. An additional in vitro digestion assay with recombinant Nln was also performed to confirm the identification of the substrates and/or products of Nln. Altogether, the data presented suggest that Nln is a key enzyme in the in vivo degradation of only a few peptides derived from proenkephalin, such as Met-enkephalin and octapeptide. Nln was found to have only a minor contribution to the intracellular peptide metabolism in the entire mouse brain. However, further studies appear necessary to investigate the contribution of Nln to the peptide metabolism in specific areas of the murine brain. Neurolysin was first identified in the synaptic membranes of the rat brain in the middle 80's by Frederic Checler and colleagues. Neurolysin was well characterized biochemically, and its brain distribution has been confirmed by immunohistochemical methods. The neurolysin contribution to the central and peripheral neurotensin-mediated functions in vivo has been delineated through inhibitor-based pharmacological approaches, but its genuine contribution to the physiological inactivation of neuropeptides remains to be firmly established. As a result, the main significance of this work is the first characterization of the brain peptidome of the neurolysin-knockout mouse. This article is part of a Special Issue entitled: Proteomics, mass spectrometry and peptidomics, Cancun 2013. Guest Editors: César López-Camarillo, Victoria Pando-Robles and Bronwyn Jane Barkla. Copyright © 2014. Published by Elsevier B.V.

Exploratory Metabolomic Analyses Reveal Compounds Correlated with Lutein Concentration in Frontal Cortex, Hippocampus, and Occipital Cortex of Human Infant Brain

PubMed Central

Lieblein-Boff, Jacqueline C.; Johnson, Elizabeth J.; Kennedy, Adam D.; Lai, Chron-Si; Kuchan, Matthew J.

2015-01-01

Lutein is a dietary carotenoid well known for its role as an antioxidant in the macula, and recent reports implicate a role for lutein in cognitive function. Lutein is the dominant carotenoid in both pediatric and geriatric brain tissue. In addition, cognitive function in older adults correlated with macular and postmortem brain lutein concentrations. Furthermore, lutein was found to preferentially accumulate in the infant brain in comparison to other carotenoids that are predominant in diet. While lutein is consistently related to cognitive function, the mechanisms by which lutein may influence cognition are not clear. In an effort to identify potential mechanisms through which lutein might influence neurodevelopment, an exploratory study relating metabolite signatures and lutein was completed. Post-mortem metabolomic analyses were performed on human infant brain tissues in three regions important for learning and memory: the frontal cortex, hippocampus, and occipital cortex. Metabolomic profiles were compared to lutein concentration, and correlations were identified and reported here. A total of 1276 correlations were carried out across all brain regions. Of 427 metabolites analyzed, 257 were metabolites of known identity. Unidentified metabolite correlations (510) were excluded. In addition, moderate correlations with xenobiotic relationships (2) or those driven by single outliers (3) were excluded from further study. Lutein concentrations correlated with lipid pathway metabolites, energy pathway metabolites, brain osmolytes, amino acid neurotransmitters, and the antioxidant homocarnosine. These correlations were often brain region—specific. Revealing relationships between lutein and metabolic pathways may help identify potential candidates on which to complete further analyses and may shed light on important roles of lutein in the human brain during development. PMID:26317757

Brain signal complexity rises with repetition suppression in visual learning.

PubMed

Lafontaine, Marc Philippe; Lacourse, Karine; Lina, Jean-Marc; McIntosh, Anthony R; Gosselin, Frédéric; Théoret, Hugo; Lippé, Sarah

2016-06-21

Neuronal activity associated with visual processing of an unfamiliar face gradually diminishes when it is viewed repeatedly. This process, known as repetition suppression (RS), is involved in the acquisition of familiarity. Current models suggest that RS results from interactions between visual information processing areas located in the occipito-temporal cortex and higher order areas, such as the dorsolateral prefrontal cortex (DLPFC). Brain signal complexity, which reflects information dynamics of cortical networks, has been shown to increase as unfamiliar faces become familiar. However, the complementarity of RS and increases in brain signal complexity have yet to be demonstrated within the same measurements. We hypothesized that RS and brain signal complexity increase occur simultaneously during learning of unfamiliar faces. Further, we expected alteration of DLPFC function by transcranial direct current stimulation (tDCS) to modulate RS and brain signal complexity over the occipito-temporal cortex. Participants underwent three tDCS conditions in random order: right anodal/left cathodal, right cathodal/left anodal and sham. Following tDCS, participants learned unfamiliar faces, while an electroencephalogram (EEG) was recorded. Results revealed RS over occipito-temporal electrode sites during learning, reflected by a decrease in signal energy, a measure of amplitude. Simultaneously, as signal energy decreased, brain signal complexity, as estimated with multiscale entropy (MSE), increased. In addition, prefrontal tDCS modulated brain signal complexity over the right occipito-temporal cortex during the first presentation of faces. These results suggest that although RS may reflect a brain mechanism essential to learning, complementary processes reflected by increases in brain signal complexity, may be instrumental in the acquisition of novel visual information. Such processes likely involve long-range coordinated activity between prefrontal and lower order visual areas. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

512-Channel and 13-Region Simultaneous Recordings Coupled with Optogenetic Manipulation in Freely Behaving Mice

PubMed Central

Xie, Kun; Fox, Grace E.; Liu, Jun; Tsien, Joe Z.

2016-01-01

The development of technologies capable of recording both single-unit activity and local field potentials (LFPs) over a wide range of brain circuits in freely behaving animals is the key to constructing brain activity maps. Although mice are the most popular mammalian genetic model, in vivo neural recording has been traditionally limited to smaller channel count and fewer brain structures because of the mouse’s small size and thin skull. Here, we describe a 512-channel tetrode system that allows us to record simultaneously over a dozen cortical and subcortical structures in behaving mice. This new technique offers two major advantages – namely, the ultra-low cost and the do-it-yourself flexibility for targeting any combination of many brain areas. We show the successful recordings of both single units and LFPs from 13 distinct neural circuits of the mouse brain, including subregions of the anterior cingulate cortices, retrosplenial cortices, somatosensory cortices, secondary auditory cortex, hippocampal CA1, dentate gyrus, subiculum, lateral entorhinal cortex, perirhinal cortex, and prelimbic cortex. This 512-channel system can also be combined with Cre-lox neurogenetics and optogenetics to further examine interactions between genes, cell types, and circuit dynamics across a wide range of brain structures. Finally, we demonstrate that complex stimuli – such as an earthquake and fear-inducing foot-shock – trigger firing changes in all of the 13 brain regions recorded, supporting the notion that neural code is highly distributed. In addition, we show that localized optogenetic manipulation in any given brain region could disrupt network oscillations and caused changes in single-unit firing patterns in a brain-wide manner, thereby raising the cautionary note of the interpretation of optogenetically manipulated behaviors. PMID:27378865

Brain Functional Connectivity Is Modified by a Hypocaloric Mediterranean Diet and Physical Activity in Obese Women.

PubMed

García-Casares, Natalia; Bernal-López, María R; Roé-Vellvé, Nuria; Gutiérrez-Bedmar, Mario; Fernández-García, Jose C; García-Arnés, Juan A; Ramos-Rodriguez, José R; Alfaro, Francisco; Santamaria-Fernández, Sonia; Steward, Trevor; Jiménez-Murcia, Susana; Garcia-Garcia, Isabel; Valdivielso, Pedro; Fernández-Aranda, Fernando; Tinahones, Francisco J; Gómez-Huelgas, Ricardo

2017-07-01

Functional magnetic resonance imaging (fMRI) in the resting state has shown altered brain connectivity networks in obese individuals. However, the impact of a Mediterranean diet on cerebral connectivity in obese patients when losing weight has not been previously explored. The aim of this study was to examine the connectivity between brain structures before and six months after following a hypocaloric Mediterranean diet and physical activity program in a group of sixteen obese women aged 46.31 ± 4.07 years. Before and after the intervention program, the body mass index (BMI) (kg/m²) was 38.15 ± 4.7 vs. 34.18 ± 4.5 ( p < 0.02), and body weight (kg) was 98.5 ± 13.1 vs. 88.28 ± 12.2 ( p < 0.03). All subjects underwent a pre- and post-intervention fMRI under fasting conditions. Functional connectivity was assessed using seed-based correlations. After the intervention, we found decreased connectivity between the left inferior parietal cortex and the right temporal cortex ( p < 0.001), left posterior cingulate ( p < 0.001), and right posterior cingulate ( p < 0.03); decreased connectivity between the left superior frontal gyrus and the right temporal cortex ( p < 0.01); decreased connectivity between the prefrontal cortex and the somatosensory cortex ( p < 0.025); and decreased connectivity between the left and right posterior cingulate ( p < 0.04). Results were considered significant at a voxel-wise threshold of p ≤ 0.05, and a cluster-level family-wise error correction for multiple comparisons of p ≤ 0.05. In conclusion, functional connectivity between brain structures involved in the pathophysiology of obesity (the inferior parietal lobe, posterior cingulate, temporo-insular cortex, prefrontal cortex) may be modified by a weight loss program including a Mediterranean diet and physical exercise.

Evaluation of Krebs cycle enzymes in the brain of rats after chronic administration of antidepressants.

PubMed

Scaini, Giselli; Santos, Patricia M; Benedet, Joana; Rochi, Natália; Gomes, Lara M; Borges, Lislaine S; Rezin, Gislaine T; Pezente, Daiana P; Quevedo, João; Streck, Emilio L

2010-05-31

Several works report brain impairment of metabolism as a mechanism underlying depression. Citrate synthase and succinate dehydrogenase are enzymes localized within cells in the mitochondrial matrix and are important steps of Krebs cycle. In addition, citrate synthase has been used as a quantitative enzyme marker for the presence of intact mitochondria. Thus, we investigated citrate synthase and succinate dehydrogenase activities from rat brain after chronic administration of paroxetine, nortriptiline and venlafaxine. Adult male Wistar rats received daily injections of paroxetine (10mg/kg), nortriptiline (15mg/kg), venlafaxine (10mg/kg) or saline in 1.0mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activities of citrate synthase and succinate dehydrogenase were measured. We verified that chronic administration of paroxetine increased citrate synthase activity in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected. Chronic administration of nortriptiline and venlafaxine did not affect the enzyme activity in these brain areas. Succinate dehydrogenase activity was increased by chronic administration of paroxetine and nortriptiline in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected either. Chronic administration of venlafaxine increased succinate dehydrogenase activity in prefrontal cortex, but did not affect the enzyme activity in cerebellum, hippocampus, striatum and cerebral cortex. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in these enzymes by antidepressants may be an important mechanism of action of these drugs. Copyright (c) 2010 Elsevier Inc. All rights reserved.

[Effects of noxious coldness and non-noxious warmth on the magnitude of cerebral cortex activation during intraoral stimulation with water].

PubMed

Xiuwen, Yang; Hongchen, Liu; Ke, Li; Zhen, Jin; Gang, Liu

2014-12-01

We used functional magnetic resonance imaging (fMRI) to explore the effects of noxious coldness and non-noxious warmth on the magnitude of cerebral cortex activation during intraoral stimulation with water. Six male and female subjects were subjected to whole-brain fMRI during the phasic delivery of non-noxious hot (23 °C) and no- xious cold (4 °C) water intraoral stimulation. A block-design blood oxygenation level-dependent fMRI scan covering the entire brain was also carried out. The activated cortical areas were as follows: left pre-/post-central gyrus, insula/operculum, anterior cingulate cortex (ACC), orbital frontal cortex (OFC), midbrain red nucleus, and thalamus. The activated cortical areas under cold condition were as follows: left occipital lobe, premotor cortex/Brodmann area (BA) 6, right motor language area BA44, lingual gyrus, parietal lobule (BA7, 40), and primary somatosensory cortex S I. Comparisons of the regional cerebral blood flow response magnitude were made among stereotactically concordant brain regions that showed significant responses under the two conditions of this study. Compared with non-noxious warmth, more regions were activated in noxious coldness, and the magnitude of activation in areas produced after non-noxious warm stimulation significantly increased. However, ACC only significantly increased the magnitude of activation under noxious coldness stimulation. Results suggested that a similar network of regions was activated common to the perception of pain and no-pain produced by either non-noxious warmth or noxious coldness stimulation. Non-noxious warmth also activated more brain regions and significantly increased the response magnitude of cerebral-cortex activation compared with noxious coldness. Noxious coldness stimulation further significantly increased the magnitude of activation in ACC areas compared with noxious warmth.

Neural Correlates of Memories of Childhood Sexual Abuse in Women With and Without Posttraumatic Stress Disorder

PubMed Central

Bremner, J. Douglas; Narayan, Meena; Staib, Lawrence H.; Southwick, Steven M.; McGlashan, Thomas; Charney, Dennis S.

2011-01-01

Objective Childhood sexual abuse is very common in our society, but little is known about the long-term effects of abuse on brain function. The purpose of this study was to measure neural correlates of memories of childhood abuse in sexually abused women with and without the diagnosis of posttraumatic stress disorder (PTSD). Method Twenty-two women with a history of childhood sexual abuse underwent injection of [15O]H2O, followed by positron emission tomography imaging of the brain while they listened to neutral and traumatic (personalized childhood sexual abuse events) scripts. Brain blood flow during exposure to traumatic and neutral scripts was compared for sexually abused women with and without PTSD. Results Memories of childhood sexual abuse were associated with greater increases in blood flow in portions of anterior prefrontal cortex (superior and middle frontal gyri—areas 6 and 9), posterior cingulate (area 31), and motor cortex in sexually abused women with PTSD than in sexually abused women without PTSD. Abuse memories were associated with alterations in blood flow in medial prefrontal cortex, with decreased blood flow in subcallosal gyrus (area 25), and a failure of activation in anterior cingulate (area 32). There was also decreased blood flow in right hippocampus, fusiform/inferior temporal gyrus, supramarginal gyrus, and visual association cortex in women with PTSD relative to women without PTSD. Conclusions These findings implicate dysfunction of medial prefrontal cortex (subcallosal gyrus and anterior cingulate), hippocampus, and visual association cortex in pathological memories of childhood abuse in women with PTSD. Increased activation in posterior cingulate and motor cortex was seen in women with PTSD. Dysfunction in these brain areas may underlie PTSD symptoms provoked by traumatic reminders in subjects with PTSD. PMID:10553744

Induction of the antimicrobial peptide CRAMP in the blood-brain barrier and meninges after meningococcal infection.

PubMed

Bergman, Peter; Johansson, Linda; Wan, Hong; Jones, Allison; Gallo, Richard L; Gudmundsson, Gudmundur H; Hökfelt, Tomas; Jonsson, Ann-Beth; Agerberth, Birgitta

2006-12-01

Antimicrobial peptides are present in most living species and constitute important effector molecules of innate immunity. Recently, we and others have detected antimicrobial peptides in the brain. This is an organ that is rarely infected, which has mainly been ascribed to the protective functions of the blood-brain barrier (BBB) and meninges. Since the bactericidal properties of the BBB and meninges are not known, we hypothesized that antimicrobial peptides could play a role in these barriers. We addressed this hypothesis by infecting mice with the neuropathogenic bacterium Neisseria meningitidis. Brains were analyzed for expression of the antimicrobial peptide CRAMP by immunohistochemistry in combination with confocal microscopy. After infection, we observed induction of CRAMP in endothelial cells of the BBB and in cells of the meninges. To explore the functional role of CRAMP in meningococcal disease, we infected mice deficient of the CRAMP gene. Even though CRAMP did not appear to protect the brain from invasion of meningococci, CRAMP knockout mice were more susceptible to meningococcal infection than wild-type mice and exhibited increased meningococcal growth in blood, liver, and spleen. Moreover, we could demonstrate that carbonate, a compound that accumulates in the circulation during metabolic acidosis, makes meningococci more susceptible to CRAMP.

Induction of the Antimicrobial Peptide CRAMP in the Blood-Brain Barrier and Meninges after Meningococcal Infection▿

PubMed Central

Bergman, Peter; Johansson, Linda; Wan, Hong; Jones, Allison; Gallo, Richard L.; Gudmundsson, Gudmundur H.; Hökfelt, Tomas; Jonsson, Ann-Beth; Agerberth, Birgitta

2006-01-01

Antimicrobial peptides are present in most living species and constitute important effector molecules of innate immunity. Recently, we and others have detected antimicrobial peptides in the brain. This is an organ that is rarely infected, which has mainly been ascribed to the protective functions of the blood-brain barrier (BBB) and meninges. Since the bactericidal properties of the BBB and meninges are not known, we hypothesized that antimicrobial peptides could play a role in these barriers. We addressed this hypothesis by infecting mice with the neuropathogenic bacterium Neisseria meningitidis. Brains were analyzed for expression of the antimicrobial peptide CRAMP by immunohistochemistry in combination with confocal microscopy. After infection, we observed induction of CRAMP in endothelial cells of the BBB and in cells of the meninges. To explore the functional role of CRAMP in meningococcal disease, we infected mice deficient of the CRAMP gene. Even though CRAMP did not appear to protect the brain from invasion of meningococci, CRAMP knockout mice were more susceptible to meningococcal infection than wild-type mice and exhibited increased meningococcal growth in blood, liver, and spleen. Moreover, we could demonstrate that carbonate, a compound that accumulates in the circulation during metabolic acidosis, makes meningococci more susceptible to CRAMP. PMID:17030578

Complex Regional Pain Syndrome Type I Affects Brain Structure in Prefrontal and Motor Cortex

PubMed Central

Pleger, Burkhard; Draganski, Bogdan; Schwenkreis, Peter; Lenz, Melanie; Nicolas, Volkmar; Maier, Christoph; Tegenthoff, Martin

2014-01-01

The complex regional pain syndrome (CRPS) is a rare but debilitating pain disorder that mostly occurs after injuries to the upper limb. A number of studies indicated altered brain function in CRPS, whereas possible influences on brain structure remain poorly investigated. We acquired structural magnetic resonance imaging data from CRPS type I patients and applied voxel-by-voxel statistics to compare white and gray matter brain segments of CRPS patients with matched controls. Patients and controls were statistically compared in two different ways: First, we applied a 2-sample ttest to compare whole brain white and gray matter structure between patients and controls. Second, we aimed to assess structural alterations specifically of the primary somatosensory (S1) and motor cortex (M1) contralateral to the CRPS affected side. To this end, MRI scans of patients with left-sided CRPS (and matched controls) were horizontally flipped before preprocessing and region-of-interest-based group comparison. The unpaired ttest of the “non-flipped” data revealed that CRPS patients presented increased gray matter density in the dorsomedial prefrontal cortex. The same test applied to the “flipped” data showed further increases in gray matter density, not in the S1, but in the M1 contralateral to the CRPS-affected limb which were inversely related to decreased white matter density of the internal capsule within the ipsilateral brain hemisphere. The gray-white matter interaction between motor cortex and internal capsule suggests compensatory mechanisms within the central motor system possibly due to motor dysfunction. Altered gray matter structure in dorsomedial prefrontal cortex may occur in response to emotional processes such as pain-related suffering or elevated analgesic top-down control. PMID:24416397

Neuroimaging and Neuromodulation: Complementary Approaches for Identifying the Neuronal Correlates of Tinnitus

PubMed Central

Langguth, Berthold; Schecklmann, Martin; Lehner, Astrid; Landgrebe, Michael; Poeppl, Timm Benjamin; Kreuzer, Peter Michal; Schlee, Winfried; Weisz, Nathan; Vanneste, Sven; De Ridder, Dirk

2012-01-01

An inherent limitation of functional imaging studies is their correlational approach. More information about critical contributions of specific brain regions can be gained by focal transient perturbation of neural activity in specific regions with non-invasive focal brain stimulation methods. Functional imaging studies have revealed that tinnitus is related to alterations in neuronal activity of central auditory pathways. Modulation of neuronal activity in auditory cortical areas by repetitive transcranial magnetic stimulation (rTMS) can reduce tinnitus loudness and, if applied repeatedly, exerts therapeutic effects, confirming the relevance of auditory cortex activation for tinnitus generation and persistence. Measurements of oscillatory brain activity before and after rTMS demonstrate that the same stimulation protocol has different effects on brain activity in different patients, presumably related to interindividual differences in baseline activity in the clinically heterogeneous study cohort. In addition to alterations in auditory pathways, imaging techniques also indicate the involvement of non-auditory brain areas, such as the fronto-parietal “awareness” network and the non-tinnitus-specific distress network consisting of the anterior cingulate cortex, anterior insula, and amygdale. Involvement of the hippocampus and the parahippocampal region putatively reflects the relevance of memory mechanisms in the persistence of the phantom percept and the associated distress. Preliminary studies targeting the dorsolateral prefrontal cortex, the dorsal anterior cingulate cortex, and the parietal cortex with rTMS and with transcranial direct current stimulation confirm the relevance of the mentioned non-auditory networks. Available data indicate the important value added by brain stimulation as a complementary approach to neuroimaging for identifying the neuronal correlates of the various clinical aspects of tinnitus. PMID:22509155

Effects of the Brain-Derived Neurotrophic Factor Val66Met polymorphism and resting brain functional connectivity on individual differences in tactile cognitive performance in healthy young adults.

PubMed

Yang, Xuejuan; Xu, Ziliang; Liu, Lin; Liu, Peng; Sun, Jinbo; Jin, Lingmin; Zhu, Yuanqiang; Fei, Ningbo; Qin, Wei

2017-07-28

Cognitive processes involve input from multiple sensory modalities and obvious differences in the level of cognitive function can be observed between individuals. Evidence to date understanding the biological basis of tactile cognitive variability, however, is limited compared with other forms of sensory cognition. Data from auditory and visual cognition research suggest that variations in both genetics and intrinsic brain function might contribute to individual differences in tactile cognitive performance. In the present study, by using the tactual performance test (TPT), a widely used neuropsychological assessment tool, we investigated the effects of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and resting-state brain functional connectivity (FC) on interindividual variability in TPT performance in healthy, young Chinese adults. Our results showed that the BDNF genotypes and resting-state FC had significant effects on the variability in TPT performance, together accounting for 32.5% and 19.1% of the variance on TPT total score and Memory subitem score respectively. Having fewer Met alleles, stronger anticorrelations between left posterior superior temporal gyrus and somatosensory areas (right postcentral gyrus and right parietal operculum cortex), and greater positive correlation between left parietal operculum cortex and left central opercular cortex, all correspond with better performance of TPT task. And FC between left parietal operculum cortex and left central opercular cortex might be a mediator of the relationship between BDNF genotypes and Memory subitem score. These data demonstrate a novel contribution of intrinsic brain function to tactile cognitive capacity, and further confirm the genetic basis of tactile cognition. Our findings might also explain the interindividual differences in cognitive ability observed in those who are blind and/or deaf from a new perspective. Copyright © 2017. Published by Elsevier Ltd.

Neuroprotective effects of yoga practice: age-, experience-, and frequency-dependent plasticity

PubMed Central

Villemure, Chantal; Čeko, Marta; Cotton, Valerie A.; Bushnell, M. Catherine

2015-01-01

Yoga combines postures, breathing, and meditation. Despite reported health benefits, yoga’s effects on the brain have received little study. We used magnetic resonance imaging to compare age-related gray matter (GM) decline in yogis and controls. We also examined the effect of increasing yoga experience and weekly practice on GM volume and assessed which aspects of weekly practice contributed most to brain size. Controls displayed the well documented age-related global brain GM decline while yogis did not, suggesting that yoga contributes to protect the brain against age-related decline. Years of yoga experience correlated mostly with GM volume differences in the left hemisphere (insula, frontal operculum, and orbitofrontal cortex) suggesting that yoga tunes the brain toward a parasympatically driven mode and positive states. The number of hours of weekly practice correlated with GM volume in the primary somatosensory cortex/superior parietal lobule (S1/SPL), precuneus/posterior cingulate cortex (PCC), hippocampus, and primary visual cortex (V1). Commonality analyses indicated that the combination of postures and meditation contributed the most to the size of the hippocampus, precuneus/PCC, and S1/SPL while the combination of meditation and breathing exercises contributed the most to V1 volume. Yoga’s potential neuroprotective effects may provide a neural basis for some of its beneficial effects. PMID:26029093

Monocrotaline: Histological Damage and Oxidant Activity in Brain Areas of Mice

PubMed Central

Honório Junior, José Eduardo Ribeiro; Vasconcelos, Germana Silva; Rodrigues, Francisca Taciana Sousa; Sena Filho, José Guedes; Barbosa-Filho, José Maria; Aguiar, Carlos Clayton Torres; Leal, Luzia Kalyne Almeida Moreira; Soares, Pedro Marcos Gomes; Woods, David John; Fonteles, Marta Maria de França; Vasconcelos, Silvânia Maria Mendes

2012-01-01

This work was designed to study MCT effect in histopathological analysis of hippocampus (HC) and parahippocampal cortex (PHC) and in oxidative stress (OS) parameters in brain areas such as hippocampus (HC), prefrontal cortex (PFC), and striatum (ST). Swiss mice (25–30 g) were administered a single i.p. dose of MCT (5, 50, or 100 mg/kg) or 4% Tween 80 in saline (control group). After 30 minutes, the animals were sacrificed by decapitation and the brain areas (HC, PHC, PFC, or ST) were removed for histopathological analysis or dissected and homogenized for measurement of OS parameters (lipid peroxidation, nitrite, and catalase) by spectrophotometry. Histological evaluation of brain structures of rats treated with MCT (50 and 100 mg/kg) revealed lesions in the hippocampus and parahippocampal cortex compared to control. Lipid peroxidation was evident in all brain areas after administration of MCT. Nitrite/nitrate content decreased in all doses administered in HC, PFC, and ST. Catalase activity was increased in the MCT group only in HC. In conclusion, monocrotaline caused cell lesions in the hippocampus and parahippocampal cortex regions and produced oxidative stress in the HC, PFC, and ST in mice. These findings may contribute to the neurological effects associated with this compound. PMID:23251721

Voxel-based comparison of brain glucose metabolism between patients with Cushing's disease and healthy subjects.

PubMed

Liu, Shuai; Wang, Yinyan; Xu, Kaibin; Ping, Fan; Li, Fang; Wang, Renzhi; Cheng, Xin

2018-01-01

Cognitive impairment and psychiatric symptoms are common in patients with Cushing's disease (CD) owing to elevated levels of glucocorticoids. Molecular neuroimaging methods may help to detect changes in the brain of patients with CD. The aim of this study was to investigate the characteristics of brain metabolism and its association with serum cortisol level in CD. We compared brain metabolism, as measured using [ 18 F]-fluorodeoxyglucose positron emission tomography (FDG PET), between 92 patients with CD and 118 normal subjects on a voxel-wise basis. Pearson correlation was performed to evaluate the association between cerebral FDG uptake and serum cortisol level in patients with CD. We demonstrated that certain brain regions in patients with CD showed significantly increased FDG uptake, including the basal ganglia, anteromedial temporal lobe, thalamus, precentral cortex, and cerebellum. The clusters that demonstrated significantly decreased uptake were mainly located in the medial and lateral frontal cortex, superior and inferior parietal lobule, medial occipital cortex, and insular cortex. The metabolic rate of the majority of these regions was found to be significantly correlated with the serum cortisol level. Our findings may help to explain the underlying mechanisms of cognitive impairment and psychiatric symptoms in patients exposed to excessive glucocorticoids and evaluate the efficacy of treatments during follow-up.

Sharing self-related information is associated with intrinsic functional connectivity of cortical midline brain regions

PubMed Central

Meshi, Dar; Mamerow, Loreen; Kirilina, Evgeniya; Morawetz, Carmen; Margulies, Daniel S.; Heekeren, Hauke R.

2016-01-01

Human beings are social animals and they vary in the degree to which they share information about themselves with others. Although brain networks involved in self-related cognition have been identified, especially via the use of resting-state experiments, the neural circuitry underlying individual differences in the sharing of self-related information is currently unknown. Therefore, we investigated the intrinsic functional organization of the brain with respect to participants’ degree of self-related information sharing using resting state functional magnetic resonance imaging and self-reported social media use. We conducted seed-based correlation analyses in cortical midline regions previously shown in meta-analyses to be involved in self-referential cognition: the medial prefrontal cortex (MPFC), central precuneus (CP), and caudal anterior cingulate cortex (CACC). We examined whether and how functional connectivity between these regions and the rest of the brain was associated with participants’ degree of self-related information sharing. Analyses revealed associations between the MPFC and right dorsolateral prefrontal cortex (DLPFC), as well as the CP with the right DLPFC, the left lateral orbitofrontal cortex and left anterior temporal pole. These findings extend our present knowledge of functional brain connectivity, specifically demonstrating how the brain’s intrinsic functional organization relates to individual differences in the sharing of self-related information. PMID:26948055

Social Distance Evaluation in Human Parietal Cortex

PubMed Central

Yamakawa, Yoshinori; Kanai, Ryota; Matsumura, Michikazu; Naito, Eiichi

2009-01-01

Across cultures, social relationships are often thought of, described, and acted out in terms of physical space (e.g. “close friends” “high lord”). Does this cognitive mapping of social concepts arise from shared brain resources for processing social and physical relationships? Using fMRI, we found that the tasks of evaluating social compatibility and of evaluating physical distances engage a common brain substrate in the parietal cortex. The present study shows the possibility of an analytic brain mechanism to process and represent complex networks of social relationships. Given parietal cortex's known role in constructing egocentric maps of physical space, our present findings may help to explain the linguistic, psychological and behavioural links between social and physical space. PMID:19204791

Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus)

PubMed Central

Freeman, Sara M.; Walum, Hasse; Inoue, Kiyoshi; Smith, Aaron L.; Goodman, Mark M.; Bales, Karen L.; Young, Larry J.

2014-01-01

The coppery titi monkey (Callicebus cupreus) is a socially monogamous New World primate that has been studied in the field and the laboratory to investigate the behavioral neuroendocrinology of primate pair bonding and parental care. Arginine vasopressin has been shown to influence male titi monkey pair-bonding behavior, and studies are currently underway to examine the effects of oxytocin on titi monkey behavior and physiology. Here, we use receptor autoradiography to identify the distribution of arginine vasopressin 1a (AVPR1a) and oxytocin receptors (OXTR) in hemispheres of titi monkey brain (n=5). AVPR1a are diffuse and widespread throughout the brain, but the OXTR distribution is much more limited, with the densest binding being in the hippocampal formation (dentate gyrus, CA1 field) and the presubiculum (layers I and III). Moderate OXTR binding was detected in the nucleus basalis of Meynert, pulvinar, superior colliculus, layer 4C of primary visual cortex, periaqueductal gray, pontine gray, nucleus prepositus, and spinal trigeminal nucleus. OXTR mRNA overlapped with OXTR radioligand binding, confirming that the radioligand was detecting OXTR protein. AVPR1a binding is present throughout the cortex, especially in cingulate, insular, and occipital cortices, as well as in the caudate, putamen, nucleus accumbens, central amygdala, endopiriform nucleus, hippocampus (CA4 field), globus pallidus, lateral geniculate nucleus, infundibulum, habenula, periaqueductal gray, substantia nigra, olivary nucleus, hypoglossal nucleus, and cerebellum. Furthermore, we show that, in titi monkey brain, the OXTR antagonist ALS-II-69 is highly selective for OXTR and that the AVPR1a antagonist SR49059 is highly selective for AVPR1a. Based on these results and the fact that both ALS-II-69 and SR49059 are non-peptide, small-molecule antagonists that should be capable of crossing the blood brain barrier, these two compounds emerge as excellent candidates for the pharmacological manipulation of OXTR and AVPR1a in future behavioral experiments in titi monkeys and other primate species. PMID:24814726

Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules.

PubMed

He, Bo; Jabouille, Arnaud; Steri, Veronica; Johansson-Percival, Anna; Michael, Iacovos P; Kotamraju, Venkata Ramana; Junckerstorff, Reimar; Nowak, Anna K; Hamzah, Juliana; Lee, Gabriel; Bergers, Gabriele; Ganss, Ruth

2018-06-01

High-grade brain cancer such as glioblastoma (GBM) remains an incurable disease. A common feature of GBM is the angiogenic vasculature, which can be targeted with selected peptides for payload delivery. We assessed the ability of micelle-tagged, vascular homing peptides RGR, CGKRK and NGR to specifically bind to blood vessels in syngeneic orthotopic GBM models. By using the peptide CGKRK to deliver the tumour necrosis factor (TNF) superfamily member LIGHT (also known as TNF superfamily member 14; TNFSF14) to angiogenic tumour vessels, we have generated a reagent that normalizes the brain cancer vasculature by inducing pericyte contractility and re-establishing endothelial barrier integrity. LIGHT-mediated vascular remodelling also activates endothelia and induces intratumoural high endothelial venules (HEVs), which are specialized blood vessels for lymphocyte infiltration. Combining CGKRK-LIGHT with anti-vascular endothelial growth factor and checkpoint blockade amplified HEV frequency and T-cell accumulation in GBM, which is often sparsely infiltrated by immune effector cells, and reduced tumour burden. Furthermore, CGKRK and RGR peptides strongly bound to blood vessels in freshly resected human GBM, demonstrating shared peptide-binding activities in mouse and human primary brain tumour vessels. Thus, peptide-mediated LIGHT targeting is a highly translatable approach in primary brain cancer to reduce vascular leakiness and enhance immunotherapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Movement preparation and execution: differential functional activation patterns after traumatic brain injury.

PubMed

Gooijers, Jolien; Beets, Iseult A M; Albouy, Genevieve; Beeckmans, Kurt; Michiels, Karla; Sunaert, Stefan; Swinnen, Stephan P

2016-09-01

Years following the insult, patients with traumatic brain injury often experience persistent motor control problems, including bimanual coordination deficits. Previous studies revealed that such deficits are related to brain structural white and grey matter abnormalities. Here, we assessed, for the first time, cerebral functional activation patterns during bimanual movement preparation and performance in patients with traumatic brain injury, using functional magnetic resonance imaging. Eighteen patients with moderate-to-severe traumatic brain injury (10 females; aged 26.3 years, standard deviation = 5.2; age range: 18.4-34.6 years) and 26 healthy young adults (15 females; aged 23.6 years, standard deviation = 3.8; age range: 19.5-33 years) performed a complex bimanual tracking task, divided into a preparation (2 s) and execution (9 s) phase, and executed either in the presence or absence of augmented visual feedback. Performance on the bimanual tracking task, expressed as the average target error, was impaired for patients as compared to controls (P < 0.001) and for trials in the absence as compared to the presence of augmented visual feedback (P < 0.001). At the cerebral level, movement preparation was characterized by reduced neural activation in the patient group relative to the control group in frontal (bilateral superior frontal gyrus, right dorsolateral prefrontal cortex), parietal (left inferior parietal lobe) and occipital (right striate and extrastriate visual cortex) areas (P's < 0.05). During the execution phase, however, the opposite pattern emerged, i.e. traumatic brain injury patients showed enhanced activations compared with controls in frontal (left dorsolateral prefrontal cortex, left lateral anterior prefrontal cortex, and left orbitofrontal cortex), parietal (bilateral inferior parietal lobe, bilateral superior parietal lobe, right precuneus, right primary somatosensory cortex), occipital (right striate and extrastriate visual cortices), and subcortical (left cerebellum crus II) areas (P's < 0.05). Moreover, a significant interaction effect between Feedback Condition and Group in the primary motor area (bilaterally) (P < 0.001), the cerebellum (left) (P < 0.001) and caudate (left) (P < 0.05), revealed that controls showed less overlap of activation patterns accompanying the two feedback conditions than patients with traumatic brain injury (i.e. decreased neural differentiation). In sum, our findings point towards poorer predictive control in traumatic brain injury patients in comparison to controls. Moreover, irrespective of the feedback condition, overactivations were observed in traumatically brain injured patients during movement execution, pointing to more controlled processing of motor task performance. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Modulation of thermal pain-related brain activity with virtual reality: evidence from fMRI.

PubMed

Hoffman, Hunter G; Richards, Todd L; Coda, Barbara; Bills, Aric R; Blough, David; Richards, Anne L; Sharar, Sam R

2004-06-07

This study investigated the neural correlates of virtual reality analgesia. Virtual reality significantly reduced subjective pain ratings (i.e. analgesia). Using fMRI, pain-related brain activity was measured for each participant during conditions of no virtual reality and during virtual reality (order randomized). As predicted, virtual reality significantly reduced pain-related brain activity in all five regions of interest; the anterior cingulate cortex, primary and secondary somatosensory cortex, insula, and thalamus (p<0.002, corrected). Results showed direct modulation of human brain pain responses by virtual reality distraction. Copyright 2004 Lippincott Williams and Wilkins

The proliferative effect of synthetic N-POMC(1-28) peptides in rat adrenal cortex: a possible role for cyclin E.

PubMed

Mendonça, Pedro O R de; Lotfi, Claudimara F P

2011-04-10

Modified synthetic N-POMC(1-28) without disulfide bridges has been shown to act as an adrenal mitogen. Cyclins and their inhibitors are the major cell cycle controls, but in the adrenal cortex the effect of ACTH and N-POMC on the expression of these proteins remains unclear. In this work, we evaluate the effect of different synthetic N-POMC peptides on the S-phase of the cell cycle. In addition, we examine the cyclin E expression in rat adrenal cortex. Rats treated with dexamethasone were injected with ACTH and/or synthetic modified N-POMC and/or synthetic N-POMC with disulfide bridges. DNA synthesis was determined by BrdU incorporation and protein expression was analyzed by immunoblotting and immunohistochemistry. The results showed that similarly to modified N-POMC without disulfide bridges, administration of synthetic N-POMC with disulfide bridges and the combination of ACTH and N-POMC promoted an increase of BrdU-positive nuclei in adrenal cortex. However, the proliferative effect of N-POMC was comparable to that of ACTH only in the zona glomerulosa. An increase in cyclin E expression was observed 6 h after N-POMC treatment in the outer fraction of the adrenal cortex, in agreement with immunohistochemical findings in the zona glomerulosa. In summary, the effect of synthetic N-POMC with disulfide bridges was similar to modified synthetic N-POMC, increasing proliferation in the adrenal cortex, confirming previous evidence that disulfide bridges are not essential to the N-POMC mitogenic effect. Moreover, cyclin E appears to be involved in the N-POMC- and ACTH-stimulated proliferation in the zona glomerulosa of the adrenal cortex. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Purification and characterization of tripeptidylpeptidase-II from post-mortem human brain.

PubMed

Wilson, C; Gibson, A M; McDermott, J R

1993-07-01

A soluble tripeptidylaminopeptidase has been isolated from human post-mortem cerebral cortex by anion exchange, hydrophobic interaction and size-exclusion chromatography. From gel filtration studies the active enzyme can exist in both high molecular weight (M(r) > 10(6) and smaller forms. The enzyme hydrolyses Ala-Ala-Phe-7-amido-4-methylcoumarin with a pH optimum of around 7.5 and Km of 148 microM. It did not hydrolyse N-succinyl-Ala-Ala-Phe-7-amido-4-methylcoumarin, aminoacyl- or dipeptidyl-7-amido-methylcoumarins and was not inhibited by bestatin. The enzyme was inhibited by phenylmethylsulphonyl-fluoride, 3,4-dichloroisocoumarin, N-hydroxymercuriphenyl-sulphonic acid and N-ethylmaleimide showing that its activity is serine and cysteine dependent. The purified enzyme released tripeptides from several naturally occurring neuropeptides with quite broad specificity. Cholecystokinin octapeptide, angiotensin III and neurokinin A were the most rapidly hydrolysed. Peptides with Pro residues around the point of cleavage were not hydrolysed.

A Neuron-Based Model of Sleep-Wake Cycles

NASA Astrophysics Data System (ADS)

Postnova, Svetlana; Peters, Achim; Braun, Hans

2008-03-01

In recent years it was discovered that a neuropeptide orexin/hypocretin plays a main role in sleep processes. This peptide is produced by the neurons in the lateral hypothalamus, which project to almost all brain areas. We present a computational model of sleep-wake cycles, which is based on the Hodgkin-Huxley type neurons and considers reciprocal glutaminergic projections between the lateral hypothalamus and the prefrontal cortex. Orexin is released as a neuromodulator and is required to keep the neurons firing, which corresponds to the wake state. When orexin is depleted the neurons are getting silent as observed in the sleep state. They can be reactivated by the circadian signal from the suprachiasmatic nucleus and/or external stimuli (alarm clock). Orexin projections to the thalamocortical neurons also can account for their transition from tonic firing activity during wakefulness to synchronized burst discharges during sleep.

A key role of the prefrontal cortex in the maintenance of chronic tinnitus: An fMRI study using a Stroop task.

PubMed

Araneda, Rodrigo; Renier, Laurent; Dricot, Laurence; Decat, Monique; Ebner-Karestinos, Daniela; Deggouj, Naïma; De Volder, Anne G

2018-01-01

Since we recently showed in behavioural tasks that the top-down cognitive control was specifically altered in tinnitus sufferers, here we wanted to establish the link between this impaired executive function and brain alterations in the frontal cortex in tinnitus patients. Using functional magnetic resonance imaging (fMRI), we monitored the brain activity changes in sixteen tinnitus patients (TP) and their control subjects (CS) while they were performing a spatial Stroop task, both in audition and vision. We observed that TP differed from CS in their functional recruitment of the dorsolateral prefrontal cortex (dlPFC, BA46), the cingulate gyrus and the ventromedial prefrontal cortex (vmPFC, BA10). This recruitment was higher during interference conditions in tinnitus participants than in controls, whatever the sensory modality. Furthermore, the brain activity level in the right dlPFC and vmPFC correlated with the performance in the Stroop task in TP. Due to the direct link between poor executive functions and prefrontal cortex alterations in TP, we postulate that a lack of inhibitory modulation following an impaired top-down cognitive control may maintain tinnitus by hampering habituation mechanisms. This deficit in executive functions caused by prefrontal cortex alterations would be a key-factor in the generation and persistence of tinnitus.

Prediction of movement intention using connectivity within motor-related network: An electrocorticography study.

PubMed

Kang, Byeong Keun; Kim, June Sic; Ryun, Seokyun; Chung, Chun Kee

2018-01-01

Most brain-machine interface (BMI) studies have focused only on the active state of which a BMI user performs specific movement tasks. Therefore, models developed for predicting movements were optimized only for the active state. The models may not be suitable in the idle state during resting. This potential maladaptation could lead to a sudden accident or unintended movement resulting from prediction error. Prediction of movement intention is important to develop a more efficient and reasonable BMI system which could be selectively operated depending on the user's intention. Physical movement is performed through the serial change of brain states: idle, planning, execution, and recovery. The motor networks in the primary motor cortex and the dorsolateral prefrontal cortex are involved in these movement states. Neuronal communication differs between the states. Therefore, connectivity may change depending on the states. In this study, we investigated the temporal dynamics of connectivity in dorsolateral prefrontal cortex and primary motor cortex to predict movement intention. Movement intention was successfully predicted by connectivity dynamics which may reflect changes in movement states. Furthermore, dorsolateral prefrontal cortex is crucial in predicting movement intention to which primary motor cortex contributes. These results suggest that brain connectivity is an excellent approach in predicting movement intention.

Experimental Traumatic Brain Injury Results in Long-Term Recovery of Functional Responsiveness in Sensory Cortex but Persisting Structural Changes and Sensorimotor, Cognitive, and Emotional Deficits.

PubMed

Johnstone, Victoria P A; Wright, David K; Wong, Kendrew; O'Brien, Terence J; Rajan, Ramesh; Shultz, Sandy R

2015-09-01

Traumatic brain injury (TBI) is a leading cause of death worldwide. In recent studies, we have shown that experimental TBI caused an immediate (24-h post) suppression of neuronal processing, especially in supragranular cortical layers. We now examine the long-term effects of experimental TBI on the sensory cortex and how these changes may contribute to a range of TBI morbidities. Adult male Sprague-Dawley rats received either a moderate lateral fluid percussion injury (n=14) or a sham surgery (n=12) and 12 weeks of recovery before behavioral assessment, magnetic resonance imaging, and electrophysiological recordings from the barrel cortex. TBI rats demonstrated sensorimotor deficits, cognitive impairments, and anxiety-like behavior, and this was associated with significant atrophy of the barrel cortex and other brain structures. Extracellular recordings from ipsilateral barrel cortex revealed normal neuronal responsiveness and diffusion tensor MRI showed increased fractional anisotropy, axial diffusivity, and tract density within this region. These findings suggest that long-term recovery of neuronal responsiveness is owing to structural reorganization within this region. Therefore, it is likely that long-term structural and functional changes within sensory cortex post-TBI may allow for recovery of neuronal responsiveness, but that this recovery does not remediate all behavioral deficits.

