Pericardium-6 Acupressure for the Prevention of Postoperative Nausea and Vomiting

DTIC Science & Technology

1999-10-01

in turn desensitizes the chemoreceptor trigger zone in the brain. This desensitization would prevent PONV caused by intravenous or Pericardium-6...indirect stimulation can occur from another center, the chemoreceptor trigger zone (CTZ) (Haynes & Bailey, 1996). The CTZ is located in the area...of the brain sensing vision and taste (Langer, 1998). For example, distention of the gastrointestinal tract initiates afferent impulses that reach

Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier.

PubMed

Biancardi, Vinicia Campana; Son, Sook Jin; Ahmadi, Sahra; Filosa, Jessica A; Stern, Javier E

2014-03-01

Angiotensin II-mediated vascular brain inflammation emerged as a novel pathophysiological mechanism in neurogenic hypertension. However, the precise underlying mechanisms and functional consequences in relation to blood-brain barrier (BBB) integrity and central angiotensin II actions mediating neurohumoral activation in hypertension are poorly understood. Here, we aimed to determine whether BBB permeability within critical hypothalamic and brain stem regions involved in neurohumoral regulation was altered during hypertension. Using digital imaging quantification after intravascularly injected fluorescent dyes and immunohistochemistry, we found increased BBB permeability, along with altered key BBB protein constituents, in spontaneously hypertensive rats within the hypothalamic paraventricular nucleus, the nucleus of the solitary tract, and the rostral ventrolateral medulla, all critical brain regions known to contribute to neurohumoral activation during hypertension. BBB disruption, including increased permeability and downregulation of constituent proteins, was prevented in spontaneously hypertensive rats treated with the AT1 receptor antagonist losartan, but not with hydralazine, a direct vasodilator. Importantly, we found circulating angiotensin II to extravasate into these brain regions, colocalizing with neurons and microglial cells. Taken together, our studies reveal a novel angiotensin II-mediated feed-forward mechanism during hypertension, by which circulating angiotensin II evokes increased BBB permeability, facilitating in turn its access to critical brain regions known to participate in blood pressure regulation.

Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma

PubMed Central

Wood, JodiAnne T.; Williams, John S.; Pandarinathan, Lakshmipathi; Janero, David R.; Lammi-Keefe, Carol J.; Makriyannis, Alexandros

2010-01-01

The endocannabinoid metabolome consists of a growing, (patho)physiologically important family of fatty-acid derived signaling lipids. Diet is a major source of fatty acid substrate for mammalian endocannabinoid biosynthesis. The principal long-chain PUFA found in mammalian brain, docosahexaenoic acid (DHA), supports neurological function, retinal development, and overall health. The extent to which dietary DHA supplementation influences endocannabinoid-related metabolites in brain, within the context of the circulating endocannabinoid profile, is currently unknown. We report the first lipidomic analysis of acute 2-week DHA dietary supplementation effects on the physiological state of 15 fatty-acid, N-acylethanolamine, and glycerol-ester endocannabinoid metabolome constituents in murine plasma and brain. The DHA-rich diet markedly elevated DHA, eicosapentaenoic acid, 2-eicosapentanoylglycerol (EPG), and docosahexanoylethanolamine in both compartments. Dietary DHA enhancement generally affected the synthesis of the N-acyl-ethanolamine and glycerol-ester metabolites to favor the docosahexaenoic and eicosapentaenoic vs. arachidonoyl and oleoyl homologs in both brain and plasma. The greater overall responsiveness of the endocannabinoid metabolome in plasma versus brain may reflect a more circumscribed homeostatic response range of brain lipids to dietary DHA supplementation. The ability of short-term DHA enhancement to modulate select constituents of the physiological brain and plasma endocannabinoid metabolomes carries metabolic and therapeutic implications. PMID:20071693

Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma.

PubMed

Wood, Jodianne T; Williams, John S; Pandarinathan, Lakshmipathi; Janero, David R; Lammi-Keefe, Carol J; Makriyannis, Alexandros

2010-06-01

The endocannabinoid metabolome consists of a growing, (patho)physiologically important family of fatty-acid derived signaling lipids. Diet is a major source of fatty acid substrate for mammalian endocannabinoid biosynthesis. The principal long-chain PUFA found in mammalian brain, docosahexaenoic acid (DHA), supports neurological function, retinal development, and overall health. The extent to which dietary DHA supplementation influences endocannabinoid-related metabolites in brain, within the context of the circulating endocannabinoid profile, is currently unknown. We report the first lipidomic analysis of acute 2-week DHA dietary supplementation effects on the physiological state of 15 fatty-acid, N-acylethanolamine, and glycerol-ester endocannabinoid metabolome constituents in murine plasma and brain. The DHA-rich diet markedly elevated DHA, eicosapentaenoic acid, 2-eicosapentanoylglycerol (EPG), and docosahexanoylethanolamine in both compartments. Dietary DHA enhancement generally affected the synthesis of the N-acyl-ethanolamine and glycerol-ester metabolites to favor the docosahexaenoic and eicosapentaenoic vs. arachidonoyl and oleoyl homologs in both brain and plasma. The greater overall responsiveness of the endocannabinoid metabolome in plasma versus brain may reflect a more circumscribed homeostatic response range of brain lipids to dietary DHA supplementation. The ability of short-term DHA enhancement to modulate select constituents of the physiological brain and plasma endocannabinoid metabolomes carries metabolic and therapeutic implications.

Identifying Potential Ventilator Auto-Triggering Among Organ Procurement Organization Referrals.

PubMed

Henry, Nicholas R; Russian, Christopher J; Nespral, Joseph

2016-06-01

Ventilator auto-trigger is the delivery of an assisted mechanical ventilated breath over the set ventilator frequency in the absence of a spontaneous inspiratory effort and can be caused by inappropriate ventilator trigger sensitivity. Ventilator auto-trigger can be misinterpreted as a spontaneous breath and has the potential to delay or prevent brain death testing and confuse health-care professionals and/or patient families. To determine the frequency of organ donor referrals from 1 Organ Procurement Organization (OPO) that could benefit from an algorithm designed to assist organ recovery coordinators to identify and correct ventilator auto-triggering. This retrospective analysis evaluated documentation of organ donor referrals from 1 OPO in central Texas during the 2013 calendar year that resulted in the withdrawal of care by the patient's family and the recovery of organs. The frequency of referrals that presented with absent brain stem reflexes except for additional respirations over the set ventilator rate was determined to assess for the need of the proposed algorithm. Documentation of 672 organ procurement organization referrals was evaluated. Documentation from 42 referrals that resulted in the withdrawal of care and 21 referrals that resulted in the recovery of organs were identified with absent brain stem reflexes except for spontaneous respirations on the mechanical ventilator. As a result, an algorithm designed to identify and correct ventilator auto-trigger could have been used 63 times during the 2013 calendar year. © 2016, NATCO.

Brain correlates of constituent structure in sign language comprehension.

PubMed

Moreno, Antonio; Limousin, Fanny; Dehaene, Stanislas; Pallier, Christophe

2018-02-15

During sentence processing, areas of the left superior temporal sulcus, inferior frontal gyrus and left basal ganglia exhibit a systematic increase in brain activity as a function of constituent size, suggesting their involvement in the computation of syntactic and semantic structures. Here, we asked whether these areas play a universal role in language and therefore contribute to the processing of non-spoken sign language. Congenitally deaf adults who acquired French sign language as a first language and written French as a second language were scanned while watching sequences of signs in which the size of syntactic constituents was manipulated. An effect of constituent size was found in the basal ganglia, including the head of the caudate and the putamen. A smaller effect was also detected in temporal and frontal regions previously shown to be sensitive to constituent size in written language in hearing French subjects (Pallier et al., 2011). When the deaf participants read sentences versus word lists, the same network of language areas was observed. While reading and sign language processing yielded identical effects of linguistic structure in the basal ganglia, the effect of structure was stronger in all cortical language areas for written language relative to sign language. Furthermore, cortical activity was partially modulated by age of acquisition and reading proficiency. Our results stress the important role of the basal ganglia, within the language network, in the representation of the constituent structure of language, regardless of the input modality. Copyright © 2017 Elsevier Inc. All rights reserved.

Linking neocortical, cognitive, and genetic variability in autism with alterations of brain plasticity: the Trigger-Threshold-Target model.

PubMed

Mottron, Laurent; Belleville, Sylvie; Rouleau, Guy A; Collignon, Olivier

2014-11-01

The phenotype of autism involves heterogeneous adaptive traits (strengths vs. disabilities), different domains of alterations (social vs. non-social), and various associated genetic conditions (syndromic vs. nonsyndromic autism). Three observations suggest that alterations in experience-dependent plasticity are an etiological factor in autism: (1) the main cognitive domains enhanced in autism are controlled by the most plastic cortical brain regions, the multimodal association cortices; (2) autism and sensory deprivation share several features of cortical and functional reorganization; and (3) genetic mutations and/or environmental insults involved in autism all appear to affect developmental synaptic plasticity, and mostly lead to its upregulation. We present the Trigger-Threshold-Target (TTT) model of autism to organize these findings. In this model, genetic mutations trigger brain reorganization in individuals with a low plasticity threshold, mostly within regions sensitive to cortical reallocations. These changes account for the cognitive enhancements and reduced social expertise associated with autism. Enhanced but normal plasticity may underlie non-syndromic autism, whereas syndromic autism may occur when a triggering mutation or event produces an altered plastic reaction, also resulting in intellectual disability and dysmorphism in addition to autism. Differences in the target of brain reorganization (perceptual vs. language regions) account for the main autistic subgroups. In light of this model, future research should investigate how individual and sex-related differences in synaptic/regional brain plasticity influence the occurrence of autism. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood–brain barrier

PubMed Central

Tominaga, Naoomi; Kosaka, Nobuyoshi; Ono, Makiko; Katsuda, Takeshi; Yoshioka, Yusuke; Tamura, Kenji; Lötvall, Jan; Nakagama, Hitoshi; Ochiya, Takahiro

2015-01-01

Brain metastasis is an important cause of mortality in breast cancer patients. A key event during brain metastasis is the migration of cancer cells through blood–brain barrier (BBB). However, the molecular mechanism behind the passage through this natural barrier remains unclear. Here we show that cancer-derived extracellular vesicles (EVs), mediators of cell–cell communication via delivery of proteins and microRNAs (miRNAs), trigger the breakdown of BBB. Importantly, miR-181c promotes the destruction of BBB through the abnormal localization of actin via the downregulation of its target gene, PDPK1. PDPK1 degradation by miR-181c leads to the downregulation of phosphorylated cofilin and the resultant activated cofilin-induced modulation of actin dynamics. Furthermore, we demonstrate that systemic injection of brain metastatic cancer cell-derived EVs promoted brain metastasis of breast cancer cell lines and are preferentially incorporated into the brain in vivo. Taken together, these results indicate a novel mechanism of brain metastasis mediated by EVs that triggers the destruction of BBB. PMID:25828099

Sterile Inflammation of Brain, due to Activation of Innate Immunity, as a Culprit in Psychiatric Disorders

PubMed Central

Ratajczak, Mariusz Z.; Pedziwiatr, Daniel; Cymer, Monika; Kucia, Magda; Kucharska-Mazur, Jolanta; Samochowiec, Jerzy

2018-01-01

Evidence has accumulated that the occurrence of psychiatric disorders is related to chronic inflammation. In support of this linkage, changes in the levels of circulating pro-inflammatory cytokines and chemokines in the peripheral blood (PB) of psychiatric patients as well as correlations between chronic inflammatory processes and psychiatric disorders have been described. Furthermore, an inflammatory process known as “sterile inflammation” when initiated directly in brain tissue may trigger the onset of psychoses. In this review, we will present the hypothesis that prolonged or chronic activation of the complement cascade (ComC) directly triggers inflammation in the brain and affects the proper function of this organ. Based on the current literature and our own work on mechanisms activating the ComC we hypothesize that inflammation in the brain is initiated by the mannan-binding lectin pathway of ComC activation. This activation is triggered by an increase in brain tissue of danger-associated molecular pattern (DAMP) mediators, including extracellular ATP and high-mobility group box 1 (HMGB1) protein, which are recognized by circulating pattern-recognition receptors, including mannan-binding lectin (MBL), that activate the ComC. On the other hand, this process is controlled by the anti-inflammatory action of heme oxygenase 1 (HO-1). In this review, we will try to connect changes in the release of DAMPs in the brain with inflammatory processes triggered by the innate immunity involving activation of the ComC as well as the inflammation-limiting effects of the anti-inflammatory HO-1 pathway. We will also discuss parallel observations that during ComC activation subsets of stem cells are mobilized into PB from bone marrow that are potentially involved in repair mechanisms. PMID:29541038

Sterile Inflammation of Brain, due to Activation of Innate Immunity, as a Culprit in Psychiatric Disorders.

PubMed

Ratajczak, Mariusz Z; Pedziwiatr, Daniel; Cymer, Monika; Kucia, Magda; Kucharska-Mazur, Jolanta; Samochowiec, Jerzy

2018-01-01

Evidence has accumulated that the occurrence of psychiatric disorders is related to chronic inflammation. In support of this linkage, changes in the levels of circulating pro-inflammatory cytokines and chemokines in the peripheral blood (PB) of psychiatric patients as well as correlations between chronic inflammatory processes and psychiatric disorders have been described. Furthermore, an inflammatory process known as "sterile inflammation" when initiated directly in brain tissue may trigger the onset of psychoses. In this review, we will present the hypothesis that prolonged or chronic activation of the complement cascade (ComC) directly triggers inflammation in the brain and affects the proper function of this organ. Based on the current literature and our own work on mechanisms activating the ComC we hypothesize that inflammation in the brain is initiated by the mannan-binding lectin pathway of ComC activation. This activation is triggered by an increase in brain tissue of danger-associated molecular pattern (DAMP) mediators, including extracellular ATP and high-mobility group box 1 (HMGB1) protein, which are recognized by circulating pattern-recognition receptors, including mannan-binding lectin (MBL), that activate the ComC. On the other hand, this process is controlled by the anti-inflammatory action of heme oxygenase 1 (HO-1). In this review, we will try to connect changes in the release of DAMPs in the brain with inflammatory processes triggered by the innate immunity involving activation of the ComC as well as the inflammation-limiting effects of the anti-inflammatory HO-1 pathway. We will also discuss parallel observations that during ComC activation subsets of stem cells are mobilized into PB from bone marrow that are potentially involved in repair mechanisms.

Does Infection-Induced Immune Activation Contribute to Dementia?

PubMed Central

Barichello, Tatiana; Generoso, Jaqueline S; Goularte, Jessica A; Collodel, Allan; Pitcher, Meagan R; Simões, Lutiana R; Quevedo, João; Dal-Pizzol, Felipe

2015-01-01

The central nervous system (CNS) is protected by a complex blood-brain barrier system; however, a broad diversity of virus, bacteria, fungi, and protozoa can gain access and cause illness. As pathogens replicate, they release molecules that can be recognized by innate immune cells. These molecules are pathogen-associated molecular patterns (PAMP) and they are identified by pattern-recognition receptors (PRR) expressed on antigen-presenting cells. Examples of PRR include toll-like receptors (TLR), receptors for advanced glycation endproducts (RAGE), nucleotide binding oligomerisation domain (NOD)-like receptors (NLR), c-type lectin receptors (CLR), RIG-I-like receptors (RLR), and intra-cytosolic DNA sensors. The reciprocal action between PAMP and PRR triggers the release of inflammatory mediators that regulate the elimination of invasive pathogens. Damage-associated molecular patterns (DAMP) are endogenous constituents released from damaged cells that also have the ability to activate the innate immune response. An increase of RAGE expression levels on neurons, astrocytes, microglia, and endothelial cells could be responsible for the accumulation of αβ-amyloid in dementia and related to the chronic inflammatory state that is found in neurodegenerative disorders. PMID:26425389

Lack of effect of oral choline supplement on the concentrations of choline metabolites in human brain.

PubMed

Tan, J; Bluml, S; Hoang, T; Dubowitz, D; Mevenkamp, G; Ross, B

1998-06-01

Recent reports suggest that oral choline supplement may alter the cerebral choline/creatine (Cho/Cr) ratio and might be used to treat neurodegenerative disorders of cholinergic transmission. Using both 1H and 31P MRS, we reexamined the Cho/Cr ratio and quantified cerebral choline and its major constituents: phosphoethanolamine (PE), phosphorylcholine (PC), glycerophosphorylethanolamine (GPE), and glycerophosphorylcholine (GPC). In the four brain locations examined, no significant increases in Cho/Cr, [Cho], or in its major constituents were found in response to an oral challenge of 50 mg/kg of choline bitartrate. Oral choline did not significantly affect human cerebral metabolism in the short term.

Connexin channels provide a target to manipulate brain endothelial calcium dynamics and blood–brain barrier permeability

PubMed Central

De Bock, Marijke; Culot, Maxime; Wang, Nan; Bol, Mélissa; Decrock, Elke; De Vuyst, Elke; da Costa, Anaelle; Dauwe, Ine; Vinken, Mathieu; Simon, Alexander M; Rogiers, Vera; De Ley, Gaspard; Evans, William Howard; Bultynck, Geert; Dupont, Geneviève; Cecchelli, Romeo; Leybaert, Luc

2011-01-01

The cytoplasmic Ca2+ concentration ([Ca2+]i) is an important factor determining the functional state of blood–brain barrier (BBB) endothelial cells but little is known on the effect of dynamic [Ca2+]i changes on BBB function. We applied different agonists that trigger [Ca2+]i oscillations and determined the involvement of connexin channels and subsequent effects on endothelial permeability in immortalized and primary brain endothelial cells. The inflammatory peptide bradykinin (BK) triggered [Ca2+]i oscillations and increased endothelial permeability. The latter was prevented by buffering [Ca2+]i with BAPTA, indicating that [Ca2+]i oscillations are crucial in the permeability changes. Bradykinin-triggered [Ca2+]i oscillations were inhibited by interfering with connexin channels, making use of carbenoxolone, Gap27, a peptide blocker of connexin channels, and Cx37/43 knockdown. Gap27 inhibition of the oscillations was rapid (within minutes) and work with connexin hemichannel-permeable dyes indicated hemichannel opening and purinergic signaling in response to stimulation with BK. Moreover, Gap27 inhibited the BK-triggered endothelial permeability increase in in vitro and in vivo experiments. By contrast, [Ca2+]i oscillations provoked by exposure to adenosine 5′ triphosphate (ATP) were not affected by carbenoxolone or Gap27 and ATP did not disturb endothelial permeability. We conclude that interfering with endothelial connexin hemichannels is a novel approach to limiting BBB-permeability alterations. PMID:21654699

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.

Alkamides from Echinacea angustifolia Interact with P-glycoprotein of primary brain capillary endothelial cells isolated from porcine brain blood vessels.

PubMed

Mahringer, Anne; Ardjomand-Woelkart, Karin; Bauer, Rudolf; Fricker, Gert; Efferth, Thomas

2013-03-01

The blood-brain barrier prevents the passage of toxic compounds from blood circulation into brain tissue. Unfortunately, drugs for the treatment of neurodegenerative diseases, brain tumors, and other diseases also do not cross the blood-brain barrier. In the present investigation, we used isolated porcine brain capillary endothelial cells and a flow cytometric calcein-AM assay to analyze inhibition of P-glycoprotein, a major constituent of the blood-brain barrier. We tested 8 alkamides isolated from Echinacea angustifolia and found that four of them inhibited P-glycoprotein-mediated calcein transport in porcine brain capillary endothelial cells. Georg Thieme Verlag KG Stuttgart · New York.

Low levels of aluminum can lead to behavioral and morphological changes associated with Alzheimer's disease and age-related neurodegeneration.

PubMed

Bondy, Stephen C

2016-01-01

Aluminum (Al) is a very common component of the earth's mineral composition. It is not essential element for life and is a constituent of rather inert minerals. Therefore, it has often been regarded as not presenting a significant health hazard. As a result, aluminum-containing agents been used in the preparation of many foodstuffs processing steps and also in elimination of particulate organic matter from water. More recently, the reduced pH of bodies of water resulting from acid rain has led to mobilization of aluminum-containing minerals into a more soluble form, and these have thus entered residential drinking water resources. By this means, the body burden of aluminum in humans has increased. Epidemiological and experimental findings indicate that aluminum is not as harmless as was previously thought, and that aluminum may contribute to the inception and advancement of Alzheimer's disease. Epidemiological data is reinforced by indications that aluminum exposure can result in excess inflammatory activity within the brain. Activation of the immune system not initiated by an infectious agent, typifies the aging brain and is even more augmented in several neurodegenerative diseases. The origin of most age-related neurological disorders is generally not known but as they are largely not of genetic derivation, their development is likely triggered by unknown environmental factors. There is a growing and consistent body of evidence that points to aluminum as being one such significant influence. Evidence is presented that reinforces the likelihood that aluminum is a factor speeding the rate of brain aging. Such acceleration would inevitably enlarge the incidence of age-related neurological diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

Opaque for the Reader but Transparent for the Brain: Neural Signatures of Morphological Complexity

ERIC Educational Resources Information Center

Meinzer, Marcus; Lahiri, Aditi; Flaisch, Tobias; Hannemann, Ronny; Eulitz, Carsten

2009-01-01

Within linguistics, words with a complex internal structure are commonly assumed to be decomposed into their constituent morphemes (e.g., un-help-ful). Nevertheless, an ongoing debate concerns the brain structures that subserve this process. Using functional magnetic resonance imaging, the present study varied the internal complexity of derived…

Molecular dialogues between the ischemic brain and the peripheral immune system: Dualistic roles in injury and repair

PubMed Central

An, Chengrui; Shi, Yejie; Li, Peiying; Hu, Xiaoming; Gan, Yu; Stetler, Ruth A.; Leak, Rehana K.; Gao, Yanqin; Sun, Bao-Liang; Zheng, Ping; Chen, Jun

2014-01-01

Immune and inflammatory responses actively modulate the pathophysiological processes of acute brain injuries such as stroke. Soon after the onset of stroke, signals such as brain-derived antigens, danger-associated molecular patterns (DAMPs), cytokines, and chemokines are released from the injured brain into the systemic circulation. The injured brain also communicates with peripheral organs through the parasympathetic and sympathetic branches of the autonomic nervous system. Many of these diverse signals not only activate resident immune cells in the brain, but also trigger robust immune responses in the periphery. Peripheral immune cells then migrate toward the site of injury and release additional cytokines, chemokines, and other molecules, causing further disruptive or protective effects in the ischemic brain. Bidirectional communication between the injured brain and the peripheral immune system is now known to regulate the progression of stroke pathology as well as tissue repair. In the end, this exquisitely coordinated crosstalk helps determine the fate of animals after stroke. This article reviews the literature on ischemic brain-derived signals through which peripheral immune responses are triggered, and the potential impact of these peripheral responses on brain injury and repair. Pharmacological strategies and cell-based therapies that target the dialogue between the brain and peripheral immune system show promise as potential novel treatments for stroke. PMID:24374228

Metyrapone prevents acute glucose hypermetabolism and short-term brain damage induced by intrahippocampal administration of 4-aminopyridine in rats.

PubMed

García-García, Luis; Fernández de la Rosa, Rubén; Delgado, Mercedes; Silván, Ágata; Bascuñana, Pablo; Bankstahl, Jens P; Gomez, Francisca; Pozo, Miguel A

2018-02-01

Intracerebral administration of the potassium channel blocker 4-aminopyridine (4-AP) triggers neuronal depolarization and intense acute seizure activity followed by neuronal damage. We have recently shown that, in the lithium-pilocarpine rat model of status epilepticus (SE), a single administration of metyrapone, an inhibitor of the 11β-hydroxylase enzyme, had protective properties of preventive nature against signs of brain damage and neuroinflammation. Herein, our aim was to investigate to which extent, pretreatment with metyrapone (150 mg/kg, i.p.) was also able to prevent eventual changes in the acute brain metabolism and short-term neuronal damage induced by intrahippocampal injection of 4-AP (7 μg/5 μl). To this end, regional brain metabolism was assessed by 2-deoxy-2-[ 18 F]fluoro-d-glucose ([ 18 F]FDG) positron emission tomography (PET) during the ictal period. Three days later, markers of neuronal death and hippocampal integrity and apoptosis (Nissl staining, NeuN and active caspase-3 immunohistochemistry), neurodegeneration (Fluoro-Jade C labeling), astrogliosis (glial fibrillary acidic protein (GFAP) immunohistochemistry) and microglia-mediated neuroinflammation (in vitro [ 18 F]GE180 autoradiography) were evaluated. 4-AP administration acutely triggered marked brain hypermetabolism within and around the site of injection as well as short-term signs of brain damage and inflammation. Most important, metyrapone pretreatment was able to reduce ictal hypermetabolism as well as all the markers of brain damage except microglia-mediated neuroinflammation. Overall, our study corroborates the neuroprotective effects of metyrapone against multiple signs of brain damage caused by seizures triggered by 4-AP. Ultimately, our data add up to the consistent protective effect of metyrapone pretreatment reported in other models of neurological disorders of different etiology. Copyright © 2017 Elsevier Ltd. All rights reserved.

Event-Related Brain Potential Correlates of Emotional Face Processing

ERIC Educational Resources Information Center

Eimer, Martin; Holmes, Amanda

2007-01-01

Results from recent event-related brain potential (ERP) studies investigating brain processes involved in the detection and analysis of emotional facial expression are reviewed. In all experiments, emotional faces were found to trigger an increased ERP positivity relative to neutral faces. The onset of this emotional expression effect was…

Vasovagal Syncope

MedlinePlus

... Combined, the drop in blood pressure and slowed heart rate quickly reduce blood flow to your brain, and you faint. Sometimes there is no classical vasovagal syncope trigger, but common triggers include: Standing for long periods of time Heat exposure Seeing blood Having blood drawn Fear of ...

Nature's Anti-Alzheimer's Drug: Isolation and Structure Elucidation of Galantamine from "Leucojum Aestivum"

ERIC Educational Resources Information Center

Halpin, Catherine M.; Reilly, Ciara; Walsh, John J.

2010-01-01

The discovery that galantamine penetrates the blood-brain barrier has led to its clinical use in the treatment of choline-deficiency conditions in the brain, such as Alzheimer's disease. This experiment involves the isolation and structure elucidation of galantamine from "Leucojum aestivum". Isolation of the alkaloid constituents in "L. aestivum"…

Voxelwise distribution of acute ischemic stroke lesions in patients with newly diagnosed atrial fibrillation: Trigger of arrhythmia or only target of embolism?

PubMed Central

Johnson, Timothy D.; Dittgen, Felix; Nichols, Thomas E.; Malzahn, Uwe; Veltkamp, Roland

2017-01-01

Objective Atrial fibrillation (AF) is frequently detected after ischemic stroke for the first time, and brain regions involved in autonomic control have been suspected to trigger AF. We examined whether specific brain regions are associated with newly detected AF after ischemic stroke. Methods Patients with acute cerebral infarctions on diffusion-weighted magnetic resonance imaging were included in this lesion mapping study. Lesions were mapped and modeled voxelwise using Bayesian Spatial Generalised Linear Mixed Modeling to determine differences in infarct locations between stroke patients with new AF, without AF and with AF already known before the stroke. Results 582 patients were included (median age 68 years; 63.2% male). AF was present in 109/582 patients [(18.7%); new AF: 39/109 (35.8%), known AF: 70/109 (64.2%)]. AF patients had larger infarct volumes than patients without AF (mean: 29.7 ± 45.8 ml vs. 15.2 ± 35.1 ml; p<0.001). Lesions in AF patients accumulated in the right central middle cerebral artery territory. Increasing stroke size predicted progressive cortical but not pontine and thalamic involvement. Patients with new AF had more frequently lesions in the right insula compared to patients without AF when stroke size was not accounted for, but no specific brain region was more frequently involved after adjustment for infarct volume. Controlled for stroke size, left parietal involvement was less likely for patients with new AF than for those without AF or with known AF. Conclusions In the search for brain areas potentially triggering cardiac arrhythmias infarct size should be accounted for. After controlling for infarct size, there is currently no evidence that ischemic stroke lesions of specific brain areas are associated with new AF compared to patients without AF. This challenges the neurogenic hypothesis of AF according to which a relevant proportion of new AF is triggered by ischemic brain lesions of particular locations. PMID:28542605

AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability

PubMed Central

Brechet, Aline; Buchert, Rebecca; Schwenk, Jochen; Boudkkazi, Sami; Zolles, Gerd; Siquier-Pernet, Karine; Schaber, Irene; Bildl, Wolfgang; Saadi, Abdelkrim; Bole-Feysot, Christine; Nitschke, Patrick; Reis, Andre; Sticht, Heinrich; Al-Sanna’a, Nouriya; Rolfs, Arndt; Kulik, Akos; Schulte, Uwe; Colleaux, Laurence; Abou Jamra, Rami; Fakler, Bernd

2017-01-01

AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Bi-allelic mutations in the human FRRS1L gene are shown to cause severe intellectual disability with cognitive impairment, speech delay and epileptic activity. Virus-directed deletion or overexpression of FRRS1l strongly impact synaptic transmission in adult rat brain by decreasing or increasing the number of AMPARs in synapses and extra-synaptic sites. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function. PMID:28675162

Insights into the molecular aspects of neuroprotective Bacoside A and Bacopaside I.

PubMed

Sekhar, Vini C; Viswanathan, Gayathri; Baby, Sabulal

2018-04-19

Bacopa monnieri, commonly known as Brahmi, has been extensively used as a neuromedicine for various disorders such as anxiety, depression and memory loss. Chemical characterization studies revealed the major active constituents of the herb as the triterpenoid saponins, bacosides. Bacoside A, the vital neuroprotective constituent, is composed of four constituents viz., bacoside A3, bacopaside II, jujubogenin isomer of bacopasaponin C (bacopaside X) and bacopasaponin C. B. monnieri extracts as well as bacosides successfully establish a healthy antioxidant environment in various tissues especially in liver and brain. Free radical scavenging, suppression of lipid peroxidation and activation of antioxidant enzymes by bacosides help to attain a physiological state of minimized oxidative stress. The molecular basis of neuroprotective activity of bacosides is attributed to the regulation of mRNA translation and surface expression of neuroreceptors such as AMPAR, NMDAR and GABAR in the various parts of the brain. Bioavailability as well as binding of neuroprotective agents (such as bacosides) to these receptors is controlled by the Blood Brain Barrier (BBB). However, nano conversion of these drug candidates easily resolves the BBB restriction and carries a promising role in future therapies. This review summarizes the neuroprotective functions of the B. monnieri extracts as well as its active compounds (bacoside A, bacopaside I) and the molecular mechanisms responsible for these pharmacological activities. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Nature plus nurture: the triggering of multiple sclerosis.

PubMed

Wekerle, Hartmut

2015-01-01

Recent clinical and experimental studies indicate that multiple sclerosis develops as consequence of a failed interplay between genetic ("nature") and environmental ("nurture") factors. A large number of risk genes favour an autoimmune response against the body's own brain matter. New experimental data indicate that the actual trigger of this attack is however provided by an interaction of brain-specific immune cells with components of the regular commensal gut flora, the intestinal microbiota. This concept opens the way for new therapeutic approaches involving modulation of the microbiota by dietary or antibiotic regimens.

Molecular dialogs between the ischemic brain and the peripheral immune system: dualistic roles in injury and repair.

PubMed

An, Chengrui; Shi, Yejie; Li, Peiying; Hu, Xiaoming; Gan, Yu; Stetler, Ruth A; Leak, Rehana K; Gao, Yanqin; Sun, Bao-Liang; Zheng, Ping; Chen, Jun

2014-04-01

Immune and inflammatory responses actively modulate the pathophysiological processes of acute brain injuries such as stroke. Soon after the onset of stroke, signals such as brain-derived antigens, danger-associated molecular patterns (DAMPs), cytokines, and chemokines are released from the injured brain into the systemic circulation. The injured brain also communicates with peripheral organs through the parasympathetic and sympathetic branches of the autonomic nervous system. Many of these diverse signals not only activate resident immune cells in the brain, but also trigger robust immune responses in the periphery. Peripheral immune cells then migrate toward the site of injury and release additional cytokines, chemokines, and other molecules, causing further disruptive or protective effects in the ischemic brain. Bidirectional communication between the injured brain and the peripheral immune system is now known to regulate the progression of stroke pathology as well as tissue repair. In the end, this exquisitely coordinated crosstalk helps determine the fate of animals after stroke. This article reviews the literature on ischemic brain-derived signals through which peripheral immune responses are triggered, and the potential impact of these peripheral responses on brain injury and repair. Pharmacological strategies and cell-based therapies that target the dialog between the brain and peripheral immune system show promise as potential novel treatments for stroke. Published by Elsevier Ltd.

Therapeutic-Ultrasound-Triggered Shape Memory of a Melamine-Enhanced Poly(vinyl alcohol) Physical Hydrogel.

PubMed

Li, Guo; Yan, Qiang; Xia, Hesheng; Zhao, Yue

2015-06-10

Therapeutic-ultrasound-triggered shape memory was demonstrated for the first time with a melamine-enhanced poly(vinyl alcohol) (PVA) physical hydrogel. The addition of a small amount of melamine (up to 1.5 wt %) in PVA results in a strong hydrogel due to the multiple H-bonding between the two constituents. A temporary shape of the hydrogel can be obtained by deformation of the hydrogel (∼65 wt % water) at room temperature, followed by fixation of the deformation by freezing/thawing the hydrogel under strain, which induces crystallization of PVA. We show that the ultrasound delivered by a commercially available device designed for the patient's pain relief could trigger the shape recovery process as a result of ultrasound-induced local heating in the hydrogel that melts the crystallized PVA cross-linking. This hydrogel is thus interesting for potential applications because it combines many desirable properties, being mechanically strong, biocompatible, and self-healable and displaying the shape memory capability triggered by a physiological stimulus.