A conserved pattern of differential expansion of cortical areas in simian primates.

PubMed

Chaplin, Tristan A; Yu, Hsin-Hao; Soares, Juliana G M; Gattass, Ricardo; Rosa, Marcello G P

2013-09-18

The layout of areas in the cerebral cortex of different primates is quite similar, despite significant variations in brain size. However, it is clear that larger brains are not simply scaled up versions of smaller brains: some regions of the cortex are disproportionately large in larger species. It is currently debated whether these expanded areas arise through natural selection pressures for increased cognitive capacity or as a result of the application of a common developmental sequence on different scales. Here, we used computational methods to map and quantify the expansion of the cortex in simian primates of different sizes to investigate whether there is any common pattern of cortical expansion. Surface models of the marmoset, capuchin, and macaque monkey cortex were registered using the software package CARET and the spherical landmark vector difference algorithm. The registration was constrained by the location of identified homologous cortical areas. When comparing marmosets with both capuchins and macaques, we found a high degree of expansion in the temporal parietal junction, the ventrolateral prefrontal cortex, and the dorsal anterior cingulate cortex, all of which are high-level association areas typically involved in complex cognitive and behavioral functions. These expanded maps correlated well with previously published macaque to human registrations, suggesting that there is a general pattern of primate cortical scaling.

Bombesin receptors and transplanted stem cells in rat brain: High-resolution scan with 99mTc BN1.1

NASA Astrophysics Data System (ADS)

Scopinaro, F.; Paschali, E.; Di Santo, G.; Antonellis, T.; Massari, R.; Trotta, C.; Gourni, H.; Bouziotis, P.; David, V.; Soluri, A.; Varvarigou, A. D.

2006-12-01

The aim of this work is to detect the presence of transplanted stem cells (TSC) in rat brain with high-resolution (HR) scintigraphy and labelled bombesin (BN). BN is a morphogen for Central Nervous System (CNS) as well as for other organs: CNS-oriented TSC over-express BN Receptors (BNR). BN is also a neurotransmitter and modulates several functions of CNS. 99mTc labelled BN-like peptide scan of CNS is the ideal method to detect growing TSC once knowing normal distribution of BNRs in CNS. HR Planar and single photon emission computerized tomography (SPECT) images of rat brain were performed with new HR detectors (Li-tech, Italy). Pertechnetate, 99mTc HMPAO and the new 99mTc BN1.1 (patented) were i.v. administered in five rats. HR SPECT of 99mTc BN1.1 detected olfactory tract, fronto-lateral cortex, cerebellum, basal ganglia and amygdale. Results of SPECT were confirmed by bio-distribution study performed after autopsy of three of the five rats. The remaining two rats underwent cerebral lesions followed by transplant of TSC. Three months later, HR scintigraphy was repeated and showed images completely different from previous basal study, with hot spot of 99mTc BN1.1 corresponding to the site of TSC transplant. Immuno-histochemistry confirmed the presence of viable TSC. Not only 99mTc BN1.1 HR scan showed viability of transplanted TSC but also the "background brain" was the still now unknown map of BNR in mammalian brain.

Neural correlates of strategic processes underlying episodic memory in women with major depression: A 15O-PET study.

PubMed

Ottowitz, William E; Deckersbach, Thilo; Savage, Cary R; Lindquist, Martin A; Dougherty, Darin D

2010-01-01

To evaluate the functional integrity of brain regions underlying strategic mnemonic processing in patients with major depressive disorder, the authors administered a modified version of the California Verbal Learning Test to depressed patients during presentation of lists of unrelated words and, conversely, during presentation of lists of related words with and without orientation regarding the relatedness of the words (eight healthy females, IQ=122, and eight depressed females, IQ=107). Brain function evaluated across all three conditions showed that patients with major depressive disorder revealed activation of the right anterior cingulate cortex, left ventrolateral prefrontal cortex, both hippocampi, and the left orbitofrontal cortex. Further analysis showed that patients with major depressive disorder had greater activation of the right anterior cingulate cortex during semantic organization and the right ventrolateral prefrontal cortex during strategy initiation.

A Single Brain-Derived Neurotrophic Factor Infusion into the Dorsomedial Prefrontal Cortex Attenuates Cocaine Self-Administration-Induced Phosphorylation of Synapsin in the Nucleus Accumbens during Early Withdrawal

PubMed Central

Sun, Wei-Lun; Eisenstein, Sarah A.; Zelek-Molik, Agnieszka

2015-01-01

Background: Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaine-seeking and normalized the cocaine-induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown. Methods: In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal. Results: Two hours after cocaine self-administration, p-synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor. Conclusions: Taken together, these findings demonstrate that brain-derived neurotrophic factor normalizes the cocaine self-administration–induced elevation of p-synapsin in nucleus accumbens that may underlie a disturbance in the probability of neurotransmitter release or represent a compensatory neuroadaptation in response to the hypofunction within the prefrontal cortex-nucleus accumbens pathway during cocaine withdrawal. PMID:25522393

Plasticity-Related PKMζ Signaling in the Insular Cortex Is Involved in the Modulation of Neuropathic Pain after Nerve Injury

PubMed Central

Han, Jeongsoo; Kwon, Minjee; Cha, Myeounghoon; Tanioka, Motomasa; Hong, Seong-Karp; Bai, Sun Joon; Lee, Bae Hwan

2015-01-01

The insular cortex (IC) is associated with important functions linked with pain and emotions. According to recent reports, neural plasticity in the brain including the IC can be induced by nerve injury and may contribute to chronic pain. Continuous active kinase, protein kinase Mζ (PKMζ), has been known to maintain the long-term potentiation. This study was conducted to determine the role of PKMζ in the IC, which may be involved in the modulation of neuropathic pain. Mechanical allodynia test and immunohistochemistry (IHC) of zif268, an activity-dependent transcription factor required for neuronal plasticity, were performed after nerve injury. After ζ-pseudosubstrate inhibitory peptide (ZIP, a selective inhibitor of PKMζ) injection, mechanical allodynia test and immunoblotting of PKMζ, phospho-PKMζ (p-PKMζ), and GluR1 and GluR2 were observed. IHC demonstrated that zif268 expression significantly increased in the IC after nerve injury. Mechanical allodynia was significantly decreased by ZIP microinjection into the IC. The analgesic effect lasted for 12 hours. Moreover, the levels of GluR1, GluR2, and p-PKMζ were decreased after ZIP microinjection. These results suggest that peripheral nerve injury induces neural plasticity related to PKMζ and that ZIP has potential applications for relieving chronic pain. PMID:26457205

Unravelling the development of the visual cortex: implications for plasticity and repair

PubMed Central

Bourne, James A

2010-01-01

The visual cortex comprises over 50 areas in the human, each with a specified role and distinct physiology, connectivity and cellular morphology. How these individual areas emerge during development still remains something of a mystery and, although much attention has been paid to the initial stages of the development of the visual cortex, especially its lamination, very little is known about the mechanisms responsible for the arealization and functional organization of this region of the brain. In recent years we have started to discover that it is the interplay of intrinsic (molecular) and extrinsic (afferent connections) cues that are responsible for the maturation of individual areas, and that there is a spatiotemporal sequence in the maturation of the primary visual cortex (striate cortex, V1) and the multiple extrastriate/association areas. Studies in both humans and non-human primates have started to highlight the specific neural underpinnings responsible for the maturation of the visual cortex, and how experience-dependent plasticity and perturbations to the visual system can impact upon its normal development. Furthermore, damage to specific nuclei of the visual cortex, such as the primary visual cortex (V1), is a common occurrence as a result of a stroke, neurotrauma, disease or hypoxia in both neonates and adults alike. However, the consequences of a focal injury differ between the immature and adult brain, with the immature brain demonstrating a higher level of functional resilience. With better techniques for examining specific molecular and connectional changes, we are now starting to uncover the mechanisms responsible for the increased neural plasticity that leads to significant recovery following injury during this early phase of life. Further advances in our understanding of postnatal development/maturation and plasticity observed during early life could offer new strategies to improve outcomes by recapitulating aspects of the developmental program in the adult brain. PMID:20722872

Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods.

PubMed

Byrne, Claire S; Chambers, Edward S; Alhabeeb, Habeeb; Chhina, Navpreet; Morrison, Douglas J; Preston, Tom; Tedford, Catriona; Fitzpatrick, Julie; Irani, Cherag; Busza, Albert; Garcia-Perez, Isabel; Fountana, Sofia; Holmes, Elaine; Goldstone, Anthony P; Frost, Gary S

2016-07-01

Short-chain fatty acids (SCFAs), metabolites produced through the microbial fermentation of nondigestible dietary components, have key roles in energy homeostasis. Animal research suggests that colon-derived SCFAs modulate feeding behavior via central mechanisms. In humans, increased colonic production of the SCFA propionate acutely reduces energy intake. However, evidence of an effect of colonic propionate on the human brain or reward-based eating behavior is currently unavailable. We investigated the effect of increased colonic propionate production on brain anticipatory reward responses during food picture evaluation. We hypothesized that elevated colonic propionate would reduce both reward responses and ad libitum energy intake via stimulation of anorexigenic gut hormone secretion. In a randomized crossover design, 20 healthy nonobese men completed a functional magnetic resonance imaging (fMRI) food picture evaluation task after consumption of control inulin or inulin-propionate ester, a unique dietary compound that selectively augments colonic propionate production. The blood oxygen level-dependent (BOLD) signal was measured in a priori brain regions involved in reward processing, including the caudate, nucleus accumbens, amygdala, anterior insula, and orbitofrontal cortex (n = 18 had analyzable fMRI data). Increasing colonic propionate production reduced BOLD signal during food picture evaluation in the caudate and nucleus accumbens. In the caudate, the reduction in BOLD signal was driven specifically by a lowering of the response to high-energy food. These central effects were partnered with a decrease in subjective appeal of high-energy food pictures and reduced energy intake during an ad libitum meal. These observations were not related to changes in blood peptide YY (PYY), glucagon-like peptide 1 (GLP-1), glucose, or insulin concentrations. Our results suggest that colonic propionate production may play an important role in attenuating reward-based eating behavior via striatal pathways, independent of changes in plasma PYY and GLP-1. This trial was registered at clinicaltrials.gov as NCT00750438.

8-week Mindfulness Based Stress Reduction induces brain changes similar to traditional long-term meditation practice - A systematic review.

PubMed

Gotink, Rinske A; Meijboom, Rozanna; Vernooij, Meike W; Smits, Marion; Hunink, M G Myriam

2016-10-01

The objective of the current study was to systematically review the evidence of the effect of secular mindfulness techniques on function and structure of the brain. Based on areas known from traditional meditation neuroimaging results, we aimed to explore a neuronal explanation of the stress-reducing effects of the 8-week Mindfulness Based Stress Reduction (MBSR) and Mindfulness Based Cognitive Therapy (MBCT) program. We assessed the effect of MBSR and MBCT (N=11, all MBSR), components of the programs (N=15), and dispositional mindfulness (N=4) on brain function and/or structure as assessed by (functional) magnetic resonance imaging. 21 fMRI studies and seven MRI studies were included (two studies performed both). The prefrontal cortex, the cingulate cortex, the insula and the hippocampus showed increased activity, connectivity and volume in stressed, anxious and healthy participants. Additionally, the amygdala showed decreased functional activity, improved functional connectivity with the prefrontal cortex, and earlier deactivation after exposure to emotional stimuli. Demonstrable functional and structural changes in the prefrontal cortex, cingulate cortex, insula and hippocampus are similar to changes described in studies on traditional meditation practice. In addition, MBSR led to changes in the amygdala consistent with improved emotion regulation. These findings indicate that MBSR-induced emotional and behavioral changes are related to functional and structural changes in the brain. Copyright © 2016 Elsevier Inc. All rights reserved.

[Psychotherapy of Depression as Neurobiological Process - Evidence from Neuroimaging].

PubMed

Rubart, Antonie; Hohagen, Fritz; Zurowski, Bartosz

2018-06-01

Research on neurobiological effects of psychotherapy in depression facilitates the improvement of treatment strategies. The cortico-limbic dysregulation model serves as a framework for numerous studies on neurobiological changes in depression. In this model, depression is described as hypoactivation of dorsal cortical brain regions in conjunction with hyperactivation of ventral paralimbic regions. This assumption has been supported by various studies of structural and functional brain abnormalities in depression. However, also regions not included in the original cortico-limbic dysregulation model, such as the dorsomedial prefrontal cortex, seem to play an important role in depression. Functional connectivity studies of depression have revealed an enhanced connectivity within the so-called default mode network which is involved in self-referential thinking. Studies also point to a normalization of limbic and cortical brain activity, especially in the anterior cingulate cortex, during psychotherapy. Some neurobiological markers like the activity of the anterior cingulate cortex, striatum and insula as well as hippocampal volume have been proposed to predict treatment response on a group-level. The activity of the anterior insula appears to be a candidate bio-marker for differential indication for psychotherapy or pharmacotherapy. The cortico-limbic dysregulation model and following research have inspired new forms of treatment for depression like deep brain stimulation of the subgenual anterior cingulate cortex, repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex, neurofeedback and attention training. © Georg Thieme Verlag KG Stuttgart · New York.

Alterations in Brain Structure and Functional Connectivity in Alcohol Dependent Patients and Possible Association with Impulsivity.

PubMed

Wang, Junkai; Fan, Yunli; Dong, Yue; Ma, Mengying; Ma, Yi; Dong, Yuru; Niu, Yajuan; Jiang, Yin; Wang, Hong; Wang, Zhiyan; Wu, Liuzhen; Sun, Hongqiang; Cui, Cailian

2016-01-01

Previous studies have documented that heightened impulsivity likely contributes to the development and maintenance of alcohol use disorders. However, there is still a lack of studies that comprehensively detected the brain changes associated with abnormal impulsivity in alcohol addicts. This study was designed to investigate the alterations in brain structure and functional connectivity associated with abnormal impulsivity in alcohol dependent patients. Brain structural and functional magnetic resonance imaging data as well as impulsive behavior data were collected from 20 alcohol dependent patients and 20 age- and sex-matched healthy controls respectively. Voxel-based morphometry was used to investigate the differences of grey matter volume, and tract-based spatial statistics was used to detect abnormal white matter regions between alcohol dependent patients and healthy controls. The alterations in resting-state functional connectivity in alcohol dependent patients were examined using selected brain areas with gray matter deficits as seed regions. Compared with healthy controls, alcohol dependent patients had significantly reduced gray matter volume in the mesocorticolimbic system including the dorsal posterior cingulate cortex, the dorsal anterior cingulate cortex, the medial prefrontal cortex, the orbitofrontal cortex and the putamen, decreased fractional anisotropy in the regions connecting the damaged grey matter areas driven by higher radial diffusivity value in the same areas and decreased resting-state functional connectivity within the reward network. Moreover, the gray matter volume of the left medial prefrontal cortex exhibited negative correlations with various impulse indices. These findings suggest that chronic alcohol dependence could cause a complex neural changes linked to abnormal impulsivity.

Cerebrospinal fluid dehydroepiandrosterone levels are correlated with brain dehydroepiandrosterone levels, elevated in Alzheimer's disease, and related to neuropathological disease stage.

PubMed

Naylor, Jennifer C; Hulette, Christine M; Steffens, David C; Shampine, Lawrence J; Ervin, John F; Payne, Victoria M; Massing, Mark W; Kilts, Jason D; Strauss, Jennifer L; Calhoun, Patrick S; Calnaido, Rohana P; Blazer, Daniel G; Lieberman, Jeffrey A; Madison, Roger D; Marx, Christine E

2008-08-01

It is currently unknown whether cerebrospinal fluid (CSF) neurosteroid levels are related to brain neurosteroid levels in humans. CSF and brain dehydroepiandrosterone (DHEA) levels are elevated in patients with Alzheimer's disease (AD), but it is unclear whether CSF DHEA levels are correlated with brain DHEA levels within the same subject cohort. We therefore determined DHEA and pregnenolone levels in AD patients (n = 25) and cognitively intact control subjects (n = 16) in both CSF and temporal cortex. DHEA and pregnenolone levels were determined by gas chromatography/mass spectrometry preceded by HPLC. Frozen CSF and temporal cortex specimens were provided by the Alzheimer's Disease Research Center at Duke University Medical Center. Data were analyzed by Mann-Whitney U test statistic and Spearman correlational analyses. CSF DHEA levels are positively correlated with temporal cortex DHEA levels (r = 0.59, P < 0.0001) and neuropathological disease stage (Braak and Braak) (r = 0.42, P = 0.007). CSF pregnenolone levels are also positively correlated with temporal cortex pregnenolone levels (r = 0.57, P < 0.0001) and tend to be correlated with neuropathological disease stage (Braak) (r = 0.30, P = 0.06). CSF DHEA levels are elevated (P = 0.032), and pregnenolone levels tend to be elevated (P = 0.10) in patients with AD, compared with cognitively intact control subjects. These findings indicate that CSF DHEA and pregnenolone levels are correlated with temporal cortex brain levels of these neurosteroids and that CSF DHEA is elevated in AD and related to neuropathological disease stage. Neurosteroids may thus be relevant to the pathophysiology of AD.

A comparison of neurodegeneration linked with neuroinflammation in different brain areas of rats after intracerebroventricular colchicine injection.

PubMed

Sil, Susmita; Ghosh, Rupsa; Sanyal, Moumita; Guha, Debjani; Ghosh, Tusharkanti

2016-01-01

Colchicine induces neurodegeneration, but the extent of neurodegeneration in different areas of the brain in relation to neuroinflammation remains unclear. Such information may be useful to allow for the development of a model to compare colchicine-induced neurodegeneration with other neurodegenerative diseases such as Alzheimer's Disease (AD). The present study was designed to investigate the extent of neurodegeneration along with neuroinflammation in different areas of the brain, e.g. frontal cortex, parietal cortex, occipital cortex, corpus striatum, amygdala and hippocampus, in rats along with memory impairment 21 days after a single intracerebroventricular (icv) injection of colchicine. Memory parameters were measured before and after icv colchicine injection in all test groups of rats (control, sham-operated, colchicine-injected [ICIR] rats). On Day 21 post-injection, rats from all groups were anesthesized and tissues from the various brain areas were collected for assessment of biomarkers of neuroinflammation (i.e. levels of ROS, nitrite and proinflammatory cytokines TNFα and IL-1β) and neurodegeneration (assessed histologically). The single injection of colchicine resulted in impaired memory and neurodegeneration (significant presence of plaques, Nissl granule chromatolysis) in various brain areas (frontal cortex, amygdala, parietal cortex, corpus striatum), with maximum severity in the hippocampus. While IL-1β, TNFα, ROS and nitrite levels were altered in different brain areas in the ICIR rats, these parameters had their greatest change in the hippocampus. This study showed that icv injection of colchicine caused strong neurodegeneration and neuroinflammation in the hippocampus of rats and the increases in neurodegeneration were corroborated with those of neuroinflammation at the site. The present study also showed that the extent of neurodegeneration and neuroinflammation in different brain areas of the colchicine-injected rats were AD-like and supported the fact that such rats might have the ability to serve as a sporadic model of AD.

FMRI activity during associative encoding is correlated with cardiorespiratory fitness and source memory performance in older adults

PubMed Central

Hayes, Scott M.; Hayes, Jasmeet P.; Williams, Victoria J.; Liu, Huiting; Verfaellie, Mieke

2017-01-01

Older adults (OA), relative to young adults (YA), exhibit age-related alterations in functional Magnetic Resonance Imaging (fMRI) activity during associative encoding, which contributes to deficits in source memory. Yet, there are remarkable individual differences in brain health and memory performance among OA. Cardiorespiratory fitness (CRF) is one individual difference factor that may attenuate brain aging, and thereby contribute to enhanced source memory in OA. To examine this possibility, 26 OA and 31 YA completed a treadmill-based exercise test to evaluate CRF (peak VO2) and fMRI to examine brain activation during a face-name associative encoding task. Our results indicated that in OA, peak VO2 was positively associated with fMRI activity during associative encoding in multiple regions including bilateral prefrontal cortex, medial frontal cortex, bilateral thalamus and left hippocampus. Next, a conjunction analysis was conducted to assess whether CRF influenced age-related differences in fMRI activation. We classified OA as high or low CRF and compared their activation to YA. High fit OA (HFOA) showed fMRI activation more similar to YA than low fit OA (LFOA) (i.e., reduced age-related differences) in multiple regions including thalamus, posterior and prefrontal cortex. Conversely, in other regions, primarily in prefrontal cortex, HFOA, but not LFOA, demonstrated greater activation than YA (i.e., increased age-related differences). Further, fMRI activity in these brain regions was positively associated with source memory among OA, with a mediation model demonstrating that associative encoding activation in medial frontal cortex indirectly influenced the relationship between peak VO2 and subsequent source memory performance. These results indicate that CRF may contribute to neuroplasticity among OA, reducing age-related differences in some brain regions, consistent with the brain maintenance hypothesis, but accentuating age-differences in other regions, consistent with the brain compensation hypothesis. PMID:28161031

In vivo Visuotopic Brain Mapping with Manganese-Enhanced MRI and Resting-State Functional Connectivity MRI

PubMed Central

Chan, Kevin C.; Fan, Shu-Juan; Chan, Russell W.; Cheng, Joe S.; Zhou, Iris Y.; Wu, Ed X.

2014-01-01

The rodents are an increasingly important model for understanding the mechanisms of development, plasticity, functional specialization and disease in the visual system. However, limited tools have been available for assessing the structural and functional connectivity of the visual brain network globally, in vivo and longitudinally. There are also ongoing debates on whether functional brain connectivity directly reflects structural brain connectivity. In this study, we explored the feasibility of manganese-enhanced MRI (MEMRI) via 3 different routes of Mn2+ administration for visuotopic brain mapping and understanding of physiological transport in normal and visually deprived adult rats. In addition, resting-state functional connectivity MRI (RSfcMRI) was performed to evaluate the intrinsic functional network and structural-functional relationships in the corresponding anatomical visual brain connections traced by MEMRI. Upon intravitreal, subcortical, and intracortical Mn2+ injection, different topographic and layer-specific Mn enhancement patterns could be revealed in the visual cortex and subcortical visual nuclei along retinal, callosal, cortico-subcortical, transsynaptic and intracortical horizontal connections. Loss of visual input upon monocular enucleation to adult rats appeared to reduce interhemispheric polysynaptic Mn2+ transfer but not intra- or inter-hemispheric monosynaptic Mn2+ transport after Mn2+ injection into visual cortex. In normal adults, both structural and functional connectivity by MEMRI and RSfcMRI was stronger interhemispherically between bilateral primary/secondary visual cortex (V1/V2) transition zones (TZ) than between V1/V2 TZ and other cortical nuclei. Intrahemispherically, structural and functional connectivity was stronger between visual cortex and subcortical visual nuclei than between visual cortex and other subcortical nuclei. The current results demonstrated the sensitivity of MEMRI and RSfcMRI for assessing the neuroarchitecture, neurophysiology and structural-functional relationships of the visual brains in vivo. These may possess great potentials for effective monitoring and understanding of the basic anatomical and functional connections in the visual system during development, plasticity, disease, pharmacological interventions and genetic modifications in future studies. PMID:24394694

FMRI activity during associative encoding is correlated with cardiorespiratory fitness and source memory performance in older adults.

PubMed

Hayes, Scott M; Hayes, Jasmeet P; Williams, Victoria J; Liu, Huiting; Verfaellie, Mieke

2017-06-01

Older adults (OA), relative to young adults (YA), exhibit age-related alterations in functional Magnetic Resonance Imaging (fMRI) activity during associative encoding, which contributes to deficits in source memory. Yet, there are remarkable individual differences in brain health and memory performance among OA. Cardiorespiratory fitness (CRF) is one individual difference factor that may attenuate brain aging, and thereby contribute to enhanced source memory in OA. To examine this possibility, 26 OA and 31 YA completed a treadmill-based exercise test to evaluate CRF (peak VO 2 ) and fMRI to examine brain activation during a face-name associative encoding task. Our results indicated that in OA, peak VO 2 was positively associated with fMRI activity during associative encoding in multiple regions including bilateral prefrontal cortex, medial frontal cortex, bilateral thalamus and left hippocampus. Next, a conjunction analysis was conducted to assess whether CRF influenced age-related differences in fMRI activation. We classified OA as high or low CRF and compared their activation to YA. High fit OA (HFOA) showed fMRI activation more similar to YA than low fit OA (LFOA) (i.e., reduced age-related differences) in multiple regions including thalamus, posterior and prefrontal cortex. Conversely, in other regions, primarily in prefrontal cortex, HFOA, but not LFOA, demonstrated greater activation than YA (i.e., increased age-related differences). Further, fMRI activity in these brain regions was positively associated with source memory among OA, with a mediation model demonstrating that associative encoding activation in medial frontal cortex indirectly influenced the relationship between peak VO 2 and subsequent source memory performance. These results indicate that CRF may contribute to neuroplasticity among OA, reducing age-related differences in some brain regions, consistent with the brain maintenance hypothesis, but accentuating age-differences in other regions, consistent with the brain compensation hypothesis. Published by Elsevier Ltd.

Interhemispheric EEG differences in olfactory bulbectomized rats with different cognitive abilities and brain beta-amyloid levels.

PubMed

Bobkova, Natalia; Vorobyov, Vasily; Medvinskaya, Natalia; Aleksandrova, Irina; Nesterova, Inna

2008-09-26

Alterations in electroencephalogram (EEG) asymmetry and deficits in interhemispheric integration of information have been shown in patients with Alzheimer's disease (AD). However, no direct evidence of an association between EEG asymmetry, morphological markers in the brain, and cognition was found either in AD patients or in AD models. In this study we used rats with bilateral olfactory bulbectomy (OBX) as one of the AD models and measured their learning/memory abilities, brain beta-amyloid levels and EEG spectra in symmetrical frontal and occipital cortices. One year after OBX or sham-surgery, the rats were tested with the Morris water paradigm and assigned to three groups: sham-operated rats, SO, and OBX rats with virtually normal, OBX(+), or abnormal, OBX(-), learning (memory) abilities. In OBX vs. SO, the theta EEG activity was enhanced to a higher extent in the right frontal cortex and in the left occipital cortex. This produced significant interhemispheric differences in the frontal cortex of the OBX(-) rats and in the occipital cortex of both OBX groups. The beta1 EEG asymmetry in SO was attenuated in OBX(+) and completely eliminated in OBX(-). OBX produced highly significant beta2 EEG decline in the right frontal cortex, with OBX(-)>OBX(+) rank order of strength. The beta-amyloid level, examined by post-mortem immunological DOT-analysis in the cortex-hippocampus samples, was about six-fold higher in OBX(-) than in SO, but significantly less (enhanced by 82% vs. SO) in OBX(+) than in OBX(-). The involvement of the brain mediatory systems in the observed EEG asymmetry differences is discussed.

Brain Peptides and Psychopharmacology

ERIC Educational Resources Information Center

Arehart-Treichel, Joan

1976-01-01

Proteins isolated from the brain and used as drugs can improve and apparently even transfer mental states and behavior. Much of the pioneering work and recent research with humans and animals is reviewed and crucial questions that are being posed about the psychologically active peptides are related. (BT)

Nose-to-brain peptide delivery - The potential of nanotechnology.

PubMed

Samaridou, Eleni; Alonso, Maria José

2018-06-01

Nose-to-brain (N-to-B) delivery offers to protein and peptide drugs the possibility to reach the brain in a non-invasive way. This article is a comprehensive review of the state-of-the-art of this emerging peptide delivery route, as well as of the challenges associated to it. Emphasis is given on the potential of nanosized drug delivery carriers to enhance the direct N-to-B transport of protein or peptide drugs. In particular, polymer- and lipid- based nanocarriers are comparatively analyzed in terms of the influence of their physicochemical characteristics and composition on their in vivo fate and efficacy. The use of biorecognitive ligands and permeation enhancers in order to enhance their brain targeting efficiency is also discussed. The article concludes highlighting the early stage of this research field and its still unveiled potential. The final message is that more explicatory PK/PD studies are required in order to achieve the translation from preclinical to the clinical development phase. Copyright © 2017 Elsevier Ltd. All rights reserved.

Regulation of energy balance by a gut-brain axis and involvement of the gut microbiota.

PubMed

Bauer, Paige V; Hamr, Sophie C; Duca, Frank A

2016-02-01

Despite significant progress in understanding the homeostatic regulation of energy balance, successful therapeutic options for curbing obesity remain elusive. One potential target for the treatment of obesity is via manipulation of the gut-brain axis, a complex bidirectional communication system that is crucial in maintaining energy homeostasis. Indeed, ingested nutrients induce secretion of gut peptides that act either via paracrine signaling through vagal and non-vagal neuronal relays, or in an endocrine fashion via entry into circulation, to ultimately signal to the central nervous system where appropriate responses are generated. We review here the current hypotheses of nutrient sensing mechanisms of enteroendocrine cells, including the release of gut peptides, mainly cholecystokinin, glucagon-like peptide-1, and peptide YY, and subsequent gut-to-brain signaling pathways promoting a reduction of food intake and an increase in energy expenditure. Furthermore, this review highlights recent research suggesting this energy regulating gut-brain axis can be influenced by gut microbiota, potentially contributing to the development of obesity.

A neuroprotective brain-penetrating endopeptidase fusion protein ameliorates Alzheimer disease pathology and restores neurogenesis.

PubMed

Spencer, Brian; Verma, Inder; Desplats, Paula; Morvinski, Dinorah; Rockenstein, Ed; Adame, Anthony; Masliah, Eliezer

2014-06-20

Alzheimer disease (AD) is characterized by widespread neurodegeneration throughout the association cortex and limbic system, deposition of amyloid-β peptide (Aβ) in the neuropil and around the blood vessels, and formation of neurofibrillary tangles. The endopeptidase neprilysin has been successfully used to reduce the accumulation of Aβ following intracranial viral vector delivery or ex vivo manipulated intracranial delivery. These therapies have relied on direct injections into the brain, whereas a clinically desirable therapy would involve i.v. infusion of a recombinant enzyme. We previously characterized a recombinant neprilysin that contained a 38-amino acid brain-targeting domain. Recombinant cell lines have been generated expressing this brain-targeted enzyme (ASN12). In this report, we characterize the ASN12 recombinant protein for pharmacology in a mouse as well as efficacy in two APPtg mouse models of AD. The recombinant ASN12 transited to the brain with a t½ of 24 h and accumulated to 1.7% of injected dose at 24 h following i.v. delivery. We examined pharmacodynamics in the tg2576 APPtg mouse with the prion promoter APP695 SWE mutation and in the Line41 mThy1 APP751 mutation mouse. Treatment of either APPtg mouse resulted in reduced Aβ, increased neuronal synapses, and improved learning and memory. In addition, the Line41 APPtg mice showed increased levels of C-terminal neuropeptide Y fragments and increased neurogenesis. These results suggest that the recombinant brain-targeted neprilysin, ASN12, may be an effective treatment for AD and warrant further investigation in clinical trials. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer.

PubMed

Yang, Lijun; Kress, Benjamin T; Weber, Harris J; Thiyagarajan, Meenakshisundaram; Wang, Baozhi; Deane, Rashid; Benveniste, Helene; Iliff, Jeffrey J; Nedergaard, Maiken

2013-05-01

Neurodegenerative diseases such as Alzheimer's are associated with the aggregation of endogenous peptides and proteins that contribute to neuronal dysfunction and loss. The glymphatic system, a brain-wide perivascular pathway along which cerebrospinal fluid (CSF) and interstitial fluid (ISF) rapidly exchange, has recently been identified as a key contributor to the clearance of interstitial solutes from the brain, including amyloid β. These findings suggest that measuring changes in glymphatic pathway function may be an important prognostic for evaluating neurodegenerative disease susceptibility or progression. However, no clinically acceptable approach to evaluate glymphatic pathway function in humans has yet been developed. Time-sequenced ex vivo fluorescence imaging of coronal rat and mouse brain slices was performed at 30-180 min following intrathecal infusion of CSF tracer (Texas Red- dextran-3, MW 3 kD; FITC- dextran-500, MW 500 kD) into the cisterna magna or lumbar spine. Tracer influx into different brain regions (cortex, white matter, subcortical structures, and hippocampus) in rat was quantified to map the movement of CSF tracer following infusion along both routes, and to determine whether glymphatic pathway function could be evaluated after lumbar intrathecal infusion. Following lumbar intrathecal infusions, small molecular weight TR-d3 entered the brain along perivascular pathways and exchanged broadly with the brain ISF, consistent with the initial characterization of the glymphatic pathway in mice. Large molecular weight FITC-d500 remained confined to the perivascular spaces. Lumbar intrathecal infusions exhibited a reduced and delayed peak parenchymal fluorescence intensity compared to intracisternal infusions. Lumbar intrathecal contrast delivery is a clinically useful approach that could be used in conjunction with dynamic contrast enhanced MRI nuclear imaging to assess glymphatic pathway function in humans.

Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer

PubMed Central

2013-01-01

Background Neurodegenerative diseases such as Alzheimer’s are associated with the aggregation of endogenous peptides and proteins that contribute to neuronal dysfunction and loss. The glymphatic system, a brain-wide perivascular pathway along which cerebrospinal fluid (CSF) and interstitial fluid (ISF) rapidly exchange, has recently been identified as a key contributor to the clearance of interstitial solutes from the brain, including amyloid β. These findings suggest that measuring changes in glymphatic pathway function may be an important prognostic for evaluating neurodegenerative disease susceptibility or progression. However, no clinically acceptable approach to evaluate glymphatic pathway function in humans has yet been developed. Methods Time-sequenced ex vivo fluorescence imaging of coronal rat and mouse brain slices was performed at 30–180 min following intrathecal infusion of CSF tracer (Texas Red- dextran-3, MW 3 kD; FITC- dextran-500, MW 500 kD) into the cisterna magna or lumbar spine. Tracer influx into different brain regions (cortex, white matter, subcortical structures, and hippocampus) in rat was quantified to map the movement of CSF tracer following infusion along both routes, and to determine whether glymphatic pathway function could be evaluated after lumbar intrathecal infusion. Results Following lumbar intrathecal infusions, small molecular weight TR-d3 entered the brain along perivascular pathways and exchanged broadly with the brain ISF, consistent with the initial characterization of the glymphatic pathway in mice. Large molecular weight FITC-d500 remained confined to the perivascular spaces. Lumbar intrathecal infusions exhibited a reduced and delayed peak parenchymal fluorescence intensity compared to intracisternal infusions. Conclusion Lumbar intrathecal contrast delivery is a clinically useful approach that could be used in conjunction with dynamic contrast enhanced MRI nuclear imaging to assess glymphatic pathway function in humans. PMID:23635358

Prevention of hypoxic brain oedema by the administration of vasopressin receptor antagonist OPC-31260.

PubMed

Molnár, Andor H; Varga, Csaba; Berkó, Anikó; Rojik, Imre; Párducz, Arpád; László, Ferenc; László, Ferenc A

2008-01-01

The numerous situations which can result in cerebral hypoxic damage occur in newborn infants and in the elderly. In research aimed at more effective therapeutic intervention in ischaemic disorders of the brain, the animal model used and the principles of the causal therapy should be better outlined. The effects of the non-peptide AVPR (V2) antagonist 5-dimethylamino-1-[4-(2-methylbenzoylamino) benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (OPC-31260) on the cerebral oedema induced by general cerebral hypoxia were studied in rats. The general cerebral hypoxia was produced by bilateral common carotid ligation in Sprague-Dawley rats of the CFY strain. By 6h after the ligation, half of the rats had died, but the survival rate was significantly higher following OPC-31260 administration. Electron microscopic examinations revealed typical ischaemic changes after the carotid ligation, and OPC-31260 treatment did not significantly reduce the hypoxic signs in the brain cortex; only a certain decrease in the pericapillary oedema was observed. The carotid ligation increased the brain contents of water and Na(+) and enhanced the plasma AVP level. The increased brain water and Na(+) accumulation was prevented by OPC-31260 administration, but the plasma AVP level was further enhanced by OPC-31260. These results demonstrate the important role of AVP in the development of the disturbances in brain water and electrolyte balance in response to general cerebral hypoxia. The carotid ligation-induced cerebral oedema was significantly reduced following oral OPC-31260 administration. The protective mechanism exerted by OPC-31260 stems from its influence on the renal AVPR (V2). These observations might suggest an effective approach to the treatment of global hypoxia-induced cerebral oedema in humans.

A Small Molecule Inhibitor of Plasminogen Activator Inhibitor-1 Reduces Brain Amyloid-β Load and Improves Memory in an Animal Model of Alzheimer's Disease.

PubMed

Akhter, Hasina; Huang, Wen-Tan; van Groen, Thomas; Kuo, Hui-Chien; Miyata, Toshio; Liu, Rui-Ming

2018-01-01

Alzheimer's disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain is a pathological hallmark of AD and is believed to be a central disease-causing and disease-promoting event. In a previous study, we showed that deletion of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), significantly reduced brain Aβ load in APP/PS1 mice, an animal model of familial AD. In this study, we further show that oral administration of TM5275, a small molecule inhibitor of PAI-1, for a period of 6 weeks, inhibits the activity of PAI-1 and increases the activities of tPA and uPA as well as plasmin, which is associated with a reduction of Aβ load in the hippocampus and cortex and improvement of learning/memory function in APP/PS1 mice. Protein abundance of low density lipoprotein related protein-1 (LRP-1), a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, as well as plasma Aβ42 are increased, whereas the expression and processing of full-length amyloid-β protein precursor is not affected by TM5275 treatment in APP/PS1 mice. In vitro studies further show that PAI-1 increases, whereas TM5275 reduces, Aβ40 level in the culture medium of SHSY5Y-APP neuroblastoma cells. Collectively, our data suggest that TM5275 improves memory function of APP/PS1 mice, probably by reducing brain Aβ accumulation through increasing plasmin-mediated degradation and LRP-1-mediated efflux of Aβ in the brain.

Two-photon microscopy for real-time monitoring of focused ultrasound-mediated drug delivery to the brain in a mouse model of Alzheimer's disease

NASA Astrophysics Data System (ADS)

Burgess, Alison; Eterman, Naomi; Aubert, Isabelle; Hynynen, Kullervo

2013-02-01

There is substantial evidence that focused ultrasound (FUS) in combination with microbubble contrast agent can cause disruption of the blood-brain barrier (BBB) to aid in drug delivery to the brain. We have previously demonstrated that FUS efficiently delivers antibodies against amyloid-β peptides (Aβ) through the BBB, leading to a reduction in amyloid pathology at 4 days in a mouse model of Alzheimer's disease. In the current study, we used two-photon microscopy to characterize the effect of FUS in real time on amyloid pathology in the mouse brain. Mice were anesthetized and a cranial window was made in the skull. A custom-built ultrasound transducer was fixed to a coverslip and attached to the skull, covering the cranial window. Methoxy-X04 [2-5mg/kg] delivered intravenously 1 hr prior to the experiment clearly labelled the Aβ surrounding the vessels and the amyloid plaques in the cortex. Dextran conjugated Texas Red (70kDa) administered intravenously, confirmed BBB disruption. BBB disruption occurred in transgenic and non-transgenic animals at similar ultrasound pressures tested. However, the time required for BBB closure following FUS was longer in the Tg mice. We have conjugated Aβ antibodies to the fluorescent molecule FITC for real time monitoring of the antibody distribution in the brain. Our current experiments are aimed at optimizing the parameters to achieve maximal fluorescent intensity of the BAM10 antibody at the plaque surface. Two-photon microscopy has proven to be a valuable tool for evaluating the efficacy of FUS mediated drug delivery, including antibodies, to the Alzheimer brain.

Greater preference consistency during the Willingness-to-Pay task is related to higher resting state connectivity between the ventromedial prefrontal cortex and the ventral striatum.

PubMed

Mackey, Scott; Olafsson, Valur; Aupperle, Robin L; Lu, Kun; Fonzo, Greg A; Parnass, Jason; Liu, Thomas; Paulus, Martin P

2016-09-01

The significance of why a similar set of brain regions are associated with the default mode network and value-related neural processes remains to be clarified. Here, we examined i) whether brain regions exhibiting willingness-to-pay (WTP) task-related activity are intrinsically connected when the brain is at rest, ii) whether these regions overlap spatially with the default mode network, and iii) whether individual differences in choice behavior during the WTP task are reflected in functional brain connectivity at rest. Blood-oxygen-level dependent (BOLD) signal was measured by functional magnetic resonance imaging while subjects performed the WTP task and at rest with eyes open. Brain regions that tracked the value of bids during the WTP task were used as seed regions in an analysis of functional connectivity in the resting state data. The seed in the ventromedial prefrontal cortex was functionally connected to core regions of the WTP task-related network. Brain regions within the WTP task-related network, namely the ventral precuneus, ventromedial prefrontal and posterior cingulate cortex overlapped spatially with publically available maps of the default mode network. Also, those individuals with higher functional connectivity during rest between the ventromedial prefrontal cortex and the ventral striatum showed greater preference consistency during the WTP task. Thus, WTP task-related regions are an intrinsic network of the brain that corresponds spatially with the default mode network, and individual differences in functional connectivity within the WTP network at rest may reveal a priori biases in choice behavior.

Greater preference consistency during the Willingness-to-Pay task is related to higher resting state connectivity between the ventromedial prefrontal cortex and the ventral striatum

PubMed Central

Mackey, Scott; Olafsson, Valur; Aupperle, Robin; Lu, Kun; Fonzo, Greg; Parnass, Jason; Liu, Thomas; Paulus, Martin P.

2015-01-01

The significance of why a similar set of brain regions are associated with the default mode network and value-related neural processes remains to be clarified. Here, we examined i) whether brain regions exhibiting willingness-to-pay (WTP) task-related activity are intrinsically connected when the brain is at rest, ii) whether these regions overlap spatially with the default mode network, and iii) whether individual differences in choice behavior during the WTP task are reflected in functional brain connectivity at rest. Blood-oxygen-level dependent (BOLD) signal was measured by functional magnetic resonance imaging while subjects performed the WTP task and at rest with eyes open. Brain regions that tracked the value of bids during the WTP task were used as seed regions in an analysis of functional connectivity in the resting state data. The seed in the ventromedial prefrontal cortex was functionally connected to core regions of the WTP task-related network. Brain regions within the WTP task-related network, namely the ventral precuneus, ventromedial prefrontal and posterior cingulate cortex overlapped spatially with publically available maps of the default mode network. Also, those individuals with higher functional connectivity during rest between the ventromedial prefrontal cortex and the ventral striatum showed greater preference consistency during the WTP task. Thus, WTP task-related regions are an intrinsic network of the brain that corresponds spatially with the default mode network, and individual differences in functional connectivity within the WTP network at rest may reveal a priori biases in choice behavior. PMID:26271206

Dissociable prefrontal brain systems for attention and emotion

NASA Astrophysics Data System (ADS)

Yamasaki, Hiroshi; Labar, Kevin S.; McCarthy, Gregory

2002-08-01

The prefrontal cortex has been implicated in a variety of attentional, executive, and mnemonic mental operations, yet its functional organization is still highly debated. The present study used functional MRI to determine whether attentional and emotional functions are segregated into dissociable prefrontal networks in the human brain. Subjects discriminated infrequent and irregularly presented attentional targets (circles) from frequent standards (squares) while novel distracting scenes, parametrically varied for emotional arousal, were intermittently presented. Targets differentially activated middle frontal gyrus, posterior parietal cortex, and posterior cingulate gyrus. Novel distracters activated inferior frontal gyrus, amygdala, and fusiform gyrus, with significantly stronger activation evoked by the emotional scenes. The anterior cingulate gyrus was the only brain region with equivalent responses to attentional and emotional stimuli. These results show that attentional and emotional functions are segregated into parallel dorsal and ventral streams that extend into prefrontal cortex and are integrated in the anterior cingulate. These findings may have implications for understanding the neural dynamics underlying emotional distractibility on attentional tasks in affective disorders. novelty | prefrontal cortex | amygdala | cingulate gyrus

Visual Learning Alters the Spontaneous Activity of the Resting Human Brain: An fNIRS Study

PubMed Central

Niu, Haijing; Li, Hao; Sun, Li; Su, Yongming; Huang, Jing; Song, Yan

2014-01-01

Resting-state functional connectivity (RSFC) has been widely used to investigate spontaneous brain activity that exhibits correlated fluctuations. RSFC has been found to be changed along the developmental course and after learning. Here, we investigated whether and how visual learning modified the resting oxygenated hemoglobin (HbO) functional brain connectivity by using functional near-infrared spectroscopy (fNIRS). We demonstrate that after five days of training on an orientation discrimination task constrained to the right visual field, resting HbO functional connectivity and directed mutual interaction between high-level visual cortex and frontal/central areas involved in the top-down control were significantly modified. Moreover, these changes, which correlated with the degree of perceptual learning, were not limited to the trained left visual cortex. We conclude that the resting oxygenated hemoglobin functional connectivity could be used as a predictor of visual learning, supporting the involvement of high-level visual cortex and the involvement of frontal/central cortex during visual perceptual learning. PMID:25243168

Visual learning alters the spontaneous activity of the resting human brain: an fNIRS study.