Atherogenic diet induced lipid accumulation induced NFκB level in heart, liver and brain of Wistar rat and diosgenin as an anti-inflammatory agent.

PubMed

Binesh, Ambika; Devaraj, Sivasithamparam Niranjali; Halagowder, Devaraj

2018-03-01

Atherogenic Diet (AD) was given to rats to understand the key role of inflammatory mediators in atherosclerotic lesion formation, as a serendipitous study, the diet induced inflammatory mediators in liver and brain, whereas pancreas, kidney and spleen were not affected. The efficacy of diosgenin in ameliorating atherosclerotic progression in heart and suppression of inflammatory mediators in liver and brain of Wistar rat fed on AD diet was investigated. Atherogenic diet triggered inflammatory mediators in heart, liver and brain by upregulating TNF-α, COX-2 and NFkBp65 which are the inflammatory hub, played a key role in pathophysiologic conditions. Endothelial dysfunction, liver tissue with prominent steatosis and the stress evoked in the brain by the atherogenic diet triggered these inflammatory mediators. TNF-α and COX-2 expression was upregulated and its elevation was associated with NFkBp65 activation in heart, liver and brain of atherogenic diet induced rat. Diosgenin downregulated these inflammatory mediators, thereby prevented the atherosclerotic disease progression and concomitant suppression of inflammatory mediators in liver and brain. Copyright © 2018. Published by Elsevier Inc.

Recent developments for realistic solar models

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

Serenelli, Aldo M.

2014-05-02

The 'solar abundance problem' has triggered a renewed interest in revising the concept of SSM from different perspectives: 1) constituent microphysics: equation of state, nuclear rates, radiative opacities; 2) constituent macrophysics: the physical processes impact the evolution of the Sun and its present-day structure, e.g. dynamical processes induced by rotation, presence of magnetic fields; 3) challenge the hypothesis that the young Sun was chemically homogeneous: the possible interaction of the young Sun with its protoplanetary disk. Here, I briefly review and then present a (personal) view on recent advances and developments on solar modeling, part of them carried out asmore » attempts to solve the solar abundance problem.« less

Correlation of vocals and lyrics with left temporal musicogenic epilepsy.

PubMed

Tseng, Wei-En J; Lim, Siew-Na; Chen, Lu-An; Jou, Shuo-Bin; Hsieh, Hsiang-Yao; Cheng, Mei-Yun; Chang, Chun-Wei; Li, Han-Tao; Chiang, Hsing-I; Wu, Tony

2018-03-15

Whether the cognitive processing of music and speech relies on shared or distinct neuronal mechanisms remains unclear. Music and language processing in the brain are right and left temporal functions, respectively. We studied patients with musicogenic epilepsy (ME) that was specifically triggered by popular songs to analyze brain hyperexcitability triggered by specific stimuli. The study included two men and one woman (all right-handed, aged 35-55 years). The patients had sound-triggered left temporal ME in response to popular songs with vocals, but not to instrumental, classical, or nonvocal piano solo versions of the same song. Sentimental lyrics, high-pitched singing, specificity/familiarity, and singing in the native language were the most significant triggering factors. We found that recognition of the human voice and analysis of lyrics are important causal factors in left temporal ME and provide observational evidence that sounds with speech structure are predominantly processed in the left temporal lobe. A literature review indicated that language-associated stimuli triggered ME in the left temporal epileptogenic zone at a nearly twofold higher rate compared with the right temporal region. Further research on ME may enhance understanding of the cognitive neuroscience of music. © 2018 New York Academy of Sciences.

The Brain Basis for Misophonia.

PubMed

Kumar, Sukhbinder; Tansley-Hancock, Olana; Sedley, William; Winston, Joel S; Callaghan, Martina F; Allen, Micah; Cope, Thomas E; Gander, Phillip E; Bamiou, Doris-Eva; Griffiths, Timothy D

2017-02-20

Misophonia is an affective sound-processing disorder characterized by the experience of strong negative emotions (anger and anxiety) in response to everyday sounds, such as those generated by other people eating, drinking, chewing, and breathing [1-8]. The commonplace nature of these sounds (often referred to as "trigger sounds") makes misophonia a devastating disorder for sufferers and their families, and yet nothing is known about the underlying mechanism. Using functional and structural MRI coupled with physiological measurements, we demonstrate that misophonic subjects show specific trigger-sound-related responses in brain and body. Specifically, fMRI showed that in misophonic subjects, trigger sounds elicit greatly exaggerated blood-oxygen-level-dependent (BOLD) responses in the anterior insular cortex (AIC), a core hub of the "salience network" that is critical for perception of interoceptive signals and emotion processing. Trigger sounds in misophonics were associated with abnormal functional connectivity between AIC and a network of regions responsible for the processing and regulation of emotions, including ventromedial prefrontal cortex (vmPFC), posteromedial cortex (PMC), hippocampus, and amygdala. Trigger sounds elicited heightened heart rate (HR) and galvanic skin response (GSR) in misophonic subjects, which were mediated by AIC activity. Questionnaire analysis showed that misophonic subjects perceived their bodies differently: they scored higher on interoceptive sensibility than controls, consistent with abnormal functioning of AIC. Finally, brain structural measurements implied greater myelination within vmPFC in misophonic individuals. Overall, our results show that misophonia is a disorder in which abnormal salience is attributed to particular sounds based on the abnormal activation and functional connectivity of AIC. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Interleukin 2 Activates Brain Microvascular Endothelial Cells Resulting in Destabilization of Adherens Junctions.

PubMed

Wylezinski, Lukasz S; Hawiger, Jacek

2016-10-28

The pleiotropic cytokine interleukin 2 (IL2) disrupts the blood-brain barrier and alters brain microcirculation, underlying vascular leak syndrome that complicates cancer immunotherapy with IL2. The microvascular effects of IL2 also play a role in the development of multiple sclerosis and other chronic neurological disorders. The mechanism of IL2-induced disruption of brain microcirculation has not been determined previously. We found that both human and murine brain microvascular endothelial cells express constituents of the IL2 receptor complex. Then we established that signaling through this receptor complex leads to activation of the transcription factor, nuclear factor κB, resulting in expression of proinflammatory interleukin 6 and monocyte chemoattractant protein 1. We also discovered that IL2 induces disruption of adherens junctions, concomitant with cytoskeletal reorganization, ultimately leading to increased endothelial cell permeability. IL2-induced phosphorylation of vascular endothelial cadherin (VE-cadherin), a constituent of adherens junctions, leads to dissociation of its stabilizing adaptor partners, p120-catenin and β-catenin. Increased phosphorylation of VE-cadherin was also accompanied by a reduction of Src homology 2 domain-containing protein-tyrosine phosphatase 2, known to maintain vascular barrier function. These results unravel the mechanism of deleterious effects induced by IL2 on brain microvascular endothelial cells and may inform the development of new measures to improve IL2 cancer immunotherapy, as well as treatments for autoimmune diseases affecting the central nervous system. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Foods and food constituents that affect the brain and human behavior

NASA Technical Reports Server (NTRS)

Lieberman, Harris R.; Wurtman, Richard J.

1986-01-01

Until recently, it was generally believed that brain function was usually independent of day-to-day metabolic changes associated with consumption of food. Although it was acknowledged that peripheral metabolic changes associated with hunger or satiety might affect brain function, other effects of foods on the brain were considered unlikely. However, in 1971, Fernstrom and Wurtman discovered that under certain conditions, the protein-to-carbohydrate ratio of a meal could affect the concentration of a particular brain neurotransmitter. That neurotransmitter, serotonin, participates in the regulation of a variety of central nervous system (CNS) functions including sleep, pain sensitivity, aggression, and patterns of nutrient selection. The activity of other neurotransmitter systems has also been shown to be, under certain conditions, affected by dietary constituents which are given either as ordinary foods or in purified form. For example, the CNS turnover of two catecholamine neurotransmitters, dopamine and norepinephrine, can be altered by ingestion of their amino acid precursor, tyrosine, when neurons that release these monoamines are firing frequently. Similarly, lecithin, a dietary source of choline, and choline itself have been shown to increase the synthesis of acetylcholine when cholinergic neurons are very active. It is possible that other neurotransmitters could also be affected by precursor availability or other, as yet undiscovered peripheral factors governed by food consumption. The effects of food on neurotransmitters and behavior are discussed.

Hyperforin modifies neuronal membrane properties in vivo.

PubMed

Eckert, Gunter P; Keller, Jan-Henning; Jourdan, Claudia; Karas, Michael; Volmer, Dietrich A; Schubert-Zsilavecz, Manfred; Müller, Walter E

2004-09-02

Hyperforin, the major active constituent of St. John Wort (SJW) extract, affects several neurotransmitter systems in the brain putatively by modulation of the physical state of neuronal membranes. Accordingly, we tested the effects of SJW extract and of hyperforin on the properties of murine brain membrane fluidity. Oral administration of SJW extract and of hyperforin sodium salt results in significant hyperforin brain levels. Treatment of mice with hyperforin leads to decreased annular- and bulk fluidity and increased acyl-chain flexibility of brain membranes. All hyperforin related changes of membrane properties were significantly correlated with the corresponding hyperforin brain levels. Our data emphasises a membrane interaction of hyperforin that possibly contributes to its pharmacological effects.

Aiming routines and their electrocortical concomitants among competitive rifle shooters.

PubMed

Konttinen, N; Landers, D M; Lyytinen, H

2000-06-01

The present study focused on an examination of competitive shooters' aiming process during a rifle shooting task. The barrel movements of the rifle, as detected by a laser system during the last 1000-ms time period preceding the triggering, were recorded from six elite and six pre-elite shooters. Electrocortical slow potentials (SPs) from frontal (Fz), centro-lateral (C3, C4), and occipital (Oz) brain areas were recorded to get an additional insight into the underlying covert processing. The results suggested that the elite shooters did not pull the trigger until they reached a sustained rifle position. In the pre-elite shooters the rifle appeared to be in a less stable position, and their strategy was to take advantage of the first appropriate moment of steadiness without a sustained rifle position so they could pull the trigger. The observed pre-trigger readiness potential (RP) shifts at Fz and Oz were more positive among the elite shooters relative to the pre-elite shooters, reflecting their more pronounced covert effort, rather than increasing preparedness for the trigger pull. The present study lends support for the view that a successful aiming strategy is mainly based on sustained rifle balancing. With regards to the brain slow potentials, it can be concluded that the RP shift does not specifically reflect the preparation for the trigger pull.

Constituent quarks and systematic errors in mid-rapidity charged multiplicity dNch/dη distributions

NASA Astrophysics Data System (ADS)

Tannenbaum, M. J.

2018-01-01

Centrality definition in A + A collisions at colliders such as RHIC and LHC suffers from a correlated systematic uncertainty caused by the efficiency of detecting a p + p collision (50 ± 5% for PHENIX at RHIC). In A + A collisions where centrality is measured by the number of nucleon collisions, Ncoll, or the number of nucleon participants, Npart, or the number of constituent quark participants, Nqp, the error in the efficiency of the primary interaction trigger (Beam-Beam Counters) for a p + p collision leads to a correlated systematic uncertainty in Npart, Ncoll or Nqp which reduces binomially as the A + A collisions become more central. If this is not correctly accounted for in projections of A + A to p + p collisions, then mistaken conclusions can result. A recent example is presented in whether the mid-rapidity charged multiplicity per constituent quark participant (dNch/dη)/Nqp in Au + Au at RHIC was the same as the value in p + p collisions.

Correlation-based model of artificially induced plasticity in motor cortex by a bidirectional brain-computer interface.

PubMed

Lajoie, Guillaume; Krouchev, Nedialko I; Kalaska, John F; Fairhall, Adrienne L; Fetz, Eberhard E

2017-02-01

Experiments show that spike-triggered stimulation performed with Bidirectional Brain-Computer-Interfaces (BBCI) can artificially strengthen connections between separate neural sites in motor cortex (MC). When spikes from a neuron recorded at one MC site trigger stimuli at a second target site after a fixed delay, the connections between sites eventually strengthen. It was also found that effective spike-stimulus delays are consistent with experimentally derived spike-timing-dependent plasticity (STDP) rules, suggesting that STDP is key to drive these changes. However, the impact of STDP at the level of circuits, and the mechanisms governing its modification with neural implants remain poorly understood. The present work describes a recurrent neural network model with probabilistic spiking mechanisms and plastic synapses capable of capturing both neural and synaptic activity statistics relevant to BBCI conditioning protocols. Our model successfully reproduces key experimental results, both established and new, and offers mechanistic insights into spike-triggered conditioning. Using analytical calculations and numerical simulations, we derive optimal operational regimes for BBCIs, and formulate predictions concerning the efficacy of spike-triggered conditioning in different regimes of cortical activity.

Correlation-based model of artificially induced plasticity in motor cortex by a bidirectional brain-computer interface

PubMed Central

Lajoie, Guillaume; Kalaska, John F.; Fairhall, Adrienne L.; Fetz, Eberhard E.

2017-01-01

Experiments show that spike-triggered stimulation performed with Bidirectional Brain-Computer-Interfaces (BBCI) can artificially strengthen connections between separate neural sites in motor cortex (MC). When spikes from a neuron recorded at one MC site trigger stimuli at a second target site after a fixed delay, the connections between sites eventually strengthen. It was also found that effective spike-stimulus delays are consistent with experimentally derived spike-timing-dependent plasticity (STDP) rules, suggesting that STDP is key to drive these changes. However, the impact of STDP at the level of circuits, and the mechanisms governing its modification with neural implants remain poorly understood. The present work describes a recurrent neural network model with probabilistic spiking mechanisms and plastic synapses capable of capturing both neural and synaptic activity statistics relevant to BBCI conditioning protocols. Our model successfully reproduces key experimental results, both established and new, and offers mechanistic insights into spike-triggered conditioning. Using analytical calculations and numerical simulations, we derive optimal operational regimes for BBCIs, and formulate predictions concerning the efficacy of spike-triggered conditioning in different regimes of cortical activity. PMID:28151957

Single mechanically-gated cation channel currents can trigger action potentials in neocortical and hippocampal pyramidal neurons.

PubMed

Nikolaev, Yury A; Dosen, Peter J; Laver, Derek R; van Helden, Dirk F; Hamill, Owen P

2015-05-22

The mammalian brain is a mechanosensitive organ that responds to different mechanical forces ranging from intrinsic forces implicated in brain morphogenesis to extrinsic forces that can cause concussion and traumatic brain injury. However, little is known of the mechanosensors that transduce these forces. In this study we use cell-attached patch recording to measure single mechanically-gated (MG) channel currents and their affects on spike activity in identified neurons in neonatal mouse brain slices. We demonstrate that both neocortical and hippocampal pyramidal neurons express stretch-activated MG cation channels that are activated by suctions of ~25mm Hg, have a single channel conductance for inward current of 50-70pS and show weak selectivity for alkali metal cations (i.e., Na(+)

Neurokernel: An Open Source Platform for Emulating the Fruit Fly Brain

PubMed Central

2016-01-01

We have developed an open software platform called Neurokernel for collaborative development of comprehensive models of the brain of the fruit fly Drosophila melanogaster and their execution and testing on multiple Graphics Processing Units (GPUs). Neurokernel provides a programming model that capitalizes upon the structural organization of the fly brain into a fixed number of functional modules to distinguish between these modules’ local information processing capabilities and the connectivity patterns that link them. By defining mandatory communication interfaces that specify how data is transmitted between models of each of these modules regardless of their internal design, Neurokernel explicitly enables multiple researchers to collaboratively model the fruit fly’s entire brain by integration of their independently developed models of its constituent processing units. We demonstrate the power of Neurokernel’s model integration by combining independently developed models of the retina and lamina neuropils in the fly’s visual system and by demonstrating their neuroinformation processing capability. We also illustrate Neurokernel’s ability to take advantage of direct GPU-to-GPU data transfers with benchmarks that demonstrate scaling of Neurokernel’s communication performance both over the number of interface ports exposed by an emulation’s constituent modules and the total number of modules comprised by an emulation. PMID:26751378

Alteration of brain activation patterns in nonallergic rhinitis patients using functional magnetic resonance imaging before and after treatment with intranasal azelastine.

PubMed

Bernstein, Jonathan A; Hastings, Lloyd; Boespflug, Erin L; Allendorfer, Jane B; Lamy, Martine; Eliassen, James C

2011-06-01

Although nonallergic rhinitis (NAR) patients tend to be more sensitive to chemical/olfactory stimuli, a suprathreshold olfactory response or the presence of specific olfactory receptor genes do not explain why their symptoms are triggered by such exposures. To investigate differential neurogenic responses to azelastine in NAR patients, using functional magnetic resonance imaging (fMRI) in response to specific olfactory triggers. A longitudinal study design on 12 subjects with a physician diagnosis of NAR previously demonstrated to be clinically responsive to intranasal azelastine (Astelin) was performed. Subjects underwent fMRI during exposure to unpleasant (hickory smoke) and pleasant (vanilla) odorants while off and then on azelastine for 2 weeks. The olfactory fMRI paradigm consisted of a visually triggered sniff every 21 seconds with synchronized delivery of a 4 second pulse of odorant. Each odorant was presented 18 times over 4-6-minute fMRI runs. Continuous fresh air was presented to wash out each odorant after presentation. Nonallergic rhinitis patients exhibited increased blood flow to several regions of the brain in response to both pleasant and unpleasant odorants, specifically in odor-sensitive regions, while off intranasal azelastine. Treatment with intranasal azelastine significantly attenuated blood flow to regions of the brain relevant to either olfactory sensation or sensory processing in response to these odorants compared with fresh air. The general reduction compared with increase in brain activation in NAR patients on versus off azelastine suggests that a possible effect of this medication may be reduction of brain responses to odorants. Copyright © 2011. Published by Elsevier Inc.

Decision Utility, Incentive Salience, and Cue-Triggered “Wanting”

PubMed Central

Berridge, Kent C.; Aldridge, J. Wayne

2010-01-01

This chapter examines brain mechanisms of reward utility operating at particular decision moments in life—moments such as when one encounters an image, sound, scent, or other cue associated in the past with a particular reward or perhaps just when one vividly imagines that cue. Such a cue can often trigger a sudden motivational urge to pursue its reward and sometimes a decision to do so. Drawing on a utility taxonomy that distinguishes among subtypes of reward utility—predicted utility, decision utility, experienced utility, and remembered utility—it is shown how cue-triggered cravings, such as an addict’s surrender to relapse, can hang on special transformations by brain mesolimbic systems of one utility subtype, namely, decision utility. The chapter focuses on a particular form of decision utility called incentive salience, a type of “wanting” for rewards that is amplified by brain mesolimbic systems. Sudden peaks of intensity of incentive salience, caused by neurobiological mechanisms, can elevate the decision utility of a particular reward at the moment its cue occurs. An understanding of what happens at such moments leads to a better understanding of the mechanisms at work in decision making in general. PMID:25309963

Decision Utility, Incentive Salience, and Cue-Triggered "Wanting"

PubMed

Berridge, Kent C; Aldridge, J Wayne

2009-01-01

This chapter examines brain mechanisms of reward utility operating at particular decision moments in life-moments such as when one encounters an image, sound, scent, or other cue associated in the past with a particular reward or perhaps just when one vividly imagines that cue. Such a cue can often trigger a sudden motivational urge to pursue its reward and sometimes a decision to do so. Drawing on a utility taxonomy that distinguishes among subtypes of reward utility-predicted utility, decision utility, experienced utility, and remembered utility-it is shown how cue-triggered cravings, such as an addict's surrender to relapse, can hang on special transformations by brain mesolimbic systems of one utility subtype, namely, decision utility. The chapter focuses on a particular form of decision utility called incentive salience, a type of "wanting" for rewards that is amplified by brain mesolimbic systems. Sudden peaks of intensity of incentive salience, caused by neurobiological mechanisms, can elevate the decision utility of a particular reward at the moment its cue occurs. An understanding of what happens at such moments leads to a better understanding of the mechanisms at work in decision making in general.

Hydrogel-Tissue Chemistry: Principles and Applications.

PubMed

Gradinaru, Viviana; Treweek, Jennifer; Overton, Kristin; Deisseroth, Karl

2018-05-20

Over the past five years, a rapidly developing experimental approach has enabled high-resolution and high-content information retrieval from intact multicellular animal (metazoan) systems. New chemical and physical forms are created in the hydrogel-tissue chemistry process, and the retention and retrieval of crucial phenotypic information regarding constituent cells and molecules (and their joint interrelationships) are thereby enabled. For example, rich data sets defining both single-cell-resolution gene expression and single-cell-resolution activity during behavior can now be collected while still preserving information on three-dimensional positioning and/or brain-wide wiring of those very same neurons-even within vertebrate brains. This new approach and its variants, as applied to neuroscience, are beginning to illuminate the fundamental cellular and chemical representations of sensation, cognition, and action. More generally, reimagining metazoans as metareactants-or positionally defined three-dimensional graphs of constituent chemicals made available for ongoing functionalization, transformation, and readout-is stimulating innovation across biology and medicine.

Project Aims to Bridge Neuroscience and Schools

ERIC Educational Resources Information Center

Samuels, Christina A.

2008-01-01

Using imaging technology that can probe the deepest workings of the brain, researchers have found that children with attention deficit hyperactivity disorder are using less of a certain part of their brains to hold back their itchy trigger fingers, compared with typically developing children performing the same task. This information was shared…

Simultaneous quantitative analyses of indole and oxindole alkaloids of Uncaria Hook in rat plasma and brain after oral administration of the traditional Japanese medicine Yokukansan using high-performance liquid chromatography with tandem mass spectrometry.

PubMed

Kushida, Hirotaka; Fukutake, Miwako; Tabuchi, Masahiro; Katsuhara, Takao; Nishimura, Hiroaki; Ikarashi, Yasushi; Kanitani, Masanao; Kase, Yoshio

2013-12-01

Uncaria Hook (UH) alkaloids are involved in the beneficial effects of Yokukansan. However, the pharmacokinetics of UH alkaloids after oral administration of Yokukansan has not yet been sufficiently investigated. Therefore, we developed and validated a sensitive and specific high-performance liquid chromatography with tandem mass spectrometry (LC/MS/MS) method for the simultaneous quantitation of seven UH alkaloids (corynoxeine, isocorynoxeine, rhynchophylline, isorhynchophylline, hirsutine, hirsuteine and geissoschizine methyl ether) in rat plasma and brain. After protein precipitation with acetonitrile, chromatographic separation was performed using an Ascentis Express RP-amide column, with gradient elution with 0.2% formic acid and acetonitrile at 0.3 mL/min. All analytes in the plasma and brain showed good linearity over a wide concentration range (r > 0.995). Intra-day and inter-day variations of each constituent were 8.6 and 8.0% or less in the plasma, and 14.9 and 15.0% or less in the brain, respectively. The validated LC/MS/MS method was applied in the pharmacokinetic studies of UH alkaloids after oral administration of Yokukansan to rats. In the plasma, rhynchophylline, hirsutine, hirsuteine and geissoschizine methyl ether were detected, but only geissoschizine methyl ether was detected in the brain. These results suggest that geissoschizine methyl ether is an important constituent of the pharmacological effects of Yokukansan. Copyright © 2013 John Wiley & Sons, Ltd.

Intravascular Inflammation Triggers Intracerebral Activated Microglia and Contributes to Secondary Brain Injury After Experimental Subarachnoid Hemorrhage (eSAH).

PubMed

Atangana, Etienne; Schneider, Ulf C; Blecharz, Kinga; Magrini, Salima; Wagner, Josephin; Nieminen-Kelhä, Melina; Kremenetskaia, Irina; Heppner, Frank L; Engelhardt, Britta; Vajkoczy, Peter

2017-04-01

Activation of innate immunity contributes to secondary brain injury after experimental subarachnoid hemorrhage (eSAH). Microglia accumulation and activation within the brain has recently been shown to induce neuronal cell death after eSAH. In isolated mouse brain capillaries after eSAH, we show a significantly increased gene expression for intercellular adhesion molecule-1 (ICAM-1) and P-selectin. Hence, we hypothesized that extracerebral intravascular inflammatory processes might initiate the previously reported microglia accumulation within the brain tissue. We therefore induced eSAH in knockout mice for ICAM-1 (ICAM-1 -/- ) and P-selectin glycoprotein ligand-1 (PSGL-1 -/- ) to find a significant decrease in neutrophil-endothelial interaction within the first 7 days after the bleeding in a chronic cranial window model. This inhibition of neutrophil recruitment to the endothelium results in significantly ameliorated microglia accumulation and neuronal cell death in knockout animals in comparison to controls. Our results suggest an outside-in activation of the CNS innate immune system at the vessel/brain interface following eSAH. Microglia cells, as part of the brain's innate immune system, are triggered by an inflammatory reaction in the microvasculature after eSAH, thus contributing to neuronal cell death. This finding offers a whole range of new research targets, as well as possible therapy options for patients suffering from eSAH.

Investigating Neuromagnetic Brain Responses against Chromatic Flickering Stimuli by Wavelet Entropies

PubMed Central

Bhagat, Mayank; Bhushan, Chitresh; Saha, Goutam; Shimjo, Shinsuke; Watanabe, Katsumi; Bhattacharya, Joydeep

2009-01-01

Background Photosensitive epilepsy is a type of reflexive epilepsy triggered by various visual stimuli including colourful ones. Despite the ubiquitous presence of colorful displays, brain responses against different colour combinations are not properly studied. Methodology/Principal Findings Here, we studied the photosensitivity of the human brain against three types of chromatic flickering stimuli by recording neuromagnetic brain responses (magnetoencephalogram, MEG) from nine adult controls, an unmedicated patient, a medicated patient, and two controls age-matched with patients. Dynamical complexities of MEG signals were investigated by a family of wavelet entropies. Wavelet entropy is a newly proposed measure to characterize large scale brain responses, which quantifies the degree of order/disorder associated with a multi-frequency signal response. In particular, we found that as compared to the unmedicated patient, controls showed significantly larger wavelet entropy values. We also found that Renyi entropy is the most powerful feature for the participant classification. Finally, we also demonstrated the effect of combinational chromatic sensitivity on the underlying order/disorder in MEG signals. Conclusions/Significance Our results suggest that when perturbed by potentially epileptic-triggering stimulus, healthy human brain manages to maintain a non-deterministic, possibly nonlinear state, with high degree of disorder, but an epileptic brain represents a highly ordered state which making it prone to hyper-excitation. Further, certain colour combination was found to be more threatening than other combinations. PMID:19779630

Investigating neuromagnetic brain responses against chromatic flickering stimuli by wavelet entropies.

PubMed

Bhagat, Mayank; Bhushan, Chitresh; Saha, Goutam; Shimjo, Shinsuke; Watanabe, Katsumi; Bhattacharya, Joydeep

2009-09-25

Photosensitive epilepsy is a type of reflexive epilepsy triggered by various visual stimuli including colourful ones. Despite the ubiquitous presence of colorful displays, brain responses against different colour combinations are not properly studied. Here, we studied the photosensitivity of the human brain against three types of chromatic flickering stimuli by recording neuromagnetic brain responses (magnetoencephalogram, MEG) from nine adult controls, an unmedicated patient, a medicated patient, and two controls age-matched with patients. Dynamical complexities of MEG signals were investigated by a family of wavelet entropies. Wavelet entropy is a newly proposed measure to characterize large scale brain responses, which quantifies the degree of order/disorder associated with a multi-frequency signal response. In particular, we found that as compared to the unmedicated patient, controls showed significantly larger wavelet entropy values. We also found that Renyi entropy is the most powerful feature for the participant classification. Finally, we also demonstrated the effect of combinational chromatic sensitivity on the underlying order/disorder in MEG signals. Our results suggest that when perturbed by potentially epileptic-triggering stimulus, healthy human brain manages to maintain a non-deterministic, possibly nonlinear state, with high degree of disorder, but an epileptic brain represents a highly ordered state which making it prone to hyper-excitation. Further, certain colour combination was found to be more threatening than other combinations.

Purinergic signaling triggers endfoot high-amplitude Ca2+ signals and causes inversion of neurovascular coupling after subarachnoid hemorrhage

PubMed Central

Pappas, Anthony C; Koide, Masayo

2016-01-01

Neurovascular coupling supports brain metabolism by matching focal increases in neuronal activity with local arteriolar dilation. Previously, we demonstrated that an emergence of spontaneous endfoot high-amplitude Ca2+ signals (eHACSs) caused a pathologic shift in neurovascular coupling from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage model animals. Extracellular purine nucleotides (e.g., ATP) can trigger astrocyte Ca2+ oscillations and may be elevated following subarachnoid hemorrhage. Here, the role of purinergic signaling in subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling was examined by imaging parenchymal arteriolar diameter and astrocyte Ca2+ signals in rat brain slices using two-photon fluorescent and infrared-differential interference contrast microscopy. We report that broad-spectrum inhibition of purinergic (P2) receptors using suramin blocked eHACSs and restored vasodilatory neurovascular coupling after subarachnoid hemorrhage. Importantly, eHACSs were also abolished using a cocktail of inhibitors targeting Gq-coupled P2Y receptors. Further, activation of P2Y receptors in brain slices from un-operated animals triggered high-amplitude Ca2+ events resembling eHACSs and disrupted neurovascular coupling. Neither tetrodotoxin nor bafilomycin A1 affected eHACSs suggesting that purine nucleotides are not released by ongoing neurotransmission and/or vesicular release after subarachnoid hemorrhage. These results indicate that purinergic signaling via P2Y receptors contributes to subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling. PMID:27207166

Purinergic signaling triggers endfoot high-amplitude Ca2+ signals and causes inversion of neurovascular coupling after subarachnoid hemorrhage.

PubMed

Pappas, Anthony C; Koide, Masayo; Wellman, George C

2016-11-01

Neurovascular coupling supports brain metabolism by matching focal increases in neuronal activity with local arteriolar dilation. Previously, we demonstrated that an emergence of spontaneous endfoot high-amplitude Ca 2+ signals (eHACSs) caused a pathologic shift in neurovascular coupling from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage model animals. Extracellular purine nucleotides (e.g., ATP) can trigger astrocyte Ca 2+ oscillations and may be elevated following subarachnoid hemorrhage. Here, the role of purinergic signaling in subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling was examined by imaging parenchymal arteriolar diameter and astrocyte Ca 2+ signals in rat brain slices using two-photon fluorescent and infrared-differential interference contrast microscopy. We report that broad-spectrum inhibition of purinergic (P2) receptors using suramin blocked eHACSs and restored vasodilatory neurovascular coupling after subarachnoid hemorrhage. Importantly, eHACSs were also abolished using a cocktail of inhibitors targeting G q -coupled P2Y receptors. Further, activation of P2Y receptors in brain slices from un-operated animals triggered high-amplitude Ca 2+ events resembling eHACSs and disrupted neurovascular coupling. Neither tetrodotoxin nor bafilomycin A1 affected eHACSs suggesting that purine nucleotides are not released by ongoing neurotransmission and/or vesicular release after subarachnoid hemorrhage. These results indicate that purinergic signaling via P2Y receptors contributes to subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling. © The Author(s) 2016.

Minocycline exacerbates apoptotic neurodegeneration induced by the NMDA receptor antagonist MK-801 in the early postnatal mouse brain.

PubMed

Inta, Ioana; Vogt, Miriam A; Vogel, Anne S; Bettendorf, Markus; Gass, Peter; Inta, Dragos

2016-10-01

NMDA receptor (NMDAR) antagonists induce in perinatal rodent cortical apoptosis and protracted schizophrenia-like alterations ameliorated by antipsychotic treatment. The broad-spectrum antibiotic minocycline elicits antipsychotic and neuroprotective effects. Here we tested, if minocycline protects also against apoptosis triggered by the NMDAR antagonist MK-801 at postnatal day 7. Surprisingly, minocycline induced widespread cortical apoptosis and exacerbated MK-801-triggered cell death. In some areas such as the subiculum, the pro-apoptotic effect of minocycline was even more pronounced than that elicited by MK-801. These data reveal among antipsychotics unique pro-apoptotic properties of minocycline, raising concerns regarding consequences for brain development and the use in children.

Lowering Temperature is the Trigger for Glycogen Build-Up and Winter Fasting in Crucian Carp (Carassius carassius).

PubMed

Varis, Joonas; Haverinen, Jaakko; Vornanen, Matti

2016-02-01

Seasonal changes in physiology of vertebrate animals are triggered by environmental cues including temperature, day-length and oxygen availability. Crucian carp (Carassius carassius) tolerate prolonged anoxia in winter by using several physiological adaptations that are seasonally activated. This study examines which environmental cues are required to trigger physiological adjustments for winter dormancy in crucian carp. To this end, crucian carp were exposed to changing environmental factors under laboratory conditions: effects of declining water temperature, shortening day-length and reduced oxygen availability, separately and in different combinations, were examined on glycogen content and enzyme activities involved in feeding (alkaline phosphatase, AP) and glycogen metabolism (glycogen synthase, GyS; glycogen phosphorylase, GP). Lowering temperature induced a fall in activity of AP and a rise in glycogen content and rate of glycogen synthesis. Relative mass of the liver, and glycogen concentration of liver, muscle and brain increased with lowering temperature. Similarly activity of GyS in muscle and expression of GyS transcripts in brain were up-regulated by lowering temperature. Shortened day-length and oxygen availability had practically no effects on measured variables. We conclude that lowering temperature is the main trigger in preparation for winter anoxia in crucian carp.

[Sleep regulatory mechanisms].

PubMed

Sei, Hiroyoshi; Shimizu, Noriyuki; Kitaoka, Kazuyoshi; Chikahisa, Sachiko

2012-07-01

The fact that resting wakefulness does not satisfy the need for sleep suggests that sleep has a critical role for the brain, probably for its maintenance or repair. Neuronal oxidative stress, neuroinflammation, or energy insufficiency in the brain is now considered to be a trigger or cause for sleep induction. And the timing for sleep is controlled by circadian clock which also exists in the brain. Sleep is occurred in the brain, which is regulated by the brain itself. "Why do we sleep ?" Although everyone wants to know the answer for this issue, scientists should still question that "How do we sleep"?

Inspiring Middle School Minds: Gifted, Creative, and Challenging

ERIC Educational Resources Information Center

Willis, Judy

2009-01-01

Teaching adolescents can be quite challenging. Dr. Judy Willis, a neurologist and teacher, explains the inner workings of the adolescent brain. She uses the findings of brain research in her classroom to explain how parents and teachers can trigger untapped inspiration in students. Middle school education has often been a "black hole" for gifted…

12 Things Teachers Must Know about Learning

ERIC Educational Resources Information Center

Page, Bill

2010-01-01

When information is presented to students, it goes into the working memory of their brain. But the information quickly fades away unless something is done to trigger its move into the brain's long-term memory where it is stored and recalled later. This article offers established facts, understandings, and practices that teachers can use to help…

Constituent quarks and systematic errors in mid-rapidity charged multiplicity dN ch/dη distributions

DOE PAGES

Tannenbaum, M. J.

2018-01-10

Centrality definition in A + A collisions at colliders such as RHIC and LHC suffers from a correlated systematic uncertainty caused by the efficiency of detecting a p + p collision (50 ± 5% for PHENIX at RHIC). In A + A collisions where centrality is measured by the number of nucleon collisions, N coll, or the number of nucleon participants, N part, or the number of constituent quark participants, N qp, the error in the efficiency of the primary interaction trigger (Beam–Beam Counters) for a p + p collision leads to a correlated systematic uncertainty in N part, Nmore » coll or N qp which reduces binomially as the A + A collisions become more central. If this is not correctly accounted for in projections of A + A to p + p collisions, then mistaken conclusions can result. Finally, a recent example is presented in whether the mid-rapidity charged multiplicity per constituent quark participant d(N ch/dη)/N qp in Au + Au at RHIC was the same as the value in p + p collisions.« less

Constituent quarks and systematic errors in mid-rapidity charged multiplicity dN ch/dη distributions

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

Tannenbaum, M. J.

Centrality definition in A + A collisions at colliders such as RHIC and LHC suffers from a correlated systematic uncertainty caused by the efficiency of detecting a p + p collision (50 ± 5% for PHENIX at RHIC). In A + A collisions where centrality is measured by the number of nucleon collisions, N coll, or the number of nucleon participants, N part, or the number of constituent quark participants, N qp, the error in the efficiency of the primary interaction trigger (Beam–Beam Counters) for a p + p collision leads to a correlated systematic uncertainty in N part, Nmore » coll or N qp which reduces binomially as the A + A collisions become more central. If this is not correctly accounted for in projections of A + A to p + p collisions, then mistaken conclusions can result. Finally, a recent example is presented in whether the mid-rapidity charged multiplicity per constituent quark participant d(N ch/dη)/N qp in Au + Au at RHIC was the same as the value in p + p collisions.« less

Sequestration of latent TGF-β binding protein 1 into CADASIL-related Notch3-ECD deposits.

PubMed

Kast, Jessica; Hanecker, Patrizia; Beaufort, Nathalie; Giese, Armin; Joutel, Anne; Dichgans, Martin; Opherk, Christian; Haffner, Christof

2014-08-13

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) represents the most common hereditary form of cerebral small vessel disease characterized by early-onset stroke and premature dementia. It is caused by mutations in the transmembrane receptor Notch3, which promote the aggregation and accumulation of the Notch3 extracellular domain (Notch3-ECD) within blood vessel walls. This process is believed to mediate the abnormal recruitment and dysregulation of additional factors including extracellular matrix (ECM) proteins resulting in brain vessel dysfunction. Based on recent evidence indicating a role for the transforming growth factor-β (TGF-β) pathway in sporadic and familial small vessel disease we studied fibronectin, fibrillin-1 and latent TGF-β binding protein 1 (LTBP-1), three ECM constituents involved in the regulation of TGF-β bioavailability, in post-mortem brain tissue from CADASIL patients and control subjects. Fibronectin and fibrillin-1 were found to be enriched in CADASIL vessels without co-localizing with Notch3-ECD deposits, likely as a result of fibrotic processes secondary to aggregate formation. In contrast, LTBP-1 showed both an accumulation and a striking co-localization with Notch3-ECD deposits suggesting specific recruitment into aggregates. We also detected increased levels of the TGF-β prodomain (also known as latency-associated peptide, LAP) indicating dysregulation of the TGF-β pathway in CADASIL development. In vitro analyses revealed a direct interaction between LTBP-1 and Notch3-ECD and demonstrated a specific co-aggregation of LTBP-1 with mutant Notch3. We propose LTBP-1 as a novel component of Notch3-ECD deposits and suggest its involvement in pathological processes triggered by Notch3-ECD aggregation.

Riboflavin and migraine: the bridge over troubled mitochondria.

PubMed

Colombo, Bruno; Saraceno, Lorenzo; Comi, Giancarlo

2014-05-01

Brain energy metabolism has been found to be disturbed in migraine. A mitochondrial defect may reduce the threshold for migraine attacks both increasing neuronal excitability and leading migrainous brain to a hyper-responsiveness to triggering stimuli. Riboflavin, a major co-factor in oxidative metabolism, may overcome this impairment. RCT studies in adult confirmed that riboflavin is safe and probably effective in migraine prophylaxis, based on level B evidence. Improving brain energy metabolism may reduce the susceptibility to migraine when brain energy demand increases due to both physiological and biopsychological factors.

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.

Loss of Interneuron-Derived Collagen XIX Leads to a Reduction in Perineuronal Nets in the Mammalian Telencephalon.

PubMed

Su, Jianmin; Cole, James; Fox, Michael A

2017-02-01

Perineuronal nets (PNNs) are lattice-like supramolecular assemblies of extracellular glycoproteins that surround subsets of neuronal cell bodies in the mammalian telencephalon. PNNs emerge at the end of the critical period of brain development, limit neuronal plasticity in the adult brain, and are lost in a variety of complex brain disorders diseases, including schizophrenia. The link between PNNs and schizophrenia led us to question whether neuronally expressed extracellular matrix (ECM) molecules associated with schizophrenia contribute to the assembly of these specialized supramolecular ECM assemblies. We focused on collagen XIX-a minor, nonfibrillar collagen expressed by subsets of telencephalic interneurons. Genetic alterations in the region encoding collagen XIX have been associated with familial schizophrenia, and loss of this collagen in mice results in altered inhibitory synapses, seizures, and the acquisition of schizophrenia-related behaviors. Here, we demonstrate that loss of collagen XIX also results in a reduction of telencephalic PNNs. Loss of PNNs was accompanied with reduced levels of aggrecan (Acan), a major component of PNNs. Despite reduced levels of PNN constituents in collagen XIX-deficient mice ( col19a1 - / - ), we failed to detect reduced expression of genes encoding these ECM molecules. Instead, we discovered a widespread upregulation of extracellular proteases capable of cleaving Acan and other PNN constituents in col19a1 - / - brains. Taken together, these results suggest a mechanism by which the loss of collagen XIX speeds PNN degradation and they identify a novel mechanism by which the loss of collagen XIX may contribute to complex brain disorders.

Heterogeneous fractionation profiles of meta-analytic coactivation networks.

PubMed

Laird, Angela R; Riedel, Michael C; Okoe, Mershack; Jianu, Radu; Ray, Kimberly L; Eickhoff, Simon B; Smith, Stephen M; Fox, Peter T; Sutherland, Matthew T

2017-04-01

Computational cognitive neuroimaging approaches can be leveraged to characterize the hierarchical organization of distributed, functionally specialized networks in the human brain. To this end, we performed large-scale mining across the BrainMap database of coordinate-based activation locations from over 10,000 task-based experiments. Meta-analytic coactivation networks were identified by jointly applying independent component analysis (ICA) and meta-analytic connectivity modeling (MACM) across a wide range of model orders (i.e., d=20-300). We then iteratively computed pairwise correlation coefficients for consecutive model orders to compare spatial network topologies, ultimately yielding fractionation profiles delineating how "parent" functional brain systems decompose into constituent "child" sub-networks. Fractionation profiles differed dramatically across canonical networks: some exhibited complex and extensive fractionation into a large number of sub-networks across the full range of model orders, whereas others exhibited little to no decomposition as model order increased. Hierarchical clustering was applied to evaluate this heterogeneity, yielding three distinct groups of network fractionation profiles: high, moderate, and low fractionation. BrainMap-based functional decoding of resultant coactivation networks revealed a multi-domain association regardless of fractionation complexity. Rather than emphasize a cognitive-motor-perceptual gradient, these outcomes suggest the importance of inter-lobar connectivity in functional brain organization. We conclude that high fractionation networks are complex and comprised of many constituent sub-networks reflecting long-range, inter-lobar connectivity, particularly in fronto-parietal regions. In contrast, low fractionation networks may reflect persistent and stable networks that are more internally coherent and exhibit reduced inter-lobar communication. Copyright © 2017 Elsevier Inc. All rights reserved.

Heterogeneous fractionation profiles of meta-analytic coactivation networks

PubMed Central

Laird, Angela R.; Riedel, Michael C.; Okoe, Mershack; Jianu, Radu; Ray, Kimberly L.; Eickhoff, Simon B.; Smith, Stephen M.; Fox, Peter T.; Sutherland, Matthew T.

2017-01-01

Computational cognitive neuroimaging approaches can be leveraged to characterize the hierarchical organization of distributed, functionally specialized networks in the human brain. To this end, we performed large-scale mining across the BrainMap database of coordinate-based activation locations from over 10,000 task-based experiments. Meta-analytic coactivation networks were identified by jointly applying independent component analysis (ICA) and meta-analytic connectivity modeling (MACM) across a wide range of model orders (i.e., d = 20 to 300). We then iteratively computed pairwise correlation coefficients for consecutive model orders to compare spatial network topologies, ultimately yielding fractionation profiles delineating how “parent” functional brain systems decompose into constituent “child” sub-networks. Fractionation profiles differed dramatically across canonical networks: some exhibited complex and extensive fractionation into a large number of sub-networks across the full range of model orders, whereas others exhibited little to no decomposition as model order increased. Hierarchical clustering was applied to evaluate this heterogeneity, yielding three distinct groups of network fractionation profiles: high, moderate, and low fractionation. BrainMap-based functional decoding of resultant coactivation networks revealed a multi-domain association regardless of fractionation complexity. Rather than emphasize a cognitive-motor-perceptual gradient, these outcomes suggest the importance of inter-lobar connectivity in functional brain organization. We conclude that high fractionation networks are complex and comprised of many constituent sub-networks reflecting long-range, inter-lobar connectivity, particularly in fronto-parietal regions. In contrast, low fractionation networks may reflect persistent and stable networks that are more internally coherent and exhibit reduced inter-lobar communication. PMID:28222386

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia.

PubMed

Nakagawa, Yutaka; Chiba, Kenji

2016-09-01

Development of social cognition, a unique and high-order function, depends on brain maturation from childhood to adulthood in humans. Autism spectrum disorder (ASD) and schizophrenia have similar social cognitive deficits, although age of onset in each disorder is different. Pathogenesis of these disorders is complex and contains several features, including genetic risk factors, environmental risk factors, and sites of abnormalities in the brain. Although several hypotheses have been postulated, they seem to be insufficient to explain how brain alterations associated with symptoms in these disorders develop at distinct developmental stages. Development of ASD appears to be related to cerebellar dysfunction and subsequent thalamic hyperactivation in early childhood. By contrast, schizophrenia seems to be triggered by thalamic hyperactivation in late adolescence, whereas hippocampal aberration has been possibly initiated in childhood. One of the possible culprits is metal homeostasis disturbances that can induce dysfunction of blood-cerebrospinal fluid barrier. Thalamic hyperactivation is thought to be induced by microglia-mediated neuroinflammation and abnormalities of intracerebral environment. Consequently, it is likely that the thalamic hyperactivation triggers dysregulation of the dorsolateral prefrontal cortex for lower brain regions related to social cognition. In this review, we summarize the brain aberration in ASD and schizophrenia and provide a possible mechanism underlying social cognitive deficits in these disorders based on their distinct ages of onset. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Reward-based hypertension control by a synthetic brain-dopamine interface.

PubMed

Rössger, Katrin; Charpin-El Hamri, Ghislaine; Fussenegger, Martin

2013-11-05

Synthetic biology has significantly advanced the design of synthetic trigger-controlled devices that can reprogram mammalian cells to interface with complex metabolic activities. In the brain, the neurotransmitter dopamine coordinates communication with target neurons via a set of dopamine receptors that control behavior associated with reward-driven learning. This dopamine transmission has recently been suggested to increase central sympathetic outflow, resulting in plasma dopamine levels that correlate with corresponding brain activities. By functionally rewiring the human dopamine receptor D1 (DRD1) via the second messenger cyclic adenosine monophosphate (cAMP) to synthetic promoters containing cAMP response element-binding protein 1(CREB1)-specific cAMP-responsive operator modules, we have designed a synthetic dopamine-sensitive transcription controller that reversibly fine-tunes specific target gene expression at physiologically relevant brain-derived plasma dopamine levels. Following implantation of circuit-transgenic human cell lines insulated by semipermeable immunoprotective microcontainers into mice, the designer device interfaced with dopamine-specific brain activities and produced a systemic expression response when the animal's reward system was stimulated by food, sexual arousal, or addictive drugs. Reward-triggered brain activities were able to remotely program peripheral therapeutic implants to produce sufficient amounts of the atrial natriuretic peptide, which reduced the blood pressure of hypertensive mice to the normal physiologic range. Seamless control of therapeutic transgenes by subconscious behavior may provide opportunities for treatment strategies of the future.

Atypical Brain Responses to Reward Cues in Autism as Revealed by Event-Related Potentials

ERIC Educational Resources Information Center

Kohls, Gregor; Peltzer, Judith; Schulte-Ruther, Martin; Kamp-Becker, Inge; Remschmidt, Helmut; Herpertz-Dahlmann, Beate; Konrad, Kerstin

2011-01-01

Social motivation deficit theories suggest that children with autism do not properly anticipate and appreciate the pleasure of social stimuli. In this study, we investigated event-related brain potentials evoked by cues that triggered social versus monetary reward anticipation in children with autism. Children with autism showed attenuated P3…

Mitochondrial dysfunction as a trigger of innate immune responses and inflammation.

PubMed

West, A Phillip

2017-11-01

A growing literature indicates that mitochondria are key participants in innate immune pathways, functioning as both signaling platforms and contributing to effector responses. In addition to regulating antiviral signaling and antibacterial immunity, mitochondria are also important drivers of inflammation caused by sterile injury. Much research on mitochondrial control of immunity now centers on understanding how mitochondrial constituents released during cellular damage simulate the innate immune system. When mitochondrial integrity is compromised, mitochondrial damage-associated molecular patterns engage pattern recognition receptors, trigger inflammation, and promote pathology in an expanding list of diseases. Here, I review the emerging knowledge of mitochondrial dysfunction in innate immune responses and discuss how environmental exposures may induce mitochondrial damage to potentiate inflammation and human disease. Copyright © 2017 Elsevier B.V. All rights reserved.

The inhibition of the mammalian DNA methyltransferase 3a (Dnmt3a) by dietary black tea and coffee polyphenols

PubMed Central

2011-01-01

Background Black tea is, second only to water, the most consumed beverage globally. Previously, the inhibition of DNA methyltransferase 1 was shown by dietary polyphenols and epi-gallocatechin gallate (EGCG), the main polyphenolic constituent of green tea, and 5-caffeoyl quinic acid, the main phenolic constituent of the green coffee bean. Results We studied the inhibition of DNA methyltransferase 3a by a series of dietary polyphenols from black tea such as theaflavins and thearubigins and chlorogenic acid derivatives from coffee. For theaflavin 3,3 digallate and thearubigins IC50 values in the lower micro molar range were observed, which when compared to pharmacokinetic data available, suggest an effect of physiological relevance. Conclusions Since Dnnmt3a has been associated with development, cancer and brain function, these data suggest a biochemical mechanism for the beneficial health effect of black tea and coffee and a possible molecular mechanism for the improvement of brain performance and mental health by dietary polyphenols. PMID:21510884

Effects of chocolate on cognitive function and mood: a systematic review.

PubMed

Scholey, Andrew; Owen, Lauren

2013-10-01

A systematic review was conducted to evaluate whether chocolate or its constituents were capable of influencing cognitive function and/or mood. Studies investigating potentially psychoactive fractions of chocolate were also included. Eight studies (in six articles) met the inclusion criteria for assessment of chocolate or its components on mood, of which five showed either an improvement in mood state or an attenuation of negative mood. Regarding cognitive function, eight studies (in six articles) met the criteria for inclusion, of which three revealed clear evidence of cognitive enhancement (following cocoa flavanols and methylxanthine). Two studies failed to demonstrate behavioral benefits but did identify significant alterations in brain activation patterns. It is unclear whether the effects of chocolate on mood are due to the orosensory characteristics of chocolate or to the pharmacological actions of chocolate constituents. Two studies have reported acute cognitive effects of supplementation with cocoa polyphenols. Further exploration of the effect of chocolate on cognitive facilitation is recommended, along with substantiation of functional brain changes associated with the components of cocoa.

Exploration of use of SenseCam to support autobiographical memory retrieval within a cognitive-behavioural therapeutic intervention following acquired brain injury.

PubMed

Brindley, Rob; Bateman, Andrew; Gracey, Fergus

2011-10-01

Delivering effective psychotherapy to address the significant emotional consequences of acquired brain injury (ABI) is challenged by the presence of acquired cognitive impairments, especially retrieval of detailed autobiographical memories of emotional trigger events. Initial studies using a wearable camera (SenseCam) suggest long-term improvements in autobiographical retrieval of recorded events. In this study a single-case experimental design was implemented to explore the use of SenseCam as a memory aid for a man with a specific anxiety disorder and memory and executive difficulties following ABI. We predicted that SenseCam supported rehearsal of memories of events that trigger high levels of anxiety would yield improved retrieval of both factual detail and internal state information (thoughts and feelings) compared with a conventional psychotherapy aid (automatic thought record sheets, ATRs) and no strategy. The findings indicated SenseCam supported retrieval of anxiety trigger events was superior to ATRs or no strategy in terms of both detail and internal state information, with 94% of the information being recalled in the SenseCam condition, compared to 39% for the "no strategy" and 22% for the ATR conditions. It is concluded that SenseCam may be of use as a compensatory aid in psychotherapies relying on retrieval of emotionally salient trigger events.

Is a subtype of autism an allergy of the brain?

PubMed

Theoharides, Theoharis C

2013-05-01

Autism spectrum disorders (ASDs) are characterized by deficits in social communication and language and the presence of repetitive behaviors that affect as many as 1 in 50 US children. Perinatal stress and environmental factors appear to play a significant role in increasing the risk for ASDs. There is no definitive pathogenesis, which therefore significantly hinders the development of a cure. We aimed to identify publications using basic or clinical data that suggest a possible association between atopic symptoms and ASDs, as well as evidence of how such an association could lead to brain disease, that may explain the pathogenesis of ASD. PubMed was searched for articles published since 1995 that reported any association between autism and/or ASDs and any one of the following terms: allergy, atopy, brain, corticotropin-releasing hormone, cytokines, eczema, food allergy, food intolerance, gene mutation, inflammation, mast cells, mitochondria, neurotensin, phenotype, stress, subtype, or treatment. Children with ASD respond disproportionally to stress and also present with food and skin allergies that involve mast cells. Brain mast cells are found primarily in the hypothalamus, which participates in the regulation of behavior and language. Corticotropin-releasing hormone is secreted from the hypothalamus under stress and, together with neurotensin, stimulates brain mast cells that could result in focal brain allergy and neurotoxicity. Neurotensin is significantly increased in serum of children with ASD and stimulates mast cell secretion of mitochondrial adenosine triphosphate and DNA, which is increased in these children; these mitochondrial components are misconstrued as innate pathogens, triggering an autoallergic response in the brain. Gene mutations associated with higher risk of ASD have been linked to reduction of the phosphatase and tensin homolog, which inhibits the mammalian target of rapamycin (mTOR). These same mutations also lead to mast cell activation and proliferation. Corticotropin-releasing hormone, neurotensin, and environmental toxins could further trigger the already activated mTOR, leading to superstimulation of brain mast cells in those areas responsible for ASD symptoms. Preliminary evidence indicates that the flavonoid luteolin is a stronger inhibitor of mTOR than rapamycin and is a potent mast cell blocker. Activation of brain mast cells by allergic, environmental, immune, neurohormonal, stress, and toxic triggers, especially in those areas associated with behavior and language, lead to focal brain allergies and subsequent focal encephalitis. This possibility is more likely in the subgroup of patients with ASD susceptibility genes that also involve mast cell activation. Copyright © 2013 Elsevier HS Journals, Inc. All rights reserved.

Unlocking the Secrets of Brain Signals (4K)

ScienceCinema

None

2018-06-21

Scientists have for the first time determined, at atomic-scale resolution, the 3-D structure of a protein complex that provides the ultrafast trigger for chemicals messages sent between nerve cells in our brains. The discovery, which provides a new understanding of the molecular machinery driving brain function, builds on decades of research at Stanford University, the Stanford School of Medicine and SLAC National Accelerator Laboratory was made possible by SLAC’s Linac Coherent Light Source, an ultrabright X-ray laser.

Unlocking the Secrets of Brain Signals (4K)

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

None

2015-08-17

Scientists have for the first time determined, at atomic-scale resolution, the 3-D structure of a protein complex that provides the ultrafast trigger for chemicals messages sent between nerve cells in our brains. The discovery, which provides a new understanding of the molecular machinery driving brain function, builds on decades of research at Stanford University, the Stanford School of Medicine and SLAC National Accelerator Laboratory was made possible by SLAC’s Linac Coherent Light Source, an ultrabright X-ray laser.

Multiple target laser ablation system

DOEpatents

Mashburn, Douglas N.

1996-01-01

A laser ablation apparatus and method are provided in which multiple targets consisting of material to be ablated are mounted on a movable support. The material transfer rate is determined for each target material, and these rates are stored in a controller. A position detector determines which target material is in a position to be ablated, and then the controller controls the beam trigger timing and energy level to achieve a desired proportion of each constituent material in the resulting film.

Liquid chromatographic determination of minocycline in brain-to-plasma distribution studies in the rat.

PubMed

Colovic, Milena; Caccia, Silvio

2003-07-05

An isocratic reversed-phase high-performance liquid chromatographic procedure was developed for the determination of minocycline in rat plasma and brain and applied to brain-to-blood (plasma) distribution studies. The procedure is based on isolation of the compound and the internal standard (either demeclocycline or tetracycline may be used) from plasma and brain constituents using the Oasis HLB cartridge, with satisfactory recovery and specificity, and separation on a Symmetry Shield RP8 (15 cm x 4.6 mm, 3.5 microm) column coupled with a UV detector set at 350 nm. The assay was linear over a wide range, with a lower limit of quantification of 50 ng ml(-1) or g(-1), using 0.2 ml of plasma and about 200 mg of brain tissue. Precision and accuracy were acceptable. In the rat minocycline crossed the blood-brain barrier slowly, achieving mean brain concentrations between 30 and 40% of the equivalent systemic exposure, regardless of the dose and route of administration.

The Association of Specific Constituents of the Fecal Microbiota with Immune-Mediated Brain Disease in Dogs

PubMed Central

Jeffery, Nick D.; Barker, Andrew K.; Alcott, Cody J.; Levine, Jon M.; Meren, Ilyssa; Wengert, Jane; Jergens, Albert E.; Suchodolski, Jan S.

2017-01-01

Meningoencephalomyelitis of unknown origin (MUO) is a common, naturally-occurring, clinical disease of pet dogs. It is an immune-mediated condition that has many similarities with experimental autoimmune encephalitis (EAE) in rodents and so investigation of its pathogenesis may aid in understanding factors that contribute to development of multiple sclerosis in people. Gut microbiota are known to modulate immune responses that influence susceptibility to immune-mediated brain disease. In this study we aimed to compare abundance of specific constituents of the fecal microbiota, namely Faecalibacterium prausnitzii and Prevotellaceae, between dogs diagnosed with MUO and matched controls. Fecal samples were obtained from 20 dogs diagnosed with MUO and 20 control dogs matched for breed, age and gender. Bacterial abundance was measured using qPCR and 16S rRNA sequencing. We found that Prevotellaceae were significantly less abundant in cases compared with controls (p = 0.003) but there was no difference in abundance of F.prausnitzii. There was no evidence of other differences in gut microbiota between groups. These data, derived from this naturally-occurring canine clinical model, provide strong corroborative evidence that high abundance of Prevotellaceae in the gut is associated with reduced risk for developing immune-mediated brain disease. PMID:28125651

The Association of Specific Constituents of the Fecal Microbiota with Immune-Mediated Brain Disease in Dogs.

PubMed

Jeffery, Nick D; Barker, Andrew K; Alcott, Cody J; Levine, Jon M; Meren, Ilyssa; Wengert, Jane; Jergens, Albert E; Suchodolski, Jan S

2017-01-01

Meningoencephalomyelitis of unknown origin (MUO) is a common, naturally-occurring, clinical disease of pet dogs. It is an immune-mediated condition that has many similarities with experimental autoimmune encephalitis (EAE) in rodents and so investigation of its pathogenesis may aid in understanding factors that contribute to development of multiple sclerosis in people. Gut microbiota are known to modulate immune responses that influence susceptibility to immune-mediated brain disease. In this study we aimed to compare abundance of specific constituents of the fecal microbiota, namely Faecalibacterium prausnitzii and Prevotellaceae, between dogs diagnosed with MUO and matched controls. Fecal samples were obtained from 20 dogs diagnosed with MUO and 20 control dogs matched for breed, age and gender. Bacterial abundance was measured using qPCR and 16S rRNA sequencing. We found that Prevotellaceae were significantly less abundant in cases compared with controls (p = 0.003) but there was no difference in abundance of F.prausnitzii. There was no evidence of other differences in gut microbiota between groups. These data, derived from this naturally-occurring canine clinical model, provide strong corroborative evidence that high abundance of Prevotellaceae in the gut is associated with reduced risk for developing immune-mediated brain disease.

Biological Effects of Electromagnetic Fields

DTIC Science & Technology

2006-11-27

cerebral activity reflected by high levels of c-Fos- positive neurons in certain brain areas (14). The brain tissue of seizure proneness can be...radiation triggers seizures and increases cerebral c-Fos positivity in rats pretreated with subconvulsive doses of...psychiatric, cardiovascular or neurological diseases); or have a cardiac or cerebral pacemaker. They have no history of head, eye or thorax injury involving

Focal brain inflammation and autism.

PubMed

Theoharides, Theoharis C; Asadi, Shahrzad; Patel, Arti B

2013-04-09

Increasing evidence indicates that brain inflammation is involved in the pathogenesis of neuropsychiatric diseases. Autism spectrum disorders (ASD) are characterized by social and learning disabilities that affect as many as 1/80 children in the USA. There is still no definitive pathogenesis or reliable biomarkers for ASD, thus significantly curtailing the development of effective therapies. Many children with ASD regress at about age 3 years, often after a specific event such as reaction to vaccination, infection, stress or trauma implying some epigenetic triggers, and may constitute a distinct phenotype. ASD children respond disproportionally to stress and are also affected by food and skin allergies. Corticotropin-releasing hormone (CRH) is secreted under stress and together with neurotensin (NT) stimulates mast cells and microglia resulting in focal brain inflammation and neurotoxicity. NT is significantly increased in serum of ASD children along with mitochondrial DNA (mtDNA). NT stimulates mast cell secretion of mtDNA that is misconstrued as an innate pathogen triggering an auto-inflammatory response. The phosphatase and tensin homolog (PTEN) gene mutation, associated with the higher risk of ASD, which leads to hyper-active mammalian target of rapamycin (mTOR) signalling that is crucial for cellular homeostasis. CRH, NT and environmental triggers could hyperstimulate the already activated mTOR, as well as stimulate mast cell and microglia activation and proliferation. The natural flavonoid luteolin inhibits mTOR, mast cells and microglia and could have a significant benefit in ASD.

Act quickly, decide later: long-latency visual processing underlies perceptual decisions but not reflexive behavior.

PubMed

Jolij, Jacob; Scholte, H Steven; van Gaal, Simon; Hodgson, Timothy L; Lamme, Victor A F

2011-12-01

Humans largely guide their behavior by their visual representation of the world. Recent studies have shown that visual information can trigger behavior within 150 msec, suggesting that visually guided responses to external events, in fact, precede conscious awareness of those events. However, is such a view correct? By using a texture discrimination task, we show that the brain relies on long-latency visual processing in order to guide perceptual decisions. Decreasing stimulus saliency leads to selective changes in long-latency visually evoked potential components reflecting scene segmentation. These latency changes are accompanied by almost equal changes in simple RTs and points of subjective simultaneity. Furthermore, we find a strong correlation between individual RTs and the latencies of scene segmentation related components in the visually evoked potentials, showing that the processes underlying these late brain potentials are critical in triggering a response. However, using the same texture stimuli in an antisaccade task, we found that reflexive, but erroneous, prosaccades, but not antisaccades, can be triggered by earlier visual processes. In other words: The brain can act quickly, but decides late. Differences between our study and earlier findings suggesting that action precedes conscious awareness can be explained by assuming that task demands determine whether a fast and unconscious, or a slower and conscious, representation is used to initiate a visually guided response.

A young infant with musicogenic epilepsy.

PubMed

Lin, Kuang-Lin; Wang, Huei-Shyong; Kao, Pan-Fu

2003-05-01

Musicogenic epilepsy is a relatively rare form of epilepsy. In its pure form, it is characterized by epileptic seizures that are provoked exclusively by listening to music. The usual type of seizure is partial complex or generalized tonic-clonic. Precipitating factors are quite specific, such as listening to only one composition or the actual playing of music on an instrument. However, simple sound also can be a trigger. We report a 6-month-old infant with musicogenic epilepsy. She manifested right-sided focal seizures with occasional generalization. The seizures were frequently triggered by loud music, especially that by the Beatles. The interictal electroencephalography results were normal. Ictal spikes were present throughout the left temporal area during continuous electroencephalograpic monitoring. Brain magnetic resonance imaging results were normal, whereas single-photon emission computed tomography of the brain revealed hypoperfusion of the left temporal area. The young age and epileptogenic left temporal lobe lesion in this patient with musicogenic epilepsy were unusual characteristics. Theoretically, three levels of integration are involved in music processing in the brain. The involved integration of this infant's brain may be the sensory level rather than the emotional level. Nevertheless, the personal musicality and musical style of the Beatles might play an important role in this patient's epilepsy.

Dynamic range in the C. elegans brain network

NASA Astrophysics Data System (ADS)

Antonopoulos, Chris G.

2016-01-01

We study external electrical perturbations and their responses in the brain dynamic network of the Caenorhabditis elegans soil worm, given by the connectome of its large somatic nervous system. Our analysis is inspired by a realistic experiment where one stimulates externally specific parts of the brain and studies the persistent neural activity triggered in other cortical regions. In this work, we perturb groups of neurons that form communities, identified by the walktrap community detection method, by trains of stereotypical electrical Poissonian impulses and study the propagation of neural activity to other communities by measuring the corresponding dynamic ranges and Steven law exponents. We show that when one perturbs specific communities, keeping the rest unperturbed, the external stimulations are able to propagate to some of them but not to all. There are also perturbations that do not trigger any response. We found that this depends on the initially perturbed community. Finally, we relate our findings for the former cases with low neural synchronization, self-criticality, and large information flow capacity, and interpret them as the ability of the brain network to respond to external perturbations when it works at criticality and its information flow capacity becomes maximal.

Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway

PubMed Central

Das, Utpal; Scott, David; Ganguly, Archan; Koo, Edward H.; Tang, Yong; Roy, Subhojit

2013-01-01

The convergence of APP (substrate) and BACE-1 (enzyme) is a rate-limiting, obligatory event triggering the amyloidogenic pathway – a key step in Alzheimer’s disease (AD) pathology. However, as both APP/BACE-1 are highly expressed in brain, mechanisms precluding their unabated convergence are unclear. Exploring dynamic localization of APP/BACE-1 in cultured hippocampal neurons, we found that after synthesis via the secretory-pathway, dendritic APP/BACE-1-containing vesicles are largely segregated in physiologic states. While BACE-1 is largely sorted into acidic recycling endosomes, APP is conveyed in Golgi-derived vesicles. However upon activity-induction – a known trigger of the amyloidogenic pathway – APP is routed into BACE-1-positive recycling endosomes via a clathrin-dependent mechanism. A partitioning/convergence of APP/BACE-1 vesicles is also apparent in control/AD brains respectively. Considering BACE-1 is optimally active in an acidic environment, our experiments suggest that neurons have evolved trafficking strategies that normally limit APP/BACE-1 proximity; and also uncover a pathway routing APP into BACE-1-containing organelles – triggering amyloidogenesis. PMID:23931995

Protective Effects of Crocus Sativus L. Extract and Crocin against Chronic-Stress Induced Oxidative Damage of Brain, Liver and Kidneys in Rats

PubMed Central

Bandegi, Ahmad Reza; Rashidy-Pour, Ali; Vafaei, Abbas Ali; Ghadrdoost, Behshid

2014-01-01

Purpose: Chronic stress has been reported to induce oxidative damage of the brain. A few studies have shown that Crocus Sativus L., commonly known as saffron and its active constituent crocin may have a protective effect against oxidative stress. The present work was designed to study the protective effects of saffron extract and crocin on chronic – stress induced oxidative stress damage of the brain, liver and kidneys. Methods: Rats were injected with a daily dose of saffron extract (30 mg/kg, IP) or crocin (30 mg/kg, IP) during a period of 21 days following chronic restraint stress (6 h/day). In order to determine the changes of the oxidative stress parameters following chronic stress, the levels of the lipid peroxidation product, malondialdehyde (MDA), the total antioxidant reactivity (TAR), as well as antioxidant enzyme activities glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD) were measured in the brain, liver and kidneys tissues after the end of chronic stress. Results: In the stressed animals that receiving of saline, levels of MDA, and the activities of GPx, GR, and SOD were significantly higher (P<0.0001) and the TAR capacity were significantly lower than those of the non-stressed animals (P<0.0001). Both saffron extract and crocin were able to reverse these changes in the stressed animals as compared with the control groups (P<0.05). Conclusion: These observations indicate that saffron and its active constituent crocin can prevent chronic stress–induced oxidative stress damage of the brain, liver and kidneys and suggest that these substances may be useful against oxidative stress. PMID:25671180

Lipopolysaccharide hyporesponsiveness: protective or damaging response to the brain?