PubMed

Niu, Haijing; Li, Hao; Sun, Li; Su, Yongming; Huang, Jing; Song, Yan

2014-01-01

Resting-state functional connectivity (RSFC) has been widely used to investigate spontaneous brain activity that exhibits correlated fluctuations. RSFC has been found to be changed along the developmental course and after learning. Here, we investigated whether and how visual learning modified the resting oxygenated hemoglobin (HbO) functional brain connectivity by using functional near-infrared spectroscopy (fNIRS). We demonstrate that after five days of training on an orientation discrimination task constrained to the right visual field, resting HbO functional connectivity and directed mutual interaction between high-level visual cortex and frontal/central areas involved in the top-down control were significantly modified. Moreover, these changes, which correlated with the degree of perceptual learning, were not limited to the trained left visual cortex. We conclude that the resting oxygenated hemoglobin functional connectivity could be used as a predictor of visual learning, supporting the involvement of high-level visual cortex and the involvement of frontal/central cortex during visual perceptual learning.

Fractal dimension as an index of brain cortical changes throughout life.

PubMed

Kalmanti, Elina; Maris, Thomas G

2007-01-01

The fractal dimension (FD) of the cerebral cortex was measured in 93 individuals, aged from 3 months to 78 years, with normal brain MRI's in order to compare the convolutions of the cerebral cortex between genders and age groups. Image J, an image processing program, was used to skeletonize cerebral cortex and the box counting method applied. FDs on slices taken from left and right hemispheres were calculated. Our results showed a significant degree of lateralization in the left hemisphere. It appears that basal ganglia development, mainly in the left hemisphere, is heavily dependent upon age until puberty. In addition, both left and right cortex development equally depends on age until puberty, while the corresponding right hemisphere convolutions continue to develop until a later stage. An increased developmental activity appears between the ages of 1 and 15 years, indicating a significant brain remodelling during childhood and adolescence. In infancy, only changes in basal ganglia are observed, while the right hemisphere continues to remodel in adulthood.

Underlying neural mechanisms of mirror therapy: Implications for motor rehabilitation in stroke.

PubMed

Arya, Kamal Narayan

2016-01-01

Mirror therapy (MT) is a valuable method for enhancing motor recovery in poststroke hemiparesis. The technique utilizes the mirror-illusion created by the movement of sound limb that is perceived as the paretic limb. MT is a simple and economical technique than can stimulate the brain noninvasively. The intervention unquestionably has neural foundation. But the underlying neural mechanisms inducing motor recovery are still unclear. In this review, the neural-modulation due to MT has been explored. Multiple areas of the brain such as the occipital lobe, dorsal frontal area and corpus callosum are involved during the simple MT regime. Bilateral premotor cortex, primary motor cortex, primary somatosensory cortex, and cerebellum also get reorganized to enhance the function of the damaged brain. The motor areas of the lesioned hemisphere receive visuo-motor processing information through the parieto-occipital lobe. The damaged motor cortex responds variably to the MT and may augment true motor recovery. Mirror neurons may also play a possible role in the cortico-stimulatory mechanisms occurring due to the MT.

Understanding the Dorsal and Ventral Systems of the Human Cerebral Cortex: Beyond Dichotomies

ERIC Educational Resources Information Center

Borst, Gregoire; Thompson, William L.; Kosslyn, Stephen M.

2011-01-01

Traditionally, characterizations of the macrolevel functional organization of the human cerebral cortex have focused on the left and right cerebral hemispheres. However, the idea of left brain versus right brain functions has been shown to be an oversimplification. We argue here that a top-bottom divide, rather than a left-right divide, is a more…

Exploratory metabolomic analyses reveal compounds correlated with lutein concentration in frontal cortex, hippocampus, and occipital cortex of human infant brain

USDA-ARS?s Scientific Manuscript database

Lutein is a dietary carotenoid well known for its role as an antioxidant in the macula and recent reports implicate a role for lutein in cognitive function. Lutein is the dominant carotenoid in both pediatric and geriatric brain tissue. In addition, cognitive function in older adults correlated with...

Technetium-99m HMPAO brain SPECT in autistic children and their families.

PubMed

Degirmenci, Berna; Miral, Süha; Kaya, Gamze Capa; Iyilikçi, Leyla; Arslan, Gulhan; Baykara, Ayşen; Evren, Ismail; Durak, Hatice

2008-04-15

The purpose of the study was to investigate perfusion patterns in autistic children (AC) and their families. Ten AC (9 boys, 1 girl; mean age: 6.9+/-1.7 years) with autistic disorder defined by DSM-III-R criteria, five age-matched children (3 boys, 2 girls) as a control group, and the immediate family members of eight AC (8 mothers, 8 fathers, 7 siblings; mean ages: 39+/-4 years, 36+/-5 years and 13+/-5 years, respectively) were included in the study. Age- and sex-matched control groups for both the parents and the siblings were also included in the study. Brain perfusion images were obtained 1 h after the intravenous injection of an adjusted dose of Tc-99m HMPAO to children and the adults. Visual and semiquantitative evaluations were performed. Hypoperfusion was seen in the right posterior parietal cortex in three AC, in bilateral parietal cortex in one AC, bilateral frontal cortex in two AC, left parietal and temporal cortex in one AC, and right parietal and temporal cortex in one AC. Asymmetric perfusion was observed in the caudate nucleus in four AC. In semiquantitative analyses, statistically significant hypoperfusion was found in the right inferior and superior frontal, left superior frontal, right parietal, right mesial temporal and right caudate nucleus. In parents of AC, significant hypoperfusion was noted in the right parietal and bilateral inferior frontal cortex. In siblings of AC, perfusion in the right frontal cortex, right nucleus caudate and left parietal cortex was significantly decreased. This preliminary study suggests the existence of regional brain perfusion alterations in frontal, temporal, and parietal cortex and in caudate nucleus in AC and in their first-degree family members.

Specialized Cortex Glial Cells Accumulate Lipid Droplets in Drosophila melanogaster.

PubMed

Kis, Viktor; Barti, Benjámin; Lippai, Mónika; Sass, Miklós

2015-01-01

Lipid droplets (LDs) are common organelles of the majority of eukaryotic cell types. Their biological significance has been extensively studied in mammalian liver cells and white adipose tissue. Although the central nervous system contains the highest relative amount and the largest number of different lipid species, neither the spatial nor the temporal distribution of LDs has been described. In this study, we used the brain of the fruitfly, Drosophila melanogaster, to investigate the neuroanatomy of LDs. We demonstrated that LDs are exclusively localised in glial cells but not in neurons in the larval nervous system. We showed that the brain's LD pool, rather than being constant, changes dynamically during development and reaches its highest value at the beginning of metamorphosis. LDs are particularly enriched in cortex glial cells located close to the brain surface. These specialized superficial cortex glial cells contain the highest amount of LDs among glial cell types and encapsulate neuroblasts and their daughter cells. Superficial cortex glial cells, combined with subperineurial glial cells, express the Drosophila fatty acid binding protein (Dfabp), as we have demonstrated through light- and electron microscopic immunocytochemistry. To the best of our best knowledge this is the first study that describes LD neuroanatomy in the Drosophila larval brain.

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain.

PubMed

Hawkes, Cheryl A; Gatherer, Maureen; Sharp, Matthew M; Dorr, Adrienne; Yuen, Ho Ming; Kalaria, Rajesh; Weller, Roy O; Carare, Roxana O

2013-04-01

Development of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is associated with failure of elimination of amyloid-β (Aβ) from the brain along perivascular basement membranes that form the pathways for drainage of interstitial fluid and solutes from the brain. In transgenic APP mouse models of AD, the severity of cerebral amyloid angiopathy is greater in the cerebral cortex and hippocampus, intermediate in the thalamus, and least in the striatum. In this study we test the hypothesis that age-related regional variation in (1) vascular basement membranes and (2) perivascular drainage of Aβ contribute to the different regional patterns of CAA in the mouse brain. Quantitative electron microscopy of the brains of 2-, 7-, and 23-month-old mice revealed significant age-related thickening of capillary basement membranes in cerebral cortex, hippocampus, and thalamus, but not in the striatum. Results from Western blotting and immunocytochemistry experiments showed a significant reduction in collagen IV in the cortex and hippocampus with age and a reduction in laminin and nidogen 2 in the cortex and striatum. Injection of soluble Aβ into the hippocampus or thalamus showed an age-related reduction in perivascular drainage from the hippocampus but not from the thalamus. The results of the study suggest that changes in vascular basement membranes and perivascular drainage with age differ between brain regions, in the mouse, in a manner that may help to explain the differential deposition of Aβ in the brain in AD and may facilitate development of improved therapeutic strategies to remove Aβ from the brain in AD. © 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Lysosomal degradation of cholecystokinin-(29-33)-amide in mouse brain is dependent on tripeptidyl peptidase-I: implications for the degradation and storage of peptides in classical late-infantile neuronal ceroid lipofuscinosis.

PubMed Central

Bernardini, Francesca; Warburton, Michael J

2002-01-01

Tripeptidyl peptidase-I (TPP-I) is a lysosomal exopeptidase which removes tripeptides from the N-terminus of small peptides. Mutations in the TPP-I gene result in a lethal neurodegenerative disease, classical late-infantile neuronal ceroid lipofuscinosis (CLN2). This disease is characterized by the accumulation of proteinaceous and autofluorescent material within the lysosomes of neurons, which undergo massive cell death during the course of the disease. The absence of TPP-I may result in the lysosomal accumulation of small peptides and proteins, which eventually compromises lysosomal functions critical to the survival of neurons. To investigate the metabolism of small peptides, we have studied the degradation of cholecystokinin-(29-33)-amide (GWMDF-NH2; cholecystokinin C-terminal pentapeptide) by lysosomal fractions isolated from mouse brain and several other tissues. GWMDF-NH2 is cleaved at only one peptide bond by brain lysosomes, to produce GWM and DF-NH2. Inhibitor studies demonstrate that this reaction is catalysed by TPP-I. In contrast, lysosomal fractions from other mouse tissues additionally cleave a second peptide bond to produce GW and MDF-NH2. Inhibitor studies indicate that this reaction is catalysed by dipeptidyl peptidase-I (DPP-I; cathepsin C). Inhibitors of TPP-I are sufficient to completely block the degradation of GWMDF-NH2 by brain, but inhibitors of both TPP-I and DPP-I are required to completely inhibit the degradation of GWMDF-NH2 by other mouse tissues. Enzyme assays confirm the low activity of DPP-I in brain. An unrelated neuropeptide, neuromedin B, is degraded by a pathway that is partially dependent on TPP-I. These results indicate that TPP-I is required for the partial or complete digestion of certain neuropeptides by brain lysosomes. In the absence of TPP-I, neuropeptides or their degradation products will accumulate in brain lysosomes and may contribute to the pathogenesis of CLN2. Other tissues are spared because they express another peptidase, DPP-I, which has extensive activity on peptides and can compensate for the loss of TPP-I. PMID:12038963

Lysosomal degradation of cholecystokinin-(29-33)-amide in mouse brain is dependent on tripeptidyl peptidase-I: implications for the degradation and storage of peptides in classical late-infantile neuronal ceroid lipofuscinosis.

PubMed

Bernardini, Francesca; Warburton, Michael J

2002-09-01

Tripeptidyl peptidase-I (TPP-I) is a lysosomal exopeptidase which removes tripeptides from the N-terminus of small peptides. Mutations in the TPP-I gene result in a lethal neurodegenerative disease, classical late-infantile neuronal ceroid lipofuscinosis (CLN2). This disease is characterized by the accumulation of proteinaceous and autofluorescent material within the lysosomes of neurons, which undergo massive cell death during the course of the disease. The absence of TPP-I may result in the lysosomal accumulation of small peptides and proteins, which eventually compromises lysosomal functions critical to the survival of neurons. To investigate the metabolism of small peptides, we have studied the degradation of cholecystokinin-(29-33)-amide (GWMDF-NH2; cholecystokinin C-terminal pentapeptide) by lysosomal fractions isolated from mouse brain and several other tissues. GWMDF-NH2 is cleaved at only one peptide bond by brain lysosomes, to produce GWM and DF-NH2. Inhibitor studies demonstrate that this reaction is catalysed by TPP-I. In contrast, lysosomal fractions from other mouse tissues additionally cleave a second peptide bond to produce GW and MDF-NH2. Inhibitor studies indicate that this reaction is catalysed by dipeptidyl peptidase-I (DPP-I; cathepsin C). Inhibitors of TPP-I are sufficient to completely block the degradation of GWMDF-NH2 by brain, but inhibitors of both TPP-I and DPP-I are required to completely inhibit the degradation of GWMDF-NH2 by other mouse tissues. Enzyme assays confirm the low activity of DPP-I in brain. An unrelated neuropeptide, neuromedin B, is degraded by a pathway that is partially dependent on TPP-I. These results indicate that TPP-I is required for the partial or complete digestion of certain neuropeptides by brain lysosomes. In the absence of TPP-I, neuropeptides or their degradation products will accumulate in brain lysosomes and may contribute to the pathogenesis of CLN2. Other tissues are spared because they express another peptidase, DPP-I, which has extensive activity on peptides and can compensate for the loss of TPP-I.

Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study.

PubMed

Rule, R R; Suhy, J; Schuff, N; Gelinas, D F; Miller, R G; Weiner, M W

2004-09-01

After replication of previous findings we aimed to: 1) determine if previously reported (1)H MRSI differences between ALS patients and control subjects are limited to the motor cortex; and 2) determine the longitudinal metabolic changes corresponding to varying levels of diagnostic certainty. Twenty-one patients with possible/suspected ALS, 24 patients with probable/definite ALS and 17 control subjects underwent multislice (1)H MRSI co-registered with tissue-segmented MRI to obtain concentrations of the brain metabolites N-acetylaspartate (NAA), creatine, and choline in the left and right motor cortex and in gray matter and white matter of non-motor regions in the brain. In the more affected hemisphere, reductions in the ratios, NAA/Cho and NAA/Cre+Cho were observed both within (12.6% and 9.5% respectively) and outside (9.2% and 7.3% respectively) the motor cortex in probable/definite ALS. However, these reductions were significantly greater within the motor cortex (P<0.05 for NAA/Cho and P<0.005 for NAA/Cre+Cho). Longitudinal changes in NAA were observed at three months within the motor cortex of both possible/suspected ALS patients (P<0.005) and at nine months outside the motor cortex of probable/definite patients (P<0.005). However, there was no clear pattern of progressive change over time. NAA ratios are reduced in the motor cortex and outside the motor cortex in ALS, suggesting widespread neuronal injury. Longitudinal changes of NAA are not reliable, suggesting that NAA may not be a useful surrogate marker for treatment trials.

Viability and neuronal differentiation of neural stem cells encapsulated in silk fibroin hydrogel functionalized with an IKVAV peptide.

PubMed

Sun, Wei; Incitti, Tania; Migliaresi, Claudio; Quattrone, Alessandro; Casarosa, Simona; Motta, Antonella

2017-05-01

Three-dimensional (3D) porous scaffolds combined with therapeutic stem cells play vital roles in tissue engineering. The adult brain has very limited regeneration ability after injuries such as trauma and stroke. In this study, injectable 3D silk fibroin-based hydrogel scaffolds with encapsulated neural stem cells were developed, aiming at supporting brain regeneration. To improve the function of the hydrogel towards neural stem cells, silk fibroin was modified by an IKVAV peptide through covalent binding. Both unmodified and modified silk fibroin hydrogels were obtained, through sonication, with mechanical stiffness comparable to that of brain tissue. Human neural stem cells were encapsulated in both hydrogels and the effects of IKVAV peptide conjugation on cell viability and neural differentiation were assessed. The silk fibroin hydrogel modified by IKVAV peptide showed increased cell viability and an enhanced neuronal differentiation capability, which contributed to understanding the effects of IKVAV peptide on the behaviour of neural stem cells. For these reasons, IKVAV-modified silk fibroin is a promising material for brain tissue engineering. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Cholecystokinin octapeptide analogues stable to brain proteolysis.

PubMed

Knight, M; Barone, P; Tamminga, C A; Steardo, L; Chase, T N

1985-01-01

Based on recent findings identifying the initial degradative cleavage of CCK-8 at the Met3-Gly4 bond by a metalloendopeptidase, two analogues of CCK-8 with D-Ala and D-Trp substitutions at the Gly4 position were synthesized as stable analogues. Their stability to proteolysis by brain membranes and their binding potency at central CCK receptors were quantified. Both peptides are stable to degradation by peptidases in cortical synaptic membrane preparations. The analogues are nearly equipotent to CCK-8 in their affinities for inhibition of 125I-CCK-33 binding to guinea pig cortical membranes. L-Ala and L-Trp substituted peptides were synthesized for comparison. Both these peptides are degraded by synaptic membranes and the L-Trp substituted peptide possesses a greatly reduced affinity for central CCK receptors. Therefore, the structure of CCK due to the D conformation of Gly is more capable of interacting with brain CCK receptors. Further conformational analysis will establish whether the stabilized structure is a beta-bend or a beta-turn. Since these peptides are highly potent and stable to brain proteolysis they may be useful as stable CCK analogues for in vivo application.

Effects of maternal separation, early handling, and gonadal sex on regional metabolic capacity of the preweanling rat brain

PubMed Central

Spivey, Jaclyn M.; Padilla, Eimeira; Shumake, Jason D.; Gonzalez-Lima, F.

2010-01-01

This is the first study to assess the effects of mother-infant separation on regional metabolic capacity in the preweanling rat brain. Mother-infant separation is generally known to be stressful for rat pups. Holtzman adolescent rats show a depressive-like behavioral phenotype after maternal separation during the preweanling period. However, information is lacking on the effects of maternal separation on the brains of rat pups. We addressed this issue by mapping the brains of preweanling Holtzman rat pups using cytochrome oxidase histochemistry, which reflects long-term changes in brain metabolic capacity, following two weeks of repeated, prolonged maternal separation, and compared this to both early handled and non-handled pups. Quantitative image analysis revealed that maternal separation reduced cytochrome oxidase activity in the medial prefrontal cortex and nucleus accumbens shell. Maternal separation reduced prefrontal cytochrome oxidase to a greater degree in female pups than in males. Early handling reduced cytochrome oxidase activity in the posterior parietal cortex, ventral tegmental area, and subiculum, but increased cytochrome oxidase activity in the lateral frontal cortex. The sex-dependent effects of early handling on cytochrome oxidase activity were limited to the medial prefrontal cortex. Regardless of separation group, females had greater cytochrome oxidase activity in the habenula and ventral tegmental area compared to males. These findings suggest that early life mother-infant separation results in dysfunction of prefrontal and mesolimbic regions in the preweanling rat brain that may contribute to behavioral changes later in life. PMID:20969837

Multi-frequency localization of aberrant brain activity in autism spectrum disorder.

PubMed

Xiang, Jing; Korostenskaja, Milena; Molloy, Cynthia; deGrauw, Xinyao; Leiken, Kimberly; Gilman, Carley; Meinzen-Derr, Jareen; Fujiwara, Hisako; Rose, Douglas F; Mitchell, Terry; Murray, Donna S

2016-01-01

The abnormality of intrinsic brain activity in autism spectrum disorders (ASDs) is still inconclusive. Contradictory results have been found pointing towards hyper-activity or hypo-activity in various brain regions. The present research aims to investigate the spatial and spectral signatures of aberrant brain activity in an unprecedented frequency range of 1-2884 Hz at source levels in ASD using newly developed methods. Seven ASD subjects and age- and gender-matched controls were studied using a high-sampling rate magnetoencephalography (MEG) system. Brain activity in delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-30 Hz), low gamma (30-55 Hz), high gamma (65-90 Hz), ripples (90-200 Hz), high-frequency oscillations (HFOs, 200-1000 Hz), and very high-frequency oscillations (VHFOs, 1000-2884 Hz) was volumetrically localized and measured using wavelet and beamforming. In comparison to controls, ASD subjects had significantly higher odds of alpha activity (8-12 Hz) in the sensorimotor cortex (mu rhythm), and generally high-frequency activity (90-2884 Hz) in the frontal cortex. The source power of HFOs (200-1000 Hz) in the frontal cortex in ASD was significantly elevated as compared with controls. The results suggest that ASD has significantly altered intrinsic brain activity in both low- and high-frequency ranges. Increased intrinsic high-frequency activity in the frontal cortex may play a key role in ASD. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Age-related changes in brain activation associated with dimensional shifts of attention: an fMRI study.

PubMed

Morton, J Bruce; Bosma, Rachael; Ansari, Daniel

2009-05-15

Brain activation associated with dimensional shifts of attention was measured in 14 children and 13 adults using 4 T fMRI. Across all participants, dimensional shifting was associated with activity in a distributed frontoparietal network, including superior parietal cortex, dorsolateral prefrontal cortex, inferior frontal junction, and the pre-supplementary motor region. There were also age-related differences in brain activity, with children but not adults showing an effect of dimension shifting in the right superior frontal sulcus, and adults but not children showing an effect of dimension shifting in the left superior parietal cortex and the right thalamus. These differences were likely not attributable to behavioral differences as children and adults performed comparably. Implications for neurodevelopmental accounts of shifting are discussed.

The von Economo neurons in apes and humans.

PubMed

Allman, John M; Tetreault, Nicole A; Hakeem, Atiya Y; Park, Soyoung

2011-01-01

The von Economo neurons (VENs) are large bipolar neurons located in frontoinsular (FI) and anterior cingulate cortex (ACC) in great apes and humans but not other primates. We stereologically counted the VENs in FI and the limbic anterior (LA) area of ACC and found them to be more numerous in humans than in apes. In humans, VENs first appear in small numbers in the 36th week postconception are rare at birth and increase in number during the first 8 months after birth. There are significantly more VENs in the right hemisphere than the left in FI and LA in postnatal brains; this may be related to asymmetries in the autonomic nervous system. The activity of the inferior anterior insula, containing FI, is related to physiological changes in the body, decision-making, error recognition, and awareness. In a preliminary diffusion tensor imaging study of the connections of FI, we found that the VEN-containing regions connect with the frontal pole as well as with other parts of frontal and insular cortex, the septum, and the amygdala. The VENs and a related cell population, the fork cells, selectively express the bombesin peptides neuromedin B (NMB) and gastrin releasing pepide, which signal satiety. The loss of VENs and fork cells may be related to the loss of satiety signaling in patients with frontotemporal dementia who have damage to FI. These cells may be morphological specializations of an ancient population of neurons involved in the control of appetite present in the insular cortex in all mammals. © 2010 Wiley-Liss, Inc.

Oxidative stress in a model of toxic demyelination in rat brain: the effect of piracetam and vinpocetine.

PubMed

Abdel-Salam, Omar M E; Khadrawy, Yasser A; Salem, Neveen A; Sleem, Amany A

2011-06-01

We studied the role of oxidative stress and the effect of vinpocetine (1.5, 3 or 6 mg/kg) and piracetam (150 or 300 mg/kg) in acute demyelination of the rat brain following intracerebral injection of ethidium bromide (10 μl of 0.1%). ethidium bromide caused (1) increased malondialdehyde (MDA) in cortex, hippocampus and striatum; (2) decreased total antioxidant capacity (TAC) in cortex, hippocampus and striatum; (3) decreased reduced glutathione (GSH) in cortex and hippocampus (4); increased serum nitric oxide and (5) increased striatal (but not cortical or hippocampal) acetylcholinesterase (AChE) activity. MDA decreased in striatum and cortex by the lower doses of vinpocetine or piracetam but increased in cortex and hippocampus and in cortex, hypothalamus and striatum by the higher dose of vinpocetine or piracetam, respectively along with decreased TAC. GSH increased by the higher dose of piracetam and by vinpocetine which also decreased serum nitric oxide. Vinpocetine and piracetam displayed variable effects on regional AChE activity.

Brain regions associated with the acquisition of conditioned place preference for cocaine vs. social interaction.

PubMed

El Rawas, Rana; Klement, Sabine; Kummer, Kai K; Fritz, Michael; Dechant, Georg; Saria, Alois; Zernig, Gerald

2012-01-01

Positive social interaction could play an essential role in switching the preference of the substance dependent individual away from drug related activities. We have previously shown that conditioned place preference (CPP) for cocaine at the dose of 15 mg/kg and CPP for four 15-min episodes of social interaction were equally strong when rats were concurrently conditioned for place preference by pairing cocaine with one compartment and social interaction with the other. The aim of the present study was to investigate the differential activation of brain regions related to the reward circuitry after acquisition/expression of cocaine CPP or social interaction CPP. Our findings indicate that cocaine CPP and social interaction CPP activated almost the same brain regions. However, the granular insular cortex and the dorsal part of the agranular insular cortex were more activated after cocaine CPP, whereas the prelimbic cortex and the core subregion of the nucleus accumbens were more activated after social interaction CPP. These results suggest that the insular cortex appears to be potently activated after drug conditioning learning while activation of the prelimbic cortex-nucleus accumbens core projection seems to be preferentially involved in the conditioning to non-drug stimuli such as social interaction.

Reference frames for spatial frequency in face representation differ in the temporal visual cortex and amygdala.

PubMed

Inagaki, Mikio; Fujita, Ichiro

2011-07-13

Social communication in nonhuman primates and humans is strongly affected by facial information from other individuals. Many cortical and subcortical brain areas are known to be involved in processing facial information. However, how the neural representation of faces differs across different brain areas remains unclear. Here, we demonstrate that the reference frame for spatial frequency (SF) tuning of face-responsive neurons differs in the temporal visual cortex and amygdala in monkeys. Consistent with psychophysical properties for face recognition, temporal cortex neurons were tuned to image-based SFs (cycles/image) and showed viewing distance-invariant representation of face patterns. On the other hand, many amygdala neurons were influenced by retina-based SFs (cycles/degree), a characteristic that is useful for social distance computation. The two brain areas also differed in the luminance contrast sensitivity of face-responsive neurons; amygdala neurons sharply reduced their responses to low luminance contrast images, while temporal cortex neurons maintained the level of their responses. From these results, we conclude that different types of visual processing in the temporal visual cortex and the amygdala contribute to the construction of the neural representations of faces.

Subtle Alterations in Brain Anatomy May Change an Individual’s Personality in Chronic Pain

PubMed Central

Gustin, Sylvia M.; McKay, Jamie G.; Petersen, Esben T.; Peck, Chris C.; Murray, Greg M.; Henderson, Luke A.

2014-01-01

It is well established that gross prefrontal cortex damage can affect an individual’s personality. It is also possible that subtle prefrontal cortex changes associated with conditions such as chronic pain, and not detectable until recent advances in human brain imaging, may also result in subtle changes in an individual’s personality. In an animal model of chronic neuropathic pain, subtle prefrontal cortex changes including altered basal dendritic length, resulted in altered decision making ability. Using multiple magnetic resonance imaging techniques, we found in humans, although gray matter volume and on-going activity were unaltered, chronic neuropathic pain was associated with reduced free and bound proton movement, indicators of subtle anatomical changes, in the medial prefrontal cortex, anterior cingulate cortex and mediodorsal thalamus. Furthermore, proton spectroscopy revealed an increase in neural integrity in the medial prefrontal cortex in neuropathic pain patients, the degree of which was significantly correlated to the personality temperament of novelty seeking. These data reveal that even subtle changes in prefrontal cortex anatomy may result in a significant change in an individual’s personality. PMID:25291361

Toxoplasma gondii Infection in Mice Impairs Long-Term Fear Memory Consolidation through Dysfunction of the Cortex and Amygdala.

PubMed

Ihara, Fumiaki; Nishimura, Maki; Muroi, Yoshikage; Mahmoud, Motamed Elsayed; Yokoyama, Naoaki; Nagamune, Kisaburo; Nishikawa, Yoshifumi

2016-10-01

Chronic infection with Toxoplasma gondii becomes established in tissues of the central nervous system, where parasites may directly or indirectly modulate neuronal function. Epidemiological studies have revealed that chronic infection in humans is a risk factor for developing mental diseases. However, the mechanisms underlying parasite-induced neuronal dysfunction in the brain remain unclear. Here, we examined memory associated with conditioned fear in mice and found that T. gondii infection impairs consolidation of conditioned fear memory. To examine the brain pathology induced by T. gondii infection, we analyzed the parasite load and histopathological changes. T. gondii infects all brain areas, yet the cortex exhibits more severe tissue damage than other regions. We measured neurotransmitter levels in the cortex and amygdala because these regions are involved in fear memory expression. The levels of dopamine metabolites but not those of dopamine were increased in the cortex of infected mice compared with those in the cortex of uninfected mice. In contrast, serotonin levels were decreased in the amygdala and norepinephrine levels were decreased in the cortex and amygdala of infected mice. The levels of cortical dopamine metabolites were associated with the time spent freezing in the fear-conditioning test. These results suggest that T. gondii infection affects fear memory through dysfunction of the cortex and amygdala. Our findings provide insight into the mechanisms underlying the neurological changes seen during T. gondii infection. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

High-intensity erotic visual stimuli de-activate the primary visual cortex in women.

PubMed

Huynh, Hieu K; Beers, Caroline; Willemsen, Antoon; Lont, Erna; Laan, Ellen; Dierckx, Rudi; Jansen, Monique; Sand, Michael; Weijmar Schultz, Willibrord; Holstege, Gert

2012-06-01

The primary visual cortex, Brodmann's area (BA 17), plays a vital role in basic survival mechanisms in humans. In most neuro-imaging studies in which the volunteers have to watch pictures or movies, the primary visual cortex is similarly activated independent of the content of the pictures or movies. However, in case the volunteers perform demanding non-visual tasks, the primary visual cortex becomes de-activated, although the amount of incoming visual sensory information is the same. Do low- and high-intensity erotic movies, compared to neutral movies, produce similar de-activation of the primary visual cortex? Brain activation/de-activation was studied by Positron Emission Tomography scanning of the brains of 12 healthy heterosexual premenopausal women, aged 18-47, who watched neutral, low- and high-intensity erotic film segments. We measured differences in regional cerebral blood flow (rCBF) in the primary visual cortex during watching neutral, low-intensity erotic, and high-intensity erotic film segments. Watching high-intensity erotic, but not low-intensity erotic movies, compared to neutral movies resulted in strong de-activation of the primary (BA 17) and adjoining parts of the secondary visual cortex. The strong de-activation during watching high-intensity erotic film might represent compensation for the increased blood supply in the brain regions involved in sexual arousal, also because high-intensity erotic movies do not require precise scanning of the visual field, because the impact is clear to the observer. © 2012 International Society for Sexual Medicine.

Task alters category representations in prefrontal but not high-level visual cortex.

PubMed

Bugatus, Lior; Weiner, Kevin S; Grill-Spector, Kalanit

2017-07-15

A central question in neuroscience is how cognitive tasks affect category representations across the human brain. Regions in lateral occipito-temporal cortex (LOTC), ventral temporal cortex (VTC), and ventro-lateral prefrontal cortex (VLFPC) constitute the extended "what" pathway, which is considered instrumental for visual category processing. However, it is unknown (1) whether distributed responses across LOTC, VTC, and VLPFC explicitly represent category, task, or some combination of both, and (2) in what way representations across these subdivisions of the extended 'what' pathway may differ. To fill these gaps in knowledge, we scanned 12 participants using fMRI to test the effect of category and task on distributed responses across LOTC, VTC, and VLPFC. Results reveal that task and category modulate responses in both high-level visual regions, as well as prefrontal cortex. However, we found fundamentally different types of representations across the brain. Distributed responses in high-level visual regions are more strongly driven by category than task, and exhibit task-independent category representations. In contrast, distributed responses in prefrontal cortex are more strongly driven by task than category, and contain task-dependent category representations. Together, these findings of differential representations across the brain support a new idea that LOTC and VTC maintain stable category representations allowing efficient processing of visual information, while prefrontal cortex contains flexible representations in which category information may emerge only when relevant to the task. Copyright © 2017 Elsevier Inc. All rights reserved.

Evolution of the cerebellar cortex: the selective expansion of prefrontal-projecting cerebellar lobules.

PubMed

Balsters, J H; Cussans, E; Diedrichsen, J; Phillips, K A; Preuss, T M; Rilling, J K; Ramnani, N

2010-02-01

It has been suggested that interconnected brain areas evolve in tandem because evolutionary pressures act on complete functional systems rather than on individual brain areas. The cerebellar cortex has reciprocal connections with both the prefrontal cortex and motor cortex, forming independent loops with each. Specifically, in capuchin monkeys cerebellar cortical lobules Crus I and Crus II connect with prefrontal cortex, whereas the primary motor cortex connects with cerebellar lobules V, VI, VIIb, and VIIIa. Comparisons of extant primate species suggest that the prefrontal cortex has expanded more than cortical motor areas in human evolution. Given the enlargement of the prefrontal cortex relative to motor cortex in humans, our hypothesis would predict corresponding volumetric increases in the parts of the cerebellum connected to the prefrontal cortex, relative to cerebellar lobules connected to the motor cortex. We tested the hypothesis by comparing the volumes of cerebellar lobules in structural MRI scans in capuchins, chimpanzees and humans. The fractions of cerebellar volume occupied by Crus I and Crus II were significantly larger in humans compared to chimpanzees and capuchins. Our results therefore support the hypothesis that in the cortico-cerebellar system, functionally related structures evolve in concert with each other. The evolutionary expansion of these prefrontal-projecting cerebellar territories might contribute to the evolution of the higher cognitive functions of humans. Copyright (c) 2009 Elsevier Inc. All rights reserved.

Tailored delivery of analgesic ziconotide across a blood brain barrier model using viral nanocontainers

NASA Astrophysics Data System (ADS)

Anand, Prachi; O'Neil, Alison; Lin, Emily; Douglas, Trevor; Holford, Mandë

2015-08-01

The blood brain barrier (BBB) is often an insurmountable obstacle for a large number of candidate drugs, including peptides, antibiotics, and chemotherapeutic agents. Devising an adroit delivery method to cross the BBB is essential to unlocking widespread application of peptide therapeutics. Presented here is an engineered nanocontainer for delivering peptidic drugs across the BBB encapsulating the analgesic marine snail peptide ziconotide (Prialt®). We developed a bi-functional viral nanocontainer based on the Salmonella typhimurium bacteriophage P22 capsid, genetically incorporating ziconotide in the interior cavity, and chemically attaching cell penetrating HIV-Tat peptide on the exterior of the capsid. Virus like particles (VLPs) of P22 containing ziconotide were successfully transported in several BBB models of rat and human brain microvascular endothelial cells (BMVEC) using a recyclable noncytotoxic endocytic pathway. This work demonstrates proof in principle for developing a possible alternative to intrathecal injection of ziconotide using a tunable VLP drug delivery nanocontainer to cross the BBB.

Routes for Drug Translocation Across the Blood-Brain Barrier: Exploiting Peptides as Delivery Vectors.

PubMed

Kristensen, Mie; Brodin, Birger

2017-09-01

A number of potent drugs for the treatment of brain diseases are available. However, in order for them to reach their target site of action, they must pass the blood-brain barrier (BBB). The capillary endothelium comprises the major barrier of the BBB and allows only passive permeation of some small lipophilic molecules. Brain delivery of the larger biopharmaceuticals, which today includes an increasing number of novel drug entities, is therefore restricted, both due to their molecular size and their hydrophilic nature. Thus, the development of novel drug entities intended for the treatment of brain diseases such as neurodegenerative diseases or brain cancers require a delivery strategy for overcoming the BBB before reaching its final target within the brain. Peptide-based delivery vector is an emerging tool as shuttles for drug delivery across the BBB and one may explore receptor-mediated transcytosis, adsorptive-mediated transcytosis, and the paracellular route. The latter, however, being controversial due to the risk of co-delivery of blood-borne potential harmful substances. On the other hand, a number of studies report on drug delivery across the BBB exploiting receptor-mediated transcytosis and adsorptive-mediated transcytosis, indicating that peptides and peptide vectors may be of use in a central nervous system delivery context. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Effect of brain structure, brain function, and brain connectivity on relapse in alcohol-dependent patients.

PubMed

Beck, Anne; Wüstenberg, Torsten; Genauck, Alexander; Wrase, Jana; Schlagenhauf, Florian; Smolka, Michael N; Mann, Karl; Heinz, Andreas

2012-08-01

In alcohol-dependent patients, brain atrophy and functional brain activation elicited by alcohol-associated stimuli may predict relapse. However, to date, the interaction between both factors has not been studied. To determine whether results from structural and functional magnetic resonance imaging are associated with relapse in detoxified alcohol-dependent patients. A cue-reactivity functional magnetic resonance experiment with alcohol-associated and neutral stimuli. After a follow-up period of 3 months, the group of 46 detoxified alcohol-dependent patients was subdivided into 16 abstainers and 30 relapsers. Faculty for Clinical Medicine Mannheim at the University of Heidelberg, Germany. A total of 46 detoxified alcohol-dependent patients and 46 age- and sex-matched healthy control subjects Local gray matter volume, local stimulus-related functional magnetic resonance imaging activation, joint analyses of structural and functional data with Biological Parametric Mapping, and connectivity analyses adopting the psychophysiological interaction approach. Subsequent relapsers showed pronounced atrophy in the bilateral orbitofrontal cortex and in the right medial prefrontal and anterior cingulate cortex, compared with healthy controls and patients who remained abstinent. The local gray matter volume-corrected brain response elicited by alcohol-associated vs neutral stimuli in the left medial prefrontal cortex was enhanced for subsequent relapsers, whereas abstainers displayed an increased neural response in the midbrain (the ventral tegmental area extending into the subthalamic nucleus) and ventral striatum. For alcohol-associated vs neutral stimuli in abstainers compared with relapsers, the analyses of the psychophysiological interaction showed a stronger functional connectivity between the midbrain and the left amygdala and between the midbrain and the left orbitofrontal cortex. Subsequent relapsers displayed increased brain atrophy in brain areas associated with error monitoring and behavioral control. Correcting for gray matter reductions, we found that, in these patients, alcohol-related cues elicited increased activation in brain areas associated with attentional bias toward these cues and that, in patients who remained abstinent, increased activation and connectivity were observed in brain areas associated with processing of salient or aversive stimuli.

Whole Brain Functional Connectivity Pattern Homogeneity Mapping.

PubMed

Wang, Lijie; Xu, Jinping; Wang, Chao; Wang, Jiaojian

2018-01-01

Mounting studies have demonstrated that brain functions are determined by its external functional connectivity patterns. However, how to characterize the voxel-wise similarity of whole brain functional connectivity pattern is still largely unknown. In this study, we introduced a new method called functional connectivity homogeneity (FcHo) to delineate the voxel-wise similarity of whole brain functional connectivity patterns. FcHo was defined by measuring the whole brain functional connectivity patterns similarity of a given voxel with its nearest 26 neighbors using Kendall's coefficient concordance (KCC). The robustness of this method was tested in four independent datasets selected from a large repository of MRI. Furthermore, FcHo mapping results were further validated using the nearest 18 and six neighbors and intra-subject reproducibility with each subject scanned two times. We also compared FcHo distribution patterns with local regional homogeneity (ReHo) to identify the similarity and differences of the two methods. Finally, FcHo method was used to identify the differences of whole brain functional connectivity patterns between professional Chinese chess players and novices to test its application. FcHo mapping consistently revealed that the high FcHo was mainly distributed in association cortex including parietal lobe, frontal lobe, occipital lobe and default mode network (DMN) related areas, whereas the low FcHo was mainly found in unimodal cortex including primary visual cortex, sensorimotor cortex, paracentral lobule and supplementary motor area. These results were further supported by analyses of the nearest 18 and six neighbors and intra-subject similarity. Moreover, FcHo showed both similar and different whole brain distribution patterns compared to ReHo. Finally, we demonstrated that FcHo can effectively identify the whole brain functional connectivity pattern differences between professional Chinese chess players and novices. Our findings indicated that FcHo is a reliable method to delineate the whole brain functional connectivity pattern similarity and may provide a new way to study the functional organization and to reveal neuropathological basis for brain disorders.

Impulsive-antisocial psychopathic traits linked to increased volume and functional connectivity within prefrontal cortex

PubMed Central

Korponay, Cole; Pujara, Maia; Deming, Philip; Philippi, Carissa; Decety, Jean; Kosson, David S.; Kiehl, Kent A.

2017-01-01

Abstract Psychopathy is a personality disorder characterized by callous lack of empathy, impulsive antisocial behavior, and criminal recidivism. Studies of brain structure and function in psychopathy have frequently identified abnormalities in the prefrontal cortex. However, findings have not yet converged to yield a clear relationship between specific subregions of prefrontal cortex and particular psychopathic traits. We performed a multimodal neuroimaging study of prefrontal cortex volume and functional connectivity in psychopathy, using a sample of adult male prison inmates (N = 124). We conducted volumetric analyses in prefrontal subregions, and subsequently assessed resting-state functional connectivity in areas where volume was related to psychopathy severity. We found that overall psychopathy severity and Factor 2 scores (which index the impulsive/antisocial traits of psychopathy) were associated with larger prefrontal subregion volumes, particularly in the medial orbitofrontal cortex and dorsolateral prefrontal cortex. Furthermore, Factor 2 scores were also positively correlated with functional connectivity between several areas of the prefrontal cortex. The results were not attributable to age, race, IQ, substance use history, or brain volume. Collectively, these findings provide evidence for co-localized increases in prefrontal cortex volume and intra-prefrontal functional connectivity in relation to impulsive/antisocial psychopathic traits. PMID:28402565

Somatosensory responses in a human motor cortex

PubMed Central

Donoghue, John P.; Hochberg, Leigh R.

2013-01-01

Somatic sensory signals provide a major source of feedback to motor cortex. Changes in somatosensory systems after stroke or injury could profoundly influence brain computer interfaces (BCI) being developed to create new output signals from motor cortex activity patterns. We had the unique opportunity to study the responses of hand/arm area neurons in primary motor cortex to passive joint manipulation in a person with a long-standing brain stem stroke but intact sensory pathways. Neurons responded to passive manipulation of the contralateral shoulder, elbow, or wrist as predicted from prior studies of intact primates. Thus fundamental properties and organization were preserved despite arm/hand paralysis and damage to cortical outputs. The same neurons were engaged by attempted arm actions. These results indicate that intact sensory pathways retain the potential to influence primary motor cortex firing rates years after cortical outputs are interrupted and may contribute to online decoding of motor intentions for BCI applications. PMID:23343902

Common medial frontal mechanisms of adaptive control in humans and rodents

PubMed Central

Frank, Michael J.; Laubach, Mark

2013-01-01

In this report, we describe how common brain networks within the medial frontal cortex facilitate adaptive behavioral control in rodents and humans. We demonstrate that low frequency oscillations below 12 Hz are dramatically modulated after errors in humans over mid-frontal cortex and in rats within prelimbic and anterior cingulate regions of medial frontal cortex. These oscillations were phase-locked between medial frontal cortex and motor areas in both rats and humans. In rats, single neurons that encoded prior behavioral outcomes were phase-coherent with low-frequency field oscillations particularly after errors. Inactivating medial frontal regions in rats led to impaired behavioral adjustments after errors, eliminated the differential expression of low frequency oscillations after errors, and increased low-frequency spike-field coupling within motor cortex. Our results describe a novel mechanism for behavioral adaptation via low-frequency oscillations and elucidate how medial frontal networks synchronize brain activity to guide performance. PMID:24141310

The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease

PubMed Central

Cuchillo-Ibañez, Inmaculada; Mata-Balaguer, Trinidad; Balmaceda, Valeria; Arranz, Juan José; Nimpf, Johannes; Sáez-Valero, Javier

2016-01-01

Reelin is a signaling protein that plays a crucial role in synaptic function, which expression is influenced by β-amyloid (Aβ). We show that Reelin and Aβ oligomers co-immunoprecipitated in human brain extracts and were present in the same size-exclusion chromatography fractions. Aβ treatment of cells led to increase expression of Reelin, but secreted Reelin results trapped together with Aβ aggregates. In frontal cortex extracts an increase in Reelin mRNA, and in soluble and insoluble (guanidine-extractable) Reelin protein, was associated with late Braak stages of Alzheimer’s disease (AD), while expression of its receptor, ApoER2, did not change. However, Reelin-dependent induction of Dab1 phosphorylation appeared reduced in AD. In cells, Aβ reduced the capacity of Reelin to induce internalization of biotinylated ApoER2 and ApoER2 processing. Soluble proteolytic fragments of ApoER2 generated after Reelin binding can be detected in cerebrospinal fluid (CSF). Quantification of these soluble fragments in CSF could be a tool to evaluate the efficiency of Reelin signaling in the brain. These CSF-ApoER2 fragments correlated with Reelin levels only in control subjects, not in AD, where these fragments diminished. We conclude that while Reelin expression is enhanced in the Alzheimer’s brain, the interaction of Reelin with Aβ hinders its biological activity. PMID:27531658

Characteristics of aquaporin expression surrounding senile plaques and cerebral amyloid angiopathy in Alzheimer disease.

PubMed

Hoshi, Akihiko; Yamamoto, Teiji; Shimizu, Keiko; Ugawa, Yoshikazu; Nishizawa, Masatoyo; Takahashi, Hitoshi; Kakita, Akiyoshi

2012-08-01

Senile plaques (SPs) containing amyloid β peptide (Aβ) 1-42 are the major species present in Alzheimer disease (AD), whereas Aβ1-40 is the major constituent of arteriolar walls affected by cerebral amyloid angiopathy. The water channel proteins astrocytic aquaporin 1 (AQP1) and aquaporin 4 (AQP4) are known to be abnormally expressed in AD brains, but the expression of AQPs surrounding SPs and cerebral amyloid angiopathy has not been described in detail. Here, we investigated whether AQP expression is associated with each species of Aβ deposited in human brains affected by either sporadic or familial AD. Immunohistochemical analysis demonstrated more numerous AQP1-positive reactive astrocytes in the AD cerebral cortex than in controls, located close to Aβ42- or Aβ40-positive SPs. In AD cases, however, AQP1-positive astrocytes were not often observed in Aβ-rich areas, and there was a significant negative correlation between the levels of AQP1 and Aβ42 assessed semiquantitatively. We also found that Aβ plaque-like AQP4 was distributed in association with Aβ42- or Aβ40-positive SPs and that the degree of AQP4 expression around Aβ40-positive vessels was variable. These findings suggest that a defined population of AQP1-positive reactive astrocytes may modify Aβ deposition in the AD brain, whereas the Aβ deposition process might alter astrocytic expression of AQP4.

Anxiety-like behavior in transgenic mice with brain expression of neuropeptide Y.

PubMed

Inui, A; Okita, M; Nakajima, M; Momose, K; Ueno, N; Teranishi, A; Miura, M; Hirosue, Y; Sano, K; Sato, M; Watanabe, M; Sakai, T; Watanabe, T; Ishida, K; Silver, J; Baba, S; Kasuga, M

1998-01-01

Neuropeptide Y (NPY), one of the most abundant peptide transmitters in the mammalian brain, is assumed to play an important role in behavior and its disorders. To understand the long-term modulation of neuronal functions by NPY, we raised transgenic mice created with a novel central nervous system (CNS) neuron-specific expression vector of human Thy- gene fragment linked to mouse NPY cDNA. In situ hybridization analysis demonstrated transgene-derived NPY expression in neurons (e.g., in the hippocampus, cerebral cortex, and the arcuate nucleus of the hypothalamus) in the transgenic mice. The modest increase of NPY protein in the brain was demonstrated by semiquantitative immunohistochemical analysis and by radioreceptor assay (115% in transgenic mice compared to control littermates). Double-staining experiments indicated colocalization of the transgene-derived NPY message and NPY protein in the same neurons, such as in the arcuate nucleus. The transgenic mice displayed behavioral signs of anxiety and hypertrophy of adrenal zona fasciculata cells, but no change in food intake was observed. The anxiety-like behavior of transgenic mice was reversed, at least in part, by administration of corticotropin-releasing factor (CRF) antagonists, alpha-helical CRF9-41, into the third cerebral ventricle. These results suggest that NPY has a role in anxiety and behavioral responses to stress partly via the CRF neuronal system. This genetic model may provide a unique opportunity to study human anxiety and emotional disorders.

Measurement and characterisation of human cholecystokinin-like immunoreactivity (CCK-LI) in tissues by radioimmunoassay.

PubMed

Bacarese-Hamilton, A J; Adrian, T E; Bloom, S R

1984-12-29

Two radioimmunoassays specific for cholecystokinin-like immunoreactivity (CCK-LI) in human tissue are described. The first assay employed an antiserum (Z-69) directed to the sulphated tyrosine at the C-terminal end of CCK-33 and measured all biologically active molecular forms of CCK except the controversial C-terminal tetrapeptide amide (CCK4). The sensitivity of this assay was 0.6 pmol/g. A second assay (employing antiserum Z-91) measured CCK-LI forms larger than the octapeptide and had a sensitivity of 0.2 pmol/g. Both assays were characterised with endogenous human peptides. Acid (pH 2.5) and neutral extracts (pH 6.5) of human intestine and brain were assessed for CCK-LI concentrations and gel chromatography performed in the presence of 6 mol/l urea to elucidate the various molecular forms. Human cerebral cortex CCK-LI was almost all sulphated CCK-8, but large molecular mass forms were present, particularly in acid extracts, forming about 10% of the whole. Human duodenum and jejunum contained approximately equal amounts of large CCK, CCK 33/39 and of CCK-8. Both intestine and brain possess not yet isolated sulphated molecular forms which eluted between the pure CCK-8 and CCK-33/39 standards. The results obtained from this study indicate that the biosynthesis of CCK in human brain and gut is quantitatively different.

Alterations in brain Protein Kinase A activity and reversal of morphine tolerance by two fragments of native Protein Kinase A inhibitor peptide (PKI).

PubMed

Dalton, George D; Smith, Forrest L; Smith, Paul A; Dewey, William L

2005-04-01

Two peptide fragments of native Protein Kinase A inhibitor (PKI), PKI-(6-22)-amide and PKI-(Myr-14-22)-amide, significantly reversed low-level morphine antinociceptive tolerance in mice. The inhibition of Protein Kinase A (PKA) activity by both peptide fragments was then measured in specific brain regions (thalamus, periaqueductal gray (PAG), and medulla) and in lumbar spinal cord (LSC), which in previous studies have been shown to play a role in morphine-induced analgesia. In drug naive animals, cytosolic PKA activity was greater than particulate PKA activity in each region, while cytosolic and particulate PKA activities were greater in thalamus and PAG compared to medulla and LSC. The addition of both peptides to homogenates from each region completely abolished cytosolic and particulate PKA activities in vitro. Following injection into the lateral ventricle of the brain of drug naive mice and morphine-tolerant mice, both peptides inhibited PKA activity in the cytosolic, but not the particulate fraction of LSC. In addition, cytosolic and particulate PKA activities were inhibited by both peptides in thalamus. These results demonstrate that the inhibition of PKA reverses morphine tolerance. Moreover, the inhibition of PKA activity in specific brain regions and LSC from morphine-tolerant mice by PKI analogs administered i.c.v. is evidence that PKA plays a role in morphine tolerance.

The role of brain peptides in the reproduction of blue gourami males (Trichogaster trichopterus).

PubMed

Levy, Gal; Degani, Gad

2013-10-01

In all vertebrates, reproduction and growth are closely linked and both are controlled by complex hormonal interactions at the brain-pituitary level. In this study, we focused on the reciprocal interactions between brain peptides that regulate growth and reproductive functions in a teleostei fish (blue gourami Trichogaster trichopterus). An increase in gonadotropin-releasing hormone 1 (GnRH1) gene expression was detected during ontogeny, and this peptide increased growth hormone (GH) and β follicle-stimulating hormone (βFSH) gene expression in pituitary cell culture. However, although no change in gonadotropin-releasing hormone 2 (GnRH2) gene expression during the reproductive cycle or sexual behavior was detected, a stimulatory effect of this peptide on β gonadotropins (βGtH) gene expression was observed. In addition, pituitary adenylate cyclase-activating polypeptide 38 (PACAP-38) inhibited GnRH-analog-induced βFSH gene expression, and co-treatment of cells with GnRH-analog and PACAP-38 inhibited GnRH-analog-stimulatory and PACAP-38-inhibitory effects on GH gene expression. These findings together with previous studies were used to create a model summarizing the mechanism of brain peptides (GnRH, PACAP and its related peptide) and the relationship to reproduction and growth through pituitary hormone gene expression during ontogenesis and reproductive stages in blue gourami. © 2013 Wiley Periodicals, Inc.

Effects of Biotin Deficiency on Biotinylated Proteins and Biotin-Related Genes in the Rat Brain.

PubMed

Yuasa, Masahiro; Aoyama, Yuki; Shimada, Ryoko; Sawamura, Hiromi; Ebara, Shuhei; Negoro, Munetaka; Fukui, Toru; Watanabe, Toshiaki

2016-01-01

Biotin is a water-soluble vitamin that functions as a cofactor for biotin-dependent carboxylases. The biochemical and physiological roles of biotin in brain regions have not yet been investigated sufficiently in vivo. Thus, in order to clarify the function of biotin in the brain, we herein examined biotin contents, biotinylated protein expression (e.g. holocarboxylases), and biotin-related gene expression in the brain of biotin-deficient rats. Three-week-old male Wistar rats were divided into a control group, biotin-deficient group, and pair-fed group. Rats were fed experimental diets from 3 wk old for 8 wk, and the cortex, hippocampus, striatum, hypothalamus, and cerebellum were then collected. In the biotin-deficient group, the maintenance of total biotin and holocarboxylases, increases in the bound form of biotin and biotinidase activity, and the expression of an unknown biotinylated protein were observed in the cortex. In other regions, total and free biotin contents decreased, holocarboxylase expression was maintained, and bound biotin and biotinidase activity remained unchanged. Biotin-related gene (pyruvate carboxylase, sodium-dependent multivitamin transporter, holocarboxylase synthetase, and biotinidase) expression in the cortex and hippocampus also remained unchanged among the dietary groups. These results suggest that biotin may be related to cortex functions by binding protein, and the effects of a biotin deficiency and the importance of biotin differ among the different brain regions.

Deep brain stimulation reveals emotional impact processing in ventromedial prefrontal cortex.

PubMed

Gjedde, Albert; Geday, Jacob

2009-12-07

We tested the hypothesis that modulation of monoaminergic tone with deep-brain stimulation (DBS) of subthalamic nucleus would reveal a site of reactivity in the ventromedial prefrontal cortex that we previously identified by modulating serotonergic and noradrenergic mechanisms by blocking serotonin-noradrenaline reuptake sites. We tested the hypothesis in patients with Parkinson's disease in whom we had measured the changes of blood flow everywhere in the brain associated with the deep brain stimulation of the subthalamic nucleus. We determined the emotional reactivity of the patients as the average impact of emotive images rated by the patients off the DBS. We then searched for sites in the brain that had significant correlation of the changes of blood flow with the emotional impact rated by the patients. The results indicate a significant link between the emotional impact when patients are not stimulated and the change of blood flow associated with the DBS. In subjects with a low emotional impact, activity measured as blood flow rose when the electrode was turned on, while in subjects of high impact, the activity at this site in the ventromedial prefrontal cortex declined when the electrode was turned on. We conclude that changes of neurotransmission in the ventromedial prefrontal cortex had an effect on the tissue that depends on changes of monoamine concentration interacting with specific combinations of inhibitory and excitatory monoamine receptors.

On the growth and form of cortical convolutions

NASA Astrophysics Data System (ADS)

Tallinen, Tuomas; Chung, Jun Young; Rousseau, François; Girard, Nadine; Lefèvre, Julien; Mahadevan, L.

2016-06-01

The rapid growth of the human cortex during development is accompanied by the folding of the brain into a highly convoluted structure. Recent studies have focused on the genetic and cellular regulation of cortical growth, but understanding the formation of the gyral and sulcal convolutions also requires consideration of the geometry and physical shaping of the growing brain. To study this, we use magnetic resonance images to build a 3D-printed layered gel mimic of the developing smooth fetal brain; when immersed in a solvent, the outer layer swells relative to the core, mimicking cortical growth. This relative growth puts the outer layer into mechanical compression and leads to sulci and gyri similar to those in fetal brains. Starting with the same initial geometry, we also build numerical simulations of the brain modelled as a soft tissue with a growing cortex, and show that this also produces the characteristic patterns of convolutions over a realistic developmental course. All together, our results show that although many molecular determinants control the tangential expansion of the cortex, the size, shape, placement and orientation of the folds arise through iterations and variations of an elementary mechanical instability modulated by early fetal brain geometry.

Distribution of temperature changes and neurovascular coupling in rat brain following 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") exposure.

PubMed

Coman, Daniel; Sanganahalli, Basavaraju G; Jiang, Lihong; Hyder, Fahmeed; Behar, Kevin L

2015-10-01

(+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is an abused psychostimulant that produces strong monoaminergic stimulation and whole-body hyperthermia. MDMA-induced thermogenesis involves activation of uncoupling proteins (UCPs), primarily a type specific to skeletal muscle (UCP-3) and absent from the brain, although other UCP types are expressed in the brain (e.g. thalamus) and might contribute to thermogenesis. Since neuroimaging of brain temperature could provide insights into MDMA action, we measured spatial distributions of systemically administered MDMA-induced temperature changes and dynamics in rat cortex and subcortex using a novel magnetic resonance method, Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), with an exogenous temperature-sensitive probe (thulium ion and macrocyclic chelate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethyl-1,4,7,10-tetraacetate (DOTMA(4-))). The MDMA-induced temperature rise was greater in the cortex than in the subcortex (1.6 ± 0.4 °C versus 1.3 ± 0.4 °C) and occurred more rapidly (2.0 ± 0.2 °C/h versus 1.5 ± 0.2 °C/h). MDMA-induced temperature changes and dynamics in the cortex and body were correlated, although the body temperature exceeded the cortex temperature before and after MDMA. Temperature, neuronal activity, and blood flow (CBF) were measured simultaneously in the cortex and subcortex (i.e. thalamus) to investigate possible differences of MDMA-induced warming across brain regions. MDMA-induced warming correlated with increases in neuronal activity and blood flow in the cortex, suggesting that the normal neurovascular response to increased neural activity was maintained. In contrast to the cortex, a biphasic relationship was seen in the subcortex (i.e. thalamus), with a decline in CBF as temperature and neural activity rose, transitioning to a rise in CBF for temperature above 37 °C, suggesting that MDMA affected CBF and neurovascular coupling differently in subcortical regions. Considering that MDMA effects on CBF and heat dissipation (as well as potential heat generation) may vary regionally, neuroprotection may require different cooling strategies. Copyright © 2015 John Wiley & Sons, Ltd.

Distribution of temperature changes and neurovascular coupling in rat brain following 3,4-methylenedioxymethamphetamine (MDMA,‘ecstasy’) exposure

PubMed Central

Coman, Daniel; Sanganahalli, Basavaraju G.; Jiang, Lihong; Hyder, Fahmeed; Behar, Kevin L.

2015-01-01

(+/−)3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is an abused psychostimulant producing strong monoaminergic stimulation and whole-body hyperthermia. MDMA-induced thermogenesis involves activation of uncoupling proteins (UCP), primarily a type specific to skeletal muscle (UCP-3) and which is absent in brain, although other UCP types are expressed in brain (e.g., thalamus) and might contribute to thermogenesis. Since neuroimaging of brain temperature could provide insights of MDMA action, we measured spatial distributions of systemically-administered MDMA-induced temperature changes and dynamics in rat cortex and subcortex using a novel magnetic resonance method, Biosensor Imaging of Redundant Deviation of Shifts (BIRDS), with an exogenous temperature-sensitive probe (thulium ion and macrocyclic chelate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethyl-1,4,7,10-tetraacetate (DOTMA4−)). The MDMA-induced temperature rise in cortex was greater than in subcortex (1.6±0.4°C vs. 1.3±0.4°C) and occurred more rapidly (2.0±0.2°C/h vs. 1.5±0.2°C/h). MDMA-induced temperature changes and dynamics in cortex and body were correlated, although body temperature exceeded cortex before and after MDMA. Temperature, neuronal activity, and blood flow (CBF) were measured simultaneously in cortex and subcortex (i.e., thalamus) to investigate possible differences of MDMA-induced warming across brain regions. MDMA-induced warming correlated with increases in neuronal activity and blood flow in cortex, suggesting that the normal neurovascular response to increased neural activity was maintained. In contrast to cortex, a biphasic relationship was seen in subcortex (i.e., thalamus), with a decline in CBF as temperature and neural activity rose, transitioning to a rise in CBF for temperature >37°C, suggesting that MDMA affected CBF and neurovascular coupling differently in subcortical regions. Considering that MDMA effects on CBF and heat dissipation (as well as potential heat generation) may vary regionally, neuroprotection may require different cooling strategies. PMID:26286889

Affective neuroscience of pleasure: reward in humans and animals

PubMed Central

2010-01-01

Introduction Pleasure and reward are generated by brain circuits that are largely shared between humans and other animals. Discussion Here, we survey some fundamental topics regarding pleasure mechanisms and explicitly compare humans and animals. Conclusion Topics surveyed include liking, wanting, and learning components of reward; brain coding versus brain causing of reward; subjective pleasure versus objective hedonic reactions; roles of orbitofrontal cortex and related cortex regions; subcortical hedonic hotspots for pleasure generation; reappraisals of dopamine and pleasure-electrode controversies; and the relation of pleasure to happiness. PMID:18311558

Changes of Visual Pathway and Brain Connectivity in Glaucoma: A Systematic Review

PubMed Central

Nuzzi, Raffaele; Dallorto, Laura; Rolle, Teresa

2018-01-01

Background: Glaucoma is a leading cause of irreversible blindness worldwide. The increasing interest in the involvement of the cortical visual pathway in glaucomatous patients is due to the implications in recent therapies, such as neuroprotection and neuroregeneration. Objective: In this review, we outline the current understanding of brain structural, functional, and metabolic changes detected with the modern techniques of neuroimaging in glaucomatous subjects. Methods: We screened MEDLINE, EMBASE, CINAHL, CENTRAL, LILACS, Trip Database, and NICE for original contributions published until 31 October 2017. Studies with at least six patients affected by any type of glaucoma were considered. We included studies using the following neuroimaging techniques: functional Magnetic Resonance Imaging (fMRI), resting-state fMRI (rs-fMRI), magnetic resonance spectroscopy (MRS), voxel- based Morphometry (VBM), surface-based Morphometry (SBM), diffusion tensor MRI (DTI). Results: Over a total of 1,901 studies, 56 case series with a total of 2,381 patients were included. Evidence of neurodegenerative process in glaucomatous patients was found both within and beyond the visual system. Structural alterations in visual cortex (mainly reduced cortex thickness and volume) have been demonstrated with SBM and VBM; these changes were not limited to primary visual cortex but also involved association visual areas. Other brain regions, associated with visual function, demonstrated a certain grade of increased or decreased gray matter volume. Functional and metabolic abnormalities resulted within primary visual cortex in all studies with fMRI and MRS. Studies with rs-fMRI found disrupted connectivity between the primary and higher visual cortex and between visual cortex and associative visual areas in the task-free state of glaucomatous patients. Conclusions: This review contributes to the better understanding of brain abnormalities in glaucoma. It may stimulate further speculation about brain plasticity at a later age and therapeutic strategies, such as the prevention of cortical degeneration in patients with glaucoma. Structural, functional, and metabolic neuroimaging methods provided evidence of changes throughout the visual pathway in glaucomatous patients. Other brain areas, not directly involved in the processing of visual information, also showed alterations. PMID:29896087

The Exercising Brain: Changes in Functional Connectivity Induced by an Integrated Multimodal Cognitive and Whole-Body Coordination Training

PubMed Central

Demirakca, Traute; Cardinale, Vita; Dehn, Sven; Ruf, Matthias; Ende, Gabriele

2016-01-01

This study investigated the impact of “life kinetik” training on brain plasticity in terms of an increased functional connectivity during resting-state functional magnetic resonance imaging (rs-fMRI). The training is an integrated multimodal training that combines motor and cognitive aspects and challenges the brain by introducing new and unfamiliar coordinative tasks. Twenty-one subjects completed at least 11 one-hour-per-week “life kinetik” training sessions in 13 weeks as well as before and after rs-fMRI scans. Additionally, 11 control subjects with 2 rs-fMRI scans were included. The CONN toolbox was used to conduct several seed-to-voxel analyses. We searched for functional connectivity increases between brain regions expected to be involved in the exercises. Connections to brain regions representing parts of the default mode network, such as medial frontal cortex and posterior cingulate cortex, did not change. Significant connectivity alterations occurred between the visual cortex and parts of the superior parietal area (BA7). Premotor area and cingulate gyrus were also affected. We can conclude that the constant challenge of unfamiliar combinations of coordination tasks, combined with visual perception and working memory demands, seems to induce brain plasticity expressed in enhanced connectivity strength of brain regions due to coactivation. PMID:26819776

Evidence for widespread, severe brain copper deficiency in Alzheimer's dementia.

PubMed

Xu, Jingshu; Church, Stephanie J; Patassini, Stefano; Begley, Paul; Waldvogel, Henry J; Curtis, Maurice A; Faull, Richard L M; Unwin, Richard D; Cooper, Garth J S

2017-08-16

Datasets comprising simultaneous measurements of many essential metals in Alzheimer's disease (AD) brain are sparse, and available studies are not entirely in agreement. To further elucidate this matter, we employed inductively-coupled-plasma mass spectrometry to measure post-mortem levels of 8 essential metals and selenium, in 7 brain regions from 9 cases with AD (neuropathological severity Braak IV-VI), and 13 controls who had normal ante-mortem mental function and no evidence of brain disease. Of the regions studied, three undergo severe neuronal damage in AD (hippocampus, entorhinal cortex and middle-temporal gyrus); three are less-severely affected (sensory cortex, motor cortex and cingulate gyrus); and one (cerebellum) is relatively spared. Metal concentrations in the controls differed among brain regions, and AD-associated perturbations in most metals occurred in only a few: regions more severely affected by neurodegeneration generally showed alterations in more metals, and cerebellum displayed a distinctive pattern. By contrast, copper levels were substantively decreased in all AD-brain regions, to 52.8-70.2% of corresponding control values, consistent with pan-cerebral copper deficiency. This copper deficiency could be pathogenic in AD, since levels are lowered to values approximating those in Menkes' disease, an X-linked recessive disorder where brain-copper deficiency is the accepted cause of severe brain damage. Our study reinforces others reporting deficient brain copper in AD, and indicates that interventions aimed at safely and effectively elevating brain copper could provide a new experimental-therapeutic approach.

Brain antibodies in the cortex and blood of people with schizophrenia and controls

PubMed Central

Glass, L J; Sinclair, D; Boerrigter, D; Naude, K; Fung, S J; Brown, D; Catts, V S; Tooney, P; O'Donnell, M; Lenroot, R; Galletly, C; Liu, D; Weickert, T W; Shannon Weickert, C

2017-01-01

The immune system is implicated in the pathogenesis of schizophrenia, with elevated proinflammatory cytokine mRNAs found in the brains of ~40% of individuals with the disorder. However, it is not clear if antibodies (specifically immunoglobulin-γ (IgG)) can be found in the brain of people with schizophrenia and if their abundance relates to brain inflammatory cytokine mRNA levels. Therefore, we investigated the localization and abundance of IgG in the frontal cortex of people with schizophrenia and controls, and the impact of proinflammatory cytokine status on IgG abundance in these groups. Brain IgGs were detected surrounding blood vessels in the human and non-human primate frontal cortex by immunohistochemistry. IgG levels did not differ significantly between schizophrenia cases and controls, or between schizophrenia cases in ‘high’ and ‘low’ proinflammatory cytokine subgroups. Consistent with the existence of IgG in the parenchyma of human brain, mRNA and protein of the IgG transporter (FcGRT) were present in the brain, and did not differ according to diagnosis or inflammatory status. Finally, brain-reactive antibody presence and abundance was investigated in the blood of living people. The plasma of living schizophrenia patients and healthy controls contained antibodies that displayed positive binding to Rhesus macaque cerebellar tissue, and the abundance of these antibodies was significantly lower in patients than controls. These findings suggest that antibodies in the brain and brain-reactive antibodies in the blood are present under normal circumstances. PMID:28786974

Brain antibodies in the cortex and blood of people with schizophrenia and controls.

PubMed

Glass, L J; Sinclair, D; Boerrigter, D; Naude, K; Fung, S J; Brown, D; Catts, V S; Tooney, P; O'Donnell, M; Lenroot, R; Galletly, C; Liu, D; Weickert, T W; Shannon Weickert, C

2017-08-08

The immune system is implicated in the pathogenesis of schizophrenia, with elevated proinflammatory cytokine mRNAs found in the brains of ~40% of individuals with the disorder. However, it is not clear if antibodies (specifically immunoglobulin-γ (IgG)) can be found in the brain of people with schizophrenia and if their abundance relates to brain inflammatory cytokine mRNA levels. Therefore, we investigated the localization and abundance of IgG in the frontal cortex of people with schizophrenia and controls, and the impact of proinflammatory cytokine status on IgG abundance in these groups. Brain IgGs were detected surrounding blood vessels in the human and non-human primate frontal cortex by immunohistochemistry. IgG levels did not differ significantly between schizophrenia cases and controls, or between schizophrenia cases in 'high' and 'low' proinflammatory cytokine subgroups. Consistent with the existence of IgG in the parenchyma of human brain, mRNA and protein of the IgG transporter (FcGRT) were present in the brain, and did not differ according to diagnosis or inflammatory status. Finally, brain-reactive antibody presence and abundance was investigated in the blood of living people. The plasma of living schizophrenia patients and healthy controls contained antibodies that displayed positive binding to Rhesus macaque cerebellar tissue, and the abundance of these antibodies was significantly lower in patients than controls. These findings suggest that antibodies in the brain and brain-reactive antibodies in the blood are present under normal circumstances.

Axonal remodeling for motor recovery after traumatic brain injury requires downregulation of γ-aminobutyric acid signaling

PubMed Central

Lee, S; Ueno, M; Yamashita, T

2011-01-01

Remodeling of the remnant neuronal network after brain injury possibly mediates spontaneous functional recovery; however, the mechanisms inducing axonal remodeling during spontaneous recovery remain unclear. Here, we show that altered γ-aminobutyric acid (GABA) signaling is crucial for axonal remodeling of the contralesional cortex after traumatic brain injury. After injury to the sensorimotor cortex in mice, we found a significant decrease in the expression of GABAAR-α1 subunits in the intact sensorimotor cortex for 2 weeks. Motor functions, assessed by grid walk and cylinder tests, spontaneously improved in 4 weeks after the injury to the sensorimotor cortex. With motor recovery, corticospinal tract (CST) axons from the contralesional cortex sprouted into the denervated side of the cervical spinal cord at 2 and 4 weeks after the injury. To determine the functional implications of the changes in the expression of GABAAR-α1 subunits, we infused muscimol, a GABA R agonist, into the contralesional cortex for a week after the injury. Compared with the vehicle-treated mice, we noted significantly inhibited recovery in the muscimol-treated mice. Further, muscimol infusion greatly suppressed the axonal sprouting into the denervated side of the cervical spinal cord. In conclusion, recovery of motor function and axonal remodeling of the CST following cortical injury requires suppressed GABAAR subunit expression and decreased GABAergic signaling. PMID:21412279

The Neural Basis of Typewriting: A Functional MRI Study.

PubMed

Higashiyama, Yuichi; Takeda, Katsuhiko; Someya, Yoshiaki; Kuroiwa, Yoshiyuki; Tanaka, Fumiaki

2015-01-01

To investigate the neural substrate of typewriting Japanese words and to detect the difference between the neural substrate of typewriting and handwriting, we conducted a functional magnetic resonance imaging (fMRI) study in 16 healthy volunteers. All subjects were skillful touch typists and performed five tasks: a typing task, a writing task, a reading task, and two control tasks. Three brain regions were activated during both the typing and the writing tasks: the left superior parietal lobule, the left supramarginal gyrus, and the left premotor cortex close to Exner's area. Although typing and writing involved common brain regions, direct comparison between the typing and the writing task revealed greater left posteromedial intraparietal cortex activation in the typing task. In addition, activity in the left premotor cortex was more rostral in the typing task than in the writing task. These findings suggest that, although the brain circuits involved in Japanese typewriting are almost the same as those involved in handwriting, there are brain regions that are specific for typewriting.

The Neural Basis of Typewriting: A Functional MRI Study

PubMed Central

Higashiyama, Yuichi; Takeda, Katsuhiko; Someya, Yoshiaki; Kuroiwa, Yoshiyuki; Tanaka, Fumiaki

2015-01-01

To investigate the neural substrate of typewriting Japanese words and to detect the difference between the neural substrate of typewriting and handwriting, we conducted a functional magnetic resonance imaging (fMRI) study in 16 healthy volunteers. All subjects were skillful touch typists and performed five tasks: a typing task, a writing task, a reading task, and two control tasks. Three brain regions were activated during both the typing and the writing tasks: the left superior parietal lobule, the left supramarginal gyrus, and the left premotor cortex close to Exner’s area. Although typing and writing involved common brain regions, direct comparison between the typing and the writing task revealed greater left posteromedial intraparietal cortex activation in the typing task. In addition, activity in the left premotor cortex was more rostral in the typing task than in the writing task. These findings suggest that, although the brain circuits involved in Japanese typewriting are almost the same as those involved in handwriting, there are brain regions that are specific for typewriting. PMID:26218431

Age-related differences in the brain areas outside the classical language areas among adults using category decision task.

PubMed

Cho, Yong Won; Song, Hui-Jin; Lee, Jae Jun; Lee, Joo Hwa; Lee, Hui Joong; Yi, Sang Doe; Chang, Hyuk Won; Berl, Madison M; Gaillard, William D; Chang, Yongmin

2012-03-01

Older adults perform much like younger adults on language. This similar level of performance, however, may come about through different underlying brain processes. In the present study, we evaluated age-related differences in the brain areas outside the typical language areas among adults using a category decision task. Our results showed that similar activation patterns were found in classical language processing areas across the three age groups although regional lateralization indices in Broca's and Wernicke's areas decreased with age. The greatest differences, however, among the three groups were found primarily in the brain areas not associated with core language functioning including the hippocampus, middle frontal gyrus, ventromedial frontal cortex, medial superior parietal cortex and posterior cingulate cortex. Therefore, the non-classical language areas may exhibit an age-related difference between three age groups while the subjects show a similar activation pattern in the core, primary language processing during a semantic decision task. Copyright © 2012 Elsevier Inc. All rights reserved.

The 10 Hz Frequency: A Fulcrum For Transitional Brain States.

PubMed

Garcia-Rill, E; D'Onofrio, S; Luster, B; Mahaffey, S; Urbano, F J; Phillips, C

A 10 Hz rhythm is present in the occipital cortex when the eyes are closed (alpha waves), in the precentral cortex at rest ( mu rhythm), in the superior and middle temporal lobe ( tau rhythm), in the inferior olive (projection to cerebellar cortex), and in physiological tremor (underlying all voluntary movement). These are all considered resting rhythms in the waking brain which are "replaced" by higher frequency activity with sensorimotor stimulation. That is, the 10 Hz frequency fulcrum is replaced on the one hand by lower frequencies during sleep, or on the other hand by higher frequencies during volition and cognition. The 10 Hz frequency fulcrum is proposed as the natural frequency of the brain during quiet waking, but is replaced by higher frequencies capable of permitting more complex functions, or by lower frequencies during sleep and inactivity. At the center of the transition shifts to and from the resting rhythm is the reticular activating system, a phylogenetically preserved area of the brain essential for preconscious awareness.

The 10 Hz Frequency: A Fulcrum For Transitional Brain States

PubMed Central

Garcia-Rill, E.; D’Onofrio, S.; Luster, B.; Mahaffey, S.; Urbano, F. J.; Phillips, C.

2016-01-01

A 10 Hz rhythm is present in the occipital cortex when the eyes are closed (alpha waves), in the precentral cortex at rest (mu rhythm), in the superior and middle temporal lobe (tau rhythm), in the inferior olive (projection to cerebellar cortex), and in physiological tremor (underlying all voluntary movement). These are all considered resting rhythms in the waking brain which are “replaced” by higher frequency activity with sensorimotor stimulation. That is, the 10 Hz frequency fulcrum is replaced on the one hand by lower frequencies during sleep, or on the other hand by higher frequencies during volition and cognition. The 10 Hz frequency fulcrum is proposed as the natural frequency of the brain during quiet waking, but is replaced by higher frequencies capable of permitting more complex functions, or by lower frequencies during sleep and inactivity. At the center of the transition shifts to and from the resting rhythm is the reticular activating system, a phylogenetically preserved area of the brain essential for preconscious awareness. PMID:27547831

Using fNIRS to Examine Occipital and Temporal Responses to Stimulus Repetition in Young Infants: Evidence of Selective Frontal Cortex Involvement

PubMed Central

Emberson, Lauren L.; Cannon, Grace; Palmeri, Holly; Richards, John E.; Aslin, Richard N.

2016-01-01

How does the developing brain respond to recent experience? Repetition suppression (RS) is a robust and well-characterized response of to recent experience found, predominantly, in the perceptual cortices of the adult brain. We use functional near-infrared spectroscopy (fNIRS) to investigate how perceptual (temporal and occipital) and frontal cortices in the infant brain respond to auditory and visual stimulus repetitions (spoken words and faces). In Experiment 1, we find strong evidence of repetition suppression in the frontal cortex but only for auditory stimuli. In perceptual cortices, we find only suggestive evidence of auditory RS in the temporal cortex and no evidence of visual RS in any ROI. In Experiments 2 and 3, we replicate and extend these findings. Overall, we provide the first evidence that infant and adult brains respond differently to stimulus repetition. We suggest that the frontal lobe may support the development of RS in perceptual cortices. PMID:28012401

[Characteristics of the glutamate decarboxylase reaction in homogenates of various regions of the rat brain].

PubMed

Rozanov, V A

1987-01-01

The glutamate decarboxylase activity in rough homogenates of cerebellum, cortex and truncal part of the rat brain was studied under different conditions of incubation: in the presence of 25 mM glutamate sodium, 0.4 mM pyridoxal-5'-phosphate and both these components. It is found that the initial glutamate decarboxylase activity in cerebellum homogenates is approximately twice as high as in the cortex and trunk homogenates. Addition of the substrate and cofactor, especially in the combination, stimulates considerably the yield of gamma-aminobutyric acid (GABA) in the glutamate decarboxylase reaction, the most pronounced activation being observed in the truncal homogenates. The glutamate/GABA relation both initial and after the completion of the reaction is the maximal in the cortex and minimal in the truncal part of the brain. The data obtained evidence for the differences in the content of the GABA-producing enzyme rather than for the presence of the specific mechanisms of the enzyme regulation in different brain areas.

Connectional Modularity of Top-Down and Bottom-Up Multimodal Inputs to the Lateral Cortex of the Mouse Inferior Colliculus

PubMed Central

Lesicko, Alexandria M.H.; Hristova, Teodora S.; Maigler, Kathleen C.

2016-01-01

The lateral cortex of the inferior colliculus receives information from both auditory and somatosensory structures and is thought to play a role in multisensory integration. Previous studies in the rat have shown that this nucleus contains a series of distinct anatomical modules that stain for GAD-67 as well as other neurochemical markers. In the present study, we sought to better characterize these modules in the mouse inferior colliculus and determine whether the connectivity of other neural structures with the lateral cortex is spatially related to the distribution of these neurochemical modules. Staining for GAD-67 and other markers revealed a single modular network throughout the rostrocaudal extent of the mouse lateral cortex. Somatosensory inputs from the somatosensory cortex and dorsal column nuclei were found to terminate almost exclusively within these modular zones. However, projections from the auditory cortex and central nucleus of the inferior colliculus formed patches that interdigitate with the GAD-67-positive modules. These results suggest that the lateral cortex of the mouse inferior colliculus exhibits connectional as well as neurochemical modularity and may contain multiple segregated processing streams. This finding is discussed in the context of other brain structures in which neuroanatomical and connectional modularity have functional consequences. SIGNIFICANCE STATEMENT Many brain regions contain subnuclear microarchitectures, such as the matrix-striosome organization of the basal ganglia or the patch-interpatch organization of the visual cortex, that shed light on circuit complexities. In the present study, we demonstrate the presence of one such micro-organization in the rodent inferior colliculus. While this structure is typically viewed as an auditory integration center, its lateral cortex appears to be involved in multisensory operations and receives input from somatosensory brain regions. We show here that the lateral cortex can be further subdivided into multiple processing streams: modular regions, which are targeted by somatosensory inputs, and extramodular zones that receive auditory information. PMID:27798184

Modality-specific spectral dynamics in response to visual and tactile sequential shape information processing tasks: An MEG study using multivariate pattern classification analysis.

PubMed

Gohel, Bakul; Lee, Peter; Jeong, Yong

2016-08-01

Brain regions that respond to more than one sensory modality are characterized as multisensory regions. Studies on the processing of shape or object information have revealed recruitment of the lateral occipital cortex, posterior parietal cortex, and other regions regardless of input sensory modalities. However, it remains unknown whether such regions show similar (modality-invariant) or different (modality-specific) neural oscillatory dynamics, as recorded using magnetoencephalography (MEG), in response to identical shape information processing tasks delivered to different sensory modalities. Modality-invariant or modality-specific neural oscillatory dynamics indirectly suggest modality-independent or modality-dependent participation of particular brain regions, respectively. Therefore, this study investigated the modality-specificity of neural oscillatory dynamics in the form of spectral power modulation patterns in response to visual and tactile sequential shape-processing tasks that are well-matched in terms of speed and content between the sensory modalities. Task-related changes in spectral power modulation and differences in spectral power modulation between sensory modalities were investigated at source-space (voxel) level, using a multivariate pattern classification (MVPC) approach. Additionally, whole analyses were extended from the voxel level to the independent-component level to take account of signal leakage effects caused by inverse solution. The modality-specific spectral dynamics in multisensory and higher-order brain regions, such as the lateral occipital cortex, posterior parietal cortex, inferior temporal cortex, and other brain regions, showed task-related modulation in response to both sensory modalities. This suggests modality-dependency of such brain regions on the input sensory modality for sequential shape-information processing. Copyright © 2016 Elsevier B.V. All rights reserved.

Energy metabolism of rat cerebral cortex, hypothalamus and hypophysis during ageing.

PubMed

Villa, R F; Ferrari, F; Gorini, A

2012-12-27

Ageing is one of the main risk factors for brain disorders. According to the neuroendocrine theory, ageing modifies the sensitivity of hypothalamus-pituitary-adrenal axis to homoeostatic signals coming from the cerebral cortex. The relationships between the energy metabolism of these areas have not been considered yet, in particular with respect to ageing. For these reasons, this study was undertaken to systematically investigate in female Sprague-Dawley rats aged 4, 6, 12, 18, 24, 28 months and in 4-month-old male ones, the catalytic properties of energy-linked enzymes of the Krebs' cycle, electron transport chain, glutamate and related amino acids on different mitochondrial subpopulations, i.e. non-synaptic perikaryal and intra-synaptic (two types) mitochondria. The biochemical enzymatic pattern of these mitochondria shows different expression of the above-mentioned enzymatic activities in the investigated brain areas, including frontal cerebral cortex, hippocampus, striatum, hypothalamus and hypophysis. The study shows that: (i) the energy metabolism of the frontal cerebral cortex is poorly affected by physiological ageing; (ii) the biochemical machinery of non-synaptic perikaryal mitochondria is differently expressed in the considered brain areas; (iii) at 4-6 months, hypothalamus and hypophysis possess lower oxidative metabolism with respect to the frontal cerebral cortex while (iv), during ageing, the opposite situation occurs. We hypothesised that these metabolic modifications likely try to grant HPA functionality in response to the incoming external stress stimuli increased during ageing. It is particularly notable that age-related changes in brain bioenergetics and in mitochondrial functionality may be considered as remarkable factors during physiological ageing and should play important roles in predisposing the brain to physiopathological events, tightly related to molecular mechanisms evoked for pharmacological treatments. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Mapping and characterization of positive and negative BOLD responses to visual stimulation in multiple brain regions at 7T.

PubMed

Jorge, João; Figueiredo, Patrícia; Gruetter, Rolf; van der Zwaag, Wietske

2018-06-01

External stimuli and tasks often elicit negative BOLD responses in various brain regions, and growing experimental evidence supports that these phenomena are functionally meaningful. In this work, the high sensitivity available at 7T was explored to map and characterize both positive (PBRs) and negative BOLD responses (NBRs) to visual checkerboard stimulation, occurring in various brain regions within and beyond the visual cortex. Recently-proposed accelerated fMRI techniques were employed for data acquisition, and procedures for exclusion of large draining vein contributions, together with ICA-assisted denoising, were included in the analysis to improve response estimation. Besides the visual cortex, significant PBRs were found in the lateral geniculate nucleus and superior colliculus, as well as the pre-central sulcus; in these regions, response durations increased monotonically with stimulus duration, in tight covariation with the visual PBR duration. Significant NBRs were found in the visual cortex, auditory cortex, default-mode network (DMN) and superior parietal lobule; NBR durations also tended to increase with stimulus duration, but were significantly less sustained than the visual PBR, especially for the DMN and superior parietal lobule. Responses in visual and auditory cortex were further studied for checkerboard contrast dependence, and their amplitudes were found to increase monotonically with contrast, linearly correlated with the visual PBR amplitude. Overall, these findings suggest the presence of dynamic neuronal interactions across multiple brain regions, sensitive to stimulus intensity and duration, and demonstrate the richness of information obtainable when jointly mapping positive and negative BOLD responses at a whole-brain scale, with ultra-high field fMRI. © 2018 Wiley Periodicals, Inc.

Ovarian Function Modulates the Effects of Long-Chain Polyunsaturated Fatty Acids on the Mouse Cerebral Cortex.