PubMed

Pardon, Marie Christine

2015-01-01

Lipopolysaccharide (LPS) endotoxins are widely used as experimental models of systemic bacterial infection and trigger robust inflammation by potently activating toll-like receptors 4 (TLR4) expressed on innate immune cells. Their ability to trigger robust neuroinflammation despite poor brain penetration can prove useful for the understanding of how inflammation induced by viral infections contributes to the pathogenesis of neurodegenerative diseases. A single LPS challenge often result in a blunted inflammatory response to subsequent stimulation by LPS and other TLR ligands, but the extent to which endotoxin tolerance occur in the brain requires further clarification. LPS is also thought to render the brain transiently resistant to subsequent brain injuries by attenuating the concomitant pro-inflammatory response. While LPS hyporesponsiveness and preconditioning are classically seen as protective mechanisms limiting the toxic effects of sustained inflammation, recent research casts doubt as to whether they have beneficial or detrimental roles on the brain and in neurodegenerative disease. These observations suggest that spatio-temporal aspects of the immune responses to LPS and the disease status are determinant factors. Endotoxin tolerance may lead to a late pro-inflammatory response with potential harmful consequences. And while reduced TLR4 signaling reduces the risk of neurodegenerative diseases, up-regulation of anti-inflammatory cytokines associated with LPS hyporesponsiveness can have deleterious consequences to the brain by inhibiting the protective phenotype of microglia, aggravating the progression of some neurodegenerative conditions such as Alzheimer's disease. Beneficial effects of LPS preconditioning, however appear to require a stimulation of anti-inflammatory mediators rather than an attenuation of the pro-inflammatory response.

Single-neuron identification of chemical constituents, physiological changes, and metabolism using mass spectrometry.

PubMed

Zhu, Hongying; Zou, Guichang; Wang, Ning; Zhuang, Meihui; Xiong, Wei; Huang, Guangming

2017-03-07

The use of single-cell assays has emerged as a cutting-edge technique during the past decade. Although single-cell mass spectrometry (MS) has recently achieved remarkable results, deep biological insights have not yet been obtained, probably because of various technical issues, including the unavoidable use of matrices, the inability to maintain cell viability, low throughput because of sample pretreatment, and the lack of recordings of cell physiological activities from the same cell. In this study, we describe a patch clamp/MS-based platform that enables the sensitive, rapid, and in situ chemical profiling of single living neurons. This approach integrates modified patch clamp technique and modified MS measurements to directly collect and detect nanoliter-scale samples from the cytoplasm of single neurons in mice brain slices. Abundant possible cytoplasmic constituents were detected in a single neuron at a relatively fast rate, and over 50 metabolites were identified in this study. The advantages of direct, rapid, and in situ sampling and analysis enabled us to measure the biological activities of the cytoplasmic constituents in a single neuron, including comparing neuron types by cytoplasmic chemical constituents; observing changes in constituent concentrations as the physiological conditions, such as age, vary; and identifying the metabolic pathways of small molecules.

Single-neuron identification of chemical constituents, physiological changes, and metabolism using mass spectrometry

PubMed Central

Zhu, Hongying; Zou, Guichang; Wang, Ning; Zhuang, Meihui; Xiong, Wei; Huang, Guangming

2017-01-01

The use of single-cell assays has emerged as a cutting-edge technique during the past decade. Although single-cell mass spectrometry (MS) has recently achieved remarkable results, deep biological insights have not yet been obtained, probably because of various technical issues, including the unavoidable use of matrices, the inability to maintain cell viability, low throughput because of sample pretreatment, and the lack of recordings of cell physiological activities from the same cell. In this study, we describe a patch clamp/MS-based platform that enables the sensitive, rapid, and in situ chemical profiling of single living neurons. This approach integrates modified patch clamp technique and modified MS measurements to directly collect and detect nanoliter-scale samples from the cytoplasm of single neurons in mice brain slices. Abundant possible cytoplasmic constituents were detected in a single neuron at a relatively fast rate, and over 50 metabolites were identified in this study. The advantages of direct, rapid, and in situ sampling and analysis enabled us to measure the biological activities of the cytoplasmic constituents in a single neuron, including comparing neuron types by cytoplasmic chemical constituents; observing changes in constituent concentrations as the physiological conditions, such as age, vary; and identifying the metabolic pathways of small molecules. PMID:28223513

Reward-related brain response and craving correlates of marijuana cue exposure: a preliminary study in treatment-seeking marijuana-dependent subjects.

PubMed

Goldman, Marina; Szucs-Reed, Regina P; Jagannathan, Kanchana; Ehrman, Ronald N; Wang, Ze; Li, Yin; Suh, Jesse J; Kampman, Kyle; O'Brien, Charles P; Childress, Anna Rose; Franklin, Teresa R

2013-01-01

: Determining the brain substrates underlying the motivation to abuse addictive drugs is critical for understanding and treating addictive disorders. Laboratory neuroimaging studies have demonstrated differential activation of limbic and motivational circuitry (eg, amygdala, hippocampus, ventral striatum, insula, and orbitofrontal cortex) triggered by cocaine, heroin, nicotine, and alcohol cues. The literature on neural responses to marijuana cues is sparse. Thus, the goals of this study were to characterize the brain's response to marijuana cues, a major motivator underlying drug use and relapse, and determine whether these responses are linked to self-reported craving in a clinically relevant population of treatment-seeking marijuana-dependent subjects. : Marijuana craving was assessed in 12 marijuana-dependent subjects using the Marijuana Craving Questionnaire-Short Form. Subsequently, blood oxygen level dependent functional magnetic resonance imaging data were acquired during exposure to alternating 20-second blocks of marijuana-related versus matched nondrug visual cues. : Brain activation during marijuana cue exposure was significantly greater in the bilateral amygdala and the hippocampus. Significant positive correlations between craving scores and brain activation were found in the ventral striatum and the medial and lateral orbitofrontal cortex (P < 0.0001). : This study presents direct evidence for a link between reward-relevant brain responses to marijuana cues and craving and extends the current literature on marijuana cue reactivity. Furthermore, the correlative relationship between craving and brain activity in reward-related regions was observed in a clinically relevant sample (treatment-seeking marijuana-dependent subjects). Results are consistent with prior findings in cocaine, heroin, nicotine, and alcohol cue studies, indicating that the brain substrates of cue-triggered drug motivation are shared across abused substances.

EEG (Electroencephalogram)

MedlinePlus

... in diagnosing brain disorders, especially epilepsy or another seizure disorder. An EEG might also be helpful for diagnosing ... Sometimes seizures are intentionally triggered in people with epilepsy during the test, but appropriate medical care is ...

Autophagy Constitutes a Protective Mechanism against Ethanol Toxicity in Mouse Astrocytes and Neurons.

PubMed

Pla, Antoni; Pascual, María; Guerri, Consuelo

2016-01-01

Ethanol induces brain damage and neurodegeneration by triggering inflammatory processes in glial cells through activation of Toll-like receptor 4 (TLR4) signaling. Recent evidence indicates the role of protein degradation pathways in neurodegeneration and alcoholic liver disease, but how these processes affect the brain remains elusive. We have demonstrated that chronic ethanol consumption impairs proteolytic pathways in mouse brain, and the immune response mediated by TLR4 receptors participates in these dysfunctions. We evaluate the in vitro effects of an acute ethanol dose on the autophagy-lysosome pathway (ALP) on WT and TLR4-/- mouse astrocytes and neurons in primary culture, and how these changes affect cell survival. Our results show that ethanol induces overexpression of several autophagy markers (ATG12, LC3-II, CTSB), and increases the number of lysosomes in WT astrocytes, effects accompanied by a basification of lysosomal pH and by lowered phosphorylation levels of autophagy inhibitor mTOR, along with activation of complexes beclin-1 and ULK1. Notably, we found only minor changes between control and ethanol-treated TLR4-/- mouse astroglial cells. Ethanol also triggers the expression of the inflammatory mediators iNOS and COX-2, but induces astroglial death only slightly. Blocking autophagy by using specific inhibitors increases both inflammation and cell death. Conversely, in neurons, ethanol down-regulates the autophagy pathway and triggers cell death, which is partially recovered by using autophagy enhancers. These results support the protective role of the ALP against ethanol-induced astroglial cell damage in a TLR4-dependent manner, and provide new insight into the mechanisms that underlie ethanol-induced brain damage and are neuronal sensitive to the ethanol effects.

Early phytocannabinoid chemistry to endocannabinoids and beyond.

PubMed

Mechoulam, Raphael; Hanuš, Lumír O; Pertwee, Roger; Howlett, Allyn C

2014-11-01

Isolation and structure elucidation of most of the major cannabinoid constituents--including Δ(9)-tetrahydrocannabinol (Δ(9)-THC), which is the principal psychoactive molecule in Cannabis sativa--was achieved in the 1960s and 1970s. It was followed by the identification of two cannabinoid receptors in the 1980s and the early 1990s and by the identification of the endocannabinoids shortly thereafter. There have since been considerable advances in our understanding of the endocannabinoid system and its function in the brain, which reveal potential therapeutic targets for a wide range of brain disorders.

Multiple target laser ablation system

DOEpatents

Mashburn, D.N.

1996-01-09

A laser ablation apparatus and method are provided in which multiple targets consisting of material to be ablated are mounted on a movable support. The material transfer rate is determined for each target material, and these rates are stored in a controller. A position detector determines which target material is in a position to be ablated, and then the controller controls the beam trigger timing and energy level to achieve a desired proportion of each constituent material in the resulting film. 3 figs.

Changes in blood flow and cellular metabolism at a myofascial trigger point with trigger point release (ischemic compression): a proof-of-principle pilot study

PubMed Central

Moraska, Albert F.; Hickner, Robert C.; Kohrt, Wendy M.; Brewer, Alan

2012-01-01

Objective To demonstrate proof-of-principle measurement for physiological change within an active myofascial trigger point (MTrP) undergoing trigger point release (ischemic compression). Design Interstitial fluid was sampled continuously at a trigger point before and after intervention. Setting A biomedical research clinic at a university hospital. Participants Two subjects from a pain clinic presenting with chronic headache pain. Interventions A single microdialysis catheter was inserted into an active MTrP of the upper trapezius to allow for continuous sampling of interstitial fluid before and after application of trigger point therapy by a massage therapist. Main Outcome Measures Procedural success, pain tolerance, feasibility of intervention during sample collection, determination of physiologically relevant values for local blood flow, as well as glucose and lactate concentrations. Results Both patients tolerated the microdialysis probe insertion into the MTrP and treatment intervention without complication. Glucose and lactate concentrations were measured in the physiological range. Following intervention, a sustained increase in lactate was noted for both subjects. Conclusions Identifying physiological constituents of MTrP’s following intervention is an important step toward understanding pathophysiology and resolution of myofascial pain. The present study forwards that aim by showing proof-of-concept for collection of interstitial fluid from an MTrP before and after intervention can be accomplished using microdialysis, thus providing methodological insight toward treatment mechanism and pain resolution. Of the biomarkers measured in this study, lactate may be the most relevant for detection and treatment of abnormalities in the MTrP. PMID:22975226

Why do bacteria divide?

PubMed Central

Norris, Vic

2015-01-01

The problem of not only how but also why cells divide can be tackled using recent ideas. One idea from the origins of life – Life as independent of its constituents – is that a living entity like a cell is a particular pattern of connectivity between its constituents. This means that if the growing cell were just to get bigger the average connectivity between its constituents per unit mass – its cellular connectivity – would decrease and the cell would lose its identity. The solution is division which restores connectivity. The corollary is that the cell senses decreasing cellular connectivity and uses this information to trigger division. A second idea from phenotypic diversity – Life on the Scales of Equilibria – is that a bacterium must find strategies that allow it to both survive and grow. This means that it has learnt to reconcile the opposing constraints that these strategies impose. The solution is that the cell cycle generates daughter cells with different phenotypes based on sufficiently complex equilibrium (E) and non-equilibrium (NE) cellular compounds and structures appropriate for survival and growth, respectively, alias ‘hyperstructures.’ The corollary is that the cell senses both the quantity of E material and the intensity of use of NE material and then uses this information to trigger the cell cycle. A third idea from artificial intelligence – Competitive Coherence – is that a cell selects the active subset of elements that actively determine its phenotype from a much larger set of available elements. This means that the selection of an active subset of a specific size and composition must be done so as to generate both a coherent cell state, in which the cell’s contents work together harmoniously, and a coherent sequence of cell states, each coherent with respect to itself and to an unpredictable environment. The solution is the use of a range of mechanisms ranging from hyperstructure dynamics to the cell cycle itself. PMID:25932025

Development of a systematic strategy for the global identification and classification of the chemical constituents and metabolites of Kai-Xin-San based on liquid chromatography with quadrupole time-of-flight mass spectrometry combined with multiple data-processing approaches.

PubMed

Wang, Xiaotong; Liu, Jing; Yang, Xiaomei; Zhang, Qian; Zhang, Yiwen; Li, Qing; Bi, Kaishun

2018-03-30

To rapidly identify and classify complicated components and metabolites for traditional Chinese medicines, a liquid chromatography with quadrupole time-of-flight mass spectrometry method combined with multiple data-processing approaches was established. In this process, Kai-Xin-San, a widely used classic traditional Chinese medicine preparation, was chosen as a model prescription. Initially, the fragmentation patterns, diagnostic product ions and neutral loss of each category of compounds were summarized by collision-induced dissociation analysis of representative standards. In vitro, the multiple product ions filtering technique was utilized to identify the chemical constituents for globally covering trace components. With this strategy, 108 constituents were identified, and compounds database was successfully established. In vivo, the prototype compounds were extracted based on the established database, and the neutral loss filtering technique combined with the drug metabolism reaction rules was employed to identify metabolites. Overall, 69 constituents including prototype and metabolites were characterized in rat plasma and nine constituents were firstly characterized in rat brain, which may be the potential active constituents resulting in curative effects by synergistic interaction. In conclusion, this study provides a generally applicable strategy to global metabolite identification for the complicated components in complex matrix and a chemical basis for further pharmacological research of Kai-Xin-San. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Glioblastoma niches: from the concept to the phenotypical reality.

PubMed

Schiffer, Davide; Mellai, Marta; Bovio, Enrica; Bisogno, Ilaria; Casalone, Cristina; Annovazzi, Laura

2018-05-08

Recently, the concept of niches as sites of tumor progression, invasion, and angiogenesis in glioblastoma (GB) has been extensively debated. Niches, considered the sites in which glioblastoma stem cells (GSCs) reside, have been classified as perivascular, perinecrotic, and invasive. However, from a neuropathological point of view, it is not easy to establish when a tumor structure can be considered a niche. The relevant literature has been reviewed in the light of our recent experience on the subject. As for perinecrotic niches, the occurrence of GSCs around necrosis is interpreted as triggered by hypoxia through HIF-1α. Our alternative hypothesis is that, together with progenitors, they are the cell constituents of hyper-proliferative areas of GB, where perinecrotic niches have developed, and they would, therefore, represent the remnants of GSCs/progenitors spared by the developing necrosis. Perivascular structures originate from both transport vessels and exchange vessels, i.e., venules, arterioles, or the undefinable neo-formed small vessels, but only those in which a direct contact between GSCs/progenitors and endothelial cells occurs can be called niches. Both pericytes and microglia/macrophages play a role in niche function: Macrophages of blood origin invade GB only after the appearance of "mother vessels" with consequent blood-brain barrier disruption. Not all vessel/tumor cell structures can be considered niches, that is, crucial sites of tumor progression, invasion, and angiogenesis.

Thalamic inflammation after brain trauma is associated with thalamo-cortical white matter damage.

PubMed

Scott, Gregory; Hellyer, Peter J; Ramlackhansingh, Anil F; Brooks, David J; Matthews, Paul M; Sharp, David J

2015-12-01

Traumatic brain injury can trigger chronic neuroinflammation, which may predispose to neurodegeneration. Animal models and human pathological studies demonstrate persistent inflammation in the thalamus associated with axonal injury, but this relationship has never been shown in vivo. Using [(11)C]-PK11195 positron emission tomography, a marker of microglial activation, we previously demonstrated thalamic inflammation up to 17 years after traumatic brain injury. Here, we use diffusion MRI to estimate axonal injury and show that thalamic inflammation is correlated with thalamo-cortical tract damage. These findings support a link between axonal damage and persistent inflammation after brain injury.

Inflammation is detrimental for neurogenesis in adult brain

NASA Astrophysics Data System (ADS)

Ekdahl, Christine T.; Claasen, Jan-Hendrik; Bonde, Sara; Kokaia, Zaal; Lindvall, Olle

2003-11-01

New hippocampal neurons are continuously generated in the adult brain. Here, we demonstrate that lipopolysaccharide-induced inflammation, which gives rise to microglia activation in the area where the new neurons are born, strongly impairs basal hippocampal neurogenesis in rats. The increased neurogenesis triggered by a brain insult is also attenuated if it is associated with microglia activation caused by tissue damage or lipopolysaccharide infusion. The impaired neurogenesis in inflammation is restored by systemic administration of minocycline, which inhibits microglia activation. Our data raise the possibility that suppression of hippocampal neurogenesis by activated microglia contributes to cognitive dysfunction in aging, dementia, epilepsy, and other conditions leading to brain inflammation.

Emotional based cognition in mice is differentially influenced by dose and lipid origin of dietary docosahexaenoic acid

USDA-ARS?s Scientific Manuscript database

Docosahexaenoic acid (DHA) is a major constituent, and primary omega-3 fatty acid, in the brain. Evidence suggests that DHA consumption may promote cognitive functioning and prevent cognitive decline, and these effects may be particularly relevant in the context of fear or stress. However, the pot...

Glycyrrhetinic Acid Triggers a Protective Autophagy by Activation of Extracellular Regulated Protein Kinases in Hepatocellular Carcinoma Cells

PubMed Central

2015-01-01

Glycyrrhetinic acid (GA), one of the main constituents of the famous Chinese medicinal herb and food additive licorice (Glycyrrhiza uralensis Fisch), has been indicated to possess potential anticancer effects and is widely utilized in hepatocellular carcinoma (HCC) targeted drug delivery systems (TDDS) due to the highly expressed target binding sites of GA on HCC cells. This study found that GA reduced the cell viability, increased the release of lactate dehydrogenase, and enhanced the expression of Bax, cleaved caspase-3, and LC3-II in HCC cells. The GA-triggered autophagy has been further confirmed by monodansylcadaverine staining as well as transmission electron microscopy analysis. The cell viability was obviously decreased whereas the expression of cleaved caspases was significantly increased when inhibition of autophagy by choloroquine or bafilomycin A1, suggesting that GA triggered a protective autophagy. Extracellular regulated protein kinase (ERK) was activated after treatment with GA in HepG2 cells and pretreatment with U0126 or PD98059, the MEK inhibitors, reversed GA-triggered autophagy as evidenced by decreased expression of LC3-II and formation of autophagosomes, respectively. Furthermore, GA-induced cell death and apoptosis were enhanced after pretreatment with PD98059. This is the first report that GA triggers a protective autophagy in HCC cells via activation of ERK, which might attenuate the anticancer effects of GA or chemotherapeutic drugs loaded with GA-modified TDDS. PMID:25403108

A strategy for comprehensive identification of sequential constituents using ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometer, application study on chlorogenic acids in Flos Lonicerae Japonicae.

PubMed

Zhang, Jia-yu; Wang, Zi-jian; Li, Yun; Liu, Ying; Cai, Wei; Li, Chen; Lu, Jian-qiu; Qiao, Yan-jiang

2016-01-15

The analytical methodologies for evaluation of multi-component system in traditional Chinese medicines (TCMs) have been inadequate or unacceptable. As a result, the unclarity of multi-component hinders the sufficient interpretation of their bioactivities. In this paper, an ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap (UPLC-LTQ-Orbitrap)-based strategy focused on the comprehensive identification of TCM sequential constituents was developed. The strategy was characterized by molecular design, multiple ion monitoring (MIM), targeted database hits and mass spectral trees similarity filter (MTSF), and even more isomerism discrimination. It was successfully applied in the HRMS data-acquisition and processing of chlorogenic acids (CGAs) in Flos Lonicerae Japonicae (FLJ), and a total of 115 chromatographic peaks attributed to 18 categories were characterized, allowing a comprehensive revelation of CGAs in FLJ for the first time. This demonstrated that MIM based on molecular design could improve the efficiency to trigger MS/MS fragmentation reactions. Targeted database hits and MTSF searching greatly facilitated the processing of extremely large information data. Besides, the introduction of diagnostic product ions (DPIs) discrimination, ClogP analysis, and molecular simulation, raised the efficiency and accuracy to characterize sequential constituents especially position and geometric isomers. In conclusion, the results expanded our understanding on CGAs in FLJ, and the strategy could be exemplary for future research on the comprehensive identification of sequential constituents in TCMs. Meanwhile, it may propose a novel idea for analyzing sequential constituents, and is promising for quality control and evaluation of TCMs. Copyright © 2015 Elsevier B.V. All rights reserved.

Guillain-Barre Syndrome

MedlinePlus

Guillain-Barre syndrome is a rare disorder that causes your immune system to attack your peripheral nervous system (PNS). The PNS ... your brain. No one knows what causes the syndrome. Sometimes it is triggered by an infection, surgery, ...

Neurotoxic Methamphetamine Doses Increase LINE-1 Expression in the Neurogenic Zones of the Adult Rat Brain

PubMed Central

Moszczynska, Anna; Flack, Amanda; Qiu, Ping; Muotri, Alysson R.; Killinger, Bryan A.

2015-01-01

Methamphetamine (METH) is a widely abused psychostimulant with the potential to cause neurotoxicity in the striatum and hippocampus. Several epigenetic changes have been described after administration of METH; however, there are no data regarding the effects of METH on the activity of transposable elements in the adult brain. The present study demonstrates that systemic administration of neurotoxic METH doses increases the activity of Long INterspersed Element (LINE-1) in two neurogenic niches in the adult rat brain in a promoter hypomethylation-independent manner. Our study also demonstrates that neurotoxic METH triggers persistent decreases in LINE-1 expression and increases the LINE-1 levels within genomic DNA in the striatum and dentate gyrus of the hippocampus, and that METH triggers LINE-1 retrotransposition in vitro. We also present indirect evidence for the involvement of glutamate (GLU) in LINE-1 activation. The results suggest that LINE-1 activation might occur in neurogenic areas in human METH users and might contribute to METH abuse-induced hippocampus-dependent memory deficits and impaired performance on several cognitive tasks mediated by the striatum. PMID:26463126

Hyperhomocysteinemia impairs regional blood flow: involvements of endothelial and neuronal nitric oxide.

PubMed

Toda, Noboru; Okamura, Tomio

2016-09-01

Increasing evidence support the idea that hyperhomocysteinemia (HHcy) is responsible for pathogenesis underlying cerebral, coronary, renal, and other vascular circulatory disorders and for hypertension. Impaired synthesis of nitric oxide (NO) in the endothelium or increased production of asymmetric dimethylarginine and activated oxygen species are involved in the impairment of vasodilator effects of NO. Impaired circulation in the brain derived from reduced synthesis and actions of NO would be an important triggering factor to dementia and Alzheimer's disease. Reduced actions of NO and brain hypoperfusion trigger increased production of amyloid-β that inhibits endothelial function, thus establishing a vicious cycle for impairing brain circulation. HHcy is involved in the genesis of anginal attack and coronary myocardial infarction. HHcy is also involved in renal circulatory diseases. The homocysteine (Hcy)-induced circulatory failure is promoted by methionine and is prevented by increased folic acid and vitamin B6/B12. Eliminating poor life styles, such as smoking and being sedentary; keeping favorable dietary habits; and early treatment maintaining constitutive NOS functions healthy, reducing oxidative stresses would be beneficial in protecting HHcy-induced circulatory failures.

Parkinson's disease and systemic inflammation.

PubMed

Ferrari, Carina C; Tarelli, Rodolfo

2011-02-22

Peripheral inflammation triggers exacerbation in the central brain's ongoing damage in several neurodegenerative diseases. Systemic inflammatory stimulus induce a general response known as sickness behaviour, indicating that a peripheral stimulus can induce the synthesis of cytokines in the brain. In Parkinson's disease (PD), inflammation was mainly associated with microglia activation that can underlie the neurodegeneration of neurons in the substantia nigra (SN). Peripheral inflammation can transform the "primed" microglia into an "active" state, which can trigger stronger responses dealing with neurodegenerative processes. Numerous evidences show that systemic inflammatory processes exacerbate ongoing neurodegeneration in PD patient and animal models. Anti-inflammatory treatment in PD patients exerts a neuroprotective effect. In the present paper, we analyse the effect of peripheral infections in the etiology and progression in PD patients and animal models, suggesting that these peripheral immune challenges can exacerbate the symptoms in the disease.

Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles

NASA Astrophysics Data System (ADS)

Baseri, Babak; Choi, James J.; Deffieux, Thomas; Samiotaki, Gesthimani; Tung, Yao-Sheng; Olumolade, Oluyemi; Small, Scott A.; Morrison, Barclay, III; Konofagou, Elisa E.

2012-04-01

The brain-derived neurotrophic factor (BDNF) has been shown to have broad neuroprotective effects in addition to its therapeutic role in neurodegenerative disease. In this study, the efficacy of delivering exogenous BDNF to the left hippocampus is demonstrated in wild-type mice (n = 7) through the noninvasively disrupted blood-brain barrier (BBB) using focused ultrasound (FUS). The BDNF bioactivity was found to be preserved following delivery as assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons. It was therefore shown for the first time that systemically administered neurotrophic factors can cross the noninvasively disrupted BBB and trigger neuronal downstream signaling effects in a highly localized region in the brain. This is the first time that the administered molecule is tracked through the BBB and localized in the neuron triggering molecular effects. Additional preliminary findings are shown in wild-type mice with two additional neurotrophic factors such as the glia-derived neurotrophic factor (n = 12) and neurturin (n = 2). This further demonstrates the impact of FUS for the early treatment of CNS diseases at the cellular and molecular level and strengthens its premise for FUS-assisted drug delivery and efficacy.

Exposure to benzidine caused apoptosis and malformation of telencephalon region in zebrafish.

PubMed

Chen, Mark Hung-Chih; Hsu, Li-Chi; Wu, Jia-Lun; Yeh, Chi-Wei; Tsai, Jen-Ning; Hseu, You-Cheng; Hsu, Li-Sung

2014-12-01

Exposure to benzidine has been known to induce human cancers, particularly bladder carcinomas. In this study, the zebrafish model was used to investigate the developmental toxicity of benzidine. Embryos at 6 h postfertilization (hpf) that were exposed to benzidine exhibited embryonic death in a dose- and time-dependent manner. Benzidine induced malformations in zebrafish, such as small brain development, shorter axes, and a slight pericardial edema. High concentrations (50, 100, and 200 µM) of benzidine triggered widespread apoptosis in the brain and dorsal neurons, as evidenced by acridine orange and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assays. Real-time polymerase chain reaction analysis also showed that benzidine treatment affected p53, bax, and noxa expression. Decreases in specific brain markers, such as emx1 in the telencephalon, ngn1 in differentiated neurons, and otx2 in the midbrain, were observed in benzidine-treated embryos at 24 hpf. Conversely, no overt changes to pax2.1 expression in the midbrain-hindbrain boundary were found. Moreover, the use of Tg(HuC:GFP) zebrafish showed that benzidine caused a malformation of the telencephalon region. Our findings show that benzidine exposure triggers widespread apoptosis in the zebrafish brain and dorsal neurons, resulting in the development of an abnormal telencephalon. © 2013 Wiley Periodicals, Inc.

ACE inhibition with captopril retards the development of signs of neurodegeneration in an animal model of Alzheimer's disease.

PubMed

AbdAlla, Said; Langer, Andreas; Fu, Xuebin; Quitterer, Ursula

2013-08-16

Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer's disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration.

ACE Inhibition with Captopril Retards the Development of Signs of Neurodegeneration in an Animal Model of Alzheimer’s Disease

PubMed Central

AbdAlla, Said; Langer, Andreas; Fu, Xuebin; Quitterer, Ursula

2013-01-01

Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer’s disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration. PMID:23959119

Complex interactions between hypoxia-ischemia and inflammation in preterm brain injury.

PubMed

Galinsky, Robert; Lear, Christopher A; Dean, Justin M; Wassink, Guido; Dhillon, Simerdeep K; Fraser, Mhoyra; Davidson, Joanne O; Bennet, Laura; Gunn, Alistair J

2018-02-01

Children surviving preterm birth have a high risk of disability, particularly cognitive and learning problems. There is extensive clinical and experimental evidence that disability is now primarily related to dysmaturation of white and gray matter, defined by failure of oligodendrocyte maturation and neuronal dendritic arborization, rather than cell death alone. The etiology of this dysmaturation is multifactorial, with contributions from hypoxia-ischemia, infection/inflammation and barotrauma. Intriguingly, these factors can interact to both increase and decrease damage. In this review we summarize preclinical and clinical evidence that all of these factors trigger secondary or chronic inflammation and gliosis. Thus, we hypothesize that these shared pathological features play a key role in a final common pathway that leads to the impaired neural maturation and connectivity and cognitive/motor impairments that are commonly observed in infants born preterm. This raises the possibility that secondary or chronic inflammation may be a viable therapeutic target for delayed interventions to improve neurodevelopmental outcomes after preterm birth. Hypoxia-ischemia, infection/inflammation, and barotrauma/volutrauma all contribute to preterm brain injury. Multiple different triggers of preterm brain injury are associated with central nervous system dysmaturation. Secondary brain inflammation may be a viable target to improve neurodevelopment after preterm birth. © 2017 Mac Keith Press.

Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats.

PubMed

Vorel, Stanislav R; Ashby, Charles R; Paul, Mousumi; Liu, Xinhe; Hayes, Robert; Hagan, Jim J; Middlemiss, Derek N; Stemp, Geoffrey; Gardner, Eliot L

2002-11-01

dopamine D3 receptor is preferentially localized to the mesocorticolimbic dopaminergic system and has been hypothesized to play a role in cocaine addiction. To study the involvement of the D3 receptor in brain mechanisms and behaviors commonly assumed to be involved in the addicting properties of cocaine, the potent and selective D3 receptor antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide (SB-277011-A) was administered to laboratory rats, and the following measures were assessed: (1) cocaine-enhanced electrical brain-stimulation reward, (2) cocaine-induced conditioned place preference, and (3) cocaine-triggered reinstatement of cocaine seeking behavior. Systemic injections of SB-277011-A were found to (1) block enhancement of electrical brain stimulation reward by cocaine, (2) dose-dependently attenuate cocaine-induced conditioned place preference, and (3) dose-dependently attenuate cocaine-triggered reinstatement of cocaine seeking behavior. Thus, D3 receptor blockade attenuates both the rewarding effects of cocaine and cocaine-induced drug-seeking behavior. These data suggest an important role for D3 receptors in mediating the addictive properties of cocaine and suggest that blockade of dopamine D3 receptors may constitute a new and useful target for prospective pharmacotherapies for cocaine addiction.

The Designed Environment and How it Affects Brain Morphology and Mental Health.

PubMed

Golembiewski, Jan A

2016-01-01

The environment is inextricably related to mental health. Recent research replicates findings of a significant, linear correlation between a childhood exposure to the urban environment and psychosis. Related studies also correlate the urban environment and aberrant brain morphologies. These findings challenge common beliefs that the mind and brain remain neutral in the face of worldly experience. There is a signature within these neurological findings that suggests that specific features of design cause and trigger mental illness. The objective in this article is to work backward from the molecular dynamics to identify features of the designed environment that may either trigger mental illness or protect against it. This review analyzes the discrete functions putatively assigned to the affected brain areas and a neurotransmitter called dopamine, which is the primary target of most antipsychotic medications. The intention is to establish what the correlations mean in functional terms, and more specifically, how this relates to the phenomenology of urban experience. In doing so, environmental mental illness risk factors are identified. Having established these relationships, the review makes practical recommendations for those in public health who wish to use the environment itself as a tool to improve the mental health of a community through design. © The Author(s) 2015.

[Imaging techniques for studying functional recovery following a stroke: I. Methodological aspects].