PubMed

Herrera, Jose L; Ordoñez-Gutierrez, Lara; Fabrias, Gemma; Casas, Josefina; Morales, Araceli; Hernandez, Guadalberto; Acosta, Nieves G; Rodriguez, Covadonga; Prieto-Valiente, Luis; Garcia-Segura, Luis M; Alonso, Rafael; Wandosell, Francisco G

2018-01-01

Different dietary ratios of n -6/ n -3 long-chain polyunsaturated fatty acids (LC-PUFAs) may alter brain lipid profile, neural activity, and brain cognitive function. To determine whether ovarian hormones influence the effect of diet on the brain, ovariectomized and sham-operated mice continuously treated with placebo or estradiol were fed for 3 months with diets containing low or high n -6/ n -3 LC-PUFA ratios. The fatty acid (FA) profile and expression of key neuronal proteins were analyzed in the cerebral cortex, with intact female mice on standard diet serving as internal controls of brain lipidome composition. Diets containing different concentrations of LC-PUFAs greatly modified total FAs, sphingolipids, and gangliosides in the cerebral cortex. Some of these changes were dependent on ovarian hormones, as they were not detected in ovariectomized animals, and in the case of complex lipids, the effect of ovariectomy was partially or totally reversed by continuous administration of estradiol. However, even though differential dietary LC-PUFA content modified the expression of neuronal proteins such as synapsin and its phosphorylation level, PSD-95, amyloid precursor protein (APP), or glial proteins such as glial fibrillary acidic protein (GFAP), an effect also dependent on the presence of the ovary, chronic estradiol treatment was unable to revert the dietary effects on brain cortex synaptic proteins. These results suggest that, in addition to stable estradiol levels, other ovarian hormones such as progesterone and/or cyclic ovarian secretory activity could play a physiological role in the modulation of dietary LC-PUFAs on the cerebral cortex, which may have clinical implications for post-menopausal women on diets enriched with different proportions of n -3 and n -6 LC-PUFAs.

Ovarian Function Modulates the Effects of Long-Chain Polyunsaturated Fatty Acids on the Mouse Cerebral Cortex

PubMed Central

Herrera, Jose L.; Ordoñez-Gutierrez, Lara; Fabrias, Gemma; Casas, Josefina; Morales, Araceli; Hernandez, Guadalberto; Acosta, Nieves G.; Rodriguez, Covadonga; Prieto-Valiente, Luis; Garcia-Segura, Luis M.; Alonso, Rafael; Wandosell, Francisco G.

2018-01-01

Different dietary ratios of n−6/n−3 long-chain polyunsaturated fatty acids (LC-PUFAs) may alter brain lipid profile, neural activity, and brain cognitive function. To determine whether ovarian hormones influence the effect of diet on the brain, ovariectomized and sham-operated mice continuously treated with placebo or estradiol were fed for 3 months with diets containing low or high n−6/n−3 LC-PUFA ratios. The fatty acid (FA) profile and expression of key neuronal proteins were analyzed in the cerebral cortex, with intact female mice on standard diet serving as internal controls of brain lipidome composition. Diets containing different concentrations of LC-PUFAs greatly modified total FAs, sphingolipids, and gangliosides in the cerebral cortex. Some of these changes were dependent on ovarian hormones, as they were not detected in ovariectomized animals, and in the case of complex lipids, the effect of ovariectomy was partially or totally reversed by continuous administration of estradiol. However, even though differential dietary LC-PUFA content modified the expression of neuronal proteins such as synapsin and its phosphorylation level, PSD-95, amyloid precursor protein (APP), or glial proteins such as glial fibrillary acidic protein (GFAP), an effect also dependent on the presence of the ovary, chronic estradiol treatment was unable to revert the dietary effects on brain cortex synaptic proteins. These results suggest that, in addition to stable estradiol levels, other ovarian hormones such as progesterone and/or cyclic ovarian secretory activity could play a physiological role in the modulation of dietary LC-PUFAs on the cerebral cortex, which may have clinical implications for post-menopausal women on diets enriched with different proportions of n−3 and n−6 LC-PUFAs. PMID:29740285

Innate defense regulator peptide 1018 protects against perinatal brain injury.

PubMed

Bolouri, Hayde; Sävman, Karin; Wang, Wei; Thomas, Anitha; Maurer, Norbert; Dullaghan, Edie; Fjell, Christopher D; Ek, C Joakim; Hagberg, Henrik; Hancock, Robert E W; Brown, Kelly L; Mallard, Carina

2014-03-01

There is currently no pharmacological treatment that provides protection against brain injury in neonates. It is known that activation of an innate immune response is a key, contributing factor in perinatal brain injury; therefore, the neuroprotective therapeutic potential of innate defense regulator peptides (IDRs) was investigated. The anti-inflammatory effects of 3 IDRs was measured in lipopolysaccharide (LPS)-activated murine microglia. IDRs were then assessed for their ability to confer neuroprotection in vivo when given 3 hours after neonatal brain injury in a clinically relevant model that combines an inflammatory challenge (LPS) with hypoxia-ischemia (HI). To gain insight into peptide-mediated effects on LPS-induced inflammation and neuroprotective mechanisms, global cerebral gene expression patterns were analyzed in pups that were treated with IDR-1018 either 4 hours before LPS or 3 hours after LPS+HI. IDR-1018 reduced inflammatory mediators produced by LPS-stimulated microglia cells in vitro and modulated LPS-induced neuroinflammation in vivo. When administered 3 hours after LPS+HI, IDR-1018 exerted effects on regulatory molecules of apoptotic (for, eg, Fadd and Tnfsf9) and inflammatory (for, eg, interleukin 1, tumor necrosis factor α, chemokines, and cell adhesion molecules) pathways and showed marked protection of both white and gray brain matter. IDR-1018 suppresses proinflammatory mediators and cell injurious mechanisms in the developing brain, and postinsult treatment is efficacious in reducing LPS-induced hypoxic-ischemic brain damage. IDR-1018 is effective in the brain when given systemically, confers neuroprotection of both gray and white matter, and lacks significant effects on the brain under normal conditions. Thus, this peptide provides the features of a promising neuroprotective agent in newborns with brain injury. © 2014 Child Neurology Society/American Neurological Association.

Brain functional network changes following Prelimbic area inactivation in a spatial memory extinction task.

PubMed

Méndez-Couz, Marta; Conejo, Nélida M; Vallejo, Guillermo; Arias, Jorge L

2015-01-01

Several studies suggest a prefrontal cortex involvement during the acquisition and consolidation of spatial memory, suggesting an active modulating role at late stages of acquisition processes. Recently, we have reported that the prelimbic and infralimbic areas of the prefrontal cortex, among other structures, are also specifically involved in the late phases of spatial memory extinction. This study aimed to evaluate whether the inactivation of the prelimbic area of the prefrontal cortex impaired spatial memory extinction. For this purpose, male Wistar rats were implanted bilaterally with cannulae into the prelimbic region of the prefrontal cortex. Animals were trained during 5 consecutive days in a hidden platform task and tested for reference spatial memory immediately after the last training session. One day after completing the training task, bilateral infusion of the GABAA receptor agonist Muscimol was performed before the extinction protocol was carried out. Additionally, cytochrome c oxidase histochemistry was applied to map the metabolic brain activity related to the spatial memory extinction under prelimbic cortex inactivation. Results show that animals acquired the reference memory task in the water maze, and the extinction task was successfully completed without significant impairment. However, analysis of the functional brain networks involved by cytochrome oxidase activity interregional correlations showed changes in brain networks between the group treated with Muscimol as compared to the saline-treated group, supporting the involvement of the mammillary bodies at a the late stage in the memory extinction process. Copyright © 2015 Elsevier B.V. All rights reserved.

Region-, age-, and sex-specific effects of fetal diazepam exposure on the postnatal development of neurosteroids

PubMed Central

Kellogg, Carol K.; Kenjarski, Thomas P.; Pleger, Gloria L.; Frye, Cheryl A.

2013-01-01

Fetal exposure to diazepam (DZ), a positive modulator of GABAA receptors and an agonist at mitochondrial benzodiazine receptors, induces long-term neural and behavioral effects. This study evaluated whether the early manipulation influenced the normal development of brain levels of neurosteroids or altered steroid action at GABAA receptors. Pregnant dams were injected over gestation days 14 through 20 with DZ (2.5 mg/kg) or the vehicle. Male and female offspring were analyzed at five postnatal ages. The levels of progesterone (P), dihydroprogesterone (DHP), 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP), testosterone (T), dihydrotestosterone, and 5α-androstan-3α,17β diol were measured in the cerebral cortex and diencephalon. The results indicated that development of brain steroid levels and the impact of fetal DZ exposure were region- and sex-specific. Age-related changes in brain steroids did not mirror associated changes in circulating P and T. Age regulated the levels of all 3 progestins in the cerebral cortex, and fetal DZ exposure interacted with the development of P and DHP. The development of 3α,5α-THP in the cortex was markedly influenced by sex, with levels in males decreasing over postnatal development whereas they increased over postpubertal development in females. An adolescent surge in T levels was observed in male cortex and fetal DZ exposure prevented that surge. Steroid levels in the diencephalon were altered by age mainly in females, and DZ exposure had little effect in this region. The data support region-specific regulation of brain steroid synthesis. Only in the cerebral cortex are relevant mechanisms readily modifiable by fetal DZ exposure. However, neither sex nor fetal DZ exposure altered the response of GABAA receptors in adult cortex to neurosteroid. PMID:16376310

Altered effective connectivity anchored in the posterior cingulate cortex and the medial prefrontal cortex in cognitively intact elderly APOE ε4 carriers: a preliminary study.

PubMed

Luo, Xiao; Li, Kaicheng; Jia, Y L; Zeng, Qingze; Jiaerken, Yeerfan; Qiu, Tiantian; Huang, Peiyu; Xu, Xiaojun; Shen, Zhujing; Guan, Xiaojun; Zhou, Jiong; Wang, Chao; Xu, J J; Zhang, Minming

2018-03-17

The APOE ε4 allele is associated with impaired intrinsic functional connectivity in neural networks, especially in the default mode network (DMN). However, effective connectivity (EC) reflects the direct causal effects of one brain region to another, which has rarely been investigated. Recently, Granger causality analysis (GCA) proved suitable for the study of directionality in neuronal interactions. Using GCA, we examined the differences in the EC between the anterior medial prefrontal cortex/posterior cingulate cortex (aMPFC/PCC) and the whole brain in 17 ε4 carrying and 32 non-carrying cognitively intact elderly individuals. Furthermore, correlation analyses were performed between the abnormal EC and cognition/neuropathological indices. Compared with the non-carriers, the results showed that the ε4 carriers exhibited decreased EC from the PCC to the whole brain in the middle temporal gyrus (MTG), the anterior cingulate cortex (ACC), and the precuneus (PCu). Meanwhile, the ε4 carriers demonstrated increased EC from the whole brain to the aMPFC in the inferior parietal lobe (IPL) and the postcentral gyrus (PCG). The correlation analyses suggested that the EC from the IPL/PCG to the aMPFC was related to episodic memory in non-carriers, while the decreased EC from the PCC to the ACC was associated with increased levels of t-tau in the ε4 carriers. In ε4 carriers, a negative influence can be traced from the PCC to both the anterior and posterior DMN subsystems; meanwhile, the anterior DMN subsystem receives compensatory effects from the parietal cortex. Early increases in AD-related pathologies in the PCC may act as first factors during this pathological process.

The effects of neck flexion on cerebral potentials evoked by visual, auditory and somatosensory stimuli and focal brain blood flow in related sensory cortices

PubMed Central

2012-01-01

Background A flexed neck posture leads to non-specific activation of the brain. Sensory evoked cerebral potentials and focal brain blood flow have been used to evaluate the activation of the sensory cortex. We investigated the effects of a flexed neck posture on the cerebral potentials evoked by visual, auditory and somatosensory stimuli and focal brain blood flow in the related sensory cortices. Methods Twelve healthy young adults received right visual hemi-field, binaural auditory and left median nerve stimuli while sitting with the neck in a resting and flexed (20° flexion) position. Sensory evoked potentials were recorded from the right occipital region, Cz in accordance with the international 10–20 system, and 2 cm posterior from C4, during visual, auditory and somatosensory stimulations. The oxidative-hemoglobin concentration was measured in the respective sensory cortex using near-infrared spectroscopy. Results Latencies of the late component of all sensory evoked potentials significantly shortened, and the amplitude of auditory evoked potentials increased when the neck was in a flexed position. Oxidative-hemoglobin concentrations in the left and right visual cortices were higher during visual stimulation in the flexed neck position. The left visual cortex is responsible for receiving the visual information. In addition, oxidative-hemoglobin concentrations in the bilateral auditory cortex during auditory stimulation, and in the right somatosensory cortex during somatosensory stimulation, were higher in the flexed neck position. Conclusions Visual, auditory and somatosensory pathways were activated by neck flexion. The sensory cortices were selectively activated, reflecting the modalities in sensory projection to the cerebral cortex and inter-hemispheric connections. PMID:23199306

Functional activity of the sensorimotor cortex and cerebellum relates to cervical dystonia symptoms.

PubMed

Burciu, Roxana G; Hess, Christopher W; Coombes, Stephen A; Ofori, Edward; Shukla, Priyank; Chung, Jae Woo; McFarland, Nikolaus R; Wagle Shukla, Aparna; Okun, Michael S; Vaillancourt, David E

2017-09-01

Cervical dystonia (CD) is the most common type of focal dystonia, causing abnormal movements of the neck and head. In this study, we used noninvasive imaging to investigate the motor system of patients with CD and uncover the neural correlates of dystonic symptoms. Furthermore, we examined whether a commonly prescribed anticholinergic medication in CD has an effect on the dystonia-related brain abnormalities. Participants included 16 patients with CD and 16 healthy age-matched controls. We collected functional MRI scans during a force task previously shown to extensively engage the motor system, and diffusion and T1-weighted MRI scans from which we calculated free-water and brain tissue densities. The dystonia group was also scanned ca. 2 h after a 2-mg dose of trihexyphenidyl. Severity of dystonia was assessed pre- and post-drug using the Burke-Fahn-Marsden Dystonia Rating Scale. Motor-related activity in CD was altered relative to controls in the primary somatosensory cortex, cerebellum, dorsal premotor and posterior parietal cortices, and occipital cortex. Most importantly, a regression model showed that increased severity of symptoms was associated with decreased functional activity of the somatosensory cortex and increased activity of the cerebellum. Structural imaging measures did not differ between CD and controls. The single dose of trihexyphenidyl altered the fMRI signal in the somatosensory cortex but not in the cerebellum. Symptom severity was not significantly reduced post-treatment. Findings show widespread changes in functional brain activity in CD and most importantly that dystonic symptoms relate to disrupted activity in the somatosensory cortex and cerebellum. Hum Brain Mapp 38:4563-4573, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Cellular scaling rules for the brain of afrotherians

PubMed Central

Neves, Kleber; Ferreira, Fernanda M.; Tovar-Moll, Fernanda; Gravett, Nadine; Bennett, Nigel C.; Kaswera, Consolate; Gilissen, Emmanuel; Manger, Paul R.; Herculano-Houzel, Suzana

2014-01-01

Quantitative analysis of the cellular composition of rodent, primate and eulipotyphlan brains has shown that non-neuronal scaling rules are similar across these mammalian orders that diverged about 95 million years ago, and therefore appear to be conserved in evolution, while neuronal scaling rules appear to be free to vary in evolution in a clade-specific manner. Here we analyze the cellular scaling rules that apply to the brain of afrotherians, believed to be the first clade to radiate from the common eutherian ancestor. We find that afrotherians share non-neuronal scaling rules with rodents, primates and eulipotyphlans, as well as the coordinated scaling of numbers of neurons in the cerebral cortex and cerebellum. Afrotherians share with rodents and eulipotyphlans, but not with primates, the scaling of number of neurons in the cortex and in the cerebellum as a function of the number of neurons in the rest of the brain. Afrotheria also share with rodents and eulipotyphlans the neuronal scaling rules that apply to the cerebral cortex. Afrotherians share with rodents, but not with eulipotyphlans nor primates, the neuronal scaling rules that apply to the cerebellum. Importantly, the scaling of the folding index of the cerebral cortex with the number of neurons in the cerebral cortex is not shared by either afrotherians, rodents, or primates. The sharing of some neuronal scaling rules between afrotherians and rodents, and of some additional features with eulipotyphlans and primates, raise the interesting possibility that these shared characteristics applied to the common eutherian ancestor. In turn, the clade-specific characteristics that relate to the distribution of neurons along the surface of the cerebral cortex and to its degree of gyrification suggest that these characteristics compose an evolutionarily plastic suite of features that may have defined and distinguished mammalian groups in evolution. PMID:24596544

Etiology of sporadic Alzheimer's disease: somatostatin, neprilysin, and amyloid beta peptide.

PubMed

Hama, E; Saido, T C

2005-01-01

We recently demonstrated that amyloid beta peptide (Abeta) is catabolized primarily by a neutral endopeptidase, neprilysin, in the brain and that a neuropeptide, somatostatin (SST), regulates brain Abeta level via modulation of neprilysin activity. Because SST expression in the brain declines upon aging in various mammals including rodents, apes and humans, we hypothesize that the aging-dependent reduction of SST triggers accumulation of Abeta in the brain by suppressing neprilysin action. This hypothesis accounts for the fact that aging is the predominant risk factor for Sporadic Alzheimer's disease.

Behavioural and brain responses related to Internet search and memory.

PubMed

Dong, Guangheng; Potenza, Marc N

2015-10-01

The ready availability of data via searches on the Internet has changed how many people seek and perhaps store and recall information, although the brain mechanisms underlying these processes are not well understood. This study investigated brain mechanisms underlying Internet-based vs. non-Internet-based searching. The results showed that Internet searching was associated with lower accuracy in recalling information as compared with traditional book searching. During functional magnetic resonance imaging, Internet searching was associated with less regional brain activation in the left ventral stream, the association area of the temporal-parietal-occipital cortices, and the middle frontal cortex. When comparing novel items with remembered trials, Internet-based searching was associated with higher brain activation in the right orbitofrontal cortex and lower brain activation in the right middle temporal gyrus when facing those novel trials. Brain activations in the middle temporal gyrus were inversely correlated with response times, and brain activations in the orbitofrontal cortex were positively correlated with self-reported search impulses. Taken together, the results suggest that, although Internet-based searching may have facilitated the information-acquisition process, this process may have been performed more hastily and be more prone to difficulties in recollection. In addition, people appear less confident in recalling information learned through Internet searching and that recent Internet searching may promote motivation to use the Internet. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

How Acute Total Sleep Loss Affects the Attending Brain: A Meta-Analysis of Neuroimaging Studies

PubMed Central

Ma, Ning; Dinges, David F.; Basner, Mathias; Rao, Hengyi

2015-01-01

Study Objectives: Attention is a cognitive domain that can be severely affected by sleep deprivation. Previous neuroimaging studies have used different attention paradigms and reported both increased and reduced brain activation after sleep deprivation. However, due to large variability in sleep deprivation protocols, task paradigms, experimental designs, characteristics of subject populations, and imaging techniques, there is no consensus regarding the effects of sleep loss on the attending brain. The aim of this meta-analysis was to identify brain activations that are commonly altered by acute total sleep deprivation across different attention tasks. Design: Coordinate-based meta-analysis of neuroimaging studies of performance on attention tasks during experimental sleep deprivation. Methods: The current version of the activation likelihood estimation (ALE) approach was used for meta-analysis. The authors searched published articles and identified 11 sleep deprivation neuroimaging studies using different attention tasks with a total of 185 participants, equaling 81 foci for ALE analysis. Results: The meta-analysis revealed significantly reduced brain activation in multiple regions following sleep deprivation compared to rested wakefulness, including bilateral intraparietal sulcus, bilateral insula, right prefrontal cortex, medial frontal cortex, and right parahippocampal gyrus. Increased activation was found only in bilateral thalamus after sleep deprivation compared to rested wakefulness. Conclusion: Acute total sleep deprivation decreases brain activation in the fronto-parietal attention network (prefrontal cortex and intraparietal sulcus) and in the salience network (insula and medial frontal cortex). Increased thalamic activation after sleep deprivation may reflect a complex interaction between the de-arousing effects of sleep loss and the arousing effects of task performance on thalamic activity. Citation: Ma N, Dinges DF, Basner M, Rao H. How acute total sleep loss affects the attending brain: a meta-analysis of neuroimaging studies. SLEEP 2015;38(2):233–240. PMID:25409102

Face Encoding and Recognition in the Human Brain

NASA Astrophysics Data System (ADS)

Haxby, James V.; Ungerleider, Leslie G.; Horwitz, Barry; Maisog, Jose Ma.; Rapoport, Stanley I.; Grady, Cheryl L.

1996-01-01

A dissociation between human neural systems that participate in the encoding and later recognition of new memories for faces was demonstrated by measuring memory task-related changes in regional cerebral blood flow with positron emission tomography. There was almost no overlap between the brain structures associated with these memory functions. A region in the right hippocampus and adjacent cortex was activated during memory encoding but not during recognition. The most striking finding in neocortex was the lateralization of prefrontal participation. Encoding activated left prefrontal cortex, whereas recognition activated right prefrontal cortex. These results indicate that the hippocampus and adjacent cortex participate in memory function primarily at the time of new memory encoding. Moreover, face recognition is not mediated simply by recapitulation of operations performed at the time of encoding but, rather, involves anatomically dissociable operations.

Ventral anterior cingulate cortex and social decision-making.

PubMed

Lockwood, Patricia L; Wittmann, Marco K

2018-06-07

Studies in the field of social neuroscience have recently made use of computational models of decision-making to provide new insights into how we learn about the self and others during social interactions. Importantly, these studies have increasingly drawn attention to brain areas outside of classical cortical "social brain" regions that may be critical for social processing. In particular, two portions of the ventral anterior cingulate cortex (vACC), subgenual anterior cingulate cortex and perigenual anterior cingulate cortex, have been linked to social and self learning signals, respectively. Here we discuss the emerging parallels between these studies. Uncovering the function of vACC during social interactions could provide important new avenues to understand social decision-making in health and disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

Mitochondrial Complex 1 Activity Measured by Spectrophotometry Is Reduced across All Brain Regions in Ageing and More Specifically in Neurodegeneration.

PubMed

Pollard, Amelia Kate; Craig, Emma Louise; Chakrabarti, Lisa

2016-01-01

Mitochondrial function, in particular complex 1 of the electron transport chain (ETC), has been shown to decrease during normal ageing and in neurodegenerative disease. However, there is some debate concerning which area of the brain has the greatest complex 1 activity. It is important to identify the pattern of activity in order to be able to gauge the effect of age or disease related changes. We determined complex 1 activity spectrophotometrically in the cortex, brainstem and cerebellum of middle aged mice (70-71 weeks), a cerebellar ataxic neurodegeneration model (pcd5J) and young wild type controls. We share our updated protocol on the measurements of complex1 activity and find that mitochondrial fractions isolated from frozen tissues can be measured for robust activity. We show that complex 1 activity is clearly highest in the cortex when compared with brainstem and cerebellum (p<0.003). Cerebellum and brainstem mitochondria exhibit similar levels of complex 1 activity in wild type brains. In the aged brain we see similar levels of complex 1 activity in all three-brain regions. The specific activity of complex 1 measured in the aged cortex is significantly decreased when compared with controls (p<0.0001). Both the cerebellum and brainstem mitochondria also show significantly reduced activity with ageing (p<0.05). The mouse model of ataxia predictably has a lower complex 1 activity in the cerebellum, and although reductions are measured in the cortex and brain stem, the remaining activity is higher than in the aged brains. We present clear evidence that complex 1 activity decreases across the brain with age and much more specifically in the cerebellum of the pcd5j mouse. Mitochondrial impairment can be a region specific phenomenon in disease, but in ageing appears to affect the entire brain, abolishing the pattern of higher activity in cortical regions.

Identification of prefrontal cortex (BA10) activation while performing Stroop test using diffuse optical tomography

NASA Astrophysics Data System (ADS)

Khadka, Sabin; Chityala, Srujan R.; Tian, Fenghua; Liu, Hanli

2011-03-01

Stroop test is commonly used as a behavior-testing tool for psychological examinations that are related to attention and cognitive control of the human brain. Studies have shown activations in Broadmann area 10 (BA10) of prefrontal cortex (PFC) during attention and cognitive process. The use of diffuse optical tomography (DOT) for human brain mapping is becoming more prevalent. In this study we expect to find neural correlates between the performed cognitive tasks and hemodynamic signals detected by a DOT system. Our initial observation showed activation of oxy-hemoglobin concentration in BA 10, which is consistent with some results seen by positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Our study demonstrates the possibility of combining DOT with Stroop test to quantitatively investigate cognitive functions of the human brain at the prefrontal cortex.

A plastic stabilizer dibutyltin dilaurate induces subchronic neurotoxicity in rats☆

PubMed Central

Jin, Minghua; Song, Peilin; Li, Na; Li, Xuejun; Chen, Jiajun

2012-01-01

Dibutyltin dilaurate functions as a stabilizer for polyvinyl chloride. In this study, experimental rats were intragastrically administered 5, 10, or 20 mg/kg dibutyltin dilaurate to model sub-chronic poisoning. After exposure, our results showed the activities of superoxide dismutase and glutathione peroxidase decreased in rat brain tissue, while the malondialdehyde and nitric oxide content, as well as nitric oxide synthase activity in rat brain tissue increased. The cell cycle in the right parietal cortex was disordered and the rate of apoptosis increased. DNA damage was aggravated in the cerebral cortex, and the ultrastructure of the right parietal cortex tissues was altered. The above changes became more apparent with exposure to increasing doses of dibutyltin dilaurate. Our experimental findings confirmed the neurotoxicity of dibutyltin dilaurate in rat brain tissues, and demonstrated that the poisoning was dose-dependent. PMID:25538742

The neural bases of cognitive conflict and control in moral judgment.

PubMed

Greene, Joshua D; Nystrom, Leigh E; Engell, Andrew D; Darley, John M; Cohen, Jonathan D

2004-10-14

Traditional theories of moral psychology emphasize reasoning and "higher cognition," while more recent work emphasizes the role of emotion. The present fMRI data support a theory of moral judgment according to which both "cognitive" and emotional processes play crucial and sometimes mutually competitive roles. The present results indicate that brain regions associated with abstract reasoning and cognitive control (including dorsolateral prefrontal cortex and anterior cingulate cortex) are recruited to resolve difficult personal moral dilemmas in which utilitarian values require "personal" moral violations, violations that have previously been associated with increased activity in emotion-related brain regions. Several regions of frontal and parietal cortex predict intertrial differences in moral judgment behavior, exhibiting greater activity for utilitarian judgments. We speculate that the controversy surrounding utilitarian moral philosophy reflects an underlying tension between competing subsystems in the brain.

Lysergic acid diethylamide-induced Fos expression in rat brain: role of serotonin-2A receptors.

PubMed

Gresch, P J; Strickland, L V; Sanders-Bush, E

2002-01-01

Lysergic acid diethylamide (LSD) produces altered mood and hallucinations in humans and binds with high affinity to serotonin-2A (5-HT(2A)) receptors. Although LSD interacts with other receptors, the activation of 5-HT(2A) receptors is thought to mediate the hallucinogenic properties of LSD. The goal of this study was to identify the brain sites activated by LSD and to determine the influence of 5-HT(2A) receptors in this activation. Rats were pretreated with the 5-HT(2A) receptor antagonist MDL 100907 (0.3 mg/kg, i.p.) or vehicle 30 min prior to LSD (500 microg/kg, i.p.) administration and killed 3 h later. Brain tissue was examined for Fos protein expression by immunohistochemistry. LSD administration produced a five- to eight-fold increase in Fos-like immunoreactivity in medial prefrontal cortex, anterior cingulate cortex, and central nucleus of amygdala. However, in dorsal striatum and nucleus accumbens no increase in Fos-like immunoreactivity was observed. Pretreatment with MDL 100907 completely blocked LSD-induced Fos-like immunoreactivity in medial prefrontal cortex and anterior cingulate cortex, but only partially blocked LSD-induced Fos-like immunoreactivity in amygdala. Double-labeled immunohistochemistry revealed that LSD did not induce Fos-like immunoreactivity in cortical cells expressing 5-HT(2A) receptors, suggesting an indirect activation of cortical neurons. These results indicate that the LSD activation of medial prefrontal cortex and anterior cingulate cortex is mediated by 5-HT(2A) receptors, whereas in amygdala 5-HT(2A) receptor activation is a component of the response. These findings support the hypothesis that the medial prefrontal cortex, anterior cingulate cortex, and perhaps the amygdala, are important regions involved in the production of hallucinations. Copyright 2002 IBRO

Cerebral Cortex Regions Selectively Vulnerable to Radiation Dose-Dependent Atrophy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seibert, Tyler M.; Karunamuni, Roshan; Kaifi, Samar

Purpose and Objectives: Neurologic deficits after brain radiation therapy (RT) typically involve decline in higher-order cognitive functions such as attention and memory rather than sensory defects or paralysis. We sought to determine whether areas of the cortex critical to cognition are selectively vulnerable to radiation dose-dependent atrophy. Methods and Materials: We measured change in cortical thickness in 54 primary brain tumor patients who underwent fractionated, partial brain RT. The study patients underwent high-resolution, volumetric magnetic resonance imaging (T1-weighted; T2 fluid-attenuated inversion recovery, FLAIR) before RT and 1 year afterward. Semiautomated software was used to segment anatomic regions of the cerebral cortex formore » each patient. Cortical thickness was measured for each region before RT and 1 year afterward. Two higher-order cortical regions of interest (ROIs) were tested for association between radiation dose and cortical thinning: entorhinal (memory) and inferior parietal (attention/memory). For comparison, 2 primary cortex ROIs were also tested: pericalcarine (vision) and paracentral lobule (somatosensory/motor). Linear mixed-effects analyses were used to test all other cortical regions for significant radiation dose-dependent thickness change. Statistical significance was set at α = 0.05 using 2-tailed tests. Results: Cortical atrophy was significantly associated with radiation dose in the entorhinal (P=.01) and inferior parietal ROIs (P=.02). By contrast, no significant radiation dose-dependent effect was found in the primary cortex ROIs (pericalcarine and paracentral lobule). In the whole-cortex analysis, 9 regions showed significant radiation dose-dependent atrophy, including areas responsible for memory, attention, and executive function (P≤.002). Conclusions: Areas of cerebral cortex important for higher-order cognition may be most vulnerable to radiation-related atrophy. This is consistent with clinical observations that brain radiation patients experience deficits in domains of memory, executive function, and attention. Correlations of regional cortical atrophy with domain-specific cognitive functioning in prospective trials are warranted.« less

Greater Activity in the Frontal Cortex on Left Curves: A Vector-Based fNIRS Study of Left and Right Curve Driving

PubMed Central

Oka, Noriyuki; Yoshino, Kayoko; Yamamoto, Kouji; Takahashi, Hideki; Li, Shuguang; Sugimachi, Toshiyuki; Nakano, Kimihiko; Suda, Yoshihiro; Kato, Toshinori

2015-01-01

Objectives In the brain, the mechanisms of attention to the left and the right are known to be different. It is possible that brain activity when driving also differs with different horizontal road alignments (left or right curves), but little is known about this. We found driver brain activity to be different when driving on left and right curves, in an experiment using a large-scale driving simulator and functional near-infrared spectroscopy (fNIRS). Research Design and Methods The participants were fifteen healthy adults. We created a course simulating an expressway, comprising straight line driving and gentle left and right curves, and monitored the participants under driving conditions, in which they drove at a constant speed of 100 km/h, and under non-driving conditions, in which they simply watched the screen (visual task). Changes in hemoglobin concentrations were monitored at 48 channels including the prefrontal cortex, the premotor cortex, the primary motor cortex and the parietal cortex. From orthogonal vectors of changes in deoxyhemoglobin and changes in oxyhemoglobin, we calculated changes in cerebral oxygen exchange, reflecting neural activity, and statistically compared the resulting values from the right and left curve sections. Results Under driving conditions, there were no sites where cerebral oxygen exchange increased significantly more during right curves than during left curves (p > 0.05), but cerebral oxygen exchange increased significantly more during left curves (p < 0.05) in the right premotor cortex, the right frontal eye field and the bilateral prefrontal cortex. Under non-driving conditions, increases were significantly greater during left curves (p < 0.05) only in the right frontal eye field. Conclusions Left curve driving was thus found to require more brain activity at multiple sites, suggesting that left curve driving may require more visual attention than right curve driving. The right frontal eye field was activated under both driving and non-driving conditions. PMID:25993263

Brain Functional Connectivity Is Modified by a Hypocaloric Mediterranean Diet and Physical Activity in Obese Women

PubMed Central

García-Casares, Natalia; Bernal-López, María R.; Roé-Vellvé, Nuria; Gutiérrez-Bedmar, Mario; García-Arnés, Juan A.; Ramos-Rodriguez, José R.; Alfaro, Francisco; Santamaria-Fernández, Sonia; Jiménez-Murcia, Susana; Garcia-Garcia, Isabel; Valdivielso, Pedro; Fernández-Aranda, Fernando; Tinahones, Francisco J.; Gómez-Huelgas, Ricardo

2017-01-01

Functional magnetic resonance imaging (fMRI) in the resting state has shown altered brain connectivity networks in obese individuals. However, the impact of a Mediterranean diet on cerebral connectivity in obese patients when losing weight has not been previously explored. The aim of this study was to examine the connectivity between brain structures before and six months after following a hypocaloric Mediterranean diet and physical activity program in a group of sixteen obese women aged 46.31 ± 4.07 years. Before and after the intervention program, the body mass index (BMI) (kg/m2) was 38.15 ± 4.7 vs. 34.18 ± 4.5 (p < 0.02), and body weight (kg) was 98.5 ± 13.1 vs. 88.28 ± 12.2 (p < 0.03). All subjects underwent a pre- and post-intervention fMRI under fasting conditions. Functional connectivity was assessed using seed-based correlations. After the intervention, we found decreased connectivity between the left inferior parietal cortex and the right temporal cortex (p < 0.001), left posterior cingulate (p < 0.001), and right posterior cingulate (p < 0.03); decreased connectivity between the left superior frontal gyrus and the right temporal cortex (p < 0.01); decreased connectivity between the prefrontal cortex and the somatosensory cortex (p < 0.025); and decreased connectivity between the left and right posterior cingulate (p < 0.04). Results were considered significant at a voxel-wise threshold of p ≤ 0.05, and a cluster-level family-wise error correction for multiple comparisons of p ≤ 0.05. In conclusion, functional connectivity between brain structures involved in the pathophysiology of obesity (the inferior parietal lobe, posterior cingulate, temporo-insular cortex, prefrontal cortex) may be modified by a weight loss program including a Mediterranean diet and physical exercise. PMID:28671558

Greater Activity in the Frontal Cortex on Left Curves: A Vector-Based fNIRS Study of Left and Right Curve Driving.

PubMed

Oka, Noriyuki; Yoshino, Kayoko; Yamamoto, Kouji; Takahashi, Hideki; Li, Shuguang; Sugimachi, Toshiyuki; Nakano, Kimihiko; Suda, Yoshihiro; Kato, Toshinori

2015-01-01

In the brain, the mechanisms of attention to the left and the right are known to be different. It is possible that brain activity when driving also differs with different horizontal road alignments (left or right curves), but little is known about this. We found driver brain activity to be different when driving on left and right curves, in an experiment using a large-scale driving simulator and functional near-infrared spectroscopy (fNIRS). The participants were fifteen healthy adults. We created a course simulating an expressway, comprising straight line driving and gentle left and right curves, and monitored the participants under driving conditions, in which they drove at a constant speed of 100 km/h, and under non-driving conditions, in which they simply watched the screen (visual task). Changes in hemoglobin concentrations were monitored at 48 channels including the prefrontal cortex, the premotor cortex, the primary motor cortex and the parietal cortex. From orthogonal vectors of changes in deoxyhemoglobin and changes in oxyhemoglobin, we calculated changes in cerebral oxygen exchange, reflecting neural activity, and statistically compared the resulting values from the right and left curve sections. Under driving conditions, there were no sites where cerebral oxygen exchange increased significantly more during right curves than during left curves (p > 0.05), but cerebral oxygen exchange increased significantly more during left curves (p < 0.05) in the right premotor cortex, the right frontal eye field and the bilateral prefrontal cortex. Under non-driving conditions, increases were significantly greater during left curves (p < 0.05) only in the right frontal eye field. Left curve driving was thus found to require more brain activity at multiple sites, suggesting that left curve driving may require more visual attention than right curve driving. The right frontal eye field was activated under both driving and non-driving conditions.

Ventromedial prefrontal cortex modulates fatigue after penetrating traumatic brain injury

PubMed Central

Pardini, Matteo; Krueger, Frank; Raymont, Vanessa; Grafman, Jordan

2010-01-01

Background: Fatigue is a common and disabling symptom in neurologic disorders including traumatic penetrating brain injury (PBI). Despite fatigue's prevalence and impact on quality of life, its pathophysiology is not understood. Studies on effort perception in healthy subjects, animal behavioral paradigms, and recent evidence in different clinical populations suggest that ventromedial prefrontal cortex could play a significant role in fatigue pathophysiology in neurologic conditions. Methods: We enrolled 97 PBI patients and 37 control subjects drawn from the Vietnam Head Injury Study registry. Fatigue was assessed with a self-report questionnaire and a clinician-rated instrument; lesion location and volume were evaluated on CT scans. PBI patients were divided in 3 groups according to lesion location: a nonfrontal lesion group, a ventromedial prefrontal cortex lesion (vmPFC) group, and a dorso/lateral prefrontal cortex (d/lPFC) group. Fatigue scores were compared among the 3 PBI groups and the healthy controls. Results: Individuals with vmPFC lesions were significantly more fatigued than individuals with d/lPFC lesions, individuals with nonfrontal lesions, and healthy controls, while these 3 latter groups were equally fatigued. VmPFC volume was correlated with fatigue scores, showing that the larger the lesion volume, the higher the fatigue scores. Conclusions: We demonstrated that ventromedial prefrontal cortex lesion (vmPFC) plays a critical role in penetrating brain injury–related fatigue, providing a rationale to link fatigue to different vmPFC functions such as effort and reward perception. The identification of the anatomic and cognitive basis of fatigue can contribute to developing pathophysiology-based treatments for this disabling symptom. GLOSSARY AAL = Automated Anatomic Labeling; ANOVA = analysis of variance; BDI = Beck Depression Inventory; d/lPFC = dorso/lateral prefrontal cortex; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; NBRS = Neurobehavioral Rating Scale; NF = nonfrontal lesion; PBI = penetrating brain injury; ROI = region of interest; SCID-I = Structured Clinical Interview for DSM-IV, Axis I; VHIS = Vietnam Head Injury Study; vmPFC = ventromedial prefrontal cortex lesion. PMID:20194914

BDNF-GSK-3β-β-Catenin Pathway in the mPFC Is Involved in Antidepressant-Like Effects of Morinda officinalis Oligosaccharides in Rats.

PubMed

Xu, Ling-Zhi; Xu, De-Feng; Han, Ying; Liu, Li-Jing; Sun, Cheng-Yu; Deng, Jia-Hui; Zhang, Ruo-Xi; Yuan, Ming; Zhang, Su-Zhen; Li, Zhi-Meng; Xu, Yi; Li, Jin-Sheng; Xie, Su-Hua; Li, Su-Xia; Zhang, Hong-Yan; Lu, Lin

2017-01-01

Morinda officinalis oligosaccharides have been reported to exert neuroprotective and antidepressant-like effects in the forced swim test in mice. However, the mechanisms that underlie the antidepressant-like effects of Morinda officinalis oligosaccharides are unclear. Chronic unpredictable stress and forced swim test were used to explore the antidepressant-like effects of Morinda officinalis oligosaccharides and resilience to stress in rats. The phosphoinositide-3 kinase inhibitor LY294002 was microinjected in the medial prefrontal cortex to explore the role of glycogen synthase kinase-3β in the antidepressant-like effects of Morinda officinalis oligosaccharides. The expression of brain-derived neurotrophic factor, phosphorylated-Ser9-glycogen synthase kinase 3β, β-catenin, and synaptic proteins was determined in the medial prefrontal cortex and the orbitofrontal cortex by western blot. We found that Morinda officinalis oligosaccharides effectively ameliorated chronic unpredictable stress-induced depression-like behaviors in the sucrose preference test and forced swim test. The Morinda officinalis oligosaccharides also significantly rescued chronic unpredictable stress-induced abnormalities in the brain-derived neurotrophic factor-glycogen synthase kinase-3β-β-catenin pathway and synaptic protein deficits in the medial prefrontal cortex but not orbitofrontal cortex. The activation of glycogen synthase kinase-3β by the phosphoinositide-3 kinase inhibitor LY294002 abolished the antidepressant-like effects of Morinda officinalis oligosaccharides in the forced swim test. Naïve rats that were treated with Morinda officinalis oligosaccharides exhibited resilience to chronic unpredictable stress, accompanied by increases in the expression of brain-derived neurotrophic factor, phosphorylated-Ser9-glycogen synthase kinase-3β, and β-catenin in the medial prefrontal cortex. Our findings indicate that the brain-derived neurotrophic factor-glycogen synthase kinase-3β-β-catenin pathway in the medial prefrontal cortex may underlie the antidepressant-like effect of Morinda officinalis oligosaccharides and resilience to stress. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Ethylene glycol ethers induce apoptosis and disturb glucose metabolism in the rat brain.

PubMed

Pomierny, Bartosz; Krzyżanowska, Weronika; Niedzielska, Ewa; Broniowska, Żaneta; Budziszewska, Bogusława

2016-02-01

Ethylene glycol ethers (EGEs) are compounds widely used in industry and household products, but their potential, adverse effect on brain is poorly understood, so far. The aim of the present study was to determine whether 4-week administration of 2-buthoxyethanol (BE), 2-phenoxyethanol (PHE), and 2-ethoxyethanol (EE) induces apoptotic process in the rat hippocampus and frontal cortex, and whether their adverse effect on the brain cells can result from disturbances in the glucose metabolism. Experiments were conducted on 40 rats, exposed to BE, PHE, EE, saline or sunflower oil for 4 weeks. Markers of apoptosis and glucose metabolism were determined in frontal cortex and hippocampus by western blot, ELISA, and fluorescent-based assays. BE and PHE, but not EE, increased expression of the active form of caspase-3 in the examined brain regions. BE and PHE increased caspase-9 level in the cortex and PHE also in the hippocampus. BE and PHE increased the level of pro-apoptotic proteins (Bax, Bak) and/or reduced the concentration of anti-apoptotic proteins (Bcl-2, Bcl-xL); whereas, the effect of BE was observed mainly in the cortex and that of PHE in the hippocampus. It has also been found that PHE increased brain glucose level, and both BE and PHE elevated pyruvate and lactate concentration. It can be concluded that chronic treatment with BE and PHE induced mitochondrial pathway of apoptosis, and disturbed glucose metabolism in the rat brain. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

The lateral prefrontal cortex mediates the hyperalgesic effects of negative cognitions in chronic pain patients.

PubMed

Loggia, Marco L; Berna, Chantal; Kim, Jieun; Cahalan, Christine M; Martel, Marc-Olivier; Gollub, Randy L; Wasan, Ajay D; Napadow, Vitaly; Edwards, Robert R

2015-08-01

Although high levels of negative affect and cognitions have been associated with greater pain sensitivity in chronic pain conditions, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation and 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing in fibromyalgia (FM) patients. Using functional magnetic resonance imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex. A bootstrapped mediation analysis revealed that pain-anticipatory activity in the lateral prefrontal cortex mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of the lateral prefrontal cortex in the pathophysiology of FM-related hyperalgesia and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well-validated measure of negative cognitions and psychological distress. This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions toward pain. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Haptic contents of a movie dynamically engage the spectator's sensorimotor cortex.

PubMed

Lankinen, Kaisu; Smeds, Eero; Tikka, Pia; Pihko, Elina; Hari, Riitta; Koskinen, Miika

2016-11-01

Observation of another person's actions and feelings activates brain areas that support similar functions in the observer, thereby facilitating inferences about the other's mental and bodily states. In real life, events eliciting this kind of vicarious brain activations are intermingled with other complex, ever-changing stimuli in the environment. One practical approach to study the neural underpinnings of real-life vicarious perception is to image brain activity during movie viewing. Here the goal was to find out how observed haptic events in a silent movie would affect the spectator's sensorimotor cortex. The functional state of the sensorimotor cortex was monitored by analyzing, in 16 healthy subjects, magnetoencephalographic (MEG) responses to tactile finger stimuli that were presented once per second throughout the session. Using canonical correlation analysis and spatial filtering, consistent single-trial responses across subjects were uncovered, and their waveform changes throughout the movie were quantified. The long-latency (85-175 ms) parts of the responses were modulated in concordance with the participants' average moment-by-moment ratings of own engagement in the haptic content of the movie (correlation r = 0.49; ratings collected after the MEG session). The results, obtained by using novel signal-analysis approaches, demonstrate that the functional state of the human sensorimotor cortex fluctuates in a fine-grained manner even during passive observation of temporally varying haptic events. Hum Brain Mapp 37:4061-4068, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Higher cortical and lower subcortical metabolism in detoxified methamphetamine abusers.