PubMed

Ramos-Cabrer, P; Agulla, J; Argibay, B; Brea, D; Campos, F; Castillo, J

2011-03-16

Many patients that survive stroke have to face serious functional disabilities for the rest of their lives, which is a personal drama for themselves and their relatives, and an elevated charge for society. Thus functional recovery following stroke should be a key objective for the development of new therapeutic approaches. In this series of two works we review the strategies and tools available nowadays for the evaluation of multiple aspects related to brain function (both in humans and research animals), and how they are helping neuroscientist to better understand the processes of restoration and reorganization of brain function that are triggered following stroke. We have mainly focused on magnetic resonance applications, probably the most versatile neuroimaging technique available nowadays, and that everyday surprises us with new and exciting applications. But we tackle other alternative and complementary techniques, since a multidisciplinary approach allows a wider perspective over the underlying mechanisms behind tissue repair, plastic reorganization of the brain and compensatory mechanisms that are triggered after stroke. The first of the works of this series is focused on methodological aspects that will help us to understand how it is possible to assess brain function based on different physical and physiological principles. In the second work we will focus on different practical issues related to the application of the techniques here discussed.

Monoamine reuptake inhibition and mood-enhancing potential of a specified oregano extract.

PubMed

Mechan, Annis O; Fowler, Ann; Seifert, Nicole; Rieger, Henry; Wöhrle, Tina; Etheve, Stéphane; Wyss, Adrian; Schüler, Göde; Colletto, Biagio; Kilpert, Claus; Aston, James; Elliott, J Martin; Goralczyk, Regina; Mohajeri, M Hasan

2011-04-01

A healthy, balanced diet is essential for both physical and mental well-being. Such a diet must include an adequate intake of micronutrients, essential fatty acids, amino acids and antioxidants. The monoamine neurotransmitters, serotonin, dopamine and noradrenaline, are derived from dietary amino acids and are involved in the modulation of mood, anxiety, cognition, sleep regulation and appetite. The capacity of nutritional interventions to elevate brain monoamine concentrations and, as a consequence, with the potential for mood enhancement, has not been extensively evaluated. The present study investigated an extract from oregano leaves, with a specified range of active constituents, identified via an unbiased, high-throughput screening programme. The oregano extract was demonstrated to inhibit the reuptake and degradation of the monoamine neurotransmitters in a dose-dependent manner, and microdialysis experiments in rats revealed an elevation of extracellular serotonin levels in the brain. Furthermore, following administration of oregano extract, behavioural responses were observed in mice that parallel the beneficial effects exhibited by monoamine-enhancing compounds when used in human subjects. In conclusion, these data show that an extract prepared from leaves of oregano, a major constituent of the Mediterranean diet, is brain-active, with moderate triple reuptake inhibitory activity, and exhibits positive behavioural effects in animal models. We postulate that such an extract may be effective in enhancing mental well-being in humans.

Importance of iodine in pregnancy.

PubMed

Carreto-Molina, Nicolás; García-Solís, Pablo; Solís-S, Juan Carlos; Robles-Osorio, Ludivina; Hernández-Montiel, Hebert Luis; Vega-Malagón, Genaro

2012-09-01

Iodine is an essential constituent of thyroid hormones (TH). TH actively take part in critical periods of brain development during embryonic, fetal and postnatal stages. Therefore the absence of TH or iodine in these critical periods produces an irreversible brain damage. In fact, it is known that iodine deficiency is the leading cause of preventable brain damage worldwide. Because of the physiological adjustments during pregnancy iodine requirements increase significantly from 150 microg per day in non-pregnant adult women to 250 microg per day. Moreover, recent epidemiological studies around the world show that iodine intake during pregnancy is insufficient in many countries, even in developed countries like Australia, Spain and Italy. In the present work an overview of the importance of iodine nutrition during pregnancy is given.

Immune dysregulation and cognitive vulnerability in the aging brain: Interactions of microglia, IL-1β, BDNF and synaptic plasticity.

PubMed

Patterson, Susan L

2015-09-01

Older individuals often experience declines in cognitive function after events (e.g. infection, or injury) that trigger activation of the immune system. This occurs at least in part because aging sensitizes the response of microglia (the brain's resident immune cells) to signals triggered by an immune challenge. In the aging brain, microglia respond to these signals by producing more pro-inflammatory cytokines (e.g. interleukin-1beta or IL-1β) and producing them for longer than microglia in younger brains. This exaggerated inflammatory response can compromise processes critical for optimal cognitive functioning. Interleukin-1β is central to the inflammatory response and is a key mediator and modulator of an array of associated biological functions; thus its production and release is usually very tightly regulated. This review will focus on the impact of dysregulated production of IL-1β on hippocampus dependent-memory systems and associated synaptic plasticity processes. The neurotrophin brain-derived neurotrophic factor (BNDF) helps to protect neurons from damage caused by infection or injury, and it plays a critical role in many of the same memory and hippocampal plasticity processes compromised by dysregulated production of IL-1β. This suggests that an exaggerated brain inflammatory response, arising from aging and a secondary immune challenge, may erode the capacity to provide the BDNF needed for memory-related plasticity processes at hippocampal synapses. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Combined brain Fe, Cu, Zn and neurometabolite analysis - a new methodology for unraveling the efficacy of transcranial direct current stimulation (tDCS) in appetite control.

PubMed

Ziomber, Agata; Surowka, Artur Dawid; Antkiewicz-Michaluk, Lucyna; Romanska, Irena; Wrobel, Pawel; Szczerbowska-Boruchowska, Magdalena

2018-03-01

Obesity is a chronic, multifactorial origin disease that has recently become one of the most frequent lifestyle disorders. Unfortunately, current obesity treatments seem to be ineffective. At present, transcranial direct current brain stimulation (tDCS) represents a promising novel treatment methodology that seems to be efficient, well-tolerated and safe for a patient. Unfortunately, the biochemical action of tDCS remains unknown, which prevents its widespread use in the clinical arena, although neurobiochemical changes in brain signaling and metal metabolism are frequently reported. Therefore, our research aimed at exploring the biochemical response to tDCS in situ, in the brain areas triggering feeding behavior in obese animals. The objective was to propose a novel neurochemical (serotoninergic and dopaminergic signaling) and trace metal analysis of Fe, Cu and Zn. In doing so, we used energy-dispersive X-ray fluorescence (EDXRF) and high-performance liquid chromatography (HPLC). Anodal-type stimulation (atDCS) of the right frontal cortex was utilized to down-regulate food intake and body weight gain in obese rats. EDXRF was coupled with the external standard method in order to quantify the chemical elements within appetite-triggering brain areas. Major dopamine metabolites were assessed in the brains, based on the HPLC assay utilizing the external standard assay. Our study confirms that elemental analysis by EDXRF and brain metabolite assay by HPLC can be considered as a useful tool for the in situ investigation of the interplay between neurochemical and Fe/Cu/Zn metabolism in the brain upon atDCS. With this methodology, an increase in both Cu and Zn in the satiety center of the stimulated group could be reported. In turn, the most significant neurochemical changes involved dopaminergic and serotoninergic signaling in the brain reward system.

Heparan sulfate storage in the cardiac conduction system triggers atrioventricular block.

PubMed

Kato, Rie; Miyahara, Hiroaki; Kawano, Tatsuya; Matsuzuka, Atsuko; Noda, Kimiko; Izumi, Tatsuro

2017-05-01

To elucidate the novel biological functions of heparan sulfate (HS) by clinic-pathologically studying a patient with paroxysmal atrioventricular (AV) block. A long-surviving male patient with Sanfilippo syndrome type A presented with paroxysmal AV block at age 33years. He then survived another 2.5years after the onset of paroxysmal AV block and pacemaker implantation. His cardiac histopathological examination at autopsy showed HS storage in the cardiac conduction system (CCS), especially in the atrioventricular node (AVN)-His bundle branches. HS storage in the CCS might trigger AV block, arising from below the AVN-His bundle branches. This is the first description to indicate that HS might be an essential constituent of life-long CCS plasticity and that its storage in the CCS results in AV block. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

A Novel Animal Model for Investigating the Neural Basis of Focal Dystonia

DTIC Science & Technology

2017-09-01

as the predisposing condition and dry eye as an environmental trigger to model blepharospasm in rodents. This reporting year we demonstrated that 7...benign essential blepharospasm, dry eye , motor plasticity, basal ganglia, deep brain stimulation, eyelids, blinking 16. SECURITY CLASSIFICATION OF: 17...basal ganglia create the predisposing condition and that  eye   irritation from  dry   eye   is the envi‐ ronmental trigger.  Our demonstration that

Review on the APP/PS1KI mouse model: intraneuronal Abeta accumulation triggers axonopathy, neuron loss and working memory impairment.

PubMed

Bayer, T A; Wirths, O

2008-02-01

Accumulating evidence points to an important role of intraneuronal Abeta as a trigger of the pathological cascade of events leading to neurodegeneration and eventually to Alzheimer's disease (AD) with its typical clinical symptoms, like memory impairment and change in personality. As a new concept, intraneuronal accumulation of Abeta instead of extracellular Abeta deposition has been introduced to be the disease-triggering event in AD. The present review compiles current knowledge on the amyloid precursor protein (APP)/PS1KI mouse model with early and massive intraneuronal Abeta42 accumulation: (1) The APP/PS1KI mouse model exhibits early robust brain and spinal cord axonal degeneration and hippocampal CA1 neuron loss. (2) At the same time-point, a dramatic, age-dependent reduced ability to perform working memory and motor tasks is observed. (3) The APP/PS1KI mice are smaller and show development of a thoracolumbar kyphosis, together with an incremental loss of body weight. (4) Onset of the observed behavioral alterations correlates well with robust axonal degeneration in brain and spinal cord and with abundant hippocampal CA1 neuron loss.

Brain glucose sensing, glucokinase and neural control of metabolism and islet function.

PubMed

Ogunnowo-Bada, E O; Heeley, N; Brochard, L; Evans, M L

2014-09-01

It is increasingly apparent that the brain plays a central role in metabolic homeostasis, including the maintenance of blood glucose. This is achieved by various efferent pathways from the brain to periphery, which help control hepatic glucose flux and perhaps insulin-stimulated insulin secretion. Also, critically important for the brain given its dependence on a constant supply of glucose as a fuel--emergency counter-regulatory responses are triggered by the brain if blood glucose starts to fall. To exert these control functions, the brain needs to detect rapidly and accurately changes in blood glucose. In this review, we summarize some of the mechanisms postulated to play a role in this and examine the potential role of the low-affinity hexokinase, glucokinase, in the brain as a key part of some of this sensing. We also discuss how these processes may become altered in diabetes and related metabolic diseases. © 2014 John Wiley & Sons Ltd.

Brain glucose sensing, glucokinase and neural control of metabolism and islet function

PubMed Central

Ogunnowo-Bada, E O; Heeley, N; Brochard, L; Evans, M L

2014-01-01

It is increasingly apparent that the brain plays a central role in metabolic homeostasis, including the maintenance of blood glucose. This is achieved by various efferent pathways from the brain to periphery, which help control hepatic glucose flux and perhaps insulin-stimulated insulin secretion. Also, critically important for the brain given its dependence on a constant supply of glucose as a fuel – emergency counter-regulatory responses are triggered by the brain if blood glucose starts to fall. To exert these control functions, the brain needs to detect rapidly and accurately changes in blood glucose. In this review, we summarize some of the mechanisms postulated to play a role in this and examine the potential role of the low-affinity hexokinase, glucokinase, in the brain as a key part of some of this sensing. We also discuss how these processes may become altered in diabetes and related metabolic diseases. PMID:25200293

Target innervation is necessary for neuronal polyploidization in the terrestrial slug Limax.

PubMed

Matsuo, Ryota; Yamagishi, Miki; Wakiya, Kyoko; Tanaka, Yoko; Ito, Etsuro

2013-08-01

The brain of gastropod mollusks contains many giant neurons with polyploid genomic DNAs. Such DNAs are generated through repeated DNA endoreplication during body growth. However, it is not known what triggers DNA endoreplication in neurons. There are two possibilities: (1) DNAs are replicated in response to some unknown molecules in the hemolymph that reflect the nutritive status of the animal; or (2) DNAs are replicated in response to some unknown factors that are retrogradely transported through axons from the innervated target organs. We first tested whether hemolymph with rich nutrition could induce DNA endoreplication. We tested whether the transplanted brain exhibits enhanced DNA endoreplication like an endogenous brain does when transplanted into the homocoel of the body of a slug whose body growth is promoted by an increased food supply. However, no enhancement was observed in the frequency of DNA endoreplication when we compared the transplanted brains in the growth-promoted and growth-suppressed host slugs, suggesting that the humoral environment is irrelevant to triggering the body growth-dependent DNA endoreplication. Next, we tested the requirement of target innervation by surgically dissecting a unilateral posterior pedal nerve of an endogenous brain. Substantially lower number of neurons exhibited DNA endoreplication in the pedal ganglion ipsilateral to the dissected nerve. These results support the view that enhanced DNA endoreplication is mediated by target innervation and is not brought about through the direct effect of humoral factors in the hemolymph during body growth. Copyright © 2013 Wiley Periodicals, Inc.

Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry.

PubMed

Sawada, Yoshikazu; Izumida, Yoshihiko; Takeuchi, Yoshinori; Aita, Yuichi; Wada, Nobuhiro; Li, EnXu; Murayama, Yuki; Piao, Xianying; Shikama, Akito; Masuda, Yukari; Nishi-Tatsumi, Makiko; Kubota, Midori; Sekiya, Motohiro; Matsuzaka, Takashi; Nakagawa, Yoshimi; Sugano, Yoko; Iwasaki, Hitoshi; Kobayashi, Kazuto; Yatoh, Shigeru; Suzuki, Hiroaki; Yagyu, Hiroaki; Kawakami, Yasushi; Kadowaki, Takashi; Shimano, Hitoshi; Yahagi, Naoya

2017-11-04

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have both anti-diabetic and anti-obesity effects. However, the precise mechanism of the anti-obesity effect remains unclear. We previously demonstrated that the glycogen depletion signal triggers lipolysis in adipose tissue via liver-brain-adipose neurocircuitry. In this study, therefore, we investigated whether the anti-obesity mechanism of SGLT2 inhibitor is mediated by this mechanism. Diet-induced obese mice were subjected to hepatic vagotomy (HVx) or sham operation and loaded with high fat diet containing 0.015% tofogliflozin (TOFO), a highly selective SGLT2 inhibitor, for 3 weeks. TOFO-treated mice showed a decrease in fat mass and the effect of TOFO was attenuated in HVx group. Although both HVx and sham mice showed a similar level of reduction in hepatic glycogen by TOFO treatment, HVx mice exhibited an attenuated response in protein phosphorylation by protein kinase A (PKA) in white adipose tissue compared with the sham group. As PKA pathway is known to act as an effector of the liver-brain-adipose axis and activate triglyceride lipases in adipocytes, these results indicated that SGLT2 inhibition triggered glycogen depletion signal and actuated liver-brain-adipose axis, resulting in PKA activation in adipocytes. Taken together, it was concluded that the effect of SGLT2 inhibition on weight loss is in part mediated via the liver-brain-adipose neurocircuitry. Copyright © 2017 Elsevier Inc. All rights reserved.

Innovation in the collective brain

PubMed Central

Muthukrishna, Michael; Henrich, Joseph

2016-01-01

Innovation is often assumed to be the work of a talented few, whose products are passed on to the masses. Here, we argue that innovations are instead an emergent property of our species' cultural learning abilities, applied within our societies and social networks. Our societies and social networks act as collective brains. We outline how many human brains, which evolved primarily for the acquisition of culture, together beget a collective brain. Within these collective brains, the three main sources of innovation are serendipity, recombination and incremental improvement. We argue that rates of innovation are heavily influenced by (i) sociality, (ii) transmission fidelity, and (iii) cultural variance. We discuss some of the forces that affect these factors. These factors can also shape each other. For example, we provide preliminary evidence that transmission efficiency is affected by sociality—languages with more speakers are more efficient. We argue that collective brains can make each of their constituent cultural brains more innovative. This perspective sheds light on traits, such as IQ, that have been implicated in innovation. A collective brain perspective can help us understand otherwise puzzling findings in the IQ literature, including group differences, heritability differences and the dramatic increase in IQ test scores over time. PMID:26926282

Innovation in the collective brain.

PubMed

Muthukrishna, Michael; Henrich, Joseph

2016-03-19

Innovation is often assumed to be the work of a talented few, whose products are passed on to the masses. Here, we argue that innovations are instead an emergent property of our species' cultural learning abilities, applied within our societies and social networks. Our societies and social networks act as collective brains. We outline how many human brains, which evolved primarily for the acquisition of culture, together beget a collective brain. Within these collective brains, the three main sources of innovation are serendipity, recombination and incremental improvement. We argue that rates of innovation are heavily influenced by (i) sociality, (ii) transmission fidelity, and (iii) cultural variance. We discuss some of the forces that affect these factors. These factors can also shape each other. For example, we provide preliminary evidence that transmission efficiency is affected by sociality--languages with more speakers are more efficient. We argue that collective brains can make each of their constituent cultural brains more innovative. This perspective sheds light on traits, such as IQ, that have been implicated in innovation. A collective brain perspective can help us understand otherwise puzzling findings in the IQ literature, including group differences, heritability differences and the dramatic increase in IQ test scores over time. © 2016 The Author(s).

Activation of Brain Somatostatin Signaling Suppresses CRF Receptor-Mediated Stress Response.

PubMed

Stengel, Andreas; Taché, Yvette F

2017-01-01

Corticotropin-releasing factor (CRF) is the hallmark brain peptide triggering the response to stress and mediates-in addition to the stimulation of the hypothalamus-pituitary-adrenal (HPA) axis-other hormonal, behavioral, autonomic and visceral components. Earlier reports indicate that somatostatin-28 injected intracerebroventricularly counteracts the acute stress-induced ACTH and catecholamine release. Mounting evidence now supports that activation of brain somatostatin signaling exerts a broader anti-stress effect by blunting the endocrine, autonomic, behavioral (with a focus on food intake) and visceral gastrointestinal motor responses through the involvement of distinct somatostatin receptor subtypes.

Parkinson's Disease and Systemic Inflammation

PubMed Central

Ferrari, Carina C.; Tarelli, Rodolfo

2011-01-01

Peripheral inflammation triggers exacerbation in the central brain's ongoing damage in several neurodegenerative diseases. Systemic inflammatory stimulus induce a general response known as sickness behaviour, indicating that a peripheral stimulus can induce the synthesis of cytokines in the brain. In Parkinson's disease (PD), inflammation was mainly associated with microglia activation that can underlie the neurodegeneration of neurons in the substantia nigra (SN). Peripheral inflammation can transform the “primed” microglia into an “active” state, which can trigger stronger responses dealing with neurodegenerative processes. Numerous evidences show that systemic inflammatory processes exacerbate ongoing neurodegeneration in PD patient and animal models. Anti-inflammatory treatment in PD patients exerts a neuroprotective effect. In the present paper, we analyse the effect of peripheral infections in the etiology and progression in PD patients and animal models, suggesting that these peripheral immune challenges can exacerbate the symptoms in the disease. PMID:21403862

Is autophagy the key mechanism by which the sphingolipid rheostat controls the cell fate decision?

PubMed

Lavieu, Gregory; Scarlatti, Francesca; Sala, Giusy; Levade, Thierry; Ghidoni, Riccardo; Botti, Joëlle; Codogno, Patrice

2007-01-01

Sphingolipids are major constituents of biological membrane and some of them behave as second messengers involved in the cell fate decision. Ceramide and sphingosine 1-phosphate (S1P) constitute a rheostat system in which ceramide promotes cell death and S1P increases cell survival. We have shown that both sphingolipids are able to trigger autophagy with opposing outcomes on cell survival. Here we discuss and speculate on the diverging functions of the autophagic pathways induced by ceramide and S1P, respectively.

Effect of constituents from samaras of Austroplenckia populnea (Celastraceae) on human cancer cells.

PubMed

Caneschi, Carolina Milagres; Muniyappa, Mohan K; Duarte, Lucienir P; Silva, Grácia D F; Dos Santos, Orlando David Henrique; Spillane, Charles; Filho, Sidney Augusto Vieira

2015-01-01

Aiming the continuity of the studies of Austroplenckia populnea, Brazilian species of the Celastraceae family, in the present study, it was investigated the effect of crude extracts obtained with ethanol, ethyl acetate and chloroform and two purified constituents, proanthocyanidin A and 4'-O-methylepigallocatechin, both isolated from its samaras, on cancer cell proliferation assays. The human cancer cells lines MCF-7 (ductal breast carcinoma), A549 (lung cancer), HS578T (ductal breast carcinoma) and non-cancer HEK293 (embryonic kidney cells) were treated with different concentrations of extracts and constituents and the effect was observed through the acid phosphatase method. The chemical structures of the purified compounds were identified by the respective IR and (1)H and (13)C nuclear magnetic resonance spectral data. While crude extracts from samaras of the folk medicine A. populnea can trigger cell proliferative effects in human cell lines, the purified compounds (proanthocyanidin A and 4'-O-methyl-epigallocatechin) isolated from the same extracts can have an opposite (anti-proliferative) effect. Based on the results, it was possible to suggest that extracts from samaras of A. populnea should be further investigated for possible cancer-promoting activities; and the active extracts can also represent a source of compounds that have anti-cancer properties.

Effect of constituents from samaras of Austroplenckia populnea (Celastraceae) on human cancer cells

PubMed Central

Caneschi, Carolina Milagres; Muniyappa, Mohan K.; Duarte, Lucienir P.; Silva, Grácia D. F.; dos Santos, Orlando David Henrique; Spillane, Charles; Filho, Sidney Augusto Vieira

2015-01-01

Background: Aiming the continuity of the studies of Austroplenckia populnea, Brazilian species of the Celastraceae family, in the present study, it was investigated the effect of crude extracts obtained with ethanol, ethyl acetate and chloroform and two purified constituents, proanthocyanidin A and 4’-O-methylepigallocatechin, both isolated from its samaras, on cancer cell proliferation assays. Materials and Methods: The human cancer cells lines MCF-7 (ductal breast carcinoma), A549 (lung cancer), HS578T (ductal breast carcinoma) and non-cancer HEK293 (embryonic kidney cells) were treated with different concentrations of extracts and constituents and the effect was observed through the acid phosphatase method. The chemical structures of the purified compounds were identified by the respective IR and 1H and 13C nuclear magnetic resonance spectral data. Results: While crude extracts from samaras of the folk medicine A. populnea can trigger cell proliferative effects in human cell lines, the purified compounds (proanthocyanidin A and 4’-O-methyl-epigallocatechin) isolated from the same extracts can have an opposite (anti-proliferative) effect. Conclusion: Based on the results, it was possible to suggest that extracts from samaras of A. populnea should be further investigated for possible cancer-promoting activities; and the active extracts can also represent a source of compounds that have anti-cancer properties. PMID:26401377

Ginkgo biloba leaf extract induces DNA damage by inhibiting topoisomerase II activity in human hepatic cells.

PubMed

Zhang, Zhuhong; Chen, Si; Mei, Hu; Xuan, Jiekun; Guo, Xiaoqing; Couch, Letha; Dobrovolsky, Vasily N; Guo, Lei; Mei, Nan

2015-09-30

Ginkgo biloba leaf extract has been shown to increase the incidence in liver tumors in mice in a 2-year bioassay conducted by the National Toxicology Program. In this study, the DNA damaging effects of Ginkgo biloba leaf extract and many of its constituents were evaluated in human hepatic HepG2 cells and the underlying mechanism was determined. A molecular docking study revealed that quercetin, a flavonoid constituent of Ginkgo biloba, showed a higher potential to interact with topoisomerase II (Topo II) than did the other Ginkgo biloba constituents; this in silico prediction was confirmed by using a biochemical assay to study Topo II enzyme inhibition. Moreover, as measured by the Comet assay and the induction of γ-H2A.X, quercetin, followed by keampferol and isorhamnetin, appeared to be the most potent DNA damage inducer in HepG2 cells. In Topo II knockdown cells, DNA damage triggered by Ginkgo biloba leaf extract or quercetin was dramatically decreased, indicating that DNA damage is directly associated with Topo II. DNA damage was also observed when cells were treated with commercially available Ginkgo biloba extract product. Our findings suggest that Ginkgo biloba leaf extract- and quercetin-induced in vitro genotoxicity may be the result of Topo II inhibition.

Ginkgo biloba leaf extract induces DNA damage by inhibiting topoisomerase II activity in human hepatic cells

PubMed Central

Zhang, Zhuhong; Chen, Si; Mei, Hu; Xuan, Jiekun; Guo, Xiaoqing; Couch, Letha; Dobrovolsky, Vasily N.; Guo, Lei; Mei, Nan

2015-01-01

Ginkgo biloba leaf extract has been shown to increase the incidence in liver tumors in mice in a 2-year bioassay conducted by the National Toxicology Program. In this study, the DNA damaging effects of Ginkgo biloba leaf extract and many of its constituents were evaluated in human hepatic HepG2 cells and the underlying mechanism was determined. A molecular docking study revealed that quercetin, a flavonoid constituent of Ginkgo biloba, showed a higher potential to interact with topoisomerase II (Topo II) than did the other Ginkgo biloba constituents; this in silico prediction was confirmed by using a biochemical assay to study Topo II enzyme inhibition. Moreover, as measured by the Comet assay and the induction of γ-H2A.X, quercetin, followed by keampferol and isorhamnetin, appeared to be the most potent DNA damage inducer in HepG2 cells. In Topo II knockdown cells, DNA damage triggered by Ginkgo biloba leaf extract or quercetin was dramatically decreased, indicating that DNA damage is directly associated with Topo II. DNA damage was also observed when cells were treated with commercially available Ginkgo biloba extract product. Our findings suggest that Ginkgo biloba leaf extract- and quercetin-induced in vitro genotoxicity may be the result of Topo II inhibition. PMID:26419945

Isoform-selective regulation of glycogen phosphorylase by energy deprivation and phosphorylation in astrocytes.

PubMed

Müller, Margit S; Pedersen, Sofie E; Walls, Anne B; Waagepetersen, Helle S; Bak, Lasse K

2015-01-01

Glycogen phosphorylase (GP) is activated to degrade glycogen in response to different stimuli, to support both the astrocyte's own metabolic demand and the metabolic needs of neurons. The regulatory mechanism allowing such a glycogenolytic response to distinct triggers remains incompletely understood. In the present study, we used siRNA-mediated differential knockdown of the two isoforms of GP expressed in astrocytes, muscle isoform (GPMM), and brain isoform (GPBB), to analyze isoform-specific regulatory characteristics in a cellular setting. Subsequently, we tested the response of each isoform to phosphorylation, triggered by incubation with norepinephrine (NE), and to AMP, increased by glucose deprivation in cells in which expression of one GP isoform had been silenced. Successful knockdown was demonstrated on the protein level by Western blot, and on a functional level by determination of glycogen content showing an increase in glycogen levels following knockdown of either GPMM or GPBB. NE triggered glycogenolysis within 15 min in control cells and after GPBB knockdown. However, astrocytes in which expression of GPMM had been silenced showed a delay in response to NE, with glycogen levels significantly reduced only after 60 min. In contrast, allosteric activation of GP by AMP, induced by glucose deprivation, seemed to mainly affect GPBB, as only knockdown of GPBB, but not of GPMM, delayed the glycogenolytic response to glucose deprivation. Our results indicate that the two GP isoforms expressed in astrocytes respond to different physiological triggers, therefore conferring distinct metabolic functions of brain glycogen. © 2014 Wiley Periodicals, Inc.

Spatiotemporal dynamics of optogenetically induced and spontaneous seizure transitions in primary generalized epilepsy

PubMed Central

Truccolo, Wilson; Wang, Jing; Nurmikko, Arto V.

2014-01-01

Transitions into primary generalized epileptic seizures occur abruptly and synchronously across the brain. Their potential triggers remain unknown. We used optogenetics to causally test the hypothesis that rhythmic population bursting of excitatory neurons in a local neocortical region can rapidly trigger absence seizures. Most previous studies have been purely correlational, and it remains unclear whether epileptiform events induced by rhythmic stimulation (e.g., sensory/electrical) mimic actual spontaneous seizures, especially regarding their spatiotemporal dynamics. In this study, we used a novel combination of intracortical optogenetic stimulation and microelectrode array recordings in freely moving WAG/Rij rats, a model of absence epilepsy with a cortical focus in the somatosensory cortex (SI). We report three main findings: 1) Brief rhythmic bursting, evoked by optical stimulation of neocortical excitatory neurons at frequencies around 10 Hz, induced seizures consisting of self-sustained spike-wave discharges (SWDs) for about 10% of stimulation trials. The probability of inducing seizures was frequency-dependent, reaching a maximum at 10 Hz. 2) Local field potential power before stimulation and response amplitudes during stimulation both predicted seizure induction, demonstrating a modulatory effect of brain states and neural excitation levels. 3) Evoked responses during stimulation propagated as cortical waves, likely reaching the cortical focus, which in turn generated self-sustained SWDs after stimulation was terminated. Importantly, SWDs during induced and spontaneous seizures propagated with the same spatiotemporal dynamics. Our findings demonstrate that local rhythmic bursting of excitatory neurons in neocortex at particular frequencies, under susceptible ongoing brain states, is sufficient to trigger primary generalized seizures with stereotypical spatiotemporal dynamics. PMID:25552645

Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy

PubMed Central

Clossen, Bryan L.; Reddy, Doodipala Samba

2017-01-01

This article describes the recent advances in epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of epileptogenesis for curing epilepsy. Here we assess animal studies and human clinical trials of epilepsy spanning 1982–2016. Epilepsy arises from a number of neuronal factors that trigger epileptogenesis, which is the process by which a brain shifts from a normal physiologic state to an epileptic condition. The events precipitating these changes can be of diverse origin, including traumatic brain injury, cerebrovascular damage, infections, chemical neurotoxicity, and emergency seizure conditions such as status epilepticus. Expectedly, the molecular and system mechanisms responsible for epileptogenesis are not well defined or understood. To date, there is no approved therapy for the prevention of epilepsy. Epigenetic dysregulation, neuroinflammation, and neurodegeneration appear to trigger epileptogenesis. Targeted drugs are being identified that can truly prevent the development of epilepsy in at-risk people. The promising agents include rapamycin, COX-2 inhibitors, TRK inhibitors, epigenetic modulators, JAK-STAT inhibitors, and neurosteroids. Recent evidence suggests that neurosteroids may play a role in modulating epileptogenesis. A number of promising drugs are under investigation for the prevention or modification of epileptogenesis to halt the development of epilepsy. Some drugs in development appear rational for preventing epilepsy because they target the initial trigger or related signaling pathways as the brain becomes progressively more prone to seizures. Additional research into the target validity and clinical investigation is essential to make new frontiers in curing epilepsy. PMID:28179120

Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy.

PubMed

Clossen, Bryan L; Reddy, Doodipala Samba

2017-06-01

This article describes the recent advances in epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of epileptogenesis for curing epilepsy. Here we assess animal studies and human clinical trials of epilepsy spanning 1982-2016. Epilepsy arises from a number of neuronal factors that trigger epileptogenesis, which is the process by which a brain shifts from a normal physiologic state to an epileptic condition. The events precipitating these changes can be of diverse origin, including traumatic brain injury, cerebrovascular damage, infections, chemical neurotoxicity, and emergency seizure conditions such as status epilepticus. Expectedly, the molecular and system mechanisms responsible for epileptogenesis are not well defined or understood. To date, there is no approved therapy for the prevention of epilepsy. Epigenetic dysregulation, neuroinflammation, and neurodegeneration appear to trigger epileptogenesis. Targeted drugs are being identified that can truly prevent the development of epilepsy in at-risk people. The promising agents include rapamycin, COX-2 inhibitors, TRK inhibitors, epigenetic modulators, JAK-STAT inhibitors, and neurosteroids. Recent evidence suggests that neurosteroids may play a role in modulating epileptogenesis. A number of promising drugs are under investigation for the prevention or modification of epileptogenesis to halt the development of epilepsy. Some drugs in development appear rational for preventing epilepsy because they target the initial trigger or related signaling pathways as the brain becomes progressively more prone to seizures. Additional research into the target validity and clinical investigation is essential to make new frontiers in curing epilepsy. Copyright © 2017 Elsevier B.V. All rights reserved.

Adaptive Automation Triggered by EEG-Based Mental Workload Index: A Passive Brain-Computer Interface Application in Realistic Air Traffic Control Environment.

PubMed

Aricò, Pietro; Borghini, Gianluca; Di Flumeri, Gianluca; Colosimo, Alfredo; Bonelli, Stefano; Golfetti, Alessia; Pozzi, Simone; Imbert, Jean-Paul; Granger, Géraud; Benhacene, Raïlane; Babiloni, Fabio

2016-01-01

Adaptive Automation (AA) is a promising approach to keep the task workload demand within appropriate levels in order to avoid both the under - and over-load conditions, hence enhancing the overall performance and safety of the human-machine system. The main issue on the use of AA is how to trigger the AA solutions without affecting the operative task. In this regard, passive Brain-Computer Interface (pBCI) systems are a good candidate to activate automation, since they are able to gather information about the covert behavior (e.g., mental workload) of a subject by analyzing its neurophysiological signals (i.e., brain activity), and without interfering with the ongoing operational activity. We proposed a pBCI system able to trigger AA solutions integrated in a realistic Air Traffic Management (ATM) research simulator developed and hosted at ENAC (É cole Nationale de l'Aviation Civile of Toulouse, France). Twelve Air Traffic Controller (ATCO) students have been involved in the experiment and they have been asked to perform ATM scenarios with and without the support of the AA solutions. Results demonstrated the effectiveness of the proposed pBCI system, since it enabled the AA mostly during the high-demanding conditions (i.e., overload situations) inducing a reduction of the mental workload under which the ATCOs were operating. On the contrary, as desired, the AA was not activated when workload level was under the threshold, to prevent too low demanding conditions that could bring the operator's workload level toward potentially dangerous conditions of underload.