PubMed

Volkow, N D; Chang, L; Wang, G J; Fowler, J S; Franceschi, D; Sedler, M J; Gatley, S J; Hitzemann, R; Ding, Y S; Wong, C; Logan, J

2001-03-01

Methamphetamine has raised concerns because it may be neurotoxic to the human brain. Although prior work has focused primarily on the effects of methamphetamine on dopamine cells, there is evidence that other neuronal types are affected. The authors measured regional brain glucose metabolism, which serves as a marker of brain function, to assess if there is evidence of functional changes in methamphetamine abusers in regions other than those innervated by dopamine cells. Fifteen detoxified methamphetamine abusers and 21 comparison subjects underwent positron emission tomography following administration of [(18)F]fluorodeoxyglucose. Whole brain metabolism in the methamphetamine abusers was 14% higher than that of comparison subjects; the differences were most accentuated in the parietal cortex (20%). After normalization for whole brain metabolism, methamphetamine abusers exhibited significantly lower metabolism in the thalamus (17% difference) and striatum (where the differences were larger for the caudate [12%] than for the putamen [6%]). Statistical parametric mapping analyses corroborated these findings, revealing higher metabolism in the parietal cortex and lower metabolism in the thalamus and striatum of methamphetamine abusers. The fact that the parietal cortex is a region devoid of any significant dopaminergic innervation suggests that the higher metabolism seen in this region in the methamphetamine abusers is the result of methamphetamine effects in circuits other than those modulated by dopamine. In addition, the lower metabolism in the striatum and thalamus (major outputs of dopamine signals into the cortex) is likely to reflect the functional consequence of methamphetamine in dopaminergic circuits. These results provide evidence that, in humans, methamphetamine abuse results in changes in function of dopamine- and nondopamine-innervated brain regions.

Different brain activation under left and right ventricular stimulation: an fMRI study in anesthetized rats.

PubMed

Suzuki, Hideaki; Sumiyoshi, Akira; Kawashima, Ryuta; Shimokawa, Hiroaki

2013-01-01

Myocardial ischemia in the anterior wall of the left ventricule (LV) and in the inferior wall and/or right ventricle (RV) shows different manifestations that can be explained by the different innervations of cardiac afferent nerves. However, it remains unclear whether information from different areas of the heart, such as the LV and RV, are differently processed in the brain. In this study, we investigated the brain regions that process information from the LV or RV using cardiac electrical stimulation and functional magnetic resonance imaging (fMRI) in anesthetized rats because the combination of these two approaches cannot be used in humans. An electrical stimulation catheter was inserted into the LV or RV (n = 12 each). Brain fMRI scans were recorded during LV or RV stimulation (9 Hz and 0.3 ms width) over 10 blocks consisting of alternating periods of 2 mA for 30 sec followed by 0.2 mA for 60 sec. The validity of fMRI signals was confirmed by first and second-level analyses and temporal profiles. Increases in fMRI signals were observed in the anterior cingulate cortex and the right somatosensory cortex under LV stimulation. In contrast, RV stimulation activated the right somatosensory cortex, which was identified more anteriorly compared with LV stimulation but did not activate the anterior cingulate cortex. This study provides the first evidence for differences in brain activation under LV and RV stimulation. These different brain processes may be associated with different clinical manifestations between anterior wall and inferoposterior wall and/or RV myocardial ischemia.

How acute total sleep loss affects the attending brain: a meta-analysis of neuroimaging studies.

PubMed

Ma, Ning; Dinges, David F; Basner, Mathias; Rao, Hengyi

2015-02-01

Attention is a cognitive domain that can be severely affected by sleep deprivation. Previous neuroimaging studies have used different attention paradigms and reported both increased and reduced brain activation after sleep deprivation. However, due to large variability in sleep deprivation protocols, task paradigms, experimental designs, characteristics of subject populations, and imaging techniques, there is no consensus regarding the effects of sleep loss on the attending brain. The aim of this meta-analysis was to identify brain activations that are commonly altered by acute total sleep deprivation across different attention tasks. Coordinate-based meta-analysis of neuroimaging studies of performance on attention tasks during experimental sleep deprivation. The current version of the activation likelihood estimation (ALE) approach was used for meta-analysis. The authors searched published articles and identified 11 sleep deprivation neuroimaging studies using different attention tasks with a total of 185 participants, equaling 81 foci for ALE analysis. The meta-analysis revealed significantly reduced brain activation in multiple regions following sleep deprivation compared to rested wakefulness, including bilateral intraparietal sulcus, bilateral insula, right prefrontal cortex, medial frontal cortex, and right parahippocampal gyrus. Increased activation was found only in bilateral thalamus after sleep deprivation compared to rested wakefulness. Acute total sleep deprivation decreases brain activation in the fronto-parietal attention network (prefrontal cortex and intraparietal sulcus) and in the salience network (insula and medial frontal cortex). Increased thalamic activation after sleep deprivation may reflect a complex interaction between the de-arousing effects of sleep loss and the arousing effects of task performance on thalamic activity. © 2015 Associated Professional Sleep Societies, LLC.

Cortical and subcortical mechanisms of brain-machine interfaces.

PubMed

Marchesotti, Silvia; Martuzzi, Roberto; Schurger, Aaron; Blefari, Maria Laura; Del Millán, José R; Bleuler, Hannes; Blanke, Olaf

2017-06-01

Technical advances in the field of Brain-Machine Interfaces (BMIs) enable users to control a variety of external devices such as robotic arms, wheelchairs, virtual entities and communication systems through the decoding of brain signals in real time. Most BMI systems sample activity from restricted brain regions, typically the motor and premotor cortex, with limited spatial resolution. Despite the growing number of applications, the cortical and subcortical systems involved in BMI control are currently unknown at the whole-brain level. Here, we provide a comprehensive and detailed report of the areas active during on-line BMI control. We recorded functional magnetic resonance imaging (fMRI) data while participants controlled an EEG-based BMI inside the scanner. We identified the regions activated during BMI control and how they overlap with those involved in motor imagery (without any BMI control). In addition, we investigated which regions reflect the subjective sense of controlling a BMI, the sense of agency for BMI-actions. Our data revealed an extended cortical-subcortical network involved in operating a motor-imagery BMI. This includes not only sensorimotor regions but also the posterior parietal cortex, the insula and the lateral occipital cortex. Interestingly, the basal ganglia and the anterior cingulate cortex were involved in the subjective sense of controlling the BMI. These results inform basic neuroscience by showing that the mechanisms of BMI control extend beyond sensorimotor cortices. This knowledge may be useful for the development of BMIs that offer a more natural and embodied feeling of control for the user. Hum Brain Mapp 38:2971-2989, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms.

PubMed

Carhart-Harris, Robin L; Roseman, Leor; Bolstridge, Mark; Demetriou, Lysia; Pannekoek, J Nienke; Wall, Matthew B; Tanner, Mark; Kaelen, Mendel; McGonigle, John; Murphy, Kevin; Leech, Robert; Curran, H Valerie; Nutt, David J

2017-10-13

Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other 'psychedelics' yet were related to clinical outcomes. A 'reset' therapeutic mechanism is proposed.

Prestimulus Network Integration of Auditory Cortex Predisposes Near-Threshold Perception Independently of Local Excitability

PubMed Central

Leske, Sabine; Ruhnau, Philipp; Frey, Julia; Lithari, Chrysa; Müller, Nadia; Hartmann, Thomas; Weisz, Nathan

2015-01-01

An ever-increasing number of studies are pointing to the importance of network properties of the brain for understanding behavior such as conscious perception. However, with regards to the influence of prestimulus brain states on perception, this network perspective has rarely been taken. Our recent framework predicts that brain regions crucial for a conscious percept are coupled prior to stimulus arrival, forming pre-established pathways of information flow and influencing perceptual awareness. Using magnetoencephalography (MEG) and graph theoretical measures, we investigated auditory conscious perception in a near-threshold (NT) task and found strong support for this framework. Relevant auditory regions showed an increased prestimulus interhemispheric connectivity. The left auditory cortex was characterized by a hub-like behavior and an enhanced integration into the brain functional network prior to perceptual awareness. Right auditory regions were decoupled from non-auditory regions, presumably forming an integrated information processing unit with the left auditory cortex. In addition, we show for the first time for the auditory modality that local excitability, measured by decreased alpha power in the auditory cortex, increases prior to conscious percepts. Importantly, we were able to show that connectivity states seem to be largely independent from local excitability states in the context of a NT paradigm. PMID:26408799

Structural Brain Changes Following Left Temporal Low-Frequency rTMS in Patients with Subjective Tinnitus

PubMed Central

Langguth, Berthold; Poeppl, Timm B.; Rupprecht, Rainer; Hajak, Göran; Landgrebe, Michael; Schecklmann, Martin

2014-01-01

Repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been used to treat patients with subjective tinnitus. While rTMS is known to induce morphological changes in healthy subjects, no study has investigated yet whether rTMS treatment induces grey matter (GM) changes in tinnitus patients as well, whether these changes are correlated with treatment success, and whether GM at baseline is a useful predictor for treatment outcome. Therefore, we examined magnetic resonance images of 77 tinnitus patients who were treated with rTMS of the left temporal cortex (10 days, 2000 stimuli/day, 1 Hz). At baseline and after the last treatment session high-resolution structural images of the brain were acquired and tinnitus severity was assessed. For a subgroup of 41 patients, additional brain scans were done after a follow-up period of 90 days. GM changes were analysed by means of voxel based morphometry. Transient GM decreases were detectable in several brain regions, especially in the insula and the inferior frontal cortex. These changes were not related to treatment outcome though. Baseline images correlated with change in tinnitus severity in the frontal cortex and the lingual gyrus, suggesting that GM at baseline might hold potential as a possible predictor for treatment outcome. PMID:24991438

The mental cost of cognitive enhancement.

PubMed

Iuculano, Teresa; Cohen Kadosh, Roi

2013-03-06

Noninvasive brain stimulation provides a potential tool for affecting brain functions in the typical and atypical brain and offers in several cases an alternative to pharmaceutical intervention. Some studies have suggested that transcranial electrical stimulation (TES), a form of noninvasive brain stimulation, can also be used to enhance cognitive performance. Critically, research so far has primarily focused on optimizing protocols for effective stimulation, or assessing potential physical side effects of TES while neglecting the possibility of cognitive side effects. We assessed this possibility by targeting the high-level cognitive abilities of learning and automaticity in the mathematical domain. Notably, learning and automaticity represent critical abilities for potential cognitive enhancement in typical and atypical populations. Over 6 d, healthy human adults underwent cognitive training on a new numerical notation while receiving TES to the posterior parietal cortex or the dorsolateral prefrontal cortex. Stimulation to the the posterior parietal cortex facilitated numerical learning, whereas automaticity for the learned material was impaired. In contrast, stimulation to the dorsolateral prefrontal cortex impaired the learning process, whereas automaticity for the learned material was enhanced. The observed double dissociation indicates that cognitive enhancement through TES can occur at the expense of other cognitive functions. These findings have important implications for the future use of enhancement technologies for neurointervention and performance improvement in healthy populations.

A Brain System for Auditory Working Memory.

PubMed

Kumar, Sukhbinder; Joseph, Sabine; Gander, Phillip E; Barascud, Nicolas; Halpern, Andrea R; Griffiths, Timothy D

2016-04-20

The brain basis for auditory working memory, the process of actively maintaining sounds in memory over short periods of time, is controversial. Using functional magnetic resonance imaging in human participants, we demonstrate that the maintenance of single tones in memory is associated with activation in auditory cortex. In addition, sustained activation was observed in hippocampus and inferior frontal gyrus. Multivoxel pattern analysis showed that patterns of activity in auditory cortex and left inferior frontal gyrus distinguished the tone that was maintained in memory. Functional connectivity during maintenance was demonstrated between auditory cortex and both the hippocampus and inferior frontal cortex. The data support a system for auditory working memory based on the maintenance of sound-specific representations in auditory cortex by projections from higher-order areas, including the hippocampus and frontal cortex. In this work, we demonstrate a system for maintaining sound in working memory based on activity in auditory cortex, hippocampus, and frontal cortex, and functional connectivity among them. Specifically, our work makes three advances from the previous work. First, we robustly demonstrate hippocampal involvement in all phases of auditory working memory (encoding, maintenance, and retrieval): the role of hippocampus in working memory is controversial. Second, using a pattern classification technique, we show that activity in the auditory cortex and inferior frontal gyrus is specific to the maintained tones in working memory. Third, we show long-range connectivity of auditory cortex to hippocampus and frontal cortex, which may be responsible for keeping such representations active during working memory maintenance. Copyright © 2016 Kumar et al.

Hominoid visual brain structure volumes and the position of the lunate sulcus.

PubMed

de Sousa, Alexandra A; Sherwood, Chet C; Mohlberg, Hartmut; Amunts, Katrin; Schleicher, Axel; MacLeod, Carol E; Hof, Patrick R; Frahm, Heiko; Zilles, Karl

2010-04-01

It has been argued that changes in the relative sizes of visual system structures predated an increase in brain size and provide evidence of brain reorganization in hominins. However, data about the volume and anatomical limits of visual brain structures in the extant taxa phylogenetically closest to humans-the apes-remain scarce, thus complicating tests of hypotheses about evolutionary changes. Here, we analyze new volumetric data for the primary visual cortex and the lateral geniculate nucleus to determine whether or not the human brain departs from allometrically-expected patterns of brain organization. Primary visual cortex volumes were compared to lunate sulcus position in apes to investigate whether or not inferences about brain reorganization made from fossil hominin endocasts are reliable in this context. In contrast to previous studies, in which all species were relatively poorly sampled, the current study attempted to evaluate the degree of intraspecific variability by including numerous hominoid individuals (particularly Pan troglodytes and Homo sapiens). In addition, we present and compare volumetric data from three new hominoid species-Pan paniscus, Pongo pygmaeus, and Symphalangus syndactylus. These new data demonstrate that hominoid visual brain structure volumes vary more than previously appreciated. In addition, humans have relatively reduced primary visual cortex and lateral geniculate nucleus volumes as compared to allometric predictions from other hominoids. These results suggest that inferences about the position of the lunate sulcus on fossil endocasts may provide information about brain organization. Copyright 2010 Elsevier Ltd. All rights reserved.

Brain RVD-haemopressin, a haemoglobin-derived peptide, inhibits bombesin-induced central activation of adrenomedullary outflow in the rat.

PubMed

Tanaka, Kenjiro; Shimizu, Takahiro; Yanagita, Toshihiko; Nemoto, Takayuki; Nakamura, Kumiko; Taniuchi, Keisuke; Dimitriadis, Fotios; Yokotani, Kunihiko; Saito, Motoaki

2014-01-01

Haemopressin and RVD-haemopressin, derived from the haemoglobin α-chain, are bioactive peptides found in brain and are ligands for cannabinoid CB1 receptors. Activation of brain CB1 receptors inhibited the secretion of adrenal catecholamines (noradrenaline and adrenaline) induced by i.c.v. bombesin in the rat. Here, we investigated the effects of two haemoglobin-derived peptides on this bombesin-induced response Anaesthetised male Wistar rats were pretreated with either haemoglobin-derived peptide, given i.c.v., 30 min before i.c.v. bombesin and plasma catecholamines were subsequently measured electrochemically after HPLC. Direct effects of bombesin on secretion of adrenal catecholamines were examined using bovine adrenal chromaffin cells. Furthermore, activation of haemoglobin α-positive spinally projecting neurons in the rat hypothalamic paraventricular nucleus (PVN, a regulatory centre of central adrenomedullary outflow) after i.c.v. bombesin was assessed by immunohistochemical techniques. Bombesin given i.c.v. dose-dependently elevated plasma catecholamines whereas incubation with bombesin had no effect on spontaneous and nicotine-induced secretion of catecholamines from chromaffin cells. The bombesin-induced increase in catecholamines was inhibited by pretreatment with i.c.v. RVD-haemopressin (CB1 receptor agonist) but not after pretreatment with haemopressin (CB1 receptor inverse agonist). Bombesin activated haemoglobin α-positive spinally projecting neurons in the PVN. The haemoglobin-derived peptide RVD-haemopressin in the brain plays an inhibitory role in bombesin-induced activation of central adrenomedullary outflow via brain CB1 receptors in the rat. These findings provide basic information for the therapeutic use of haemoglobin-derived peptides in the modulation of central adrenomedullary outflow. © 2013 The British Pharmacological Society.

Neural correlates of prospective memory impairments in schizophrenia.

PubMed

Chen, Xing-jie; Wang, Ya; Wang, Yi; Yang, Tian-xiao; Zou, Lai-quan; Huang, Jia; Li, Feng-hua; Chen, An-tao; Wang, Wei-hong; Zheng, Han-feng; Cheung, Eric F C; Shum, David H K; Chan, Raymond C K

2016-02-01

Prospective memory (PM) refers to the ability to remember to carry out intended actions after a delay. PM impairments are common in schizophrenia patients and are thought to be related to their prefrontal cortex dysfunction; however, this has not yet been examined directly in the research literature. The current study aimed to examine abnormalities in brain activation during PM task performance in schizophrenia patients. Twenty-two schizophrenia patients and 25 matched healthy controls were scanned in a 3-T MRI machine while performing a PM task. The results showed that compared to the healthy controls, schizophrenia patients performed significantly worse on the PM task. Furthermore, they exhibited decreased brain activation in frontal cortex including the right superior frontal gyri (Brodmann area 10), and other related brain areas like the anterior cingulate gyrus, parietal and temporal cortex, including precuneus, and some subcortext, including parahippocampal gyrus and putamen. These findings confirm the involvement and importance of the prefrontal cortex in PM and show evidence of hypofrontality in schizophrenia patients while performing a PM task. PsycINFO Database Record (c) 2016 APA, all rights reserved.

PET Mapping for Brain-Computer Interface Stimulation of the Ventroposterior Medial Nucleus of the Thalamus in Rats with Implanted Electrodes.

PubMed

Zhu, Yunqi; Xu, Kedi; Xu, Caiyun; Zhang, Jiacheng; Ji, Jianfeng; Zheng, Xiaoxiang; Zhang, Hong; Tian, Mei

2016-07-01

Brain-computer interface (BCI) technology has great potential for improving the quality of life for neurologic patients. This study aimed to use PET mapping for BCI-based stimulation in a rat model with electrodes implanted in the ventroposterior medial (VPM) nucleus of the thalamus. PET imaging studies were conducted before and after stimulation of the right VPM. Stimulation induced significant orienting performance. (18)F-FDG uptake increased significantly in the paraventricular thalamic nucleus, septohippocampal nucleus, olfactory bulb, left crus II of the ansiform lobule of the cerebellum, and bilaterally in the lateral septum, amygdala, piriform cortex, endopiriform nucleus, and insular cortex, but it decreased in the right secondary visual cortex, right simple lobule of the cerebellum, and bilaterally in the somatosensory cortex. This study demonstrated that PET mapping after VPM stimulation can identify specific brain regions associated with orienting performance. PET molecular imaging may be an important approach for BCI-based research and its clinical applications. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Motor Deficits Are Produced By Removing Some Cortical Transplants Grafted Into Injured Sensorimotor Cortex of Neonatal Rats

PubMed Central

Sandor, Rick; Gonzalez, Manuel F.; Moseley, Michael; Sharp, Frank R.

1991-01-01

Fetal frontal cortex was transplanted into cavities formed in the right, motor cortex of neonatal rats. As adults, the animals were trained to press two levers in rapid succession with their left forelimb to receive food rewards. Once they had reached an optimal level of performance, the effect of removing their transplants was assessed. Surgical removal of transplants significantly impaired the performance of 2 of 4 subjects. Placing a crossstrain skin graft to induce the immunological rejection of the transplants produced a behavioral deficit in 1 of 2 subjects with complete transplant removal. Skin grafts produced no behavioral effects in four subjects that had surviving transplants. Since the motor deficit produced by transplant removal resembled those observed following the removal of normal motor cortex, we propose that these three transplants functioned within the host brain. Histology Showed that the procedures used to remove cortical grafts did not injure any host brains. Therefore, host brain damage is unlikely to account for the behavioral deterioration that followed transplant removals. PMID:1782254

Creativity and the default network: A functional connectivity analysis of the creative brain at rest☆

PubMed Central

Beaty, Roger E.; Benedek, Mathias; Wilkins, Robin W.; Jauk, Emanuel; Fink, Andreas; Silvia, Paul J.; Hodges, Donald A.; Koschutnig, Karl; Neubauer, Aljoscha C.

2014-01-01

The present research used resting-state functional magnetic resonance imaging (fMRI) to examine whether the ability to generate creative ideas corresponds to differences in the intrinsic organization of functional networks in the brain. We examined the functional connectivity between regions commonly implicated in neuroimaging studies of divergent thinking, including the inferior prefrontal cortex and the core hubs of the default network. Participants were prescreened on a battery of divergent thinking tests and assigned to high- and low-creative groups based on task performance. Seed-based functional connectivity analysis revealed greater connectivity between the left inferior frontal gyrus (IFG) and the entire default mode network in the high-creative group. The right IFG also showed greater functional connectivity with bilateral inferior parietal cortex and the left dorsolateral prefrontal cortex in the high-creative group. The results suggest that the ability to generate creative ideas is characterized by increased functional connectivity between the inferior prefrontal cortex and the default network, pointing to a greater cooperation between brain regions associated with cognitive control and low-level imaginative processes. PMID:25245940

C-type natriuretic peptide-modified lipid vesicles: fabrication and use for the treatment of brain glioma.

PubMed

Wu, Jia-Shuan; Mu, Li-Min; Bu, Ying-Zi; Liu, Lei; Yan, Yan; Hu, Ying-Jie; Bai, Jing; Zhang, Jing-Ying; Lu, Weiyue; Lu, Wan-Liang

2017-06-20

Chemotherapy of brain glioma faces a major obstacle owing to the inability of drug transport across the blood-brain barrier (BBB). Besides, neovasculatures in brain glioma site result in a rapid infiltration, making complete surgical removal virtually impossible. Herein, we reported a novel kind of C-type natriuretic peptide (CNP) modified vinorelbine lipid vesicles for transferring drug across the BBB, and for treating brain glioma along with disrupting neovasculatures. The studies were performed on brain glioma U87-MG cells in vitro and on glioma-bearing nude mice in vivo. The results showed that the CNP-modified vinorelbine lipid vesicles could transport vinorelbine across the BBB, kill the brain glioma, and destroy neovasculatures effectively. The above mechanisms could be associated with the following aspects, namely, long circulation in the blood; drug transport across the BBB via natriuretic peptide receptor B (NPRB)-mediated transcytosis; elimination of brain glioma cells and disruption of neovasculatures by targeting uptake and cytotoxic injury. Besides, CNP-modified vinorelbine lipid vesicles could induce apoptosis of the glioma cells. The mechanisms could be related to the activations of caspase 8, caspase 3, p53, and reactive oxygen species (ROS), and inhibition of survivin. Hence, CNP-modified lipid vesicles could be used as a carrier material for treating brain glioma and disabling glioma neovasculatures.

Autoradiographic analysis of alpha 1-noradrenergic receptors in the human brain postmortem. Effect of suicide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gross-Isseroff, R.; Dillon, K.A.; Fieldust, S.J.

In vitro quantitative autoradiography of alpha 1-noradrenergic receptors, using tritiated prazosin as a ligand, was performed on 24 human brains postmortem. Twelve brains were obtained from suicide victims and 12 from matched controls. We found significant lower binding to alpha 1 receptors in several brain regions of the suicide group as compared with matched controls. This decrease in receptor density was evident in portions of the prefrontal cortex, as well as the temporal cortex and in the caudate nucleus. Age, sex, presence of alcohol, and time of death to autopsy did not affect prazosin binding, in our sample, as measuredmore » by autoradiography.« less

Three-dimensional Speckle Tracking Echocardiography in Light Chain Cardiac Amyloidosis: Examination of Left and Right Ventricular Myocardial Mechanics Parameters.

PubMed

Urbano-Moral, Jose Angel; Gangadharamurthy, Dakshin; Comenzo, Raymond L; Pandian, Natesa G; Patel, Ayan R

2015-08-01

The study of myocardial mechanics has a potential role in the detection of cardiac involvement in patients with amyloidosis. This study aimed to characterize 3-dimensional-speckle tracking echocardiography-derived left and right ventricular myocardial mechanics in light chain amyloidosis and examine their relationship with brain natriuretic peptide. In patients with light chain amyloidosis, left ventricular longitudinal and circumferential strain (n=40), and right ventricular longitudinal strain and radial displacement (n=26) were obtained by 3-dimensional-speckle tracking echocardiography. Brain natriuretic peptide levels were determined. All myocardial mechanics measurements showed differences when compared by brain natriuretic peptide level tertiles. Left and right ventricular longitudinal strain were highly correlated (r=0.95, P<.001). Left ventricular longitudinal and circumferential strain were reduced in patients with cardiac involvement (-9±4 vs -16±2; P<.001, and -24±6 vs -29±4; P=.01, respectively), with the most prominent impairment at the basal segments. Right ventricular longitudinal strain and radial displacement were diminished in patients with cardiac involvement (-9±3 vs -17±3; P<.001, and 2.7±0.8 vs 3.8±0.3; P=.002). On multivariate analysis, left ventricular longitudinal strain was associated with the presence of cardiac involvement (odds ratio = 1.6; 95% confidence interval, 1.04 to 2.37; P=.03) independent of the presence of brain natriuretic peptide and troponin I criteria for cardiac amyloidosis. Three-dimensional-speckle tracking echocardiography-derived left and right ventricular myocardial mechanics are increasingly altered as brain natriuretic peptide increases in light chain amyloidosis. There appears to be a strong association between left ventricular longitudinal strain and cardiac involvement, beyond biomarkers such as brain natriuretic peptide and troponin I. Copyright © 2015 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Assessment of Traumatic Brain Injury by Increased 64Cu Uptake on 64CuCl2 PET/CT

PubMed Central

Peng, Fangyu; Muzik, Otto; Gatson, Joshua; Kernie, Steven G.; Diaz-Arrastia, Ramon

2015-01-01

Copper is a nutritional trace element required for cell proliferation and wound repair. Methods To explore increased copper uptake as a biomarker for noninvasive assessment of traumatic brain injury (TBI), experimental TBI in C57BL/6 mice was induced by controlled cortical impact, and 64Cu uptake in the injured cortex was assessed with 64CuCl2 PET/CT. Results At 24 h after intravenous injection of the tracer, uptake was significantly higher in the injured cortex of TBI mice (1.15 ± 0.53 percentage injected dose per gram of tissue [%ID/g]) than in the uninjured cortex of mice without TBI (0.53 ± 0.07 %ID/g, P = 0.027) or the cortex of mice that received an intracortical injection of zymosan A (0.62 ± 0.22 %ID/g, P = 0.025). Furthermore, uptake in the traumatized cortex of untreated TBI mice (1.15 ± 0.53 %ID/g) did not significantly differ from that in minocycline-treated TBI mice (0.93 ± 0.30 %ID/g, P = 0.33). Conclusion Overall, the data suggest that increased 64Cu uptake in traumatized brain tissues holds potential as a new biomarker for noninvasive assessment of TBI with 64CuCl2 PET/CT. PMID:26112025

Facilitated beam-walking recovery during acute phase by kynurenic acid treatment in a rat model of photochemically induced thrombosis causing focal cerebral ischemia.

PubMed

Abo, Masahiro; Yamauchi, Hideki; Suzuki, Masahiko; Sakuma, Mio; Urashima, Mitsuyoshi

We previously demonstrated the presence of activated areas in the non-injured contralateral sensorimotor cortex in addition to the ipsilateral sensorimotor cortex of the area surrounding a brain infarction, using a rat model of focal photochemically induced thrombosis (PIT) and functional magnetic resonance imaging. Using this model, we next applied gene expression profiling to screen key molecules upregulated in the activated area. RNA was extracted from the ipsilateral and contralateral sensorimotor cortex to the focal brain infarction and from the sham controlled cortex, and hybridized to gene-expression profiling arrays containing 1,322 neurology-related genes. Results showed that glycine receptors were upregulated in both the ipsilateral and contralateral cortex to the focal ischemic lesion. To prove the preclinical significance of upregulated glycine receptors, kynurenic acid, an endogenous antagonist to glycine receptors on neuronal cells, was administered intrathecally. As a result, the kynurenic acid significantly improved behavioral recovery within 10 days from paralysis induced by the focal PIT (p < 0.0001), as evaluated with beam walking. These results suggest that intrathecal administration of a glycine receptor antagonist may facilitate behavioral recovery during the acute phase after brain infarction. Copyright (c) 2006 S. Karger AG, Basel.

Behavioral activation system modulation on brain activation during appetitive and aversive stimulus processing.

PubMed

Barrós-Loscertales, Alfonso; Ventura-Campos, Noelia; Sanjuán-Tomás, Ana; Belloch, Vicente; Parcet, Maria-Antònia; Avila, César

2010-03-01

The reinforcement sensitivity theory (RST) proposed the behavioral activation system (BAS) as a neurobehavioral system that is dependent on dopamine-irrigated structures and that mediates the individual differences in sensitivity and reactivity to appetitive stimuli associated with BAS-related personality traits. Theoretical developments propose that high BAS sensitivity is associated with both enhanced appetitive stimuli processing and the diminished processing of aversive stimuli. The objective of this study was to analyze how individual differences in BAS functioning were associated with brain activation during erotic and aversive picture processing while subjects were involved in a simple goal-directed task. Forty-five male participants took part in this study. The task activation results confirm the activation of the reward and punishment brain-related structures while viewing erotic and aversive pictures, respectively. The SR scores show a positive correlation with activation of the left lateral prefrontal cortex, the mesial prefrontal cortex and the right occipital cortex while viewing erotic pictures, and a negative correlation with the right lateral prefrontal cortex and the left occipital cortex while viewing aversive pictures. In summary, the SR scores modulate the activity of the cortical areas in the prefrontal and the occipital cortices that are proposed to modulate the BAS and the BIS-FFFS.

Non-Invasive Electrical Brain Stimulation Montages for Modulation of Human Motor Function.

PubMed

Curado, Marco; Fritsch, Brita; Reis, Janine

2016-02-04

Non-invasive electrical brain stimulation (NEBS) is used to modulate brain function and behavior, both for research and clinical purposes. In particular, NEBS can be applied transcranially either as direct current stimulation (tDCS) or alternating current stimulation (tACS). These stimulation types exert time-, dose- and in the case of tDCS polarity-specific effects on motor function and skill learning in healthy subjects. Lately, tDCS has been used to augment the therapy of motor disabilities in patients with stroke or movement disorders. This article provides a step-by-step protocol for targeting the primary motor cortex with tDCS and transcranial random noise stimulation (tRNS), a specific form of tACS using an electrical current applied randomly within a pre-defined frequency range. The setup of two different stimulation montages is explained. In both montages the emitting electrode (the anode for tDCS) is placed on the primary motor cortex of interest. For unilateral motor cortex stimulation the receiving electrode is placed on the contralateral forehead while for bilateral motor cortex stimulation the receiving electrode is placed on the opposite primary motor cortex. The advantages and disadvantages of each montage for the modulation of cortical excitability and motor function including learning are discussed, as well as safety, tolerability and blinding aspects.

Cognitive and affective theory of mind share the same local patterns of activity in posterior temporal but not medial prefrontal cortex

PubMed Central

Hofstetter, Christoph; Vuilleumier, Patrik

2014-01-01

Understanding emotions in others engages specific brain regions in temporal and medial prefrontal cortices. These activations are often attributed to more general cognitive ‘mentalizing’ functions, associated with theory of mind and also necessary to represent people’s non-emotional mental states, such as beliefs or intentions. Here, we directly investigated whether understanding emotional feelings recruit similar or specific brain systems, relative to other non-emotional mental states. We used functional magnetic resonance imaging with multivoxel pattern analysis in 46 volunteers to compare activation patterns in theory-of-mind tasks for emotions, relative to beliefs or somatic states accompanied with pain. We found a striking dissociation between the temporoparietal cortex, that exhibited a remarkable voxel-by-voxel pattern overlap between emotions and beliefs (but not pain), and the dorsomedial prefrontal cortex, that exhibited distinct (and yet nearby) patterns of activity during the judgment of beliefs and emotions in others. Pain judgment was instead associated with activity in the supramarginal gyrus, middle cingulate cortex and middle insular cortex. Our data reveal for the first time a functional dissociation within brain networks sub-serving theory of mind for different mental contents, with a common recruitment for cognitive and affective states in temporal regions, and distinct recruitment in prefrontal areas. PMID:23770622

Simultaneous Detection of c-Fos Activation from Mesolimbic and Mesocortical Dopamine Reward Sites Following Naive Sugar and Fat Ingestion in Rats.

PubMed

Dela Cruz, Julie A D; Coke, Tricia; Bodnar, Richard J

2016-08-24

This study uses cellular c-fos activation to assess effects of novel ingestion of fat and sugar on brain dopamine (DA) pathways in rats. Intakes of sugars and fats are mediated by their innate attractions as well as learned preferences. Brain dopamine, especially meso-limbic and meso-cortical projections from the ventral tegmental area (VTA), has been implicated in both of these unlearned and learned responses. The concept of distributed brain networks, wherein several sites and transmitter/peptide systems interact, has been proposed to mediate palatable food intake, but there is limited evidence empirically demonstrating such actions. Thus, sugar intake elicits DA release and increases c-fos-like immunoreactivity (FLI) from individual VTA DA projection zones including the nucleus accumbens (NAC), amygdala (AMY) and medial prefrontal cortex (mPFC) as well as the dorsal striatum. Further, central administration of selective DA receptor antagonists into these sites differentially reduce acquisition and expression of conditioned flavor preferences elicited by sugars or fats. One approach by which to determine whether these sites interacted as a distributed brain network in response to sugar or fat intake would be to simultaneous evaluate whether the VTA and its major mesotelencephalic DA projection zones (prelimbic and infralimbic mPFC, core and shell of the NAc, basolateral and central-cortico-medial AMY) as well as the dorsal striatum would display coordinated and simultaneous FLI activation after oral, unconditioned intake of corn oil (3.5%), glucose (8%), fructose (8%) and saccharin (0.2%) solutions. This approach is a successful first step in identifying the feasibility of using cellular c-fos activation simultaneously across relevant brain sites to study reward-related learning in ingestion of palatable food in rodents.

Forebrain networks and the control of feeding by environmental learned cues

PubMed Central

Petrovich, Gorica D.

2013-01-01

The motivation to eat is driven by a complex sum of physiological and non-physiological influences computed by the brain. Physiological signals that inform the brain about energy and nutrient needs are the primary drivers, but environmental signals unrelated to energy balance also control appetite and eating. The two components could act in concert to support the homeostatic regulation of food intake. Often, however, environmental influences rival physiological control and stimulate eating irrespective of satiety, or inhibit eating irrespective of hunger. If persistent, such maladaptive challenges to the physiological system could lead to dysregulated eating and ultimately to eating disorders. Nevertheless, the brain mechanisms underlying environmental contribution in the control of food intake are poorly understood. This paper provides an overview in recent advances in deciphering the critical brain systems using rodent models for environmental control by learned cues. These models use associative learning to compete with the physiological control, and in one preparation food cues stimulate a meal despite satiety, while in another preparation fear cues stop a meal despite hunger. Thus far, four forebrain regions have been identified as part of the essential cue induced feeding circuitry. These are telencephalic areas critical for associative learning, memory encoding, and decision making, the amygdala, hippocampus and prefrontal cortex and the lateral hypothalamus, which functions to integrate feeding, reward, and motivation. This circuitry also engages two orexigenic peptides, ghrelin and orexin. A parallel amygdalar circuitry supports fear cue cessation of feeding. These findings illuminate the brain mechanisms underlying environmental control of food intake and might be also relevant to aspects of human appetite and maladaptive overeating and undereating. PMID:23562305

Suckling induced activation pattern in the brain of rat pups.

PubMed

Barna, János; Renner, Eva; Arszovszki, Antónia; Cservenák, Melinda; Kovács, Zsolt; Palkovits, Miklós; Dobolyi, Arpád

2018-06-01

The aim of the study was to understand the effects of suckling on the brain of the pups by mapping their brain activation pattern in response to suckling. The c-fos method was applied to identify activated neurons. Fasted rat pups were returned to their mothers for suckling and sacrificed 2 hours later for Fos immunohistochemistry. Double labeling was also performed to characterize some of the activated neurons. For comparison, another group of fasted pups were given dry food before Fos mapping. After suckling, we found an increase in the number of Fos-immunoreactive neurons in the insular and somatosensory cortices, central amygdaloid nucleus (CAm), paraventricular (PVN) and supraoptic hypothalamic nuclei, lateral parabrachial nucleus (LPB), nucleus of the solitary tract (NTS), and the area postrema. Double labeling experiments demonstrated the activation of calcitonin gene-related peptide-ir (CGRP-ir) neurons in the LPB, corticotropin-releasing hormone-ir (CRH-ir) but not oxytocin-ir neurons in the PVN, and noradrenergic neurons in the NTS. In the CAm, Fos-ir neurons did not contain CRH but were apposed to CGRP-ir fiber terminals. Refeeding with dry food-induced Fos activation in all brain areas activated by suckling. The degree of activation was higher following dry food consumption than suckling in the insular cortex, and lower in the supraoptic nucleus and the NTS. Furthermore, the accumbens, arcuate, and dorsomedial hypothalamic nuclei, and the lateral hypothalamic area, which were not activated by suckling, showed activation by dry food. Neurons in a number of brain areas are activated during suckling, and may participate in the signaling of satiety, taste perception, reward, food, and salt balance regulation.

Development of Active Control within Working Memory: Active Retrieval versus Monitoring in Children

ERIC Educational Resources Information Center

Blain-Brière, Bénédicte; Bouchard, Caroline; Bigras, Nathalie; Cadoret, Geneviève

2014-01-01

This study aimed to compare children's performance on two mnemonic functions that engage the lateral prefrontal cortex. Brain imaging studies in adults have shown that the mid-ventrolateral prefrontal cortex is specifically involved in active controlled retrieval, and the mid-dorsolateral prefrontal cortex is specifically involved in monitoring…

Impulsive-antisocial psychopathic traits linked to increased volume and functional connectivity within prefrontal cortex.

PubMed

Korponay, Cole; Pujara, Maia; Deming, Philip; Philippi, Carissa; Decety, Jean; Kosson, David S; Kiehl, Kent A; Koenigs, Michael

2017-07-01

Psychopathy is a personality disorder characterized by callous lack of empathy, impulsive antisocial behavior, and criminal recidivism. Studies of brain structure and function in psychopathy have frequently identified abnormalities in the prefrontal cortex. However, findings have not yet converged to yield a clear relationship between specific subregions of prefrontal cortex and particular psychopathic traits. We performed a multimodal neuroimaging study of prefrontal cortex volume and functional connectivity in psychopathy, using a sample of adult male prison inmates (N = 124). We conducted volumetric analyses in prefrontal subregions, and subsequently assessed resting-state functional connectivity in areas where volume was related to psychopathy severity. We found that overall psychopathy severity and Factor 2 scores (which index the impulsive/antisocial traits of psychopathy) were associated with larger prefrontal subregion volumes, particularly in the medial orbitofrontal cortex and dorsolateral prefrontal cortex. Furthermore, Factor 2 scores were also positively correlated with functional connectivity between several areas of the prefrontal cortex. The results were not attributable to age, race, IQ, substance use history, or brain volume. Collectively, these findings provide evidence for co-localized increases in prefrontal cortex volume and intra-prefrontal functional connectivity in relation to impulsive/antisocial psychopathic traits. © The Author (2017). Published by Oxford University Press.

Haptic contents of a movie dynamically engage the spectator's sensorimotor cortex

PubMed Central

Smeds, Eero; Tikka, Pia; Pihko, Elina; Hari, Riitta; Koskinen, Miika

2016-01-01

Abstract Observation of another person's actions and feelings activates brain areas that support similar functions in the observer, thereby facilitating inferences about the other's mental and bodily states. In real life, events eliciting this kind of vicarious brain activations are intermingled with other complex, ever‐changing stimuli in the environment. One practical approach to study the neural underpinnings of real‐life vicarious perception is to image brain activity during movie viewing. Here the goal was to find out how observed haptic events in a silent movie would affect the spectator's sensorimotor cortex. The functional state of the sensorimotor cortex was monitored by analyzing, in 16 healthy subjects, magnetoencephalographic (MEG) responses to tactile finger stimuli that were presented once per second throughout the session. Using canonical correlation analysis and spatial filtering, consistent single‐trial responses across subjects were uncovered, and their waveform changes throughout the movie were quantified. The long‐latency (85–175 ms) parts of the responses were modulated in concordance with the participants’ average moment‐by‐moment ratings of own engagement in the haptic content of the movie (correlation r = 0.49; ratings collected after the MEG session). The results, obtained by using novel signal‐analysis approaches, demonstrate that the functional state of the human sensorimotor cortex fluctuates in a fine‐grained manner even during passive observation of temporally varying haptic events. Hum Brain Mapp 37:4061–4068, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID:27364184

Regional homogeneity associated with overgeneral autobiographical memory of first-episode treatment-naive patients with major depressive disorder in the orbitofrontal cortex: A resting-state fMRI study.

PubMed

Liu, Yansong; Zhao, Xudong; Cheng, Zaohuo; Zhang, Fuquan; Chang, Jun; Wang, Haosen; Xie, Rukui; Wang, Zhiqiang; Cao, Leiming; Wang, Guoqiang

2017-02-01

Overgeneral autobiographical memory (OGM) is involved in the onset and maintenance of depression. Recent studies have shown correlations between OGM and alterations of some brain regions by using task-state functional magnetic resonance imaging (fMRI). However, the correlation between OGM and spontaneous brain activity in depression remains unclear. The purpose of this study was to determine whether patients with major depressive disorder (MDD) show abnormal regional homogeneity (ReHo) and, if so, whether the brain areas with abnormal ReHo are associated with OGM. Twenty five patients with MDD and 25 age-matched, sex-matched, and education-matched healthy controls underwent resting-state fMRI. All participants were also assessed by 17-item Hamilton Depression Rating Scale and autobiographical memory test. The ReHo method was used to analyze regional synchronization of spontaneous neuronal activity. Patients with MDD, compared to healthy controls, exhibited extensive ReHo abnormalities in some brain regions, including the frontal, temporal, and occipital cortex. Moreover, ReHo value of the orbitofrontal cortex was negatively correlated with OGM scores in patients with MDD. The sample size of this study was relatively small, and the influence of physiological noise was not completely excluded. These results suggest that abnormal ReHo of spontaneous brain activity in the orbitofrontal cortex may be involved in the pathophysiology of OGM in patients with MDD. Copyright © 2016 Elsevier B.V. All rights reserved.

Brain-based decoding of mentally imagined film clips and sounds reveals experience-based information patterns in film professionals.

PubMed

de Borst, Aline W; Valente, Giancarlo; Jääskeläinen, Iiro P; Tikka, Pia

2016-04-01

In the perceptual domain, it has been shown that the human brain is strongly shaped through experience, leading to expertise in highly-skilled professionals. What has remained unclear is whether specialization also shapes brain networks underlying mental imagery. In our fMRI study, we aimed to uncover modality-specific mental imagery specialization of film experts. Using multi-voxel pattern analysis we decoded from brain activity of professional cinematographers and sound designers whether they were imagining sounds or images of particular film clips. In each expert group distinct multi-voxel patterns, specific for the modality of their expertise, were found during classification of imagery modality. These patterns were mainly localized in the occipito-temporal and parietal cortex for cinematographers and in the auditory cortex for sound designers. We also found generalized patterns across perception and imagery that were distinct for the two expert groups: they involved frontal cortex for the cinematographers and temporal cortex for the sound designers. Notably, the mental representations of film clips and sounds of cinematographers contained information that went beyond modality-specificity. We were able to successfully decode the implicit presence of film genre from brain activity during mental imagery in cinematographers. The results extend existing neuroimaging literature on expertise into the domain of mental imagery and show that experience in visual versus auditory imagery can alter the representation of information in modality-specific association cortices. Copyright © 2016 Elsevier Inc. All rights reserved.