Adaptive Automation Triggered by EEG-Based Mental Workload Index: A Passive Brain-Computer Interface Application in Realistic Air Traffic Control Environment

PubMed Central

Aricò, Pietro; Borghini, Gianluca; Di Flumeri, Gianluca; Colosimo, Alfredo; Bonelli, Stefano; Golfetti, Alessia; Pozzi, Simone; Imbert, Jean-Paul; Granger, Géraud; Benhacene, Raïlane; Babiloni, Fabio

2016-01-01

Adaptive Automation (AA) is a promising approach to keep the task workload demand within appropriate levels in order to avoid both the under- and over-load conditions, hence enhancing the overall performance and safety of the human-machine system. The main issue on the use of AA is how to trigger the AA solutions without affecting the operative task. In this regard, passive Brain-Computer Interface (pBCI) systems are a good candidate to activate automation, since they are able to gather information about the covert behavior (e.g., mental workload) of a subject by analyzing its neurophysiological signals (i.e., brain activity), and without interfering with the ongoing operational activity. We proposed a pBCI system able to trigger AA solutions integrated in a realistic Air Traffic Management (ATM) research simulator developed and hosted at ENAC (École Nationale de l'Aviation Civile of Toulouse, France). Twelve Air Traffic Controller (ATCO) students have been involved in the experiment and they have been asked to perform ATM scenarios with and without the support of the AA solutions. Results demonstrated the effectiveness of the proposed pBCI system, since it enabled the AA mostly during the high-demanding conditions (i.e., overload situations) inducing a reduction of the mental workload under which the ATCOs were operating. On the contrary, as desired, the AA was not activated when workload level was under the threshold, to prevent too low demanding conditions that could bring the operator's workload level toward potentially dangerous conditions of underload. PMID:27833542

Neurotoxicogenomic investigations to assess mechanisms of action of the munitions constituents RDX and 2,6-DNT in Northern bobwhite (Colinus virginianus).

PubMed

Gust, Kurt A; Pirooznia, Mehdi; Quinn, Michael J; Johnson, Mark S; Escalon, Lynn; Indest, Karl J; Guan, Xin; Clarke, Joan; Deng, Youping; Gong, Ping; Perkins, Edward J

2009-07-01

Munitions constituents (MCs) including hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), 2,4,6-trinitrotoluene (TNT), and TNT derivatives are recognized to elicit aberrant neuromuscular responses in many species. The onset of seizures resulting in death was observed in the avian model Northern bobwhite after oral dosing with RDX beginning at 8 mg/kg/day in subacute (14 days) exposures, whereas affective doses of the TNT derivative, 2,6-dinitrotoluene (2,6-DNT), caused gastrointestinal impacts, lethargy, and emaciation in subacute and subchronic (60 days) exposures. To assess and contrast the potential neurotoxicogenomic effects of these MCs, a Northern bobwhite microarray was developed consisting of 4119 complementary DNA (cDNA) features enriched for differentially-expressed brain transcripts from exposures to RDX and 2,6-DNT. RDX affected hundreds of genes in brain tissue, whereas 2,6-DNT affected few (

Embryonic Cerebrospinal Fluid Increases Neurogenic Activity in the Brain Ventricular-Subventricular Zone of Adult Mice.

PubMed

Alonso, Maria I; Lamus, Francisco; Carnicero, Estela; Moro, Jose A; de la Mano, Anibal; Fernández, Jose M F; Desmond, Mary E; Gato, Angel

2017-01-01

Neurogenesis is a very intensive process during early embryonic brain development, becoming dramatically restricted in the adult brain in terms of extension and intensity. We have previously demonstrated the key role of embryonic cerebrospinal fluid (CSF) in developing brain neurogenic activity. We also showed that cultured adult brain neural stem cells (NSCs) remain competent when responding to the neurogenic influence of embryonic CSF. However, adult CSF loses its neurogenic inductive properties. Here, by means of an organotypic culture of adult mouse brain sections, we show that local administration of embryonic CSF in the subventricular zone (SVZ) niche is able to trigger a neurogenic program in NSCs. This leads to a significant increase in the number of non-differentiated NSCs, and also in the number of new neurons which show normal migration, differentiation and maturation. These new data reveal that embryonic CSF activates adult brain NSCs, supporting the previous idea that it contains key instructive components which could be useful in adult brain neuroregenerative strategies.

Maternal-fetal unit interactions and eutherian neocortical development and evolution

PubMed Central

Montiel, Juan F.; Kaune, Heidy; Maliqueo, Manuel

2013-01-01

The conserved brain design that primates inherited from early mammals differs from the variable adult brain size and species-specific brain dominances observed across mammals. This variability relies on the emergence of specialized cerebral cortical regions and sub-compartments, triggering an increase in brain size, areal interconnectivity and histological complexity that ultimately lies on the activation of developmental programs. Structural placental features are not well correlated with brain enlargement; however, several endocrine pathways could be tuned with the activation of neuronal progenitors in the proliferative neocortical compartments. In this article, we reviewed some mechanisms of eutherians maternal–fetal unit interactions associated with brain development and evolution. We propose a hypothesis of brain evolution where proliferative compartments in primates become activated by “non-classical” endocrine placental signals participating in different steps of corticogenesis. Changes in the inner placental structure, along with placenta endocrine stimuli over the cortical proliferative activity would allow mammalian brain enlargement with a concomitant shorter gestation span, as an evolutionary strategy to escape from parent-offspring conflict. PMID:23882189

Embryonic Cerebrospinal Fluid Increases Neurogenic Activity in the Brain Ventricular-Subventricular Zone of Adult Mice

PubMed Central

Alonso, Maria I.; Lamus, Francisco; Carnicero, Estela; Moro, Jose A.; de la Mano, Anibal; Fernández, Jose M. F.; Desmond, Mary E.; Gato, Angel

2017-01-01

Neurogenesis is a very intensive process during early embryonic brain development, becoming dramatically restricted in the adult brain in terms of extension and intensity. We have previously demonstrated the key role of embryonic cerebrospinal fluid (CSF) in developing brain neurogenic activity. We also showed that cultured adult brain neural stem cells (NSCs) remain competent when responding to the neurogenic influence of embryonic CSF. However, adult CSF loses its neurogenic inductive properties. Here, by means of an organotypic culture of adult mouse brain sections, we show that local administration of embryonic CSF in the subventricular zone (SVZ) niche is able to trigger a neurogenic program in NSCs. This leads to a significant increase in the number of non-differentiated NSCs, and also in the number of new neurons which show normal migration, differentiation and maturation. These new data reveal that embryonic CSF activates adult brain NSCs, supporting the previous idea that it contains key instructive components which could be useful in adult brain neuroregenerative strategies. PMID:29311854

Perinatal stress, brain inflammation and risk of autism-review and proposal.

PubMed

Angelidou, Asimenia; Asadi, Shahrzad; Alysandratos, Konstantinos-Dionysios; Karagkouni, Anna; Kourembanas, Stella; Theoharides, Theoharis C

2012-07-02

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication, and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Premature babies are also more vulnerable to infections and inflammation leading to neurodevelopmental problems and higher risk of developing ASD. Many autism "susceptibility" genes have been identified, but "environmental" factors appear to play a significant role. Increasing evidence suggests that there are different ASD endophenotypes. We review relevant literature suggesting in utero inflammation can lead to preterm labor, while insufficient development of the gut-blood-brain barriers could permit exposure to potential neurotoxins. This risk apparently may increase in parents with "allergic" or autoimmune problems during gestation, or if they had been exposed to stressors. The presence of circulating auto-antibodies against fetal brain proteins in mothers is associated with higher risk of autism and suggests disruption of the blood-brain-barrier (BBB). A number of papers have reported increased brain expression or cerebrospinal fluid (CSF) levels of pro-inflammatory cytokines, especially TNF, which is preformed in mast cells. Recent evidence also indicates increased serum levels of the pro-inflammatory mast cell trigger neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which is immunogenic. Gene mutations of phosphatase and tensin homolog (PTEN), the negative regulator of the mammalian target of rapamycin (mTOR), have been linked to higher risk of autism, but also to increased proliferation and function of mast cells. Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers that could stimulate mast cell release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in an endophenotype of ASD patients.

Oxcarbazepine causes neurocyte apoptosis and developing brain damage by triggering Bax/Bcl-2 signaling pathway mediated caspase 3 activation in neonatal rats.

PubMed

Song, Y; Zhong, M; Cai, F-C

2018-01-01

Anti-epileptic drugs (AEDs) are the main methods for treatment of neonatal seizures; however, a few AEDs may cause developing brain damage of neonate. This study aims to investigate effects of oxcarbazepine (OXC) on developing brain damage of neonatal rats. Both of neonatal and adult rats were divided into 6 groups, including Control, OXC 187.5 mg/kg, OXC 281.25 mg/kg, OXC 375 mg/kg group, LEV and PHT group. Body weight and brain weight were evaluated. Hematoxylin and eosin (HE) and Nissl staining were used to observe neurocyte morphology and Nissl bodies, respectively. Apoptosis was examined using TUNEL assay, and caspase 8 activity was evaluated using spectrophotometer method. Cytochrome C-release was evaluated using flow cytometry. Western blot was used to examine Bax and Bcl-2 expression. OXC 375 mg/kg treatment significantly decreased brain weight compared to Control group in neonatal rats (P5 rats) (p<0.05). OXC administration causes histological changes of neurocytes. OXC 281.25 mg/kg or more concentration significantly decreased neurocytes counts and increased TUNEL-staining positive neurocytes compared to Control group (p<0.05). OXC 281.25 mg/kg and OXC 375 mg/kg significantly increased caspase 3 activity compared to Control group in P5 rats (p<0.05). OXC 281.25 mg/kg and OXC 375 mg/kg significantly increased Bax, Bax/Bcl-2 ratio and cytochrome C release in frontal lobes compared to Control group in P5 rats (p<0.05). Oxcarbazepine at a concentration of 281.25 mg/kg or more causes neurocyte apoptosis and developing brain damage by triggering Bax/Bcl-2 signaling pathway mediated caspase 3 activation in neonatal rats.

Air pollution and children: neural and tight junction antibodies and combustion metals, the role of barrier breakdown and brain immunity in neurodegeneration.

PubMed

Calderón-Garcidueñas, Lilian; Vojdani, Aristo; Blaurock-Busch, Eleonore; Busch, Yvette; Friedle, Albrecht; Franco-Lira, Maricela; Sarathi-Mukherjee, Partha; Martínez-Aguirre, Xavier; Park, Su-Bin; Torres-Jardón, Ricardo; D'Angiulli, Amedeo

2015-01-01

Millions of children are exposed to concentrations of air pollutants, including fine particulate matter (PM2.5), above safety standards. In the Mexico City Metropolitan Area (MCMA) megacity, children show an early brain imbalance in oxidative stress, inflammation, innate and adaptive immune response-associated genes, and blood-brain barrier breakdown. We investigated serum and cerebrospinal fluid (CSF) antibodies to neural and tight junction proteins and environmental pollutants in 139 children ages 11.91 ± 4.2 y with high versus low air pollution exposures. We also measured metals in serum and CSF. MCMA children showed significantly higher serum actin IgG, occludin/zonulin 1 IgA, IgG, myelin oligodendrocyte glycoprotein IgG and IgM (p < 0.01), myelin basic protein IgA and IgG, S-100 IgG and IgM, and cerebellar IgG (p < 0.001). Serum IgG antibodies to formaldehyde, benzene, and bisphenol A, and concentrations of Ni and Cd were significantly higher in exposed children (p < 0.001). CSF MBP antibodies and nickel concentrations were higher in MCMA children (p = 0.03). Air pollution exposure damages epithelial and endothelial barriers and is a robust trigger of tight junction and neural antibodies. Cryptic 'self' tight junction antigens can trigger an autoimmune response potentially contributing to the neuroinflammatory and Alzheimer and Parkinson's pathology hallmarks present in megacity children. The major factor determining the impact of neural antibodies is the integrity of the blood-brain barrier. Defining the air pollution linkage of the brain/immune system interactions and damage to physical and immunological barriers with short and long term neural detrimental effects to children's brains ought to be of pressing importance for public health.

Antimicrobial Peptides and Complement in Neonatal Hypoxia-Ischemia Induced Brain Damage

PubMed Central

Rocha-Ferreira, Eridan; Hristova, Mariya

2015-01-01

Hypoxic-ischemic encephalopathy (HIE) is a clinical condition in the neonate, resulting from oxygen deprivation around the time of birth. HIE affects 1–5/1000 live births worldwide and is associated with the development of neurological deficits, including cerebral palsy, epilepsy, and cognitive disabilities. Even though the brain is considered as an immune-privileged site, it has innate and adaptive immune response and can produce complement (C) components and antimicrobial peptides (AMPs). Dysregulation of cerebral expression of AMPs and C can exacerbate or ameliorate the inflammatory response within the brain. Brain ischemia triggers a prolonged inflammatory response affecting the progression of injury and secondary energy failure and involves both innate and adaptive immune systems, including immune-competent and non-competent cells. Following injury to the central nervous system (CNS), including neonatal hypoxia-ischemia (HI), resident microglia, and astroglia are the main cells providing immune defense to the brain in a stimulus-dependent manner. They can express and secrete pro-inflammatory cytokines and therefore trigger prolonged inflammation, resulting in neurodegeneration. Microglial cells express and release a wide range of inflammation-associated molecules including several components of the complement system. Complement activation following neonatal HI injury has been reported to contribute to neurodegeneration. Astrocytes can significantly affect the immune response of the CNS under pathological conditions through production and release of pro-inflammatory cytokines and immunomodulatory AMPs. Astrocytes express β-defensins, which can chemoattract and promote maturation of dendritic cells (DC), and can also limit inflammation by controlling the viability of these same DC. This review will focus on the balance of complement components and AMPs within the CNS following neonatal HI injury and the effect of that balance on the subsequent brain damage. PMID:25729383

EKG-based detection of deep brain stimulation in fMRI studies.

PubMed

Fiveland, Eric; Madhavan, Radhika; Prusik, Julia; Linton, Renee; Dimarzio, Marisa; Ashe, Jeffrey; Pilitsis, Julie; Hancu, Ileana

2018-04-01

To assess the impact of synchronization errors between the assumed functional MRI paradigm timing and the deep brain stimulation (DBS) on/off cycling using a custom electrocardiogram-based triggering system METHODS: A detector for measuring and predicting the on/off state of cycling deep brain stimulation was developed and tested in six patients in office visits. Three-electrode electrocardiogram measurements, amplified by a commercial bio-amplifier, were used as input for a custom electronics box (e-box). The e-box transformed the deep brain stimulation waveforms into transistor-transistor logic pulses, recorded their timing, and propagated it in time. The e-box was used to trigger task-based deep brain stimulation functional MRI scans in 5 additional subjects; the impact of timing accuracy on t-test values was investigated in a simulation study using the functional MRI data. Following locking to each patient's individual waveform, the e-box was shown to predict stimulation onset with an average absolute error of 112 ± 148 ms, 30 min after disconnecting from the patients. The subsecond accuracy of the e-box in predicting timing onset is more than adequate for our slow varying, 30-/30-s on/off stimulation paradigm. Conversely, the experimental deep brain stimulation onset prediction accuracy in the absence of the e-box, which could be off by as much as 4 to 6 s, could significantly decrease activation strength. Using this detector, stimulation can be accurately synchronized to functional MRI acquisitions, without adding any additional hardware in the MRI environment. Magn Reson Med 79:2432-2439, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

Pharmacokinetics, brain distribution, release and blood-brain barrier transport of Shunaoxin pills.

PubMed

Wu, Kai; Wang, Zhan-Zhang; Liu, Dan; Qi, Xian-Rong

2014-02-12

Shunaoxin pills, a traditional Chinese medicine (TCM) product, have been used to treat cerebrovascular diseases in China since 2005. The main active components of Shunaoxin pills are ferulic acid and ligustilide from Chuanxiong (Ligusticum chuanxiong Hort, Umbelliferae) and Danggui (Angelica sinensis radix, Umbelliferae). As Shunaoxin shows excellent activity in the central nervous system (CNS), the extent to which the major constituents of Shunaoxin reach the CNS should be investigated. Moreover, the in vivo-in vitro correlations (IVIVC) of the formulation should be studied to elucidate the mechanisms of action of TCM in the CNS. However, these data have not previously been available. Thus we intended to investigate what the extent when these constituents of Shunaoxin pills reach the CNS, and evaluate the IVIVC of release and pharmacokinetics. In this study, we evaluated the release of ferulic acid and ligustilide from Shunaoxin pills, and their transport across an in vitro model of the BBB. We also evaluated their pharmacokinetics and brain distribution in vivo. High-performance liquid chromatography (HPLC) was used to quantify both compounds simultaneously. Based on the release in vitro and absorption of ferulic acid and ligustilide in vivo, IVIVC permitted prediction of the pharmacokinetics of these compounds. The release of ferulic acid and ligustilide reached a platform phase within 1h. Ferulic acid and ligustilide rapidly crossed the BBB in different patterns; the transport ratio increased over time. After intragastric (i.g.) administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed into brain, which may result in a rapid onset of action. Ferulic acid and ligustilide were transported across a model BBB. After i.g. administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed in brain; this may lead to rapid pharmacological onset. The IVIVC can be used to predict in vivo pharmacokinetics from in vitro experimental results. These results provide support for the clinical use of Shunaoxin pills. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

The Psychoactive Designer Drug and Bath Salt Constituent MDPV Causes Widespread Disruption of Brain Functional Connectivity

PubMed Central

Colon-Perez, Luis M; Tran, Kelvin; Thompson, Khalil; Pace, Michael C; Blum, Kenneth; Goldberger, Bruce A; Gold, Mark S; Bruijnzeel, Adriaan W; Setlow, Barry; Febo, Marcelo

2016-01-01

The abuse of ‘bath salts' has raised concerns because of their adverse effects, which include delirium, violent behavior, and suicide ideation in severe cases. The bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) has been closely linked to these and other adverse effects. The abnormal behavioral pattern produced by acute high-dose MDPV intake suggests possible disruptions of neural communication between brain regions. Therefore, we determined if MDPV exerts disruptive effects on brain functional connectivity, particularly in areas of the prefrontal cortex. Male rats were imaged following administration of a single dose of MDPV (0.3, 1.0, or 3.0 mg/kg) or saline. Resting state brain blood oxygenation level-dependent (BOLD) images were acquired at 4.7 T. To determine the role of dopamine transmission in MDPV-induced changes in functional connectivity, a group of rats received the dopamine D1/D2 receptor antagonist cis-flupenthixol (0.5 mg/kg) 30 min before MDPV. MDPV dose-dependently reduced functional connectivity. Detailed analysis of its effects revealed that connectivity between frontal cortical and striatal areas was reduced. This included connectivity between the prelimbic prefrontal cortex and other areas of the frontal cortex and the insular cortex with hypothalamic, ventral, and dorsal striatal areas. Although the reduced connectivity appeared widespread, connectivity between these regions and somatosensory cortex was not as severely affected. Dopamine receptor blockade did not prevent the MDPV-induced decrease in functional connectivity. The results provide a novel signature of MDPV's in vivo mechanism of action. Reduced brain functional connectivity has been reported in patients suffering from psychosis and has been linked to cognitive dysfunction, audiovisual hallucinations, and negative affective states akin to those reported for MDPV-induced intoxication. The present results suggest that disruption of functional connectivity networks involving frontal cortical and striatal regions could contribute to the adverse effects of MDPV. PMID:26997298

Effects of expectancy and abstinence on the neural response to smoking cues in cigarette smokers: an fMRI study.

PubMed

McBride, Dharma; Barrett, Sean P; Kelly, Jared T; Aw, Andrew; Dagher, Alain

2006-12-01

Cues associated with drug taking can trigger relapse, drug seeking, and craving in addicted individuals. Behavioral studies suggest that drug availability and withdrawal can affect the individual response to drug cues. Moreover, the importance of subjective craving in cue-induced relapse has been questioned and an alternative model put forward according to which drug cues trigger habitual drug-seeking behaviors independently of craving. We used functional magnetic resonance imaging to compare the brain response to smoking and control videotapes in 20 healthy smokers, while varying their expectancy to smoke and abstinence levels. The neural response to cigarette cues was strongly modulated by expectancy and, to a lesser extent, abstinence. In people expecting to smoke immediately after the scan, smoking cues activated brain areas implicated in arousal, attention, and cognitive control. However, when subjects knew they would not be allowed to smoke for 4 h, there was almost no brain activation in response to smoking cues, despite equivalent reported levels of craving. In the dorsolateral prefrontal cortex, the neural response was a function of both craving and expectancy. Thalamo-cingulate connectivity, thought to be an index of arousal, was greater during expectancy than nonexpectancy. Our findings confirm the importance of expectancy in the neural response to drug cues, and lend support to the theory that these cues act on brain areas involved in arousal and attention.

Sex differences in the developing brain as a source of inherent risk.

PubMed

McCarthy, Margaret M

2016-12-01

Brain development diverges in males and females in response to androgen production by the fetal testis. This sexual differentiation of the brain occurs during a sensitive window and induces enduring neuroanatomical and physiological changes that profoundly impact behavior. What we know about the contribution of sex chromosomes is still emerging, highlighting the need to integrate multiple factors into understanding sex differences, including the importance of context. The cellular mechanisms are best modeled in rodents and have provided both unifying principles and surprising specifics. Markedly distinct signaling pathways direct differentiation in specific brain regions, resulting in mosaicism of relative maleness, femaleness, and sameness through-out the brain, while canalization both exaggerates and constrains sex differences. Non-neuronal cells and inflammatory mediators are found in greater number and at higher levels in parts of male brains. This higher baseline of inflammation is speculated to increase male vulnerability to developmental neuropsychiatric disorders that are triggered by inflammation.

Near-infrared deep brain stimulation via upconversion nanoparticle–mediated optogenetics

NASA Astrophysics Data System (ADS)

Chen, Shuo; Weitemier, Adam Z.; Zeng, Xiao; He, Linmeng; Wang, Xiyu; Tao, Yanqiu; Huang, Arthur J. Y.; Hashimotodani, Yuki; Kano, Masanobu; Iwasaki, Hirohide; Parajuli, Laxmi Kumar; Okabe, Shigeo; Teh, Daniel B. Loong; All, Angelo H.; Tsutsui-Kimura, Iku; Tanaka, Kenji F.; Liu, Xiaogang; McHugh, Thomas J.

2018-02-01

Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.

Addiction and brain reward and antireward pathways.

PubMed

Gardner, Eliot L

2011-01-01

Addictive drugs have in common that they are voluntarily self-administered by laboratory animals (usually avidly), and that they enhance the functioning of the reward circuitry of the brain (producing the 'high' that the drug user seeks). The core reward circuitry consists of an 'in-series' circuit linking the ventral tegmental area, nucleus accumbens and ventral pallidum via the medial forebrain bundle. Although originally believed to simply encode the set point of hedonic tone, these circuits are now believed to be functionally far more complex, also encoding attention, expectancy of reward, disconfirmation of reward expectancy, and incentive motivation. 'Hedonic dysregulation' within these circuits may lead to addiction. The 'second-stage' dopaminergic component in this reward circuitry is the crucial addictive-drug-sensitive component. All addictive drugs have in common that they enhance (directly or indirectly or even transsynaptically) dop-aminergic reward synaptic function in the nucleus accumbens. Drug self-administration is regulated by nucleus accumbens dopamine levels, and is done to keep nucleus accumbens dopamine within a specific elevated range (to maintain a desired hedonic level). For some classes of addictive drugs (e.g. opiates), tolerance to the euphoric effects develops with chronic use. Postuse dysphoria then comes to dominate reward circuit hedonic tone, and addicts no longer use drugs to get high, but simply to get back to normal ('get straight'). The brain circuits mediating the pleasurable effects of addictive drugs are anatomically, neurophysiologically and neurochemically different from those mediating physical dependence, and from those mediating craving and relapse. There are important genetic variations in vulnerability to drug addiction, yet environmental factors such as stress and social defeat also alter brain-reward mechanisms in such a manner as to impart vulnerability to addiction. In short, the 'bio-psycho-social' model of etiology holds very well for addiction. Addiction appears to correlate with a hypodopaminergic dysfunctional state within the reward circuitry of the brain. Neuroimaging studies in humans add credence to this hypothesis. Credible evidence also implicates serotonergic, opioid, endocannabinoid, GABAergic and glutamatergic mechanisms in addiction. Critically, drug addiction progresses from occasional recreational use to impulsive use to habitual compulsive use. This correlates with a progression from reward-driven to habit-driven drug-seeking behavior. This behavioral progression correlates with a neuroanatomical progression from ventral striatal (nucleus accumbens) to dorsal striatal control over drug-seeking behavior. The three classical sets of craving and relapse triggers are (a) reexposure to addictive drugs, (b) stress, and (c) reexposure to environmental cues (people, places, things) previously associated with drug-taking behavior. Drug-triggered relapse involves the nucleus accumbens and the neurotransmitter dopamine. Stress-triggered relapse involves (a) the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the neurotransmitter corticotrophin-releasing factor, and (b) the lateral tegmental noradrenergic nuclei of the brain stem and the neurotransmitter norepinephrine. Cue-triggered relapse involves the basolateral nucleus of the amygdala, the hippocampus and the neurotransmitter glutamate. Knowledge of the neuroanatomy, neurophysiology, neurochemistry and neuropharmacology of addictive drug action in the brain is currently producing a variety of strategies for pharmacotherapeutic treatment of drug addiction, some of which appear promising. Copyright © 2011 S. Karger AG, Basel.

Black Seed (Nigella Sativa) and its Constituent Thymoquinone as an Antidote or a Protective Agent Against Natural or Chemical Toxicities

PubMed Central

Tavakkoli, Alireza; Ahmadi, Ali; Razavi, Bibi Marjan; Hosseinzadeh, Hossein

2017-01-01

Nigella sativa (N. sativa), which belongs to the botanical family of Ranunculaceae, is a widely used medicinal plant all over the world. N. sativa seeds and oil have been used in the treatment of different diseases. Various studies on N. sativa have been carried out and a broad spectrum of its pharmacological actions have been established which include antioxidant, antidiabetic, anticancer, antitussive, immunomodulator, analgesic, antimicrobial, anti-inflammatory, spasmolytic, and bronchodilator. This is also indicated that the majority of the therapeutic effects of N. sativa are due to the presence of thymoquinone (TQ) that is the main bioactive constituent of the essential oil. According to several lines of evidence, the protective effects of this plant and its main constituent in different tissues including brain, heart, liver, kidney, and lung have been proved against some toxic agents either natural or chemical toxins in animal studies. In this review article, several in-vitro and animal studies in scientific databases which investigate the antidotal and protective effects of N. sativa and its main constituents against natural and chemical induced toxicities are introduced. Because human reports are rare, further studies are required to determine the efficacy of this plant as an antidote or protective agent in human intoxication. PMID:29844772

Cardiovascular effects of air pollution.

PubMed

Brook, Robert D

2008-09-01

Air pollution is a heterogeneous mixture of gases, liquids and PM (particulate matter). In the modern urban world, PM is principally derived from fossil fuel combustion with individual constituents varying in size from a few nanometres to 10 microm in diameter. In addition to the ambient concentration, the pollution source and chemical composition may play roles in determining the biological toxicity and subsequent health effects. Nevertheless, studies from across the world have consistently shown that both short- and long-term exposures to PM are associated with a host of cardiovascular diseases, including myocardial ischaemia and infarctions, heart failure, arrhythmias, strokes and increased cardiovascular mortality. Evidence from cellular/toxicological experiments, controlled animal and human exposures and human panel studies have demonstrated several mechanisms by which particle exposure may both trigger acute events as well as prompt the chronic development of cardiovascular diseases. PM inhaled into the pulmonary tree may instigate remote cardiovascular health effects via three general pathways: instigation of systemic inflammation and/or oxidative stress, alterations in autonomic balance, and potentially by direct actions upon the vasculature of particle constituents capable of reaching the systemic circulation. In turn, these responses have been shown to trigger acute arterial vasoconstriction, endothelial dysfunction, arrhythmias and pro-coagulant/thrombotic actions. Finally, long-term exposure has been shown to enhance the chronic genesis of atherosclerosis. Although the risk to one individual at any single time point is small, given the prodigious number of people continuously exposed, PM air pollution imparts a tremendous burden to the global public health, ranking it as the 13th leading cause of morality (approx. 800,000 annual deaths).

Age-related cognitive decline in hypercholesterolemic LDL receptor knockout mice (LDLr-/-): evidence of antioxidant imbalance and increased acetylcholinesterase activity in the prefrontal cortex.

PubMed

Moreira, Eduardo Luiz Gasnhar; de Oliveira, Jade; Nunes, Jean Costa; Santos, Danúbia Bonfanti; Nunes, Fernanda Costa; Vieira, Daniella Serafim Couto; Ribeiro-do-Valle, Rosa Maria; Pamplona, Fabrício Alano; de Bem, Andreza Fabro; Farina, Marcelo; Walz, Roger; Prediger, Rui Daniel

2012-01-01

There is increasing evidence that hypercholesterolemia during midlife may represent a predictor of subsequent mild cognitive impairments and dementia decades later. However, the exact mechanism underlying this phenomenon remains unknown since plasmatic cholesterol is not able to cross the blood-brain barrier. In the present study, we evaluated the hypothesis that cognitive impairments triggered by hypercholesterolemia during aging may be related to brain oxidative stress and altered brain acetylcholinesterase (AChE) activity. We also performed a neuropathological investigation in order to analyze whether the cognitive impairments may be associated with stroke-related features. To address these questions we used three- and fourteen-month-old low-density lipoprotein receptor-deficient mice (LDLr-/-). The current findings provide new evidence that aged LDLr-/- mice, exposed to over three-fold cholesterol levels from early life, show working, spatial reference, and procedural memory impairments, without alterations in motor function. Antioxidant imbalance and oxidative damage were evidenced by a marked increase in lipid peroxidation (thiobarbituric acid reactive substances levels) and glutathione metabolism (increase in glutathione levels, glutathione reductase, and glutathione peroxidase activities) together with a significant increase in the AChE activity in the prefrontal cortex of aged hypercholesterolemic LDLr-/- mice. Notably, hypercholesterolemia was not related to brain infarcts and neurodegeneration in mice, independent of their age. These observations provide new evidence that hypercholesterolemia during aging triggers cognitive impairments on different types of learning and memory, accompanied by antioxidant imbalance, oxidative damage, and alterations of cholinergic signaling in brain areas associated with learning and memory processes, particularly in the prefrontal cortex.

Target innervation is necessary for neuronal polyploidization in the terrestrial slug Limax.

PubMed

Matsuo, Ryota; Yamagishi, Miki; Wakiya, Kyoko; Tanaka, Yoko; Ito, Etsuro

2013-05-30

The brain of gastropod mollusks contains many giant neurons with polyploid genomic DNAs. Such DNAs are generated through repeated DNA endoreplication during body growth. However, it is not known what triggers DNA endoreplication in neurons. There are two possibilities: (1) DNAs are replicated in response to some unknown molecules in the hemolymph that reflect the nutritive status of the animal; or (2) DNAs are replicated in response to some unknown factors that are retrogradely transported through axons from the innervated target organs. We first tested whether hemolymph with rich nutrition could induce DNA endoreplication. We tested whether the transplanted brain exhibits enhanced DNA endoreplication like an endogenous brain does when transplanted into the homocoel of the body of a slug whose body growth is promoted by an increased food supply. However, no enhancement was observed in the frequency of DNA endoreplication when we compared the transplanted brains in the growth-promoted and growth-suppressed host slugs, suggesting that the humoral environment is irrelevant to triggering the body growth-dependent DNA endoreplication. Next, we tested the requirement of target innervation by surgically dissecting a unilateral posterior pedal nerve of an endogenous brain. Substantially lower number of neurons exhibited DNA endoreplication in the pedal ganglion ipsilateral to the dissected nerve. These results support the view that enhanced DNA endoreplication is mediated by target innervation and is not brought about through the direct effect of humoral factors in the hemolymph during body growth. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013. Copyright © 2013 Wiley Periodicals, Inc.

Gene Transfer of Brain-derived Neurotrophic Factor (BDNF) Prevents Neurodegeneration Triggered by FXN Deficiency.

PubMed

Katsu-Jiménez, Yurika; Loría, Frida; Corona, Juan Carlos; Díaz-Nido, Javier

2016-05-01

Friedreich's ataxia is a predominantly neurodegenerative disease caused by recessive mutations that produce a deficiency of frataxin (FXN). Here, we have used a herpesviral amplicon vector carrying a gene encoding for brain-derived neurotrophic factor (BDNF) to drive its overexpression in neuronal cells and test for its effect on FXN-deficient neurons both in culture and in the mouse cerebellum in vivo. Gene transfer of BDNF to primary cultures of mouse neurons prevents the apoptosis which is triggered by the knockdown of FXN gene expression. This neuroprotective effect of BDNF is also observed in vivo in a viral vector-based knockdown mouse cerebellar model. The injection of a lentiviral vector carrying a minigene encoding for a FXN-specific short hairpin ribonucleic acid (shRNA) into the mouse cerebellar cortex triggers a FXN deficit which is accompanied by significant apoptosis of granule neurons as well as loss of calbindin in Purkinje cells. These pathological changes are accompanied by a loss of motor coordination of mice as assayed by the rota-rod test. Coinjection of a herpesviral vector encoding for BDNF efficiently prevents both the development of cerebellar neuropathology and the ataxic phenotype. These data demonstrate the potential therapeutic usefulness of neurotrophins like BDNF to protect FXN-deficient neurons from degeneration.

Tracing Activity Across the Whole Brain Neural Network with Optogenetic Functional Magnetic Resonance Imaging

PubMed Central

Lee, Jin Hyung

2011-01-01

Despite the overwhelming need, there has been a relatively large gap in our ability to trace network level activity across the brain. The complex dense wiring of the brain makes it extremely challenging to understand cell-type specific activity and their communication beyond a few synapses. Recent development of the optogenetic functional magnetic resonance imaging (ofMRI) provides a new impetus for the study of brain circuits by enabling causal tracing of activities arising from defined cell types and firing patterns across the whole brain. Brain circuit elements can be selectively triggered based on their genetic identity, cell body location, and/or their axonal projection target with temporal precision while the resulting network response is monitored non-invasively with unprecedented spatial and temporal accuracy. With further studies including technological innovations to bring ofMRI to its full potential, ofMRI is expected to play an important role in our system-level understanding of the brain circuit mechanism. PMID:22046160

Is biological aging accelerated in drug addiction?

PubMed

Bachi, Keren; Sierra, Salvador; Volkow, Nora D; Goldstein, Rita Z; Alia-Klein, Nelly

2017-02-01

Drug-addiction may trigger early onset of age-related disease, due to drug-induced multi-system toxicity and perilous lifestyle, which remains mostly undetected and untreated. We present the literature on pathophysiological processes that may hasten aging and its relevance to addiction, including: oxidative stress and cellular aging, inflammation in periphery and brain, decline in brain volume and function, and early onset of cardiac, cerebrovascular, kidney, and liver disease. Timely detection of accelerated aging in addiction is crucial for the prevention of premature morbidity and mortality.

Content of endoplasmic reticulum and Golgi complex membranes positively correlates with the proliferative status of brain cells.

PubMed

Silvestre, David C; Maccioni, Hugo J F; Caputto, Beatriz L

2009-03-01

Although the molecular and cellular basis of particular events that lead to the biogenesis of membranes in eukaryotic cells has been described in detail, understanding of the intrinsic complexity of the pleiotropic response by which a cell adjusts the overall activity of its endomembrane system to accomplish these requirements is limited. Here we carried out an immunocytochemical and biochemical examination of the content and quality of the endoplasmic reticulum (ER) and Golgi apparatus membranes in two in vivo situations characterized by a phase of active cell proliferation followed by a phase of declination in proliferation (rat brain tissue at early and late developmental stages) or by permanent active proliferation (gliomas and their most malignant manifestation, glioblastomas multiforme). It was found that, in highly proliferative phases of brain development (early embryo brain cells), the content of ER and Golgi apparatus membranes, measured as total lipid phosphorous content, is higher than in adult brain cells. In addition, the concentration of protein markers of ER and Golgi is also higher in early embryo brain cells and in human glioblastoma multiforme cells than in adult rat brain or in nonpathological human brain cells. Results suggest that the amount of endomembranes and the concentration of constituent functional proteins diminish as cells decline in their proliferative activity.

Food and drug cues activate similar brain regions: a meta-analysis of functional MRI studies.

PubMed

Tang, D W; Fellows, L K; Small, D M; Dagher, A

2012-06-06

In healthy individuals, food cues can trigger hunger and feeding behavior. Likewise, smoking cues can trigger craving and relapse in smokers. Brain imaging studies report that structures involved in appetitive behaviors and reward, notably the insula, striatum, amygdala and orbital frontal cortex, tend to be activated by both visual food and smoking cues. Here, by carrying out a meta-analysis of human neuro-imaging studies, we investigate the neural network activated by: 1) food versus neutral cues (14 studies, 142 foci) 2) smoking versus neutral cues (15 studies, 176 foci) 3) smoking versus neutral cues when correlated with craving scores (7 studies, 108 foci). PubMed was used to identify cue-reactivity imaging studies that compared brain response to visual food or smoking cues to neutral cues. Fourteen articles were identified for the food meta-analysis and fifteen articles were identified for the smoking meta-analysis. Six articles were identified for the smoking cue correlated with craving analysis. Meta-analyses were carried out using activation likelihood estimation. Food cues were associated with increased blood oxygen level dependent (BOLD) response in the left amygdala, bilateral insula, bilateral orbital frontal cortex, and striatum. Smoking cues were associated with increased BOLD signal in the same areas, with the exception of the insula. However, the smoking meta-analysis of brain maps correlating cue-reactivity with subjective craving did identify the insula, suggesting that insula activation is only found when craving levels are high. The brain areas identified here are involved in learning, memory and motivation, and their cue-induced activity is an index of the incentive salience of the cues. Using meta-analytic techniques to combine a series of studies, we found that food and smoking cues activate comparable brain networks. There is significant overlap in brain regions responding to conditioned cues associated with natural and drug rewards. Copyright © 2012 Elsevier Inc. All rights reserved.

The endocannabinoid system and the brain.

PubMed

Mechoulam, Raphael; Parker, Linda A

2013-01-01

The psychoactive constituent in cannabis, Δ(9)-tetrahydrocannabinol (THC), was isolated in the mid-1960s, but the cannabinoid receptors, CB1 and CB2, and the major endogenous cannabinoids (anandamide and 2-arachidonoyl glycerol) were identified only 20 to 25 years later. The cannabinoid system affects both central nervous system (CNS) and peripheral processes. In this review, we have tried to summarize research--with an emphasis on recent publications--on the actions of the endocannabinoid system on anxiety, depression, neurogenesis, reward, cognition, learning, and memory. The effects are at times biphasic--lower doses causing effects opposite to those seen at high doses. Recently, numerous endocannabinoid-like compounds have been identified in the brain. Only a few have been investigated for their CNS activity, and future investigations on their action may throw light on a wide spectrum of brain functions.

Signaling through three chemokine receptors triggers the migration of transplanted neural precursor cells in a model of multiple sclerosis.

PubMed

Cohen, Mikhal E; Fainstein, Nina; Lavon, Iris; Ben-Hur, Tamir

2014-09-01

Multiple sclerosis (MS) is a multifocal disease, and precursor cells need to migrate into the multiple lesions in order to exert their therapeutic effects. Therefore, cell migration is a crucial element in regenerative processes in MS, dictating the route of delivery, when cell transplantation is considered. We have previously shown that inflammation triggers migration of multi-potential neural precursor cells (NPCs) into the white matter of experimental autoimmune encephalomyelitis (EAE) rodents, a widely used model of MS. Here we investigated the molecular basis of this attraction. NPCs were grown from E13 embryonic mouse brains and transplanted into the lateral cerebral ventricles of EAE mice. Transplanted NPC migration was directed by three tissue-derived chemokines. Stromal cell-derived factor-1α, monocyte chemo-attractant protein-1 and hepatocyte growth factor were expressed in the EAE brain and specifically in microglia and astrocytes. Their cognate receptors, CXCR4, CCR2 or c-Met were constitutively expressed on NPCs. Selective blockage of CXCR4, CCR2 or c-Met partially inhibited NPC migration in EAE brains. Blocking all three receptors had an additive effect and resulted in profound inhibition of NPC migration, as compared to extensive migration of control NPCs. The inflammation-triggered NPC migration into white matter tracts was dependent on a motile NPC phenotype. Specifically, depriving NPCs from epidermal growth factor (EGF) prevented the induction of glial commitment and a motile phenotype (as indicated by an in vitro motility assay), hampering their response to neuroinflammation. In conclusion, signaling via three chemokine systems accounts for most of the inflammation-induced, tissue-derived attraction of transplanted NPCs into white matter tracts during EAE. Copyright © 2014. Published by Elsevier B.V.

Triggering Receptor Expressed on Myeloid Cells 2 Deficiency Alters Acute Macrophage Distribution and Improves Recovery after Traumatic Brain Injury.

PubMed

Saber, Maha; Kokiko-Cochran, Olga; Puntambekar, Shweta S; Lathia, Justin D; Lamb, Bruce T

2017-01-15

Traumatic brain injury (TBI) affects 1.7 million persons annually in the United States (Centers for Disease Control and Prevention). There is increasing evidence that persons exposed to TBI have increased risk of the development of multiple neurodegenerative conditions, including Alzheimer disease (AD). TBI triggers a strong neuroinflammatory response characterized by astrogliosis, activation of microglia, and infiltration of peripheral monocytes. Recent evidence suggests that alterations in innate immunity promote neurodegeneration. This includes genetic studies demonstrating that mutations in triggering receptor expressed on myeloid cells 2 (TREM2) is associated with a higher risk for not only AD but also multiple neurodegenerative diseases. To examine whether TREM2 deficiency affects pathological outcomes of TBI, Trem2 knockout (Trem2 -/- ) and C57BL/6J (B6) mice were given a lateral fluid percussion injury (FPI) and sacrificed at 3 and 120 days post-injury (DPI) to look at both acute and chronic consequences of TREM2 deficiency. Notably, at 3 DPI, B6 mice exposed to TBI exhibited increased expression of TREM2 in the brain. Further, Trem2 -/- mice exposed to TBI exhibited enhanced macrophage activation near the lesion, but significantly less macrophage activation away from the lesion when compared with B6 mice exposed to TBI. In addition, at 120 DPI, Trem2 -/- mice exposed to TBI demonstrated reduced hippocampal atrophy and rescue of TBI-induced behavioral changes when compared with B6 mice exposed to TBI. Taken together, this study suggests that TREM2 deficiency influences both acute and chronic responses to TBI, leading to an altered macrophage response at early time points, and improved pathological and functional outcomes at later time points.

Cinnamon (Cinnamomum zeylanicum) as an antidote or a protective agent against natural or chemical toxicities: a review.

PubMed

Dorri, Mahyar; Hashemitabar, Shirin; Hosseinzadeh, Hossein

2018-01-10

Cinnamon (Cinnamomum zeylanicum, Lauraceae) is a food additive greatly used for its taste. However, recently this medicinal plant has been brought to attention due to its medical effects. Cinnamon has constituents such as cinnamaldehyde and cinnamic acid that offers some health benefits including antioxidant and free-radical scavenging properties, lowering of blood glucose, anti-cholesterolemic, analgesic, antimicrobial, anti-inflammatory, anti-yeast, anti-secretagogue, and anti-gastric ulcer effects. This review summarizes various in vitro and animal studies on the protective effects of cinnamon against natural and chemical toxins. These studies consider the antidotal and/or protective effects of cinnamon and its major constituents against natural toxins and chemical-induced toxicities. It has been mentioned that cinnamon and its main constituents can ameliorate the toxicity of chemical toxins in liver, kidney, blood, brain, embryo, reproductive system, heart, spleen in part through antioxidant effect, radical scavenging, reducing lipid peroxidation, anti-inflammatory, fungistatic and fungicidal activities, modulation of CK-MB, LDH, TNF-α, IL-6, mitogen-activated protein kinase (MAPK), and nuclear factor-ĸB (NF-ĸB) signaling pathways.

Microvascular perfusion during focal vasogenic brain edema: a scanning laser fluorescence microscopy study.

PubMed

Lindsberg, P J; Sirén, A L; Hallenbeck, J M

1997-01-01

Controversy exists about the effect of tissue edema on cerebral microcirculation. High spatial resolution is required for observation of extravasation and microcirculation during focal vasogenic edema formation. To study the relationship between tissue edema and perfusion, we developed a technique for simultaneous visualization of extravasation and microvessel perfusion in rats. Focal intracortical microvascular injury was generated with a 1-sec Nd-YAG laser pulse. Evans blue albumin (EBA) was infused 30 min before decapitation to study extravasation and FITC-dextran was injected 30 sec prior to decapitation to examine microvessel perfusion. Computerized scanning laser-excited fluorescence microscopy followed by high resolution image analysis permitted quantitative assessment of both parameters on single fresh-frozen brain sections. Studied at 30 min (3.66 +/- 0.15 mm), 2 hr (4.14 +/- 0.08 mm, P < .05), and 8 hr (4.69 +/- 0.18 mm, P < .01) after injury, the diameter of the circular, sharply demarcated zone of EBA-extravasation increased progressively. At 30 min, microvessels at a zone surrounding the area of EBA-extravasation contained 69 +/- 14% (P < .05) more fluorescent FITC-filling than in the control hemisphere, but the density of perfused microvessels was unchanged. At 2 hr, secondary tissue changes had already occurred in a zone surrounding the initial laser lesion. While severe reduction in the density (-76 +/- 13%, P < .05) of perfused microvessels was observed within 400 to 240 microm inside the border of EBA extravasation, perfusion indexes were normal despite the presence of extravasated plasma constituents within 0-80 microm from the border. In a narrow zone (80 microm) outside the border of extravasation, individual microvessels contained 34 +/- 9% (P < .01) less FITC-fluorescence than those in a homologous area of the uninjured contralateral hemisphere. This report demonstrates the feasibility of simultaneous measurement and high-resolution mapping of indices of microvascular perfusion (density, filling) and extravasated plasma constituents in damaged and intact brain areas. In this model, the presence of extravasated plasma constituents the size of proteins did not immediately influence indices of cortical microcirculation. However, microvascular perfusion may be perturbed surrounding such an area of advancing vasogenic edema formation.

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

Effect of salt acclimation on digitalis-like compounds in the toad.

PubMed

Lichtstein, D; Gati, I; Babila, T; Haver, E; Katz, U

1991-01-23

Digitalis-like compounds (DLC) were shown to be a normal constituent of the skin and plasma of toads. In order to assess the possible physiological role of these compounds in the toad, their levels were determined in the brain, plasma and skin following acclimation in different NaCl solutions. We demonstrate that an increase in salt concentrations in the animal medium from 0 to 1.2% decreased the levels of DLC in the brain by 50% without altering significantly its levels in the plasma and skin. An increase in medium salt concentration to 1.5% resulted in a 50% increase of DLC levels in the skin without changing its levels in the plasma or brain. These results suggest that skin and brain DLC may participate in the long-term salt and water homeostasis in the toad, while the plasma compound either participates in the short-term regulations of salt and water homeostasis or have some other, unknown, function.

Tidal influence through LOD variations on the temporal distribution of earthquake occurrences

NASA Astrophysics Data System (ADS)

Varga, P.; Gambis, D.; Bizouard, Ch.; Bus, Z.; Kiszely, M.

2006-10-01

Stresses generated by the body tides are very small at the depth of crustal earth- quakes (~10^2 N/m2). The maximum value of the lunisolar stress within the depth range of earthquakes is 10^3 N/m2 (at depth of about 600 km). Surface loads, due to oceanic tides, in coastal areas are ~ 104 N/m2. These influences are however too small to affect the outbreak time of seismic events. Authors show the effect on time distribution of seismic activity due to ΔLOD generated by zonal tides for the case of Mf, Mm, Ssa and Sa tidal constituents can be much more effective to trigger earthquakes. According to this approach we show that the tides are not directly triggering the seismic events but through the generated length of day variations. That is the reason why in case of zonal tides a correlation of the lunisolar effect and seismic activity exists, what is not the case for the tesseral and sectorial tides.

Gap Junction Proteins in the Blood-Brain Barrier Control Nutrient-Dependent Reactivation of Drosophila Neural Stem Cells

PubMed Central

Spéder, Pauline; Brand, Andrea H.

2014-01-01

Summary Neural stem cells in the adult brain exist primarily in a quiescent state but are reactivated in response to changing physiological conditions. How do stem cells sense and respond to metabolic changes? In the Drosophila CNS, quiescent neural stem cells are reactivated synchronously in response to a nutritional stimulus. Feeding triggers insulin production by blood-brain barrier glial cells, activating the insulin/insulin-like growth factor pathway in underlying neural stem cells and stimulating their growth and proliferation. Here we show that gap junctions in the blood-brain barrier glia mediate the influence of metabolic changes on stem cell behavior, enabling glia to respond to nutritional signals and reactivate quiescent stem cells. We propose that gap junctions in the blood-brain barrier are required to translate metabolic signals into synchronized calcium pulses and insulin secretion. PMID:25065772

The brain of the horse: weight and cephalization quotients.

PubMed

Cozzi, Bruno; Povinelli, Michele; Ballarin, Cristina; Granato, Alberto

2014-01-01

The horse is a common domestic animal whose anatomy has been studied since the XVI century. However, a modern neuroanatomy of this species does not exist and most of the data utilized in textbooks and reviews derive from single specimens or relatively old literature. Here, we report information on the brain of Equus caballus obtained by sampling 131 horses, including brain weight (as a whole and subdivided into its constituents), encephalization quotient (EQ), and cerebellar quotient (CQ), and comparisons with what is known about other relevant species. The mean weight of the fresh brains in our experimental series was 598.63 g (SEM ± 7.65), with a mean body weight of 514.12 kg (SEM ± 15.42). The EQ was 0.78 and the CQ was 0.841. The data we obtained indicate that the horse possesses a large, convoluted brain, with a weight similar to that of other hoofed species of like mass. However, the shape of the brain, the noteworthy folding of the neocortex, and the peculiar longitudinal distribution of the gyri suggest an evolutionary specificity at least partially separate from that of the Cetartiodactyla (even-toed mammals and cetaceans) with whom Perissodactyla (odd-toed mammals) are often grouped.

DHA Effects in Brain Development and Function

PubMed Central

Lauritzen, Lotte; Brambilla, Paolo; Mazzocchi, Alessandra; Harsløf, Laurine B. S.; Ciappolino, Valentina; Agostoni, Carlo

2016-01-01

Docosahexaenoic acid (DHA) is a structural constituent of membranes specifically in the central nervous system. Its accumulation in the fetal brain takes place mainly during the last trimester of pregnancy and continues at very high rates up to the end of the second year of life. Since the endogenous formation of DHA seems to be relatively low, DHA intake may contribute to optimal conditions for brain development. We performed a narrative review on research on the associations between DHA levels and brain development and function throughout the lifespan. Data from cell and animal studies justify the indication of DHA in relation to brain function for neuronal cell growth and differentiation as well as in relation to neuronal signaling. Most data from human studies concern the contribution of DHA to optimal visual acuity development. Accumulating data indicate that DHA may have effects on the brain in infancy, and recent studies indicate that the effect of DHA may depend on gender and genotype of genes involved in the endogenous synthesis of DHA. While DHA levels may affect early development, potential effects are also increasingly recognized during childhood and adult life, suggesting a role of DHA in cognitive decline and in relation to major psychiatric disorders. PMID:26742060

DHA Effects in Brain Development and Function.

PubMed

Lauritzen, Lotte; Brambilla, Paolo; Mazzocchi, Alessandra; Harsløf, Laurine B S; Ciappolino, Valentina; Agostoni, Carlo

2016-01-04

Docosahexaenoic acid (DHA) is a structural constituent of membranes specifically in the central nervous system. Its accumulation in the fetal brain takes place mainly during the last trimester of pregnancy and continues at very high rates up to the end of the second year of life. Since the endogenous formation of DHA seems to be relatively low, DHA intake may contribute to optimal conditions for brain development. We performed a narrative review on research on the associations between DHA levels and brain development and function throughout the lifespan. Data from cell and animal studies justify the indication of DHA in relation to brain function for neuronal cell growth and differentiation as well as in relation to neuronal signaling. Most data from human studies concern the contribution of DHA to optimal visual acuity development. Accumulating data indicate that DHA may have effects on the brain in infancy, and recent studies indicate that the effect of DHA may depend on gender and genotype of genes involved in the endogenous synthesis of DHA. While DHA levels may affect early development, potential effects are also increasingly recognized during childhood and adult life, suggesting a role of DHA in cognitive decline and in relation to major psychiatric disorders.

Neuronal Representation of Social Information in the Medial Amygdala of Awake Behaving Mice.

PubMed

Li, Ying; Mathis, Alexander; Grewe, Benjamin F; Osterhout, Jessica A; Ahanonu, Biafra; Schnitzer, Mark J; Murthy, Venkatesh N; Dulac, Catherine

2017-11-16

The medial amygdala (MeA) plays a critical role in processing species- and sex-specific signals that trigger social and defensive behaviors. However, the principles by which this deep brain structure encodes social information is poorly understood. We used a miniature microscope to image the Ca 2+ dynamics of large neural ensembles in awake behaving mice and tracked the responses of MeA neurons over several months. These recordings revealed spatially intermingled subsets of MeA neurons with distinct temporal dynamics. The encoding of social information in the MeA differed between males and females and relied on information from both individual cells and neuronal populations. By performing long-term Ca 2+ imaging across different social contexts, we found that sexual experience triggers lasting and sex-specific changes in MeA activity, which, in males, involve signaling by oxytocin. These findings reveal basic principles underlying the brain's representation of social information and its modulation by intrinsic and extrinsic factors. Copyright © 2017 Elsevier Inc. All rights reserved.

Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis

PubMed Central

Schuchmann, Sebastian; Schmitz, Dietmar; Rivera, Claudio; Vanhatalo, Sampsa; Salmen, Benedikt; Mackie, Ken; Sipilä, Sampsa T; Voipio, Juha; Kaila, Kai

2006-01-01

Febrile seizures are frequent during early childhood, and prolonged (complex) febrile seizures are associated with an increased susceptibility to temporal lobe epilepsy. The pathophysiological consequences of febrile seizures have been extensively studied in rat pups exposed to hyperthermia. The mechanisms that trigger these seizures are unknown, however. A rise in brain pH is known to enhance neuronal excitability. Here we show that hyperthermia causes respiratory alkalosis in the immature brain, with a threshold of 0.2–0.3 pH units for seizure induction. Suppressing alkalosis with 5% ambient CO2 abolished seizures within 20 s. CO2 also prevented two long-term effects of hyperthermic seizures in the hippocampus: the upregulation of the Ih current and the upregulation of CB1 receptor expression. The effects of hyperthermia were closely mimicked by intraperitoneal injection of bicarbonate. Our work indicates a mechanism for triggering hyperthermic seizures and suggests new strategies in the research and therapy of fever-related epileptic syndromes. PMID:16819552

Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis.

PubMed

Schuchmann, Sebastian; Schmitz, Dietmar; Rivera, Claudio; Vanhatalo, Sampsa; Salmen, Benedikt; Mackie, Ken; Sipilä, Sampsa T; Voipio, Juha; Kaila, Kai

2006-07-01

Febrile seizures are frequent during early childhood, and prolonged (complex) febrile seizures are associated with an increased susceptibility to temporal lobe epilepsy. The pathophysiological consequences of febrile seizures have been extensively studied in rat pups exposed to hyperthermia. The mechanisms that trigger these seizures are unknown, however. A rise in brain pH is known to enhance neuronal excitability. Here we show that hyperthermia causes respiratory alkalosis in the immature brain, with a threshold of 0.2-0.3 pH units for seizure induction. Suppressing alkalosis with 5% ambient CO2 abolished seizures within 20 s. CO2 also prevented two long-term effects of hyperthermic seizures in the hippocampus: the upregulation of the I(h) current and the upregulation of CB1 receptor expression. The effects of hyperthermia were closely mimicked by intraperitoneal injection of bicarbonate. Our work indicates a mechanism for triggering hyperthermic seizures and suggests new strategies in the research and therapy of fever-related epileptic syndromes.

Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

PubMed Central

Arloth, Janine; Bogdan, Ryan; Weber, Peter; Frishman, Goar; Menke, Andreas; Wagner, Klaus V.; Balsevich, Georgia; Schmidt, Mathias V.; Karbalai, Nazanin; Czamara, Darina; Altmann, Andre; Trümbach, Dietrich; Wurst, Wolfgang; Mehta, Divya; Uhr, Manfred; Klengel, Torsten; Erhardt, Angelika; Carey, Caitlin E.; Conley, Emily Drabant; Ripke, Stephan; Wray, Naomi R.; Lewis, Cathryn M.; Hamilton, Steven P.; Weissman, Myrna M.; Breen, Gerome; Byrne, Enda M.; Blackwood, Douglas H.R.; Boomsma, Dorret I.; Cichon, Sven; Heath, Andrew C.; Holsboer, Florian; Lucae, Susanne; Madden, Pamela A.F.; Martin, Nicholas G.; McGuffin, Peter; Muglia, Pierandrea; Noethen, Markus M.; Penninx, Brenda P.; Pergadia, Michele L.; Potash, James B.; Rietschel, Marcella; Lin, Danyu; Müller-Myhsok, Bertram; Shi, Jianxin; Steinberg, Stacy; Grabe, Hans J.; Lichtenstein, Paul; Magnusson, Patrik; Perlis, Roy H.; Preisig, Martin; Smoller, Jordan W.; Stefansson, Kari; Uher, Rudolf; Kutalik, Zoltan; Tansey, Katherine E.; Teumer, Alexander; Viktorin, Alexander; Barnes, Michael R.; Bettecken, Thomas; Binder, Elisabeth B.; Breuer, René; Castro, Victor M.; Churchill, Susanne E.; Coryell, William H.; Craddock, Nick; Craig, Ian W.; Czamara, Darina; De Geus, Eco J.; Degenhardt, Franziska; Farmer, Anne E.; Fava, Maurizio; Frank, Josef; Gainer, Vivian S.; Gallagher, Patience J.; Gordon, Scott D.; Goryachev, Sergey; Gross, Magdalena; Guipponi, Michel; Henders, Anjali K.; Herms, Stefan; Hickie, Ian B.; Hoefels, Susanne; Hoogendijk, Witte; Hottenga, Jouke Jan; Iosifescu, Dan V.; Ising, Marcus; Jones, Ian; Jones, Lisa; Jung-Ying, Tzeng; Knowles, James A.; Kohane, Isaac S.; Kohli, Martin A.; Korszun, Ania; Landen, Mikael; Lawson, William B.; Lewis, Glyn; MacIntyre, Donald; Maier, Wolfgang; Mattheisen, Manuel; McGrath, Patrick J.; McIntosh, Andrew; McLean, Alan; Middeldorp, Christel M.; Middleton, Lefkos; Montgomery, Grant M.; Murphy, Shawn N.; Nauck, Matthias; Nolen, Willem A.; Nyholt, Dale R.; O’Donovan, Michael; Oskarsson, Högni; Pedersen, Nancy; Scheftner, William A.; Schulz, Andrea; Schulze, Thomas G.; Shyn, Stanley I.; Sigurdsson, Engilbert; Slager, Susan L.; Smit, Johannes H.; Stefansson, Hreinn; Steffens, Michael; Thorgeirsson, Thorgeir; Tozzi, Federica; Treutlein, Jens; Uhr, Manfred; van den Oord, Edwin J.C.G.; Van Grootheest, Gerard; Völzke, Henry; Weilburg, Jeffrey B.; Willemsen, Gonneke; Zitman, Frans G.; Neale, Benjamin; Daly, Mark; Levinson, Douglas F.; Sullivan, Patrick F.; Ruepp, Andreas; Müller-Myhsok, Bertram; Hariri, Ahmad R.; Binder, Elisabeth B.

2015-01-01

Summary Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain. Video Abstract PMID:26050039

Supply-demand mismatch transients in susceptible peri-infarct hot zones explain the origins of spreading injury depolarizations.

PubMed

von Bornstädt, Daniel; Houben, Thijs; Seidel, Jessica L; Zheng, Yi; Dilekoz, Ergin; Qin, Tao; Sandow, Nora; Kura, Sreekanth; Eikermann-Haerter, Katharina; Endres, Matthias; Boas, David A; Moskowitz, Michael A; Lo, Eng H; Dreier, Jens P; Woitzik, Johannes; Sakadžić, Sava; Ayata, Cenk

2015-03-04

Peri-infarct depolarizations (PIDs) are seemingly spontaneous spreading depression-like waves that negatively impact tissue outcome in both experimental and human stroke. Factors triggering PIDs are unknown. Here, we show that somatosensory activation of peri-infarct cortex triggers PIDs when the activated cortex is within a critical range of ischemia. We show that the mechanism involves increased oxygen utilization within the activated cortex, worsening the supply-demand mismatch. We support the concept by clinical data showing that mismatch predisposes stroke patients to PIDs as well. Conversely, transient worsening of mismatch by episodic hypoxemia or hypotension also reproducibly triggers PIDs. Therefore, PIDs are triggered upon supply-demand mismatch transients in metastable peri-infarct hot zones due to increased demand or reduced supply. Based on the data, we propose that minimizing sensory stimulation and hypoxic or hypotensive transients in stroke and brain injury would reduce PID incidence and their adverse impact on outcome. Copyright © 2015 Elsevier Inc. All rights reserved.

Supply-demand mismatch transients in susceptible peri-infarct hot zones explain the origin of spreading injury depolarizations

PubMed Central

von Bornstädt, Daniel; Houben, Thijs; Seidel, Jessica; Zheng, Yi; Dilekoz, Ergin; Qin, Tao; Sandow, Nora; Kura, Sreekanth; Eikermann-Haerter, Katharina; Endres, Matthias; Boas, David A.; Moskowitz, Michael A.; Lo, Eng H.; Dreier, Jens P.; Woitzik, Johannes; Sakadžić, Sava; Ayata, Cenk

2015-01-01

SUMMARY Peri-infarct depolarizations (PIDs) are seemingly spontaneous spreading depression-like waves that negatively impact tissue outcome in both experimental and human stroke. Factors triggering PIDs are unknown. Here, we show that somatosensory activation of peri-infarct cortex triggers PIDs when the activated cortex is within a critical range of ischemia. We show that the mechanism involves increased oxygen utilization within the activated cortex, worsening the supply-demand mismatch. We support the concept by clinical data showing that mismatch predisposes to PIDs in human stroke as well. Conversely, transient worsening of mismatch by episodic hypoxemia or hypotension also reproducibly triggers PIDs. Therefore, PIDs are triggered upon supply-demand mismatch transients in metastable peri-infarct hot zones due to increased demand or reduced supply. Based on the data, we propose that minimizing sensory stimulation and hypoxic or hypotensive transients in stroke and brain injury would reduce PID incidence and their adverse impact on outcome. PMID:25741731

Antibacterial activity and mechanism of action of Monarda punctata essential oil and its main components against common bacterial pathogens in respiratory tract.

PubMed

Li, Hong; Yang, Tian; Li, Fei-Yan; Yao, Yan; Sun, Zhong-Min

2014-01-01

The aim of the current research work was to study the chemical composition of the essential oil of Monarda punctata along with evaluating the essential oil and its major components for their antibacterial effects against some frequently encountered respiratory infection causing pathogens. Gas chromatographic mass spectrometric analysis revealed the presence of 13 chemical constituents with thymol (75.2%), p-cymene (6.7%), limonene (5.4), and carvacrol (3.5%) as the major constituents. The oil composition was dominated by the oxygenated monoterpenes. Antibacterial activity of the essential oil and its major constituents (thymol, p-cymene, limonene) was evaluated against Streptococcus pyogenes, methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae, Haemophilus influenzae and Escherichia coli. The study revealed that the essential oil and its constituents exhibited a broad spectrum and variable degree of antibacterial activity against different strains. Among the tested strains, Streptococcus pyogenes, Escherichia coli and Streptococcus pneumoniae were the most susceptible bacterial strain showing lowest MIC and MBC values. Methicillin-resistant Staphylococcus aureus was the most resistant bacterial strain to the essential oil treatment showing relatively higher MIC and MBC values. Scanning electron microscopy revealed that the essential oil induced potent and dose-dependent membrane damage in S. pyogenes and MRSA bacterial strains. The reactive oxygen species generated by the Monarda punctata essential oil were identified using 2', 7'-dichlorofluorescein diacetate (DCFDA).This study indicated that the Monarda punctata essential oil to a great extent and thymol to a lower extent triggered a substantial increase in the ROS levels in S. pyogenes bacterial cultures which ultimately cause membrane damage as revealed by SEM results.

Antibacterial activity and mechanism of action of Monarda punctata essential oil and its main components against common bacterial pathogens in respiratory tract

PubMed Central

Li, Hong; Yang, Tian; Li, Fei-Yan; Yao, Yan; Sun, Zhong-Min

2014-01-01

The aim of the current research work was to study the chemical composition of the essential oil of Monarda punctata along with evaluating the essential oil and its major components for their antibacterial effects against some frequently encountered respiratory infection causing pathogens. Gas chromatographic mass spectrometric analysis revealed the presence of 13 chemical constituents with thymol (75.2%), p-cymene (6.7%), limonene (5.4), and carvacrol (3.5%) as the major constituents. The oil composition was dominated by the oxygenated monoterpenes. Antibacterial activity of the essential oil and its major constituents (thymol, p-cymene, limonene) was evaluated against Streptococcus pyogenes, methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae, Haemophilus influenzae and Escherichia coli. The study revealed that the essential oil and its constituents exhibited a broad spectrum and variable degree of antibacterial activity against different strains. Among the tested strains, Streptococcus pyogenes, Escherichia coli and Streptococcus pneumoniae were the most susceptible bacterial strain showing lowest MIC and MBC values. Methicillin-resistant Staphylococcus aureus was the most resistant bacterial strain to the essential oil treatment showing relatively higher MIC and MBC values. Scanning electron microscopy revealed that the essential oil induced potent and dose-dependent membrane damage in S. pyogenes and MRSA bacterial strains. The reactive oxygen species generated by the Monarda punctata essential oil were identified using 2’, 7’-dichlorofluorescein diacetate (DCFDA).This study indicated that the Monarda punctata essential oil to a great extent and thymol to a lower extent triggered a substantial increase in the ROS levels in S. pyogenes bacterial cultures which ultimately cause membrane damage as revealed by SEM results. PMID:25550774

Aftershocks halted by static stress shadows

USGS Publications Warehouse

Toda, Shinji; Stein, Ross S.; Beroza, Gregory C.; Marsan, David

2012-01-01

Earthquakes impart static and dynamic stress changes to the surrounding crust. Sudden fault slip causes small but permanent—static—stress changes, and passing seismic waves cause large, but brief and oscillatory—dynamic—stress changes. Because both static and dynamic stresses can trigger earthquakes within several rupture dimensions of a mainshock, it has proven difficult to disentangle their contributions to the triggering process1–3. However, only dynamic stress can trigger earthquakes far from the source4,5, and only static stress can create stress shadows, where the stress and thus the seismicity rate in the shadow area drops following an earthquake6–9 . Here we calculate the stress imparted by the magnitude 6.1 Joshua Tree and nearby magnitude 7.3 Landers earthquakes that occurred in California in April and June 1992, respectively, and measure seismicity through time. We show that, where the aftershock zone of the first earthquake was subjected to a static stress increase from the second, the seismicity rate jumped. In contrast, where the aftershock zone of the first earthquake fell under the stress shadow of the second and static stress dropped, seismicity shut down. The arrest of seismicity implies that static stress is a requisite element of spatial clustering of large earthquakes and should be a constituent of hazard assessment.