Human brain activity with functional NIR optical imager

NASA Astrophysics Data System (ADS)

Luo, Qingming

2001-08-01

In this paper we reviewed the applications of functional near infrared optical imager in human brain activity. Optical imaging results of brain activity, including memory for new association, emotional thinking, mental arithmetic, pattern recognition ' where's Waldo?, occipital cortex in visual stimulation, and motor cortex in finger tapping, are demonstrated. It is shown that the NIR optical method opens up new fields of study of the human population, in adults under conditions of simulated or real stress that may have important effects upon functional performance. It makes practical and affordable for large populations the complex technology of measuring brain function. It is portable and low cost. In cognitive tasks subjects could report orally. The temporal resolution could be millisecond or less in theory. NIR method will have good prospects in exploring human brain secret.

Preserved speech abilities and compensation following prefrontal damage.

PubMed

Buckner, R L; Corbetta, M; Schatz, J; Raichle, M E; Petersen, S E

1996-02-06

Lesions to left frontal cortex in humans produce speech production impairments (nonfluent aphasia). These impairments vary from subject to subject and performance on certain speech production tasks can be relatively preserved in some patients. A possible explanation for preservation of function under these circumstances is that areas outside left prefrontal cortex are used to compensate for the injured brain area. We report here a direct demonstration of preserved language function in a stroke patient (LF1) apparently due to the activation of a compensatory brain pathway. We used functional brain imaging with positron emission tomography (PET) as a basis for this study.

Ethanol fixed brain imaging by phase-contrast X-ray technique

NASA Astrophysics Data System (ADS)

Takeda, Tohoru; Thet-Thet-Lwin; Kunii, Takuya; Sirai, Ryota; Ohizumi, Takahito; Maruyama, Hiroko; Hyodo, Kazuyuki; Yoneyama, Akio; Ueda, Kazuhiro

2013-03-01

The two-crystal phase-contrast X-ray imaging technique using an X-ray crystal interferometer can depict the fine structures of rat's brain such as cerebral cortex, white matter, and basal ganglia. Image quality and contrast by ethanol fixed brain showed significantly better than those by usually used formalin fixation at 35 keV X-ray energy. Image contrast of cortex by ethanol fixation was more than 3-times higher than that by formalin fixation. Thus, the technique of ethanol fixation might be better suited to image cerebral structural detail at 35 keV X-ray energy.

Functional Connectivity of Multiple Brain Regions Required for the Consolidation of Social Recognition Memory.

PubMed

Tanimizu, Toshiyuki; Kenney, Justin W; Okano, Emiko; Kadoma, Kazune; Frankland, Paul W; Kida, Satoshi

2017-04-12

Social recognition memory is an essential and basic component of social behavior that is used to discriminate familiar and novel animals/humans. Previous studies have shown the importance of several brain regions for social recognition memories; however, the mechanisms underlying the consolidation of social recognition memory at the molecular and anatomic levels remain unknown. Here, we show a brain network necessary for the generation of social recognition memory in mice. A mouse genetic study showed that cAMP-responsive element-binding protein (CREB)-mediated transcription is required for the formation of social recognition memory. Importantly, significant inductions of the CREB target immediate-early genes c-fos and Arc were observed in the hippocampus (CA1 and CA3 regions), medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and amygdala (basolateral region) when social recognition memory was generated. Pharmacological experiments using a microinfusion of the protein synthesis inhibitor anisomycin showed that protein synthesis in these brain regions is required for the consolidation of social recognition memory. These findings suggested that social recognition memory is consolidated through the activation of CREB-mediated gene expression in the hippocampus/mPFC/ACC/amygdala. Network analyses suggested that these four brain regions show functional connectivity with other brain regions and, more importantly, that the hippocampus functions as a hub to integrate brain networks and generate social recognition memory, whereas the ACC and amygdala are important for coordinating brain activity when social interaction is initiated by connecting with other brain regions. We have found that a brain network composed of the hippocampus/mPFC/ACC/amygdala is required for the consolidation of social recognition memory. SIGNIFICANCE STATEMENT Here, we identify brain networks composed of multiple brain regions for the consolidation of social recognition memory. We found that social recognition memory is consolidated through CREB-meditated gene expression in the hippocampus, medial prefrontal cortex, anterior cingulate cortex (ACC), and amygdala. Importantly, network analyses based on c-fos expression suggest that functional connectivity of these four brain regions with other brain regions is increased with time spent in social investigation toward the generation of brain networks to consolidate social recognition memory. Furthermore, our findings suggest that hippocampus functions as a hub to integrate brain networks and generate social recognition memory, whereas ACC and amygdala are important for coordinating brain activity when social interaction is initiated by connecting with other brain regions. Copyright © 2017 the authors 0270-6474/17/374103-14$15.00/0.

Promising techniques to illuminate neuromodulatory control of the cerebral cortex in sleeping and waking states.

PubMed

Kanda, Takeshi; Ohyama, Kaoru; Muramoto, Hiroki; Kitajima, Nami; Sekiya, Hiroshi

2017-05-01

Sleep, a common event in daily life, has clear benefits for brain function, but what goes on in the brain when we sleep remains unclear. Sleep was long regarded as a silent state of the brain because the brain seemingly lacks interaction with the surroundings during sleep. Since the discovery of electrical activities in the brain at rest, electrophysiological methods have revealed novel concepts in sleep research. During sleep, the brain generates oscillatory activities that represent characteristic states of sleep. In addition to electrophysiology, opto/chemogenetics and two-photon Ca 2+ imaging methods have clarified that the sleep/wake states organized by neuronal and glial ensembles in the cerebral cortex are transitioned by neuromodulators. Even with these methods, however, it is extremely difficult to elucidate how and when neuromodulators spread, accumulate, and disappear in the extracellular space of the cortex. Thus, real-time monitoring of neuromodulator dynamics at high spatiotemporal resolution is required for further understanding of sleep. Toward direct detection of neuromodulator behavior during sleep and wakefulness, in this review, we discuss developing imaging techniques based on the activation of G-protein-coupled receptors that allow for visualization of neuromodulator dynamics. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

The motilin agonist erythromycin increases hunger by modulating homeostatic and hedonic brain circuits in healthy women: a randomized, placebo-controlled study.

PubMed

Zhao, Dongxing; Meyer-Gerspach, Anne Christin; Deloose, Eveline; Iven, Julie; Weltens, Nathalie; Depoortere, Inge; O'daly, Owen; Tack, Jan; Van Oudenhove, Lukas

2018-01-29

The motilin agonist, erythromycin, induces gastric phase III of the migrating motor complex, which in turn generates hunger peaks. To identify the brain mechanisms underlying these orexigenic effects, 14 healthy women participated in a randomized, placebo-controlled crossover study. Functional magnetic resonance brain images were acquired for 50 minutes interprandially. Intravenous infusion of erythromycin (40 mg) or saline started 10 minutes after the start of scanning. Blood samples (for glucose and hormone levels) and hunger ratings were collected at fixed timepoints. Thirteen volunteers completed the study, without any adverse events. Brain regions involved in homeostatic and hedonic control of appetite and food intake responded to erythromycin, including pregenual anterior cingulate cortex, anterior insula cortex, orbitofrontal cortex, amygdala, caudate, pallidum and putamen bilaterally, right accumbens, hypothalamus, and midbrain. Octanoylated ghrelin levels decreased, whereas both glucose and insulin increased after erythromycin. Hunger were higher after erythromycin, and these differences covaried with the brain response in most of the abovementioned regions. The motilin agonist erythromycin increases hunger by modulating neurocircuitry related to homeostatic and hedonic control of appetite and feeding. These results confirm recent behavioural findings identifying motilin as a key orexigenic hormone in humans, and identify the brain mechanisms underlying its effect.

Liposome-based glioma targeted drug delivery enabled by stable peptide ligands.

PubMed

Wei, Xiaoli; Gao, Jie; Zhan, Changyou; Xie, Cao; Chai, Zhilan; Ran, Danni; Ying, Man; Zheng, Ping; Lu, Weiyue

2015-11-28

The treatment of glioma is one of the most challenging tasks in clinic. As an intracranial tumor, glioma exhibits many distinctive characteristics from other tumors. In particular, various barriers including enzymatic barriers in the blood and brain capillary endothelial cells, blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) rigorously prevent drug and drug delivery systems from reaching the tumor site. To tackle this dilemma, we developed a liposomal formulation to circumvent multiple-barriers by modifying the liposome surface with proteolytically stable peptides, (D)CDX and c(RGDyK). (D)CDX is a D-peptide ligand of nicotine acetylcholine receptors (nAChRs) on the BBB, and c(RGDyK) is a ligand of integrin highly expressed on the BBTB and glioma cells. Lysosomal compartments of brain capillary endothelial cells are implicated in the transcytosis of those liposomes. However, both peptide ligands displayed exceptional stability in lysosomal homogenate, ensuring that intact ligands could exert subsequent exocytosis from brain capillary endothelial cells and glioma targeting. In the cellular uptake studies, dually labeled liposomes could target both brain capillary endothelial cells and tumor cells, effectively traversing the BBB and BBTB monolayers, overcoming enzymatic barrier and targeting three-dimensional tumor spheroids. Its targeting ability to intracranial glioma was further verified in vivo by ex vivo imaging and histological studies. As a result, doxorubicin liposomes modified with both (D)CDX and c(RGDyK) presented better anti-glioma effect with prolonged median survival of nude mice bearing glioma than did unmodified liposomes and liposomes modified with individual peptide ligand. In conclusion, the liposome suggested in the present study could effectively overcome multi-barriers and accomplish glioma targeted drug delivery, validating its potential value in improving the therapeutic efficacy of doxorubicin for glioma. Copyright © 2015 Elsevier B.V. All rights reserved.

Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier.

PubMed

Molino, Yves; David, Marion; Varini, Karine; Jabès, Françoise; Gaudin, Nicolas; Fortoul, Aude; Bakloul, Karima; Masse, Maxime; Bernard, Anne; Drobecq, Lucile; Lécorché, Pascaline; Temsamani, Jamal; Jacquot, Guillaume; Khrestchatisky, Michel

2017-05-01

The blood-brain barrier (BBB) prevents the entry of many drugs into the brain and, thus, is a major obstacle in the treatment of CNS diseases. There is some evidence that the LDL receptor (LDLR) is expressed at the BBB and may participate in the transport of endogenous ligands from blood to brain, a process referred to as receptor-mediated transcytosis. We previously described a family of peptide vectors that were developed to target the LDLR. In the present study, in vitro BBB models that were derived from wild-type and LDLR-knockout animals ( ldlr -/- ) were used to validate the specific LDLR-dependent transcytosis of LDL via a nondegradative route. We next showed that LDLR-targeting peptide vectors, whether in fusion or chemically conjugated to an Ab Fc fragment, promote binding to apical LDLR and transendothelial transfer of the Fc fragment across BBB monolayers via the same route as LDL. Finally, we demonstrated in vivo that LDLR significantly contributes to the brain uptake of vectorized Fc. We thus provide further evidence that LDLR is a relevant receptor for CNS drug delivery via receptor-mediated transcytosis and that the peptide vectors we developed have the potential to transport drugs, including proteins or Ab based, across the BBB.-Molino, Y., David, M., Varini, K., Jabès, F., Gaudin, N., Fortoul, A., Bakloul, K., Masse, M., Bernard, A., Drobecq, L., Lécorché, P., Temsamani, J., Jacquot, G., Khrestchatisky, M. Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier. © FASEB.

Brain Responses to High-Protein Diets12

PubMed Central

Journel, Marion; Chaumontet, Catherine; Darcel, Nicolas; Fromentin, Gilles; Tomé, Daniel

2012-01-01

Proteins are suspected to have a greater satiating effect than the other 2 macronutrients. After protein consumption, peptide hormones released from the gastrointestinal tract (mainly anorexigenic gut peptides such as cholecystokinin, glucagon peptide 1, and peptide YY) communicate information about the energy status to the brain. These hormones and vagal afferents control food intake by acting on brain regions involved in energy homeostasis such as the brainstem and the hypothalamus. In fact, a high-protein diet leads to greater activation than a normal-protein diet in the nucleus tractus solitarius and in the arcuate nucleus. More specifically, neural mechanisms triggered particularly by leucine consumption involve 2 cellular energy sensors: the mammalian target of rapamycin and AMP-activated protein kinase. In addition, reward and motivation aspects of eating behavior, controlled mainly by neurons present in limbic regions, play an important role in the reduced hedonic response of a high-protein diet. This review examines how metabolic signals emanating from the gastrointestinal tract after protein ingestion target the brain to control feeding, energy expenditure, and hormones. Understanding the functional roles of brain areas involved in the satiating effect of proteins and their interactions will demonstrate how homeostasis and reward are integrated with the signals from peripheral organs after protein consumption. PMID:22585905

Complement mRNA in the mammalian brain: responses to Alzheimer's disease and experimental brain lesioning.

PubMed

Johnson, S A; Lampert-Etchells, M; Pasinetti, G M; Rozovsky, I; Finch, C E

1992-01-01

This study describes evidence in the adult human and rat brain for mRNAs that encode two complement (C) proteins, C1qB and C4. C proteins are important effectors of humoral immunity and inflammation in peripheral tissues but have not been considered as normally present in brain. Previous immunocytochemical studies showed that C proteins are associated with plaques, tangles, and dystrophic neurites in Alzheimer's disease (AD), but their source is unknown. Combined immunocytochemistry and in situ hybridization techniques show C4 mRNA in pyramidal neurons and C1qB mRNA in microglia. Primary rat neuron cultures also show C1qB mRNA. In the cortex from AD brains, there were two- to threefold increases of C1qB mRNA and C4 mRNA, and increased C1qB mRNA prevalence was in part associated with microglia. As a model for AD, we examined entorhinal cortex perforant path transection in the rat brain, which caused rapid increases of C1qB mRNA in the ipsilateral, but not contralateral, hippocampus and entorhinal cortex. The role of brain-derived acute and chronic C induction during AD and experimental lesions can now be considered in relation to functions of C proteins that pertain to cell degeneration and/or cell preservation and synaptic plasticity.

Removing the effect of response time on brain activity reveals developmental differences in conflict processing in the posterior medial prefrontal cortex.

PubMed

Carp, Joshua; Fitzgerald, Kate Dimond; Taylor, Stephan F; Weissman, Daniel H

2012-01-02

In functional magnetic resonance imaging (fMRI) studies, researchers often attempt to ensure that group differences in brain activity are not confounded with group differences in mean reaction time (RT). However, even when groups are matched for performance, they may differ in terms of the RT-BOLD relationship: the degree to which brain activity varies with RT on a trial-by-trial basis. Group activation differences might therefore be influenced by group differences in the relationship between brain activity and time on task. Here, we investigated whether correcting for this potential confound alters group differences in brain activity. Specifically, we reanalyzed data from a functional MRI study of response conflict in children and adults, in which conventional analyses indicated that conflict-related activity did not differ between groups. We found that the RT-BOLD relationship was weaker in children than in adults. Consequently, after removing the effect of RT on brain activity, children exhibited greater conflict-related activity than adults in both the posterior medial prefrontal cortex and the right dorsolateral prefrontal cortex. These results identify the RT-BOLD relationship as an important potential confound in fMRI studies of group differences. They also suggest that the magnitude of the RT-BOLD relationship may be a useful biomarker of brain maturity. Copyright © 2011 Elsevier Inc. All rights reserved.

Decision-making deficit of a patient with axonal damage after traumatic brain injury.

PubMed

Yasuno, Fumihiko; Matsuoka, Kiwamu; Kitamura, Soichiro; Kiuchi, Kuniaki; Kosaka, Jun; Okada, Koji; Tanaka, Syohei; Shinkai, Takayuki; Taoka, Toshiaki; Kishimoto, Toshifumi

2014-02-01

Patients with traumatic brain injury (TBI) were reported to have difficulty making advantageous decisions, but the underlying deficits of the network of brain areas involved in this process were not directly examined. We report a patient with TBI who demonstrated problematic behavior in situations of risk and complexity after cerebral injury from a traffic accident. The Iowa gambling task (IGT) was used to reveal his deficits in the decision-making process. To examine underlying deficits of the network of brain areas, we examined T1-weighted structural MRI, diffusion tensor imaging (DTI) and Tc-ECD SPECT in this patient. The patient showed abnormality in IGT. DTI-MRI results showed a significant decrease in fractional anisotropy (FA) in the fasciculus between the brain stem and cortical regions via the thalamus. He showed significant decrease in gray matter volumes in the bilateral insular cortex, hypothalamus, and posterior cingulate cortex, possibly reflecting Wallerian degeneration secondary to the fasciculus abnormalities. SPECT showed significant blood flow decrease in the broad cortical areas including the ventromedial prefrontal cortex (VM). Our study showed that the patient had dysfunctional decision-making process. Microstructural abnormality in the fasciculus, likely from the traffic accident, caused reduced afferent feedback to the brain, resulting in less efficient decision-making. Our findings support the somatic-marker hypothesis (SMH), where somatic feedback to the brain influences the decision-making process. Copyright © 2013 Elsevier Inc. All rights reserved.

Prefrontal transcranial direct current stimulation alters activation and connectivity in cortical and subcortical reward systems: a tDCS-fMRI study.

PubMed

Weber, Matthew J; Messing, Samuel B; Rao, Hengyi; Detre, John A; Thompson-Schill, Sharon L

2014-08-01

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique used both experimentally and therapeutically to modulate regional brain function. However, few studies have directly measured the aftereffects of tDCS on brain activity or examined changes in task-related brain activity consequent to prefrontal tDCS. To investigate the neural effects of tDCS, we collected fMRI data from 22 human subjects, both at rest and while performing the Balloon Analog Risk Task (BART), before and after true or sham transcranial direct current stimulation. TDCS decreased resting blood perfusion in orbitofrontal cortex and the right caudate and increased task-related activity in the right dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in response to losses but not wins or increasing risk. Network analysis showed that whole-brain connectivity of the right ACC correlated positively with the number of pumps subjects were willing to make on the BART, and that tDCS reduced connectivity between the right ACC and the rest of the brain. Whole-brain connectivity of the right DLPFC also correlated negatively with pumps on the BART, as prior literature would suggest. Our results suggest that tDCS can alter activation and connectivity in regions distal to the electrodes. Copyright © 2014 Wiley Periodicals, Inc.

Distribution of vesicular glutamate transporters in the human brain

PubMed Central

Vigneault, Érika; Poirel, Odile; Riad, Mustapha; Prud'homme, Josée; Dumas, Sylvie; Turecki, Gustavo; Fasano, Caroline; Mechawar, Naguib; El Mestikawy, Salah

2015-01-01

Glutamate is the major excitatory transmitter in the brain. Vesicular glutamate transporters (VGLUT1-3) are responsible for uploading glutamate into synaptic vesicles. VGLUT1 and VGLUT2 are considered as specific markers of canonical glutamatergic neurons, while VGLUT3 is found in neurons previously shown to use other neurotransmitters than glutamate. Although there exists a rich literature on the localization of these glutamatergic markers in the rodent brain, little is currently known about the distribution of VGLUT1-3 in the human brain. In the present study, using subtype specific probes and antisera, we examined the localization of the three vesicular glutamate transporters in the human brain by in situ hybridization, immunoautoradiography and immunohistochemistry. We found that the VGLUT1 transcript was highly expressed in the cerebral cortex, hippocampus and cerebellum, whereas VGLUT2 mRNA was mainly found in the thalamus and brainstem. VGLUT3 mRNA was localized in scarce neurons within the cerebral cortex, hippocampus, striatum and raphe nuclei. Following immunoautoradiographic labeling, intense VGLUT1- and VGLUT2-immunoreactivities were observed in all regions investigated (cerebral cortex, hippocampus, caudate-putamen, cerebellum, thalamus, amygdala, substantia nigra, raphe) while VGLUT3 was absent from the thalamus and cerebellum. This extensive mapping of VGLUT1-3 in human brain reveals distributions that correspond for the most part to those previously described in rodent brains. PMID:25798091

Distribution of vesicular glutamate transporters in the human brain.

PubMed

Vigneault, Érika; Poirel, Odile; Riad, Mustapha; Prud'homme, Josée; Dumas, Sylvie; Turecki, Gustavo; Fasano, Caroline; Mechawar, Naguib; El Mestikawy, Salah

2015-01-01

Glutamate is the major excitatory transmitter in the brain. Vesicular glutamate transporters (VGLUT1-3) are responsible for uploading glutamate into synaptic vesicles. VGLUT1 and VGLUT2 are considered as specific markers of canonical glutamatergic neurons, while VGLUT3 is found in neurons previously shown to use other neurotransmitters than glutamate. Although there exists a rich literature on the localization of these glutamatergic markers in the rodent brain, little is currently known about the distribution of VGLUT1-3 in the human brain. In the present study, using subtype specific probes and antisera, we examined the localization of the three vesicular glutamate transporters in the human brain by in situ hybridization, immunoautoradiography and immunohistochemistry. We found that the VGLUT1 transcript was highly expressed in the cerebral cortex, hippocampus and cerebellum, whereas VGLUT2 mRNA was mainly found in the thalamus and brainstem. VGLUT3 mRNA was localized in scarce neurons within the cerebral cortex, hippocampus, striatum and raphe nuclei. Following immunoautoradiographic labeling, intense VGLUT1- and VGLUT2-immunoreactivities were observed in all regions investigated (cerebral cortex, hippocampus, caudate-putamen, cerebellum, thalamus, amygdala, substantia nigra, raphe) while VGLUT3 was absent from the thalamus and cerebellum. This extensive mapping of VGLUT1-3 in human brain reveals distributions that correspond for the most part to those previously described in rodent brains.

Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer's disease.

PubMed

Franzmeier, Nicolai; Düzel, Emrah; Jessen, Frank; Buerger, Katharina; Levin, Johannes; Duering, Marco; Dichgans, Martin; Haass, Christian; Suárez-Calvet, Marc; Fagan, Anne M; Paumier, Katrina; Benzinger, Tammie; Masters, Colin L; Morris, John C; Perneczky, Robert; Janowitz, Daniel; Catak, Cihan; Wolfsgruber, Steffen; Wagner, Michael; Teipel, Stefan; Kilimann, Ingo; Ramirez, Alfredo; Rossor, Martin; Jucker, Mathias; Chhatwal, Jasmeer; Spottke, Annika; Boecker, Henning; Brosseron, Frederic; Falkai, Peter; Fliessbach, Klaus; Heneka, Michael T; Laske, Christoph; Nestor, Peter; Peters, Oliver; Fuentes, Manuel; Menne, Felix; Priller, Josef; Spruth, Eike J; Franke, Christiana; Schneider, Anja; Kofler, Barbara; Westerteicher, Christine; Speck, Oliver; Wiltfang, Jens; Bartels, Claudia; Araque Caballero, Miguel Ángel; Metzger, Coraline; Bittner, Daniel; Weiner, Michael; Lee, Jae-Hong; Salloway, Stephen; Danek, Adrian; Goate, Alison; Schofield, Peter R; Bateman, Randall J; Ewers, Michael

2018-04-01

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.

Involvement of specific macrophage-lineage cells surrounding arterioles in barrier and scavenger function in brain cortex.

PubMed Central

Mato, M; Ookawara, S; Sakamoto, A; Aikawa, E; Ogawa, T; Mitsuhashi, U; Masuzawa, T; Suzuki, H; Honda, M; Yazaki, Y; Watanabe, E; Luoma, J; Yla-Herttuala, S; Fraser, I; Gordon, S; Kodama, T

1996-01-01

The transport of solutes between blood and brain is regulated by a specific barrier. Capillary endothelial cells of brain are known to mediate barrier function and facilitate transport. Here we report that specific cells surrounding arterioles, known as Mato's fluorescent granular perithelial (FGP) cells or perivascular microglial cells, contribute to the barrier function. Immunohistochemical and in situ hybridization studies indicate that, in normal brain cortex, type I and type II macrophage scavenger receptors are expressed only in FGP/perivascular microglial cells, and surface markers of macrophage lineage are also detected on them. These cells mediate the uptake of macromolecules, including modified low density lipoprotein, horseradish peroxidase, and ferritin injected either into the blood or into the cerebral ventricles. Accumulation of scavenged materials with aging or after the administration of a high-fat diet results in the formation of honeycomb-like foam cells and the narrowing of the lumen of arterioles in the brain cortex. These results indicate involvement of FGP/perivascular microglial cells in the barrier and scavenger functions in the central nervous system. Images Fig. 1 Fig. 2 Fig. 4 Fig. 5 Fig. 6 PMID:8622926

Neurochemical abnormalities in brains of renal failure patients treated by repeated hemodialysis.

PubMed

Perry, T L; Yong, V W; Kish, S J; Ito, M; Foulks, J G; Godolphin, W J; Sweeney, V P

1985-10-01

We examined autopsied brain from 10 patients with end-stage renal failure who had undergone repeated hemodialysis. Eight had classic symptoms, and two had suggestive symptoms of dialysis encephalopathy. Findings were compared with those in autopsied brain from control adults who had never been hemodialyzed. Mean gamma-aminobutyric acid (GABA) contents were significantly reduced in frontal and occipital cortex, cerebellar cortex, dentate nucleus, caudate nucleus, and medial-dorsal thalamus of the hemodialyzed patients, the reduction being greater than 40% in cerebral cortex and thalamus. Choline acetyltransferase activity was reduced by 25-35% in three cortical regions in the hemodialyzed patients. These two abnormalities were observed in the brain of each hemodialyzed patient, regardless of whether or not the patient died with unequivocal dialysis encephalopathy. Pyridoxal phosphate contents were substantially reduced in brains of the hemodialyzed patients, but metabolites of noradrenaline, 3,4-dihydroxyphenylethylamine (dopamine), and 5-hydroxytryptamine (serotonin) were present in normal amounts. Aluminum levels were abnormally high in frontal cortical gray matter in the hemodialyzed patients. Although this study does not clarify the role played by aluminum toxicity in the pathogenesis of dialysis encephalopathy, the abnormalities we found suggest the need for further neurochemical investigations in this disorder.

Glucagon‐related peptides and the regulation of food intake in chickens

PubMed Central

2016-01-01

Abstract The regulatory mechanisms underlying food intake in chickens have been a focus of research in recent decades to improve production efficiency when raising chickens. Lines of evidence have revealed that a number of brain‐gut peptides function as a neurotransmitter or peripheral satiety hormone in the regulation of food intake both in mammals and chickens. Glucagon, a 29 amino acid peptide hormone, has long been known to play important roles in maintaining glucose homeostasis in mammals and birds. However, the glucagon gene encodes various peptides that are produced by tissue‐specific proglucagon processing: glucagon is produced in the pancreas, whereas oxyntomodulin (OXM), glucagon‐like peptide (GLP)‐1 and GLP‐2 are produced in the intestine and brain. Better understanding of the roles of these peptides in the regulation of energy homeostasis has led to various physiological roles being proposed in mammals. For example, GLP‐1 functions as an anorexigenic neurotransmitter in the brain and as a postprandial satiety hormone in the peripheral circulation. There is evidence that OXM and GLP‐2 also induce anorexia in mammals. Therefore, it is possible that the brain‐gut peptides OXM, GLP‐1 and GLP‐2 play physiological roles in the regulation of food intake in chickens. More recently, a novel GLP and its specific receptor were identified in the chicken brain. This review summarizes current knowledge about the role of glucagon‐related peptides in the regulation of food intake in chickens. PMID:27150835

The Neurofilament-Derived Peptide NFL-TBS.40-63 Targets Neural Stem Cells and Affects Their Properties.

PubMed

Lépinoux-Chambaud, Claire; Barreau, Kristell; Eyer, Joël

2016-07-01

Targeting neural stem cells (NSCs) in the adult brain represents a promising approach for developing new regenerative strategies, because these cells can proliferate, self-renew, and differentiate into new neurons, astrocytes, and oligodendrocytes. Previous work showed that the NFL-TBS.40-63 peptide, corresponding to the sequence of a tubulin-binding site on neurofilaments, can target glioblastoma cells, where it disrupts their microtubules and inhibits their proliferation. We show that this peptide targets NSCs in vitro and in vivo when injected into the cerebrospinal fluid. Although neurosphere formation was not altered by the peptide, the NSC self-renewal capacity and proliferation were reduced and were associated with increased adhesion and differentiation. These results indicate that the NFL-TBS.40-63 peptide represents a new molecular tool to target NSCs to develop new strategies for regenerative medicine and the treatment of brain tumors. In the present study, the NFL-TBS.40-63 peptide targeted neural stem cells in vitro when isolated from the subventricular zone and in vivo when injected into the cerebrospinal fluid present in the lateral ventricle. The in vitro formation of neurospheres was not altered by the peptide; however, at a high concentration of the peptide, the neural stem cell (NSC) self-renewal capacity and proliferation were reduced and associated with increased adhesion and differentiation. These results indicate that the NFL-TBS.40-63 peptide represents a new molecular tool to target NSCs to develop new strategies for regenerative medicine and the treatment of brain tumors. ©AlphaMed Press.

Changes in the brain biogenic monoamines of rats, induced by piracetam and aniracetam.

PubMed

Petkov, V D; Grahovska, T; Petkov, V V; Konstantinova, E; Stancheva, S

1984-01-01

Single oral dose of 600 mg/kg weight piracetam, respectively 50 mg/kg aniracetam, causes essential changes in the level and turnover of dopamine (DA) and serotonin (5-HT) in some rat cerebral structures. When the animals were killed one hour after the administration of the drugs, piracetam significantly increased the DA level in the cerebral cortex and in the striatum, as well as the 5-HT level in the cortex, reducing the 5-HT level in the striatum, brain stem and hypothalamus. At the same time, under the effect of piracetam the DA turnover was accelerated in the cortex and hypothalamus and delayed in the striatum, the noradrenaline turnover was accelerated in the brain stem, the 5-HT turnover was accelerated in the cortex and delayed in the striatum, stem and hypothalamus. Under the effect of aniracetam the DA level was reduced in the striatum and hypothalamus; the 5-HT level was also decreased in the hypothalamus and increased in the cortex and striatum. Aniracetam delayed the DA turnover in the striatum and the 5-HT turnover in the hypothalamus, accelerating the 5-HT turnover in the cortex, striatum and stem. The results obtained show that the changes induced in the cerebral biogenic monoamines participate in the mechanism of action of piracetam and aniracetam, whereby it seems that the analogies and differences in their effects on the cerebral biogenic monoamines play a definite role for the observed analogies and differences in the behavioural effects of these two "nootropic" compounds.

High-Definition Transcranial Direct Current Stimulation Enhances Conditioned Pain Modulation in Healthy Volunteers: A Randomized Trial.

PubMed

Flood, Andrew; Waddington, Gordon; Cathcart, Stuart

2016-05-01

Transcranial direct current stimulation (tDCS) is a form of brain stimulation that allows for the selective increase or decrease in the cortical excitability of a targeted region. When applied over the motor cortex it has been shown to induce changes in cortical and subcortical brain regions involved in descending pain inhibition or conditioned pain modulation (CPM). The aim of the current study was to assess whether activation of pain inhibitory pathways via tDCS of the motor cortex facilitates the CPM response. Elevated CPM after active tDCS of the motor cortex was hypothesized. Thirty healthy male volunteers attended 2 experimental sessions separated by 7 days. Both sessions consisted of CPM assessment after 20 minutes of either active or sham (placebo) tDCS over the motor cortex. CPM capacity was assessed via the pain-inhibits-pain protocol; CPM responses were shown to be elevated after active compared with sham tDCS. This report concludes that tDCS of the motor cortex enhances the CPM response in healthy men. This finding supports the potential utility of tDCS interventions in clinical pain treatment. The use of noninvasive brain stimulation over the motor cortex was shown to enhance the CPM effect. This finding supports the use of tDCS in the treatment of chronic pain, particularly in sufferers exhibiting maladaptive CPM. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Women's clitoris, vagina and cervix mapped on the sensory cortex: fMRI evidence

PubMed Central

Komisaruk, Barry R.; Wise, Nan; Frangos, Eleni; Liu, Wen-Ching; Allen, Kachina; Brody, Stuart

2011-01-01

Introduction The projection of vagina, uterine cervix, and nipple to the sensory cortex in humans has not been reported. Aims To map the sensory cortical fields of the clitoris, vagina, cervix and nipple, toward an elucidation of the neural systems underlying sexual response. Methods Using functional Magnetic Resonance Imaging (fMRI) we mapped sensory cortical responses to clitoral, vaginal, cervical, and nipple self-stimulation. For points of reference on the homunculus, we also mapped responses to the thumb and great toe (hallux) stimulation. Main Outcome Measures fMRI of brain regions activated by the various sensory stimuli. Results Clitoral, vaginal, and cervical self-stimulation activate differentiable sensory cortical regions, all clustered in the medial cortex (medial paracentral lobule). Nipple self-stimulation activated the genital sensory cortex (as well as the thoracic) region of the homuncular map. Conclusion The genital sensory cortex, identified in the classical Penfield homunculus based on electrical stimulation of the brain only in men, was confirmed for the first time in the literature by the present study in women, applying clitoral, vaginal, and cervical self-stimulation, and observing their regional brain responses using fMRI. Vaginal, clitoral, and cervical regions of activation were differentiable, consistent with innervation by different afferent nerves and different behavioral correlates. Activation of the genital sensory cortex by nipple self-stimulation was unexpected, but suggests a neurological basis for women’s reports of its erotogenic quality. PMID:21797981

Imbalance in subregional connectivity of the right temporoparietal junction in major depression.

PubMed

Poeppl, Timm B; Müller, Veronika I; Hoffstaedter, Felix; Bzdok, Danilo; Laird, Angela R; Fox, Peter T; Langguth, Berthold; Rupprecht, Rainer; Sorg, Christian; Riedl, Valentin; Goya-Maldonado, Roberto; Gruber, Oliver; Eickhoff, Simon B

2016-08-01

Major depressive disorder (MDD) involves impairment in cognitive and interpersonal functioning. The right temporoparietal junction (RTPJ) is a key brain region subserving cognitive-attentional and social processes. Yet, findings on the involvement of the RTPJ in the pathophysiology of MDD have so far been controversial. Recent connectivity-based parcellation data revealed a topofunctional dualism within the RTPJ, linking its anterior and posterior part (aRTPJ/pRTPJ) to antagonistic brain networks for attentional and social processing, respectively. Comparing functional resting-state connectivity of the aRTPJ and pRTPJ in 72 MDD patients and 76 well-matched healthy controls, we found a seed (aRTPJ/pRTPJ) × diagnosis (MDD/controls) interaction in functional connectivity for eight regions. Employing meta-data from a large-scale neuroimaging database, functional characterization of these regions exhibiting differentially altered connectivity with the aRTPJ/pRTPJ revealed associations with cognitive (dorsolateral prefrontal cortex, parahippocampus) and behavioral (posterior medial frontal cortex) control, visuospatial processing (dorsal visual cortex), reward (subgenual anterior cingulate cortex, medial orbitofrontal cortex, posterior cingulate cortex), as well as memory retrieval and social cognition (precuneus). These findings suggest that an imbalance in connectivity of subregions, rather than disturbed connectivity of the RTPJ as a whole, characterizes the connectional disruption of the RTPJ in MDD. This imbalance may account for key symptoms of MDD in cognitive, emotional, and social domains. Hum Brain Mapp 37:2931-2942, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Abnormal Resting-State Functional Connectivity of the Anterior Cingulate Cortex in Unilateral Chronic Tinnitus Patients

PubMed Central

Chen, Yu-Chen; Liu, Shenghua; Lv, Han; Bo, Fan; Feng, Yuan; Chen, Huiyou; Xu, Jin-Jing; Yin, Xindao; Wang, Shukui; Gu, Jian-Ping

2018-01-01

Purpose: The anterior cingulate cortex (ACC) has been suggested to be involved in chronic subjective tinnitus. Tinnitus may arise from aberrant functional coupling between the ACC and cerebral cortex. To explore this hypothesis, we used resting-state functional magnetic resonance imaging (fMRI) to illuminate the functional connectivity (FC) network of the ACC subregions in chronic tinnitus patients. Methods: Resting-state fMRI scans were obtained from 31 chronic right-sided tinnitus patients and 40 healthy controls (age, sex, and education well-matched) in this study. Rostral ACC and dorsal ACC were selected as seed regions to investigate the intrinsic FC with the whole brain. The resulting FC patterns were correlated with clinical tinnitus characteristics including the tinnitus duration and tinnitus distress. Results: Compared with healthy controls, chronic tinnitus patients showed disrupted FC patterns of ACC within several brain networks, including the auditory cortex, prefrontal cortex, visual cortex, and default mode network (DMN). The Tinnitus Handicap Questionnaires (THQ) scores showed positive correlations with increased FC between the rostral ACC and left precuneus (r = 0.507, p = 0.008) as well as the dorsal ACC and right inferior parietal lobe (r = 0.447, p = 0.022). Conclusions: Chronic tinnitus patients have abnormal FC networks originating from ACC to other selected brain regions that are associated with specific tinnitus characteristics. Resting-state ACC-cortical FC disturbances may play an important role in neuropathological features underlying chronic tinnitus. PMID:29410609

Sialic acid (SA)-modified selenium nanoparticles coated with a high blood-brain barrier permeability peptide-B6 peptide for potential use in Alzheimer's disease.

PubMed

Yin, Tiantian; Yang, Licong; Liu, Yanan; Zhou, Xianbo; Sun, Jing; Liu, Jie

2015-10-01

The blood-brain barrier (BBB) is a formidable gatekeeper toward exogenous substances, playing an important role in brain homeostasis and maintaining a healthy microenvironment for complex neuronal activities. However, it also greatly hinders drug permeability into the brain and limits the management of brain diseases. The development of new drugs that show improved transport across the BBB represents a promising strategy for Alzheimer's disease (AD) intervention. Whereas, previous study of receptor-mediated endogenous BBB transport systems has focused on a strategy of using transferrin to facilitate brain drug delivery system, a system that still suffers from limitations including synthesis procedure, stability and immunological response. In the present study, we synthetised sialic acid (SA)-modified selenium (Se) nanoparticles conjugated with an alternative peptide-B6 peptide (B6-SA-SeNPs, a synthetic selenoprotein analogue), which shows high permeability across the BBB and has the potential to serve as a novel nanomedicine for disease modification in AD. Laser-scanning confocal microscopy, flow cytometry analysis and inductively coupled plasma-atomic emission spectroscopy ICP-AES revealed high cellular uptake of B6-SA-SeNPs by cerebral endothelial cells (bEnd.3). The transport efficiency of B6-SA-SeNPs was evaluated in a Transwell experiment based on in vitro BBB model. It provided direct evidence for B6-SA-SeNPs crossing the BBB and being absorbed by PC12 cells. Moreover, inhibitory effects of B6-SA-SeNPs on amyloid-β peptide (Aβ) fibrillation could be demonstrated in PC12 cells and bEnd3 cells. B6-SA-SeNPs could not only effectively inhibit Aβ aggregation but could disaggregate preformed Aβ fibrils into non-toxic amorphous oligomers. These results suggested that B6-SA-SeNPs may provide a promising platform, particularly for the application of nanoparticles in the treatment of brain diseases. Alzheimer's disease (AD) is the world's most common form of dementia characterized by intracellular neurofibrillary tangles in the brain. Over the past decades, the blood-brain barrier (BBB) limits access of therapeutic or diagnostic agents into the brain, which greatly hinders the development of new drugs for treating AD. In this work, we evaluated the efficiency of B6-SA-SeNPs across BBB and investigated the interactions between B6-SA-SeNPs and amyloid-β peptide (Aβ). We confirm that B6-SA-SeNPs could provide a promising platform because of its high brain delivery efficiency, anti-amyloid properties and anti-oxidant properties, which may serve as a novel nanomedicine for the application in the treatment of brain diseases. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Dichoptic training enables the adult amblyopic brain to learn.

PubMed

Li, Jinrong; Thompson, Benjamin; Deng, Daming; Chan, Lily Y L; Yu, Minbin; Hess, Robert F

2013-04-22

Adults with amblyopia, a common visual cortex disorder caused primarily by binocular disruption during an early critical period, do not respond to conventional therapy involving occlusion of one eye. But it is now clear that the adult human visual cortex has a significant degree of plasticity, suggesting that something must be actively preventing the adult brain from learning to see through the amblyopic eye. One possibility is an inhibitory signal from the contralateral eye that suppresses cortical inputs from the amblyopic eye. Such a gating mechanism could explain the apparent lack of plasticity within the adult amblyopic visual cortex. Here we provide direct evidence that alleviating suppression of the amblyopic eye through dichoptic stimulus presentation induces greater levels of plasticity than forced use of the amblyopic eye alone. This indicates that suppression is a key gating mechanism that prevents the amblyopic brain from learning to see. Copyright © 2013 Elsevier Ltd. All rights reserved.

Brain glucose metabolism in chronic marijuana users at baseline and during marijuana intoxication.

PubMed

Volkow, N D; Gillespie, H; Mullani, N; Tancredi, L; Grant, C; Valentine, A; Hollister, L

1996-05-31

Despite the widespread abuse of marijuana, knowledge about its effects in the human brain is limited. Brain glucose metabolism with and without delta 9 tetrahydrocannabinol (THC) (main psychoactive component of marijuana) was evaluated in eight normal subjects and eight chronic marijuana abusers with positron emission tomography. At baseline, marijuana abusers showed lower relative cerebellar metabolism than normal subjects. THC increased relative cerebellar metabolism in all subjects, but only abusers showed increases in orbitofrontal cortex, prefrontal cortex, and basal ganglia. Cerebellar metabolism during THC intoxication was significantly correlated with the subjective sense of intoxication. The decreased cerebellar metabolism in marijuana abusers at baseline could account for the motor deficits previously reported in these subjects. The activation of orbitofrontal cortex and basal ganglia by THC in the abusers but not in the normal subjects could underlie one of the mechanisms leading to the drive and the compulsion to self-administer the drug observed in addicted individuals.

Neural coding of basic reward terms of animal learning theory, game theory, microeconomics and behavioural ecology.

PubMed

Schultz, Wolfram

2004-04-01

Neurons in a small number of brain structures detect rewards and reward-predicting stimuli and are active during the expectation of predictable food and liquid rewards. These neurons code the reward information according to basic terms of various behavioural theories that seek to explain reward-directed learning, approach behaviour and decision-making. The involved brain structures include groups of dopamine neurons, the striatum including the nucleus accumbens, the orbitofrontal cortex and the amygdala. The reward information is fed to brain structures involved in decision-making and organisation of behaviour, such as the dorsolateral prefrontal cortex and possibly the parietal cortex. The neural coding of basic reward terms derived from formal theories puts the neurophysiological investigation of reward mechanisms on firm conceptual grounds and provides neural correlates for the function of rewards in learning, approach behaviour and decision-making.

Empathy for social exclusion involves the sensory-discriminative component of pain: a within-subject fMRI study

PubMed Central

Novembre, Giovanni; Zanon, Marco

2015-01-01

Recent research has shown that experiencing events that represent a significant threat to social bonds activates a network of brain areas associated with the sensory-discriminative aspects of pain. In the present study, we investigated whether the same brain areas are involved when witnessing social exclusion threats experienced by others. Using a within-subject design, we show that an ecologically valid experience of social exclusion recruits areas coding the somatosensory components of physical pain (posterior insular cortex and secondary somatosensory cortex). Furthermore, we show that this pattern of activation not only holds for directly experienced social pain, but also during empathy for social pain. Finally, we report that subgenual cingulate cortex is the only brain area conjointly active during empathy for physical and social pain. This supports recent theories that affective processing and homeostatic regulation are at the core of empathic responses. PMID:24563529

A network of networks model to study phase synchronization using structural connection matrix of human brain

NASA Astrophysics Data System (ADS)

Ferrari, F. A. S.; Viana, R. L.; Reis, A. S.; Iarosz, K. C.; Caldas, I. L.; Batista, A. M.

2018-04-01

The cerebral cortex plays a key role in complex cortical functions. It can be divided into areas according to their function (motor, sensory and association areas). In this paper, the cerebral cortex is described as a network of networks (cortex network), we consider that each cortical area is composed of a network with small-world property (cortical network). The neurons are assumed to have bursting properties with the dynamics described by the Rulkov model. We study the phase synchronization of the cortex network and the cortical networks. In our simulations, we verify that synchronization in cortex network is not homogeneous. Besides, we focus on the suppression of neural phase synchronization. Synchronization can be related to undesired and pathological abnormal rhythms in the brain. For this reason, we consider the delayed feedback control to suppress the synchronization. We show that delayed feedback control is efficient to suppress synchronous behavior in our network model when an appropriate signal intensity and time delay are defined.

Speech Rhythms and Multiplexed Oscillatory Sensory Coding in the Human Brain

PubMed Central

Gross, Joachim; Hoogenboom, Nienke; Thut, Gregor; Schyns, Philippe; Panzeri, Stefano; Belin, Pascal; Garrod, Simon

2013-01-01

Cortical oscillations are likely candidates for segmentation and coding of continuous speech. Here, we monitored continuous speech processing with magnetoencephalography (MEG) to unravel the principles of speech segmentation and coding. We demonstrate that speech entrains the phase of low-frequency (delta, theta) and the amplitude of high-frequency (gamma) oscillations in the auditory cortex. Phase entrainment is stronger in the right and amplitude entrainment is stronger in the left auditory cortex. Furthermore, edges in the speech envelope phase reset auditory cortex oscillations thereby enhancing their entrainment to speech. This mechanism adapts to the changing physical features of the speech envelope and enables efficient, stimulus-specific speech sampling. Finally, we show that within the auditory cortex, coupling between delta, theta, and gamma oscillations increases following speech edges. Importantly, all couplings (i.e., brain-speech and also within the cortex) attenuate for backward-presented speech, suggesting top-down control. We conclude that segmentation and coding of speech relies on a nested hierarchy of entrained cortical oscillations. PMID:24391472

PLGA nanoparticles modified with a BBB-penetrating peptide co-delivering Aβ generation inhibitor and curcumin attenuate memory deficits and neuropathology in Alzheimer's disease mice.

PubMed

Huang, Na; Lu, Shuai; Liu, Xiao-Ge; Zhu, Jie; Wang, Yu-Jiong; Liu, Rui-Tian

2017-10-06

Alzheimer's disease (AD) is the most common form of dementia, characterized by the formation of extracellular senile plaques and neuronal loss caused by amyloid β (Aβ) aggregates in the brains of AD patients. Conventional strategies failed to treat AD in clinical trials, partly due to the poor solubility, low bioavailability and ineffectiveness of the tested drugs to cross the blood-brain barrier (BBB). Moreover, AD is a complex, multifactorial neurodegenerative disease; one-target strategies may be insufficient to prevent the processes of AD. Here, we designed novel kind of poly(lactide-co-glycolic acid) (PLGA) nanoparticles by loading with Aβ generation inhibitor S1 (PQVGHL peptide) and curcumin to target the detrimental factors in AD development and by conjugating with brain targeting peptide CRT (cyclic CRTIGPSVC peptide), an iron-mimic peptide that targets transferrin receptor (TfR), to improve BBB penetration. The average particle size of drug-loaded PLGA nanoparticles and CRT-conjugated PLGA nanoparticles were 128.6 nm and 139.8 nm, respectively. The results of Y-maze and new object recognition test demonstrated that our PLGA nanoparticles significantly improved the spatial memory and recognition in transgenic AD mice. Moreover, PLGA nanoparticles remarkably decreased the level of Aβ, reactive oxygen species (ROS), TNF-α and IL-6, and enhanced the activities of super oxide dismutase (SOD) and synapse numbers in the AD mouse brains. Compared with other PLGA nanoparticles, CRT peptide modified-PLGA nanoparticles co-delivering S1 and curcumin exhibited most beneficial effect on the treatment of AD mice, suggesting that conjugated CRT peptide, and encapsulated S1 and curcumin exerted their corresponding functions for the treatment.

Challenges and new strategies for therapeutic peptide delivery to the CNS.

PubMed

McGowan, Jeremy Wd; Bidwell, Gene L; Vig, Parminder Js

2015-07-01

Therapeutic peptides represent a largely untapped resource in medicine today, especially in the central nervous system. Despite their ease of design and remarkably high target specificity, it is difficult to deliver them beyond the blood-brain barrier or into the required intracellular compartments. In addition, the instability of these peptides in vivo precludes their use to combat the symptoms of numerous neurological disorders including Alzheimer's disease and spinocerebellar ataxia. In this review, we aim to characterize recent advances in the delivery of therapeutic peptides to the central nervous system past the blood-brain barrier and discuss the advantages and disadvantages of the examined methods as well as explore new potential directions.

Peptides at the blood brain barrier: Knowing me knowing you.

PubMed

Davis, Thomas P; Abbruscato, Thomas J; Egleton, Richard D

2015-10-01

When the Davis Lab was first asked to contribute to this special edition of Peptides to celebrate the career and influence of Abba Kastin on peptide research, it felt like a daunting task. It is difficult to really understand and appreciate the influence that Abba has had, not only on a generation of peptide researchers, but also on the field of blood brain barrier (BBB) research, unless you lived it as we did. When we look back at our careers and those of our former students, one can truly see that several of Abba's papers played an influential role in the development of our personal research programs. Copyright © 2015 Elsevier Inc. All rights reserved.

Optogenetic fMRI and electrophysiological identification of region-specific connectivity between the cerebellar cortex and forebrain.

PubMed

Choe, Katrina Y; Sanchez, Carlos F; Harris, Neil G; Otis, Thomas S; Mathews, Paul J

2018-06-01

Complex animal behavior is produced by dynamic interactions between discrete regions of the brain. As such, defining functional connections between brain regions is critical in gaining a full understanding of how the brain generates behavior. Evidence suggests that discrete regions of the cerebellar cortex functionally project to the forebrain, mediating long-range communication potentially important in motor and non-motor behaviors. However, the connectivity map remains largely incomplete owing to the challenge of driving both reliable and selective output from the cerebellar cortex, as well as the need for methods to detect region specific activation across the entire forebrain. Here we utilize a paired optogenetic and fMRI (ofMRI) approach to elucidate the downstream forebrain regions modulated by activating a region of the cerebellum that induces stereotypical, ipsilateral forelimb movements. We demonstrate with ofMRI, that activating this forelimb motor region of the cerebellar cortex results in functional activation of a variety of forebrain and midbrain areas of the brain, including the hippocampus and primary motor, retrosplenial and anterior cingulate cortices. We further validate these findings using optogenetic stimulation paired with multi-electrode array recordings and post-hoc staining for molecular markers of activated neurons (i.e. c-Fos). Together, these findings demonstrate that a single discrete region of the cerebellar cortex is capable of influencing motor output and the activity of a number of downstream forebrain as well as midbrain regions thought to be involved in different aspects of behavior. Copyright © 2018 Elsevier Inc. All rights reserved.

Therapy-related longitudinal brain perfusion changes in patients with chronic pelvic pain syndrome.

PubMed

Weisstanner, Christian; Mordasini, Livio; Thalmann, George N; Verma, Rajeev K; Rummel, Christian; Federspiel, Andrea; Kessler, Thomas M; Wiest, Roland

2017-08-03

The imaging method most frequently employed to identify brain areas involved in neuronal processing of nociception and brain pain perception is blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI). Arterial spin labelling (ASL), in contrast, offers advantages when slow varying changes in brain function are investigated. Chronic pelvic pain syndrome (CPPS) is a disorder of, mostly, young males that leads to altered pain perceptions in structures related to the pelvis. We aimed to investigate the potential of ASL to monitor longitudinal cranial blood flow (CBF) changes in patients with CPPS. In a randomised, placebo-controlled, double-blind single centre trial, we investigated treatment effects in CPPS after 12 weeks in patients that underwent sono-electro-magnetic therapy vs placebo. We investigated changes of CBF related to treatment outcome using pseudo-continuous arterial spin labelling (pCASL)-MRI. We observed CBF downregulation in the prefrontal cortex and anterior cingulate cortex and upregulation in the dorsolateral prefrontal cortex in responders. Nonresponders presented with CBF upregulation in the hippocampus. In patients with a history of CPPS of less than 12 months, there were significant correlations between longitudinal CBF changes and the Chronic Prostatitis Symptom Index pain subscore within the joint clusters anterior cingulate cortex and left anterior prefrontal cortex in responders, and the right hippocampus in nonresponders. We demonstrated therapy-related and stimulus-free longitudinal CBF changes in core areas of the pain matrix using ASL. ASL may act as a complementary noninvasive method to functional MRI and single-photon emission computed tomography / positron emission tomography, especially in the longitudinal assessment of pain response in clinical trials.

Changes in the Brain Endocannabinoid System in Rat Models of Depression.

PubMed

Smaga, Irena; Jastrzębska, Joanna; Zaniewska, Magdalena; Bystrowska, Beata; Gawliński, Dawid; Faron-Górecka, Agata; Broniowska, Żaneta; Miszkiel, Joanna; Filip, Małgorzata

2017-04-01

A growing body of evidence implicates the endocannabinoid (eCB) system in the pathophysiology of depression. The aim of this study was to investigate the influence of changes in the eCB system, such as levels of neuromodulators, eCB synthesizing and degrading enzymes, and cannabinoid (CB) receptors, in different brain structures in animal models of depression using behavioral and biochemical analyses. Both models used, i.e., bulbectomized (OBX) and Wistar Kyoto (WKY) rats, were characterized at the behavioral level by increased immobility time. In the OBX rats, anandamide (AEA) levels were decreased in the prefrontal cortex, hippocampus, and striatum and increased in the nucleus accumbens, while 2-arachidonoylglycerol (2-AG) levels were increased in the prefrontal cortex and decreased in the nucleus accumbens with parallel changes in the expression of eCB metabolizing enzymes in several structures. It was also observed that CB 1 receptor expression decreased in the hippocampus, dorsal striatum, and nucleus accumbens, and CB 2 receptor expression decreased in the prefrontal cortex and hippocampus. In WKY rats, the levels of eCBs were reduced in the prefrontal cortex (2-AG) and dorsal striatum (AEA) and increased in the prefrontal cortex (AEA) with different changes in the expression of eCB metabolizing enzymes, while the CB 1 receptor density was increased in several brain regions. These findings suggest that dysregulation in the eCB system is implicated in the pathogenesis of depression, although neurochemical changes were linked to the particular brain structure and the factor inducing depression (surgical removal of the olfactory bulbs vs. genetic modulation).

Prolonged hemodynamic response during incidental facial emotion processing in inter-episode bipolar I disorder.

PubMed

Rosenfeld, Ethan S; Pearlson, Godfrey D; Sweeney, John A; Tamminga, Carol A; Keshavan, Matcheri S; Nonterah, Camilla; Stevens, Michael C

2014-03-01

This fMRI study examined whether hemodynamic responses to affectively-salient stimuli were abnormally prolonged in remitted bipolar disorder, possibly representing a novel illness biomarker. A group of 18 DSM-IV bipolar I-diagnosed adults in remission and a demographically-matched control group performed an event-related fMRI gender-discrimination task in which face stimuli had task-irrelevant neutral, happy or angry expressions designed to elicit incidental emotional processing. Participants' brain activation was modeled using a "fully informed" SPM5 basis set. Mixed-model ANOVA tested for diagnostic group differences in BOLD response amplitude and shape within brain regions-of-interest selected from ALE meta-analysis of previous comparable fMRI studies. Bipolar-diagnosed patients had a generally longer duration and/or later-peaking hemodynamic response in amygdala and numerous prefrontal cortex brain regions. Data are consistent with existing models of bipolar limbic hyperactivity, but the prolonged frontolimbic response more precisely details abnormalities recognized in previous studies. Prolonged hemodynamic responses were unrelated to stimulus type, task performance, or degree of residual mood symptoms, suggesting an important novel trait vulnerability brain dysfunction in bipolar disorder. Bipolar patients also failed to engage pregenual cingulate and left orbitofrontal cortex-regions important to models of automatic emotion regulation-while engaging a delayed dorsolateral prefrontal cortex response not seen in controls. These results raise questions about whether there are meaningful relationships between bipolar dysfunction of specific ventromedial prefrontal cortex regions believed to automatically regulate emotional reactions and the prolonged responses in more lateral aspects of prefrontal cortex.

Acute and chronic changes in brain activity with deep brain stimulation for refractory depression.

PubMed

Conen, Silke; Matthews, Julian C; Patel, Nikunj K; Anton-Rodriguez, José; Talbot, Peter S

2018-04-01

Deep brain stimulation is a potential option for patients with treatment-refractory depression. Deep brain stimulation benefits have been reported when targeting either the subgenual cingulate or ventral anterior capsule/nucleus accumbens. However, not all patients respond and optimum stimulation-site is uncertain. We compared deep brain stimulation of the subgenual cingulate and ventral anterior capsule/nucleus accumbens separately and combined in the same seven treatment-refractory depression patients, and investigated regional cerebral blood flow changes associated with acute and chronic deep brain stimulation. Deep brain stimulation-response was defined as reduction in Montgomery-Asberg Depression Rating Scale score from baseline of ≥50%, and remission as a Montgomery-Asberg Depression Rating Scale score ≤8. Changes in regional cerebral blood flow were assessed using [ 15 O]water positron emission tomography. Remitters had higher relative regional cerebral blood flow in the prefrontal cortex at baseline and all subsequent time-points compared to non-remitters and non-responders, with prefrontal cortex regional cerebral blood flow generally increasing with chronic deep brain stimulation. These effects were consistent regardless of stimulation-site. Overall, no significant regional cerebral blood flow changes were apparent when deep brain stimulation was acutely interrupted. Deep brain stimulation improved treatment-refractory depression severity in the majority of patients, with consistent changes in local and distant brain regions regardless of target stimulation. Remission of depression was reached in patients with higher baseline prefrontal regional cerebral blood flow. Because of the small sample size these results are preliminary and further evaluation is necessary to determine whether prefrontal cortex regional cerebral blood flow could be a predictive biomarker of treatment response.

Decreased prefrontal functional brain response during memory testing in women with Cushing's syndrome in remission.

PubMed

Ragnarsson, Oskar; Stomby, Andreas; Dahlqvist, Per; Evang, Johan A; Ryberg, Mats; Olsson, Tommy; Bollerslev, Jens; Nyberg, Lars; Johannsson, Gudmundur

2017-08-01

Neurocognitive dysfunction is an important feature of Cushing's syndrome (CS). Our hypothesis was that patients with CS in remission have decreased functional brain responses in the prefrontal cortex and hippocampus during memory testing. In this cross-sectional study we included 19 women previously treated for CS and 19 controls matched for age, gender, and education. The median remission time was 7 (IQR 6-10) years. Brain activity was studied with functional magnetic resonance imaging during episodic- and working-memory tasks. The primary regions of interest were the prefrontal cortex and the hippocampus. A voxel-wise comparison of functional brain responses in patients and controls was performed. During episodic-memory encoding, patients displayed lower functional brain responses in the left and right prefrontal gyrus (p<0.001) and in the right inferior occipital gyrus (p<0.001) compared with controls. There was a trend towards lower functional brain responses in the left posterior hippocampus in patients (p=0.05). During episodic-memory retrieval, the patients displayed lower functional brain responses in several brain areas with the most predominant difference in the right prefrontal cortex (p<0.001). During the working memory task, patients had lower response in the prefrontal cortices bilaterally (p<0.005). Patients, but not controls, had lower functional brain response during a more complex working memory task compared with a simpler one. In conclusion, women with CS in long-term remission have reduced functional brain responses during episodic and working memory testing. This observation extends previous findings showing long-term adverse effects of severe hypercortisolaemia on brain function. Copyright © 2017 Elsevier Ltd. All rights reserved.

Interaction of D-LSD with binding sites in brain: a study in vivo and in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ebersole, B.L.J.

The localization of (/sup 3/H)-d-lysergic acid diethylamide ((/sup 3/H)LSD) binding sites in the mouse brain was compared in vivo and in vitro. Radioautography of brain sections incubated with (/sup 3/H)LSD in vitro revealed substantial specific (/sup 3/H)LSD binding in cortical layers III-IV and areas CA1 and dentate gyrus in hippocampus. In contrast, in brain sections from animals that received (/sup 3/H)LSD in vivo, binding in hippocampus was scant and diffuse, although the pattern of labeling in cortex was similar to that seen in vitro. The low specific binding in hippocampus relative to cortex was confirmed by homogenate filtration studies ofmore » brain areas from mice that received injections of (/sup 3/H)LSD. Time-course studies established that peak specific binding at ten minutes was the same in cortex and hippocampus. At all times, binding in hippocampus was about one-third of that in cortex; in contrast, the concentration of free (/sup 3/H)LSD did not vary between regions. This finding was unexpected, because binding studies in vitro in membrane preparations indicated that the density and affinity of (/sup 3/H)LSD binding sites were similar in both brain regions. Saturation binding studies in vivo showed that the lower amount of (/sup 3/H)LSD binding in hippocampus was attributable to a lower density of sites labeled by (/sup 3/H)LSD. The pharmacological identify of (/sub 3/H)LSD binding sites in vivo may be relevant to the hallucinogenic properties of LSD and of other related hallucinogens.« less

A computational study of whole-brain connectivity in resting state and task fMRI

PubMed Central

Goparaju, Balaji; Rana, Kunjan D.; Calabro, Finnegan J.; Vaina, Lucia Maria

2014-01-01

Background We compared the functional brain connectivity produced during resting-state in which subjects were not actively engaged in a task with that produced while they actively performed a visual motion task (task-state). Material/Methods In this paper we employed graph-theoretical measures and network statistics in novel ways to compare, in the same group of human subjects, functional brain connectivity during resting-state fMRI with brain connectivity during performance of a high level visual task. We performed a whole-brain connectivity analysis to compare network statistics in resting and task states among anatomically defined Brodmann areas to investigate how brain networks spanning the cortex changed when subjects were engaged in task performance. Results In the resting state, we found strong connectivity among the posterior cingulate cortex (PCC), precuneus, medial prefrontal cortex (MPFC), lateral parietal cortex, and hippocampal formation, consistent with previous reports of the default mode network (DMN). The connections among these areas were strengthened while subjects actively performed an event-related visual motion task, indicating a continued and strong engagement of the DMN during task processing. Regional measures such as degree (number of connections) and betweenness centrality (number of shortest paths), showed that task performance induces stronger inter-regional connections, leading to a denser processing network, but that this does not imply a more efficient system as shown by the integration measures such as path length and global efficiency, and from global measures such as small-worldness. Conclusions In spite of the maintenance of connectivity and the “hub-like” behavior of areas, our results suggest that the network paths may be rerouted when performing the task condition. PMID:24947491

Regional Brain Shrinkage over Two Years: Individual Differences and Effects of Pro-Inflammatory Genetic Polymorphisms

PubMed Central

Persson, N.; Ghisletta, P.; Dahle, C.L.; Bender, A.R.; Yang, Y.; Yuan, P.; Daugherty, A.M.; Raz, N.

2014-01-01

We examined regional changes in brain volume in healthy adults (N = 167, age 19-79 years at baseline; N = 90 at follow-up) over approximately two years. With latent change score models, we evaluated mean change and individual differences in rates of change in 10 anatomically-defined and manually-traced regions of interest (ROIs): lateral prefrontal cortex (LPFC), orbital frontal cortex (OF), prefrontal white matter (PFw), hippocampus (HC), parahippocampal gyrus (PhG), caudate nucleus (Cd), putamen (Pt), insula (In), cerebellar hemispheres (CbH), and primary visual cortex (VC). Significant mean shrinkage was observed in the HC, CbH, In, OF, and the PhG, and individual differences in change were noted in all regions, except the OF. Pro-inflammatory genetic variants mediated shrinkage in PhG and CbH. Carriers of two T alleles of interleukin-1β (IL-1βC-511T, rs16944) and a T allele of methylenetetrahydrofolate reductase (MTHFRC677T, rs1801133) polymorphisms showed increased PhG shrinkage. No effects of a pro-inflammatory polymorphism for C-reactive protein (CRP-286C>A>T, rs3091244) or apolipoprotein (APOE) ε4 allele were noted. These results replicate the pattern of brain shrinkage observed in previous studies, with a notable exception of the LPFC thus casting doubt on the unique importance of prefrontal cortex in aging. Larger baseline volumes of CbH and In were associated with increased shrinkage, in conflict with the brain reserve hypothesis. Contrary to previous reports, we observed no significant linear effects of age and hypertension on regional brain shrinkage. Our findings warrant further investigation of the effects of neuroinflammation on structural brain change throughout the lifespan. PMID:25264227

Neural correlates of the severity of cocaine, heroin, alcohol, MDMA and cannabis use in polysubstance abusers: a resting-PET brain metabolism study.

PubMed

Moreno-López, Laura; Stamatakis, Emmanuel A; Fernández-Serrano, Maria José; Gómez-Río, Manuel; Rodríguez-Fernández, Antonio; Pérez-García, Miguel; Verdejo-García, Antonio

2012-01-01

Functional imaging studies of addiction following protracted abstinence have not been systematically conducted to look at the associations between severity of use of different drugs and brain dysfunction. Findings from such studies may be relevant to implement specific interventions for treatment. The aim of this study was to examine the association between resting-state regional brain metabolism (measured with 18F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and the severity of use of cocaine, heroin, alcohol, MDMA and cannabis in a sample of polysubstance users with prolonged abstinence from all drugs used. Our sample consisted of 49 polysubstance users enrolled in residential treatment. We conducted correlation analyses between estimates of use of cocaine, heroin, alcohol, MDMA and cannabis and brain metabolism (BM) (using Statistical Parametric Mapping voxel-based (VB) whole-brain analyses). In all correlation analyses conducted for each of the drugs we controlled for the co-abuse of the other drugs used. The analysis showed significant negative correlations between severity of heroin, alcohol, MDMA and cannabis use and BM in the dorsolateral prefrontal cortex (DLPFC) and temporal cortex. Alcohol use was further associated with lower metabolism in frontal premotor cortex and putamen, and stimulants use with parietal cortex. Duration of use of different drugs negatively correlated with overlapping regions in the DLPFC, whereas severity of cocaine, heroin and alcohol use selectively impact parietal, temporal, and frontal-premotor/basal ganglia regions respectively. The knowledge of these associations could be useful in the clinical practice since different brain alterations have been associated with different patterns of execution that may affect the rehabilitation of these patients.

Extrinsic Origins of the Somatostatin and Neuropeptide Y innervation of the Rat Basolateral Amygdala

PubMed Central

McDonald, Alexander J.; Zaric, Violeta

2015-01-01

The amygdalar basolateral nuclear complex (BLC) is a cortex-like structure that receives inputs from many cortical areas. It has long been assumed that cortico-amygdalar projections, as well as inter-areal intracortical connections, arise from cortical pyramidal cells. However, recent studies have shown that GABAergic long-range nonpyramidal neurons (LRNP neurons) in the cortex also contribute to inter-areal connections. The present study combined Fluorogold (FG) retrograde tract tracing with immunohistochemistry for cortical nonpyramidal neuronal markers to determine if cortical LRNP neurons project to the BLC in the rat. Injections of FG into the BLC produced widespread retrograde labeling in the cerebral hemispheres and diencephalon. Triple-labeling for FG, somatostatin (SOM), and neuropeptide Y (NPY) revealed a small number of FG+/SOM+/NPY+ neurons and FG+/SOM+/NPY− neurons in the lateral entorhinal area, amygdalopiriform transition area, and piriform cortex, but not in the prefrontal and insular cortices, or in the diencephalon. In addition, FG+/SOM+/NPY+ neurons were observed in the amygdalostriatal transition area and in a zone surrounding the intercalated nuclei. About half of the SOM+ neurons in the lateral entorhinal area labeled by FG were GABA+. FG+ neurons containing parvalbumin were only seen in the basal forebrain, and no FG+ neurons containing vasoactive intestinal peptide were observed in any brain region. Since LRNP neurons involved in corticocortical connections are critical for synchronous oscillations that allow temporal coordination between distant cortical regions, the LRNP neurons identified in this study may play a role in the synchronous oscillations of the BLC and hippocampal region that are involved in the retrieval of fear memories. PMID:25769940

Guided Saccades Modulate Face- and Body-Sensitive Activation in the Occipitotemporal Cortex during Social Perception

ERIC Educational Resources Information Center

Morris, James P.; Green, Steven R.; Marion, Brian; McCarthy, Gregory

2008-01-01

Functional magnetic resonance imaging (fMRI) has identified distinct brain regions in ventral occipitotemporal cortex (VOTC) and lateral occipitotemporal cortex (LOTC) that are differentially activated by pictures of faces and bodies. Recent work from our laboratory has shown that the strong LOTC activation evoked by bodies in which the face is…

6-Methyluracil derivatives as acetylcholinesterase inhibitors for treatment of Alzheimer's disease.

PubMed

Zueva, I V; Semenov, V E; Mukhamedyarov, M A; Lushchekina, S V; Kharlamova, A D; Petukhova, E O; Mikhailov, A S; Podyachev, S N; Saifina, L F; Petrov, K A; Minnekhanova, O A; Zobov, V V; Nikolsky, E E; Masson, P; Reznik, V S

2015-01-01

Alzheimer's disease (AD) is the major age-related progressive neurodegenerative disorder. The brain of AD patients suffers from loss of cholinergic neurons and decreased number of synapses [1]. AD is caused by an imbalance between Aβ production and clearance, resulting in increased amount of Aβ in various forms [2]. Reduction of Aβ production and increasing clearance of Aβ pathogenic forms are key targets in the development of potential therapeutic agents for AD treatment. Unfortunately, only nosotropic approaches for treatment of AD are currently effective in humans. These approaches mainly focus on the inhibition of brain acetyl-cholinesterase (AChE) to increase lifetime of cerebral acetylcholine [3]. It is important to emphasize that AChE itself promotes the formation of Aβ fibrils in vitro and Aβ plaques in the cerebral cortex of transgenic mouse models of AD [4]. This property of AChE results from interaction between Aβ and the peripheral anionic site of the enzyme (PAS) [5]. Dual binding site inhibitors of both catalytic active site (CAS) and PAS can simultaneously improve cognition and slow down the rate of Aβ-induced neural degeneration. Unfortunately, the assortment of AChE PAS ligands is still extremely limited. To study putative advantages of AChE non-charged PAS inhibitors based on 6-methyluracil derivatives for the treatment of Alzheimer's disease. In vitro studies. Concentration of drug producing 50% of AChE/BuChE activity inhibition (IC50) was measured using the method of Ellman et al. [6]. Toxicological experiments were performed using IP injection of the different compounds in mice. LD50, dose (in mg/kg) causing lethal effects in 50% of animals was taken as a criterion of toxicity [7]. The ability of compound to block in vitro AChE-induced Aβ1-40 aggregation was studied using a thioflavin T (ThT) fluorescent probe [8].In vivo biological assays. For in vivo blood-brain barrier permeation assay brains were removed 30 min after IP injection of LD50 dose of tested compound injection. The inhibitory potency was measured using the method of Ellman.Scopolamine and transgenic models of AD were used to evaluate the influence of compound 35 on spatial memory performance.Water solution of scopolamine was injected to mice (ip) 20 minutes before starting memory test during 14 days [9]. Mice were assigned to 7 groups, including 4 groups receiving injection (ip) of compound in different dosages, donepezil-treated mice (donepezil is conventionally used to treat Alzheimer's disease), positive and negative control groups. Double transgenic (APP/PS1) mice expressing a chimeric mouse/human amyloid precursor protein and a mutant of human presenilin-1 [10] were assigned to 4 groups, including transgenic animals injected (ip) with compound 35 or donepezil solution, positive (transgenes injected with water) and negative (wild-type mice) controls.To evaluate spatial memory performance, mice were trained on a reward alternation task using a conventional T-maze [11]. The criterion for a mouse having learned the rewarded alternation task was 3 consecutive days of at least 5 correct responses out of the 6 free trials.For β-amyloid peptide load was evaluated quantitatively as a number and summary area of Thioflavine S fluorescent spots in cerebral cortex and hippocampal images using Image J program. Statistical analyses were performed using the Mann-Whitney test. We evaluated the acute toxicity of the most active compounds. The most potent AChE inhibitor compound 35 (IC50 (AChE) = 5 ± 0.5 nM) exhibited the lowest LD50 values (51 mg/kg) and inhibited brain AChE by more than 71 ± 1%. Compound 35 at 10 nM, exhibited a significant (35 ± 9%) inhibitory activity toward human AChE-induced Aβ aggregation.Scopolamine injection induced significant decrease in correct choice percentage in T-maze, as well as decrease in percentage of mice reaching criterion for learning the task by day 14. This memory deficit was relieved to some extent either by compound 35 (5 mg/kg) or donepezil (reference compound) treatment (0.75 mg/kg). Interestingly, higher doses of compound 35 (10 and 15 mg/kg) produced less therapeutic effect on spatial memory deficit.Group of APP/PS1 mice showed 3 times lower percentage of reaching behavioral criterion and lower percentage of correct choice in T-maze alternation task comparing to WT mice, whereas compound 35 (5 mg/kg) or Donepezil treatment effectively improved these parameters in APP/PS1 mice.Compound 35 treatment (5 mg/kg) during 14 days significantly reduced percentage of summary area and number of β-amyloid peptide (βAP) deposits visualized in sections of cerebral cortex, dentate gyrus, and hippocampal CA3 area in APP/PS1 mice. The most prominent reduction of βAP load by compound 35 treatment was found in CA3 area and cerebral cortex. Meanwhile, Donepezil treatment (1 mg/kg) during 14 days significantly reduced βAP load in cerebral cortex but not in dentate gyrus and CA3 area. Experiments showed that the most potent AChE inhibitor compound 35 (6-methyluracil derivative) permeated the blood-brain barrier, improved working memory in the APP/PS1 transgenic mice and significantly reduced the number and area of Aβ plaques in the brain. Thus, compound 35 is a promising candidate as a bi-functional inhibitor of AChE for treatment of AD.

Comparative measurement of N-terminal pro-brain natriuretic peptide and brain natriuretic peptide in ambulatory patients with heart failure.

PubMed

Masson, Serge; Vago, Tarcisio; Baldi, Gabriella; Salio, Monica; De Angelis, Noeleen; Nicolis, Enrico; Maggioni, Aldo P; Latini, Roberto; Norbiato, Guido; Bevilacqua, Maurizio

2002-08-01

It is not clear whether brain natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) is superior as a diagnostic and prognostic indicator in cardiac diseases. Here, we compare the clinical correlations of both peptides in a population of 92 ambulatory patients with heart failure, using a well-established immunoradiometric assay (IRMA) for BNP and an automated electrochemiluminescence immunoassay for NT-proBNP. The analytical correlation between the two peptides was satisfactory over a wide range of concentrations (1-686 pM for BNP) with the equation: NT-proBNP = 3.48 x BNP -19 and a correlation coefficient r2=0.94. In addition, the concentration of both peptides increased in a similar fashion according to the severity of the disease New York Heart Association (NYHA) functional class, left ventricular ejection fraction, etiology) and age; for instance, the ratios between median levels measured in NYHA class III vs. class II patients were comparable for BNP (383 vs. 16 pM, ratio 24) and NT-proBNP (1306 vs. 57 pM, ratio 23). We conclude that N-terminal proBNP, as assayed in the present study, correlates equally to BNP with clinical variables in patients with heart failure.

The role of the posterior cingulate cortex in cognition and disease

PubMed Central

Sharp, David J.

2014-01-01

The posterior cingulate cortex is a highly connected and metabolically active brain region. Recent studies suggest it has an important cognitive role, although there is no consensus about what this is. The region is typically discussed as having a unitary function because of a common pattern of relative deactivation observed during attentionally demanding tasks. One influential hypothesis is that the posterior cingulate cortex has a central role in supporting internally-directed cognition. It is a key node in the default mode network and shows increased activity when individuals retrieve autobiographical memories or plan for the future, as well as during unconstrained ‘rest’ when activity in the brain is ‘free-wheeling’. However, other evidence suggests that the region is highly heterogeneous and may play a direct role in regulating the focus of attention. In addition, its activity varies with arousal state and its interactions with other brain networks may be important for conscious awareness. Understanding posterior cingulate cortex function is likely to be of clinical importance. It is well protected against ischaemic stroke, and so there is relatively little neuropsychological data about the consequences of focal lesions. However, in other conditions abnormalities in the region are clearly linked to disease. For example, amyloid deposition and reduced metabolism is seen early in Alzheimer’s disease. Functional neuroimaging studies show abnormalities in a range of neurological and psychiatric disorders including Alzheimer’s disease, schizophrenia, autism, depression and attention deficit hyperactivity disorder, as well as ageing. Our own work has consistently shown abnormal posterior cingulate cortex function following traumatic brain injury, which predicts attentional impairments. Here we review the anatomy and physiology of the region and how it is affected in a range of clinical conditions, before discussing its proposed functions. We synthesize key findings into a novel model of the region’s function (the ‘Arousal, Balance and Breadth of Attention’ model). Dorsal and ventral subcomponents are functionally separated and differences in regional activity are explained by considering: (i) arousal state; (ii) whether attention is focused internally or externally; and (iii) the breadth of attentional focus. The predictions of the model can be tested within the framework of complex dynamic systems theory, and we propose that the dorsal posterior cingulate cortex influences attentional focus by ‘tuning’ whole-brain metastability and so adjusts how stable brain network activity is over time. PMID:23869106

Homeostatic circuits selectively gate food cue responses in insular cortex

PubMed Central

Livneh, Yoav; Ramesh, Rohan n.; Burgess, christian R.; Levandowski, Kirsten M.; Madara, Joseph c.; Fenselau, henning; Goldey, Glenn J.; Diaz, Veronica E.; Jikomes, nick; Resch, Jon M.; Lowell, Bradford B.; Andermann, Mark L.

2017-01-01

Physiological needs bias perception and attention to relevant sensory cues. This process is ‘hijacked’ by drug addiction, causing cue-induced cravings and relapse. Similarly, its dysregulation contributes to failed diets, obesity, and eating disorders. Neuroimaging studies in humans have implicated insular cortex in these phenomena. However, it remains unclear how ‘cognitive’ cortical representations of motivationally relevant cues are biased by subcortical circuits that drive specific motivational states. Here we develop a microprism-based cellular imaging approach to monitor visual cue responses in the insular cortex of behaving mice across hunger states. Insular cortex neurons demonstrate food- cue-biased responses that are abolished during satiety. Unexpectedly, while multiple satiety-related visceral signals converge in insular cortex, chemogenetic activation of hypothalamic ‘hunger neurons’ (expressing agouti-related peptide (AgRP)) bypasses these signals to restore hunger-like response patterns in insular cortex. Circuit mapping and pathway-specific manipulations uncover a pathway from AgRP neurons to insular cortex via the paraventricular thalamus and basolateral amygdala. These results reveal a neural basis for state-specific biased processing of motivationally relevant cues. PMID:28614299

Regional gray matter density associated with emotional conflict resolution: evidence from voxel-based morphometry.

PubMed

Deng, Z; Wei, D; Xue, S; Du, X; Hitchman, G; Qiu, J

2014-09-05

Successful emotion regulation is a fundamental prerequisite for well-being and dysregulation may lead to psychopathology. The ability to inhibit spontaneous emotions while behaving in accordance with desired goals is an important dimension of emotion regulation and can be measured using emotional conflict resolution tasks. Few studies have investigated the gray matter correlates underlying successful emotional conflict resolution at the whole-brain level. We had 190 adults complete an emotional conflict resolution task (face-word task) and examined the brain regions significantly correlated with successful emotional conflict resolution using voxel-based morphometry. We found successful emotional conflict resolution was associated with increased regional gray matter density in widely distributed brain regions. These regions included the dorsal anterior cingulate/dorsal medial prefrontal cortex, ventral medial prefrontal cortex, supplementary motor area, amygdala, ventral striatum, precuneus, posterior cingulate cortex, inferior parietal lobule, superior temporal gyrus and fusiform face area. Together, our results indicate that individual differences in emotional conflict resolution ability may be attributed to regional structural differences across widely distributed brain regions. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Conduction aphasia as a function of the dominant posterior perisylvian cortex. Report of two cases.

PubMed

Quigg, Mark; Geldmacher, David S; Elias, W Jeff

2006-05-01

Assessment of eloquent functions during brain mapping usually relies on testing reading, speech, and comprehension to uncover transient deficits during electrical stimulation. These tests stem from findings predicted by the Geschwind-Wernicke hypothesis of receptive and expressive cortices connected by white matter tracts. Later work, however, has emphasized cortical mechanisms of language function. The authors report two cases that demonstrate that conduction aphasia is cortically mediated and can be inadequately assessed if not specifically evaluated during brain mapping. To determine the distribution of language on the dominant cortex, electrical cortical stimulation was performed in two cases by using implanted subdural electrodes during brain mapping before epilepsy surgery. A transient isolated deficit in repetition of language was reported during stimulation of the posterior portion of the dominant superior temporal gyrus in one patient and during stimulation of the supramarginal gyrus in the other patient. These cases demonstrate a localization of language repetition to the posterior perisylvian cortex. Brain mapping of this region should include assessment of verbal repetition to avoid potential deficits resembling conduction aphasia.

Addiction Related Alteration in Resting-state Brain Connectivity

PubMed Central

Ma, Ning; Liu, Ying; Li, Nan; Wang, Chang-Xin; Zhang, Hao; Jiang, Xiao-Feng; Xu, Hu-Sheng; Fu, Xian-Ming; Hu, Xiaoping; Zhang, Da-Ren

2009-01-01

It is widely accepted that addictive drug use is related to abnormal functional organization in the user’s brain. The present study aimed to identify this type of abnormality within the brain networks implicated in addiction by resting-state functional connectivity measured with functional magnetic resonance imaging (fMRI). With fMRI data acquired during resting state from 14 chronic heroin users (12 of whom were being treated with methadone) and 13 non-addicted controls, we investigated the addiction related alteration in functional connectivity between the regions in the circuits implicated in addiction with seed-based correlation analysis. Compared with controls, chronic heroin users showed increased functional connectivity between nucleus accumbens and ventral/rostral anterior cingulate cortex (ACC), and orbital frontal cortex (OFC), between amygdala and OFC; and reduced functional connectivity between prefrontal cortex and OFC, and ACC. These observations of altered resting-state functional connectivity suggested abnormal functional organization in the addicted brain and may provide additional evidence supporting the theory of addiction that emphasizes enhanced salience value of a drug and its related cues but weakened cognitive control in the addictive state. PMID:19703568

GSK-3β inhibitors suppressed neuroinflammation in rat cortex by activating autophagy in ischemic brain injury.

PubMed

Zhou, Xiaogang; Zhou, Jian; Li, Xilei; Guo, Chang'an; Fang, Taolin; Chen, Zhengrong

2011-07-29

Previous studies have shown that GSK-3β inhibitor could reduce infarct volume after ischemia brain injury. However, the underlying mechanisms of GSK-3β inhibitor involving neuroprotection remain poorly understood. In the present study, we demonstrated that GSK-3β inhibitor suppressed insult-induced neuroinflammation in rat cortex by increasing autophagy activation in ischemic injury. Male rats were subjected to pMCAO (permanent middle cerebral artery occlusion) followed by treating with SB216763, a GSK-3β inhibitor. We found that insult-induced inflammatory response was significantly decreased by intraperitoneal infusion of SB216763 in rat cortex. A higher level of autophagy was also detected after SB216763 treatment. In the cultured primary microglia, SB216763 activated autophagy and suppressed inflammatory response. Importantly, inhibition of autophagy by Beclin1-siRNA increased inflammatory response in the SB216763-treated microglia. These data suggest that GSK-3β inhibitor suppressed neuroinflammation by activating autophagy after ischemic brain injury, thus offering a new target for prevention of ischemic brain injury. Copyright © 2011 Elsevier Inc. All rights reserved.

Cortical thinning in type 2 diabetes mellitus and recovering effects of insulin therapy.

PubMed

Chen, Zhiye; Sun, Jie; Yang, Yang; Lou, Xin; Wang, Yulin; Wang, Yan; Ma, Lin

2015-02-01

The purpose of this study was to explore the brain structural changes in type 2 diabetes and the effect of insulin on the brain using a surface-based cortical thickness analysis. High-resolution three-dimensional T1-weighted fast spoiled gradient recalled echo MRI were obtained from 11 patients with type 2 diabetes before and after insulin therapy. The cortical thickness over the entire brain was calculated, and cross-sectional and longitudinal surface-based cortical thickness analyses were also performed. Regional cortical thinning was demonstrated in the middle temporal gyrus, posterior cingulate gyrus, precuneus, right lateral occipital gyrus and entorhinal cortex bilaterally for patients with type 2 diabetes mellitus compared with normal controls. Cortical thickening was seen in the middle temporal gyrus, entorhinal cortex and left inferior temporal gyrus bilaterally after patients underwent 1 year of insulin therapy. These findings suggest that insulin therapy may have recovering effects on the brain cortex in type 2 diabetes mellitus. The precise mechanism should be investigated further. Copyright © 2014 Elsevier Ltd. All rights reserved.

Signal or noise: brain network interactions underlying the experience and training of mindfulness.

PubMed

Mooneyham, Benjamin W; Mrazek, Michael D; Mrazek, Alissa J; Schooler, Jonathan W

2016-04-01

A broad set of brain regions has been associated with the experience and training of mindfulness. Many of these regions lie within key intrinsic brain networks, including the executive control, salience, and default networks. In this paper, we review the existing literature on the cognitive neuroscience of mindfulness through the lens of network science. We describe the characteristics of the intrinsic brain networks implicated in mindfulness and summarize the relevant findings pertaining to changes in functional connectivity (FC) within and between these networks. Convergence across these findings suggests that mindfulness may be associated with increased FC between two regions within the default network: the posterior cingulate cortex and the ventromedial prefrontal cortex. Additionally, extensive meditation experience may be associated with increased FC between the insula and the dorsolateral prefrontal cortex. However, little consensus has emerged within the existing literature owing to the diversity of operational definitions of mindfulness, neuroimaging methods, and network characterizations. We describe several challenges to develop a coherent cognitive neuroscience of mindfulness and to provide detailed recommendations for future research. © 2016 New York Academy of Sciences.

c-Fos expression predicts long-term social memory retrieval in mice.

PubMed

Lüscher Dias, Thomaz; Fernandes Golino, Hudson; Moura de Oliveira, Vinícius Elias; Dutra Moraes, Márcio Flávio; Schenatto Pereira, Grace

2016-10-15

The way the rodent brain generally processes socially relevant information is rather well understood. How social information is stored into long-term social memory, however, is still under debate. Here, brain c-Fos expression was measured after adult mice were exposed to familiar or novel juveniles and expression was compared in several memory and socially relevant brain areas. Machine Learning algorithm Random Forest was then used to predict the social interaction category of adult mice based on c-Fos expression in these areas. Interaction with a familiar co-specific altered brain activation in the olfactory bulb, amygdala, hippocampus, lateral septum and medial prefrontal cortex. Remarkably, Random Forest was able to predict interaction with a familiar juvenile with 100% accuracy. Activity in the olfactory bulb, amygdala, hippocampus and the medial prefrontal cortex were crucial to this prediction. From our results, we suggest long-term social memory depends on initial social olfactory processing in the medial amygdala and its output connections synergistically with non-social contextual integration by the hippocampus and medial prefrontal cortex top-down modulation of primary olfactory structures. Copyright © 2016 Elsevier B.V. All rights reserved.