Guided episodic sampling for capturing and characterizing industrial plumes

NASA Astrophysics Data System (ADS)

Ou-Yang, Chang-Feng; Liao, Wei-Cheng; Chang, Chih-Chung; Hsieh, Hsin-Cheng; Wang, Jia-Lin

2018-02-01

An integrated sampling technique, dubbed trigger sampling, was developed to capture characteristic industrial emissions or plumes. In the field experiment, a hydrogen sulfide (H2S) analyzer was used as the triggering instrument at the boundary of a refinery plant due to frequent complaints of foul smell from local residents. Ten episodic samples were captured when the H2S level surpassed the prescribed trigger level of 8.5 ppbv over a three-day period. Three non-episodic (blank) samples and 23 road-side samples were also collected for comparison. All the 36 flask samples were analyzed by gas chromatography-mass spectrometry/flame ionization detection (GC-MS/FID) for 108 volatile organic compounds (VOCs). The total VOC abundance of the event samples was exceedingly higher than the non-episodic samples by over 80 times in the extreme case. Alkanes were found to be the dominant constituents in the event samples, amounting to over 90% of the total VOC concentrations vs. only 30-40% for the blank and metropolitan samples. In addition, light alkanes in the event samples were highly correlated with the trigger species H2S (R2 = 0.82), implying their common origin. The matrix of chemical composition vs. sample types permitted easy visualization of the dominance of light alkanes for the event samples compared to other types of samples. Principle component analysis (PCA) identified two major contributors to cover 93% of the total variance arising from the 36 samples, further quantifying the distinction of the triggered episodic samples from the contrast samples. The proposed trigger sampling is a coupling of fast-and-slow measurement techniques. In this example, the fast-response H2S analyzer served to "guide" sampling to capture industrial plumes which were then characterized by a relatively slow method of GC-MS/FID for detailed chemical composition representative of the prominent sources.

Functional mechanisms involved in the internal inhibition of taboo words.

PubMed

Severens, Els; Kühn, Simone; Hartsuiker, Robert J; Brass, Marcel

2012-04-01

The present study used functional magnetic resonance imaging to investigate brain processes associated with the inhibition of socially undesirable speech. It is tested whether the inhibition of undesirable speech is solely related to brain areas associated with classical stop signal tasks or rather also involves brain areas involved in endogenous self-control. During the experiment, subjects had to do a SLIP task, which was designed to elicit taboo or neutral spoonerisms. Here we show that the internal inhibition of taboo words activates the right inferior frontal gyrus, an area that has previously been associated with externally triggered inhibition. This finding strongly suggests that external social rules become internalized and act as a stop-signal.

Functional mechanisms involved in the internal inhibition of taboo words

PubMed Central

Kühn, Simone; Hartsuiker, Robert J.; Brass, Marcel

2012-01-01

The present study used functional magnetic resonance imaging to investigate brain processes associated with the inhibition of socially undesirable speech. It is tested whether the inhibition of undesirable speech is solely related to brain areas associated with classical stop signal tasks or rather also involves brain areas involved in endogenous self-control. During the experiment, subjects had to do a SLIP task, which was designed to elicit taboo or neutral spoonerisms. Here we show that the internal inhibition of taboo words activates the right inferior frontal gyrus, an area that has previously been associated with externally triggered inhibition. This finding strongly suggests that external social rules become internalized and act as a stop-signal. PMID:21609970

Self-amplification of nigral degeneration in Parkinson's disease: a hypothesis.

PubMed

Ionov, Ilya D

2008-12-01

This review analyzes current evidence regarding possible mechanisms of nigral damage in idiopathic Parkinson's disease (iPD). In normal brain, a specific interplay among the blood-brain barrier (BBB), substantia nigra (SN), and locus coeruleus (LC) creates the condition for a self-accelerating damage to the SN. Three vicious circles involving SN-BBB, LC-SN-BBB, and histamine-BBB-SN interactions are described. In iPD, a self-accelerating loss of nigral cells can be triggered by brain hypoperfusion and by an increased blood histamine level. iPD-associated factors such as decreased CSF levels of substance P, somatostatin, and glutamate can aggravate the vicious-circle-induced damage to the SN.

Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation

PubMed Central

Clarke, Julia R; Lyra e Silva, Natalia M; Figueiredo, Claudia P; Frozza, Rudimar L; Ledo, Jose H; Beckman, Danielle; Katashima, Carlos K; Razolli, Daniela; Carvalho, Bruno M; Frazão, Renata; Silveira, Marina A; Ribeiro, Felipe C; Bomfim, Theresa R; Neves, Fernanda S; Klein, William L; Medeiros, Rodrigo; LaFerla, Frank M; Carvalheira, Jose B; Saad, Mario J; Munoz, Douglas P; Velloso, Licio A; Ferreira, Sergio T; De Felice, Fernanda G

2015-01-01

Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AβOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation (eIF2α-P). AβOs further induced eIF2α-P and activated pro-inflammatory IKKβ/NF-κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor-α (TNF-α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AβOs act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that AβOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD. PMID:25617315

Role of hormones and neurosteroids in epileptogenesis

PubMed Central

Reddy, Doodipala Samba

2013-01-01

This article describes the emerging evidence of hormonal influence on epileptogenesis, which is a process whereby a brain becomes progressively epileptic due to an initial precipitating event of diverse origin such as brain injury, stroke, infection, or prolonged seizures. The molecular mechanisms underlying the development of epilepsy are poorly understood. Neuroinflammation and neurodegeneration appear to trigger epileptogenesis. There is an intense search for drugs that truly prevent the development of epilepsy in people at risk. Hormones play an important role in children and adults with epilepsy. Corticosteroids, progesterone, estrogens, and neurosteroids have been shown to affect seizure activity in animal models and in clinical studies. However, the impact of hormones on epileptogenesis has not been investigated widely. There is emerging new evidence that progesterone, neurosteroids, and endogenous hormones may play a role in regulating the epileptogenesis. Corticosterone has excitatory effects and triggers epileptogenesis in animal models. Progesterone has disease-modifying activity in epileptogenic models. The antiepileptogenic effect of progesterone has been attributed to its conversion to neurosteroids, which binds to GABA-A receptors and enhances phasic and tonic inhibition in the brain. Neurosteroids are robust anticonvulsants. There is pilot evidence that neurosteroids may have antiepileptogenic properties. Future studies may generate new insight on the disease-modifying potential of hormonal agents and neurosteroids in epileptogenesis. PMID:23914154

Sex differences in the developing brain as a source of inherent risk

PubMed Central

McCarthy, Margaret M.

2016-01-01

Brain development diverges in males and females in response to androgen production by the fetal testis. This sexual differentiation of the brain occurs during a sensitive window and induces enduring neuroanatomical and physiological changes that profoundly impact behavior. What we know about the contribution of sex chromosomes is still emerging, highlighting the need to integrate multiple factors into understanding sex differences, including the importance of context. The cellular mechanisms are best modeled in rodents and have provided both unifying principles and surprising specifics. Markedly distinct signaling pathways direct differentiation in specific brain regions, resulting in mosaicism of relative maleness, femaleness, and sameness through-out the brain, while canalization both exaggerates and constrains sex differences. Non-neuronal cells and inflammatory mediators are found in greater number and at higher levels in parts of male brains. This higher baseline of inflammation is speculated to increase male vulnerability to developmental neuropsychiatric disorders that are triggered by inflammation. PMID:28179808

Neural effects of environmental advertising: An fMRI analysis of voice age and temporal framing.

PubMed

Casado-Aranda, Luis-Alberto; Martínez-Fiestas, Myriam; Sánchez-Fernández, Juan

2018-01-15

Ecological information offered to society through advertising enhances awareness of environmental issues, encourages development of sustainable attitudes and intentions, and can even alter behavior. This paper, by means of functional Magnetic Resonance Imaging (fMRI) and self-reports, explores the underlying mechanisms of processing ecological messages. The study specifically examines brain and behavioral responses to persuasive ecological messages that differ in temporal framing and in the age of the voice pronouncing them. The findings reveal that attitudes are more positive toward future-framed messages presented by young voices. The whole-brain analysis reveals that future-framed (FF) ecological messages trigger activation in brain areas related to imagery, prospective memories and episodic events, thus reflecting the involvement of past behaviors in future ecological actions. Past-framed messages (PF), in turn, elicit brain activations within the episodic system. Young voices (YV), in addition to triggering stronger activation in areas involved with the processing of high-timbre, high-pitched and high-intensity voices, are perceived as more emotional and motivational than old voices (OV) as activations in anterior cingulate cortex and amygdala. Messages expressed by older voices, in turn, exhibit stronger activation in areas formerly linked to low-pitched voices and voice gender perception. Interestingly, a link is identified between neural and self-report responses indicating that certain brain activations in response to future-framed messages and young voices predicted higher attitudes toward future-framed and young voice advertisements, respectively. The results of this study provide invaluable insight into the unconscious origin of attitudes toward environmental messages and indicate which voice and temporal frame of a message generate the greatest subconscious value. Copyright © 2017 Elsevier Ltd. All rights reserved.

Spontaneous pre-stimulus fluctuations in the activity of right fronto-parietal areas influence inhibitory control performance

PubMed Central

Chavan, Camille F.; Manuel, Aurelie L.; Mouthon, Michael; Spierer, Lucas

2013-01-01

Inhibitory control refers to the ability to suppress planned or ongoing cognitive or motor processes. Electrophysiological indices of inhibitory control failure have been found to manifest even before the presentation of the stimuli triggering the inhibition, suggesting that pre-stimulus brain-states modulate inhibition performance. However, previous electrophysiological investigations on the state-dependency of inhibitory control were based on averaged event-related potentials (ERPs), a method eliminating the variability in the ongoing brain activity not time-locked to the event of interest. These studies thus left unresolved whether spontaneous variations in the brain-state immediately preceding unpredictable inhibition-triggering stimuli also influence inhibitory control performance. To address this question, we applied single-trial EEG topographic analyses on the time interval immediately preceding NoGo stimuli in conditions where the responses to NoGo trials were correctly inhibited [correct rejection (CR)] vs. committed [false alarms (FAs)] during an auditory spatial Go/NoGo task. We found a specific configuration of the EEG voltage field manifesting more frequently before correctly inhibited responses to NoGo stimuli than before FAs. There was no evidence for an EEG topography occurring more frequently before FAs than before CR. The visualization of distributed electrical source estimations of the EEG topography preceding successful response inhibition suggested that it resulted from the activity of a right fronto-parietal brain network. Our results suggest that the fluctuations in the ongoing brain activity immediately preceding stimulus presentation contribute to the behavioral outcomes during an inhibitory control task. Our results further suggest that the state-dependency of sensory-cognitive processing might not only concern perceptual processes, but also high-order, top-down inhibitory control mechanisms. PMID:23761747

Peripheral inflammation is associated with remote global gene expression changes in the brain

PubMed Central

2014-01-01

Background Although the central nervous system (CNS) was once considered an immunologically privileged site, in recent years it has become increasingly evident that cross talk between the immune system and the CNS does occur. As a result, patients with chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease or psoriasis, are often further burdened with neuropsychiatric symptoms, such as depression, anxiety and fatigue. Despite the recent advances in our understanding of neuroimmune communication pathways, the precise effect of peripheral immune activation on neural circuitry remains unclear. Utilizing transcriptomics in a well-characterized murine model of systemic inflammation, we have started to investigate the molecular mechanisms by which inflammation originating in the periphery can induce transcriptional modulation in the brain. Methods Several different systemic and tissue-specific models of peripheral toll-like-receptor-(TLR)-driven (lipopolysaccharide (LPS), lipoteichoic acid and Imiquimod) and sterile (tumour necrosis factor (TNF) and 12-O-tetradecanoylphorbol-13-acetate (TPA)) inflammation were induced in C57BL/6 mice. Whole brain transcriptional profiles were assessed and compared 48 hours after intraperitoneal injection of lipopolysaccharide or vehicle, using Affymetrix GeneChip microarrays. Target gene induction, identified by microarray analysis, was validated independently using qPCR. Expression of the same panel of target genes was then investigated in a number of sterile and other TLR-dependent models of peripheral inflammation. Results Microarray analysis of whole brains collected 48 hr after LPS challenge revealed increased transcription of a range of interferon-stimulated genes (ISGs) in the brain. In addition to acute LPS challenge, ISGs were induced in the brain following both chronic LPS-induced systemic inflammation and Imiquimod-induced skin inflammation. Unique to the brain, this transcriptional response is indicative of peripherally triggered, interferon-mediated CNS inflammation. Similar models of sterile inflammation and lipoteichoic-acid-induced systemic inflammation did not share the capacity to trigger ISG induction in the brain. Conclusions These data highlight ISG induction in the brain as being a consequence of a TLR-induced type I interferon response. As considerable evidence links type I interferons to psychiatric disorders, we hypothesize that interferon production in the brain could represent an important mechanism, linking peripheral TLR-induced inflammation with behavioural changes. PMID:24708794

Introduction: Addiction and Brain Reward and Anti-Reward Pathways

PubMed Central

Gardner, Eliot L.

2013-01-01

Addictive drugs have in common that they are voluntarily self-administered by laboratory animals (usually avidly) and that they enhance the functioning of the reward circuitry of the brain (producing the “high” that the drug-user seeks). The core reward circuitry consists of an “in series” circuit linking the ventral tegmental area, nucleus accumbens, and ventral pallidum - via the medial forebrain bundle. Although originally believed to encode simply the set-point of hedonic tone, these circuits are now believed to be functionally far more complex - also encoding attention, expectancy of reward, disconfirmation of reward expectancy, and incentive motivation. “Hedonic dysregulation” within these circuits may lead to addiction. The “second-stage” dopaminergic component in this reward circuitry is the crucial addictive-drug-sensitive component. All addictive drugs have in common that they enhance (directly or indirectly or even transsynaptically) dopaminergic reward synaptic function in the nucleus accumbens. Drug self-administration is regulated by nucleus accumbens dopamine levels, and is done to keep nucleus accumbens dopamine within a specific elevated range (to maintain a desired hedonic level). For some classes of addictive drugs (e.g., opiates), tolerance to the euphoric effects develops with chronic use. Post-use dysphoria then comes to dominate reward circuit hedonic tone, and addicts no longer use drugs to get “high,” but simply to get back to normal (“get straight”). The brain circuits mediating the pleasurable effects of addictive drugs are anatomically, neurophysiologically, and neurochemically different from those mediating physical dependence, and from those mediating craving and relapse. There are important genetic variations in vulnerability to drug addiction, yet environmental factors such as stress and social defeat also alter brain-reward mechanisms in such a manner as to impart vulnerability to addiction. In short, the “bio-psycho-social” model of etiology holds very well for addiction. Addiction appears to correlate with a hypo-dopaminergic dysfunctional state within the reward circuitry of the brain. Neuroimaging studies in humans add credence to this hypothesis. Credible evidence also implicates serotonergic, opioid, endocannabinoid, GABAergic, and glutamatergic mechanisms in addiction. Critically, drug addiction progresses from occasional recreational use to impulsive use to habitual compulsive use. This correlates with a progression from reward-driven to habit-driven drug-seeking behavior. This behavioral progression correlates with a neuroanatomical progression from ventral striatal (nucleus accumbens) to dorsal striatal control over drug-seeking behavior. The three classical sets of craving and relapse triggers are a) re-exposure to addictive drugs, b) stress, and c) re-exposure to environmental cues (“people, places, things”) previously associated with drug-taking behavior. Drug-triggered relapse involves the nucleus accumbens and the neurotransmitter dopamine. Stress-triggered relapse involves a) the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the neurotransmitter CRF; and b) the lateral tegmental noradrenergic nuclei of the brain stem and the neurotransmitter norepinephrine. Cue-triggered relapse involves the basolateral nucleus of the amygdala, the hippocampus, and the neurotransmitter glutamate. Knowledge of the neuroanatomy, neurophysiology, neurochemistry, and neuropharmacology of addictive drug action in the brain is currently producing a variety of strategies for pharmacotherapeutic treatment of drug addiction, some of which appear promising. PMID:21508625

Solubilization of active opiate receptors.

PubMed Central

Simonds, W F; Koski, G; Streaty, R A; Hjelmeland, L M; Klee, W A

1980-01-01

Receptors that reversibly bind opiates and opioid peptides have been solubilized from brain and neuroblastoma-glioma hybrid cell NG108-15 membranes. Active receptors are specifically solubilized with a new type of detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, which is a zwitterionic derivative of cholic acid. The solubilized receptor complexes behave as large molecules with a Stokes radius of 70 A and contain protein as an essential constituent. PMID:6254034

Using the endocannabinoid system as a neuroprotective strategy in perinatal hypoxic-ischemic brain injury

PubMed Central

Lara-Celador, I.; Goñi-de-Cerio, F.; Alvarez, Antonia; Hilario, Enrique

2013-01-01

One of the most important causes of brain injury in the neonatal period is a perinatal hypoxic-ischemic event. This devastating condition can lead to long-term neurological deficits or even death. After hypoxic-ischemic brain injury, a variety of specific cellular mechanisms are set in motion, triggering cell damage and finally producing cell death. Effective therapeutic treatments against this phenomenon are still unavailable because of complex molecular mechanisms underlying hypoxic-ischemic brain injury. After a thorough understanding of the mechanism underlying neural plasticity following hypoxic-ischemic brain injury, various neuroprotective therapies have been developed for alleviating brain injury and improving long-term outcomes. Among them, the endocannabinoid system emerges as a natural system of neuroprotection. The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury, acting as a natural neuroprotectant. The aim of this review is to study the use of different therapies to induce long-term therapeutic effects after hypoxic-ischemic brain injury, and analyze the important role of the endocannabinoid system as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury. PMID:25206720

The glia doctrine: addressing the role of glial cells in healthy brain ageing.

PubMed

Nagelhus, Erlend A; Amiry-Moghaddam, Mahmood; Bergersen, Linda H; Bjaalie, Jan G; Eriksson, Jens; Gundersen, Vidar; Leergaard, Trygve B; Morth, J Preben; Storm-Mathisen, Jon; Torp, Reidun; Walhovd, Kristine B; Tønjum, Tone

2013-10-01

Glial cells in their plurality pervade the human brain and impact on brain structure and function. A principal component of the emerging glial doctrine is the hypothesis that astrocytes, the most abundant type of glial cells, trigger major molecular processes leading to brain ageing. Astrocyte biology has been examined using molecular, biochemical and structural methods, as well as 3D brain imaging in live animals and humans. Exosomes are extracelluar membrane vesicles that facilitate communication between glia, and have significant potential for biomarker discovery and drug delivery. Polymorphisms in DNA repair genes may indirectly influence the structure and function of membrane proteins expressed in glial cells and predispose specific cell subgroups to degeneration. Physical exercise may reduce or retard age-related brain deterioration by a mechanism involving neuro-glial processes. It is most likely that additional information about the distribution, structure and function of glial cells will yield novel insight into human brain ageing. Systematic studies of glia and their functions are expected to eventually lead to earlier detection of ageing-related brain dysfunction and to interventions that could delay, reduce or prevent brain dysfunction. Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

The Specialization of Function: Cognitive and Neural Perspectives

PubMed Central

Mahon, Bradford Z.; Cantlon, Jessica F.

2014-01-01

A unifying theme that cuts across all research areas and techniques in the cognitive and brain sciences is whether there is specialization of function at levels of processing that are ‘abstracted away’ from sensory inputs and motor outputs. Any theory that articulates claims about specialization of function in the mind/brain confronts the following types of interrelated questions, each of which carries with it certain theoretical commitments. What methods are appropriate for decomposing complex cognitive and neural processes into their constituent parts? How do cognitive processes map onto neural processes, and at what resolution are they related? What types of conclusions can be drawn about the structure of mind from dissociations observed at the neural level, and vice versa? The contributions that form this Special Issue of Cognitive Neuropsychology represent recent reflections on these and other issues from leading researchers in different areas of the cognitive and brain sciences. PMID:22185234

Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model

PubMed Central

Tagge, Chad A; Fisher, Andrew M; Minaeva, Olga V; Gaudreau-Balderrama, Amanda; Moncaster, Juliet A; Zhang, Xiao-Lei; Wojnarowicz, Mark W; Casey, Noel; Lu, Haiyan; Kokiko-Cochran, Olga N; Saman, Sudad; Ericsson, Maria; Onos, Kristen D; Veksler, Ronel; Senatorov, Vladimir V; Kondo, Asami; Zhou, Xiao Z; Miry, Omid; Vose, Linnea R; Gopaul, Katisha R; Upreti, Chirag; Nowinski, Christopher J; Cantu, Robert C; Alvarez, Victor E; Hildebrandt, Audrey M; Franz, Erich S; Konrad, Janusz; Hamilton, James A; Hua, Ning; Tripodis, Yorghos; Anderson, Andrew T; Howell, Gareth R; Kaufer, Daniela; Hall, Garth F; Lu, Kun P; Ransohoff, Richard M; Cleveland, Robin O; Kowall, Neil W; Stein, Thor D; Lamb, Bruce T; Huber, Bertrand R; Moss, William C; Friedman, Alon; Stanton, Patric K; McKee, Ann C; Goldstein, Lee E

2018-01-01

Abstract The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood–brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood–brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath. PMID:29360998

Neuronal survival in the brain: neuron type-specific mechanisms.

PubMed

Pfisterer, Ulrich; Khodosevich, Konstantin

2017-03-02

Neurogenic regions of mammalian brain produce many more neurons that will eventually survive and reach a mature stage. Developmental cell death affects both embryonically produced immature neurons and those immature neurons that are generated in regions of adult neurogenesis. Removal of substantial numbers of neurons that are not yet completely integrated into the local circuits helps to ensure that maturation and homeostatic function of neuronal networks in the brain proceed correctly. External signals from brain microenvironment together with intrinsic signaling pathways determine whether a particular neuron will die. To accommodate this signaling, immature neurons in the brain express a number of transmembrane factors as well as intracellular signaling molecules that will regulate the cell survival/death decision, and many of these factors cease being expressed upon neuronal maturation. Furthermore, pro-survival factors and intracellular responses depend on the type of neuron and region of the brain. Thus, in addition to some common neuronal pro-survival signaling, different types of neurons possess a variety of 'neuron type-specific' pro-survival constituents that might help them to adapt for survival in a certain brain region. This review focuses on how immature neurons survive during normal and impaired brain development, both in the embryonic/neonatal brain and in brain regions associated with adult neurogenesis, and emphasizes neuron type-specific mechanisms that help to survive for various types of immature neurons. Importantly, we mainly focus on in vivo data to describe neuronal survival specifically in the brain, without extrapolating data obtained in the PNS or spinal cord, and thus emphasize the influence of the complex brain environment on neuronal survival during development.

Obesity and neuroinflammatory phenotype in mice lacking endothelial megalin.

PubMed

Bartolome, Fernando; Antequera, Desiree; Tavares, Eva; Pascual, Consuelo; Maldonado, Rosario; Camins, Antoni; Carro, Eva

2017-01-31

The multiligand receptor megalin controls the brain uptake of a number of ligands, including insulin and leptin. Despite the role of megalin in the transport of these metabolically relevant hormones, the role of megalin at the blood-brain-barrier (BBB) has not yet been explored in the context of metabolic regulation. Here we investigate the role of brain endothelial megalin in energy metabolism and leptin signaling using an endothelial cell-specific megalin deficient (EMD) mouse model. We found megalin is important to protect mice from developing obesity and metabolic syndrome when mice are fed a normal chow diet. EMD mice developed neuroinflammation, by triggering several pro-inflammatory cytokines, displayed reduced neurogenesis and mitochondrial deregulation. These results implicate brain endothelial megalin expression in obesity-related metabolic changes through the leptin signaling pathway proposing a potential link between obesity and neurodegeneration.

Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence

NASA Astrophysics Data System (ADS)

Xue, Jingwei; Zhao, Zekai; Zhang, Lei; Xue, Lingjing; Shen, Shiyang; Wen, Yajing; Wei, Zhuoyuan; Wang, Lu; Kong, Lingyi; Sun, Hongbin; Ping, Qineng; Mo, Ran; Zhang, Can

2017-07-01

Cell-mediated drug-delivery systems have received considerable attention for their enhanced therapeutic specificity and efficacy in cancer treatment. Neutrophils (NEs), the most abundant type of immune cells, are known to penetrate inflamed brain tumours. Here we show that NEs carrying liposomes that contain paclitaxel (PTX) can penetrate the brain and suppress the recurrence of glioma in mice whose tumour has been resected surgically. Inflammatory factors released after tumour resection guide the movement of the NEs into the inflamed brain. The highly concentrated inflammatory signals in the brain trigger the release of liposomal PTX from the NEs, which allows delivery of PTX into the remaining invading tumour cells. We show that this NE-mediated delivery of drugs efficiently slows the recurrent growth of tumours, with significantly improved survival rates, but does not completely inhibit the regrowth of tumours.

The Role of Sleep in Emotional Brain Function

PubMed Central

Goldstein, Andrea N.; Walker, Matthew P.

2014-01-01

Rapidly emerging evidence continues to describe an intimate and causal relationship between sleep and emotional brain function. These findings are mirrored by longstanding clinical observations demonstrating that nearly all mood and anxiety disorders co-occur with one or more sleep abnormalities. This review aims to (1) provide a synthesis of recent findings describing the emotional brain and behavioral benefits triggered by sleep, and conversely, the detrimental impairments following a lack of sleep, (2) outline a proposed framework in which sleep, and specifically rapid-eye movement (REM) sleep, supports a process of affective brain homeostasis, optimally preparing the organism for next-day social and emotional functioning, and (3) describe how this hypothesized framework can explain the prevalent relationships between sleep and psychiatric disorders, with a particular focus on post-traumatic stress disorder and major depression. PMID:24499013

The role of auditory transient and deviance processing in distraction of task performance: a combined behavioral and event-related brain potential study

PubMed Central

Berti, Stefan

2013-01-01

Distraction of goal-oriented performance by a sudden change in the auditory environment is an everyday life experience. Different types of changes can be distracting, including a sudden onset of a transient sound and a slight deviation of otherwise regular auditory background stimulation. With regard to deviance detection, it is assumed that slight changes in a continuous sequence of auditory stimuli are detected by a predictive coding mechanisms and it has been demonstrated that this mechanism is capable of distracting ongoing task performance. In contrast, it is open whether transient detection—which does not rely on predictive coding mechanisms—can trigger behavioral distraction, too. In the present study, the effect of rare auditory changes on visual task performance is tested in an auditory-visual cross-modal distraction paradigm. The rare changes are either embedded within a continuous standard stimulation (triggering deviance detection) or are presented within an otherwise silent situation (triggering transient detection). In the event-related brain potentials, deviants elicited the mismatch negativity (MMN) while transients elicited an enhanced N1 component, mirroring pre-attentive change detection in both conditions but on the basis of different neuro-cognitive processes. These sensory components are followed by attention related ERP components including the P3a and the reorienting negativity (RON). This demonstrates that both types of changes trigger switches of attention. Finally, distraction of task performance is observable, too, but the impact of deviants is higher compared to transients. These findings suggest different routes of distraction allowing for the automatic processing of a wide range of potentially relevant changes in the environment as a pre-requisite for adaptive behavior. PMID:23874278

Entropic effects, shape, and size of mixed micelles formed by copolymers with complex architectures

NASA Astrophysics Data System (ADS)

Kalogirou, Andreas; Gergidis, Leonidas N.; Moultos, Othonas; Vlahos, Costas

2015-11-01

The entropic effects in the comicellization behavior of amphiphilic A B copolymers differing in the chain size of solvophilic A parts were studied by means of molecular dynamics simulations. In particular, mixtures of miktoarm star copolymers differing in the molecular weight of solvophilic arms were investigated. We found that the critical micelle concentration values show a positive deviation from the analytical predictions of the molecular theory of comicellization for chemically identical copolymers. This can be attributed to the effective interactions between copolymers originated from the arm size asymmetry. The effective interactions induce a very small decrease in the aggregation number of preferential micelles triggering the nonrandom mixing between the solvophilic moieties in the corona. Additionally, in order to specify how the chain architecture affects the size distribution and the shape of mixed micelles we studied star-shaped, H-shaped, and homo-linked-rings-linear mixtures. In the first case the individual constituents form micelles with preferential and wide aggregation numbers and in the latter case the individual constituents form wormlike and spherical micelles.

Entropic effects, shape, and size of mixed micelles formed by copolymers with complex architectures.

PubMed

Kalogirou, Andreas; Gergidis, Leonidas N; Moultos, Othonas; Vlahos, Costas

2015-11-01

The entropic effects in the comicellization behavior of amphiphilic AB copolymers differing in the chain size of solvophilic A parts were studied by means of molecular dynamics simulations. In particular, mixtures of miktoarm star copolymers differing in the molecular weight of solvophilic arms were investigated. We found that the critical micelle concentration values show a positive deviation from the analytical predictions of the molecular theory of comicellization for chemically identical copolymers. This can be attributed to the effective interactions between copolymers originated from the arm size asymmetry. The effective interactions induce a very small decrease in the aggregation number of preferential micelles triggering the nonrandom mixing between the solvophilic moieties in the corona. Additionally, in order to specify how the chain architecture affects the size distribution and the shape of mixed micelles we studied star-shaped, H-shaped, and homo-linked-rings-linear mixtures. In the first case the individual constituents form micelles with preferential and wide aggregation numbers and in the latter case the individual constituents form wormlike and spherical micelles.

Di-jet Hadron Correlations in Central Au+Au Collisions at √{sNN} = 200 GeV at STAR

NASA Astrophysics Data System (ADS)

Elsey, Nicholas; STAR Collaboration

2017-09-01

Jets and their modifications due to partonic energy loss provide a powerful tool to study the properties of the QGP created in ultrarelativistic heavy-ion collisions. For jets reconstructed with the anti-kT algorithm with resolution parameter R = 0.4 , previous measurements of the di-jet asymmetry AJ at STAR) indicate that the observed imbalance of an initial ``hard-core'' di-jet selection with pTconst > 2.0 GeV/c, pTlead > 20.0 GeV/c and pTsub > 10.0 GeV/c is restored to the balance of the pp reference when soft constituents are included. The lost energy recovered with soft constituents suggests soft gluon radiation by high pT partons. Jet-hadron correlations with respect to di-jets allow a differential assessment of the kinematic properties of the soft gluon radiation spectrum induced by partonic energy loss in the QGP. We present charged hadron correlations with respect to the di-jets found in the above AJ analysis, and compare to similar measurements using a jet trigger at RHIC.

Perinatal stress, brain inflammation and risk of autism-Review and proposal

PubMed Central

2012-01-01

Background Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication, and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Premature babies are also more vulnerable to infections and inflammation leading to neurodevelopmental problems and higher risk of developing ASD. Many autism “susceptibility” genes have been identified, but “environmental” factors appear to play a significant role. Increasing evidence suggests that there are different ASD endophenotypes. Discussion We review relevant literature suggesting in utero inflammation can lead to preterm labor, while insufficient development of the gut-blood–brain barriers could permit exposure to potential neurotoxins. This risk apparently may increase in parents with “allergic” or autoimmune problems during gestation, or if they had been exposed to stressors. The presence of circulating auto-antibodies against fetal brain proteins in mothers is associated with higher risk of autism and suggests disruption of the blood–brain-barrier (BBB). A number of papers have reported increased brain expression or cerebrospinal fluid (CSF) levels of pro-inflammatory cytokines, especially TNF, which is preformed in mast cells. Recent evidence also indicates increased serum levels of the pro-inflammatory mast cell trigger neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which is immunogenic. Gene mutations of phosphatase and tensin homolog (PTEN), the negative regulator of the mammalian target of rapamycin (mTOR), have been linked to higher risk of autism, but also to increased proliferation and function of mast cells. Summary Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers that could stimulate mast cell release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in an endophenotype of ASD patients. PMID:22747567

Exercise and neuromodulators: choline and acetylcholine in marathon runners

NASA Technical Reports Server (NTRS)

Conlay, L. A.; Sabounjian, L. A.; Wurtman, R. J.

1992-01-01

Certain neurotransmitters (i.e., acetylcholine, catecholamines, and serotonin) are formed from dietary constituents (i.e., choline, tyrosine and tryptophan). Changing the consumption of these precursors alters release of their respective neurotransmitter products. The neurotransmitter acetylcholine is released from the neuromuscular junction and from brain. It is formed from choline, a common constituent in fish, liver, and eggs. Choline is also incorporated into cell membranes; membranes may likewise serve as an alternative choline source for acetylcholine synthesis. In trained athletes, running a 26 km marathon reduced plasma choline by approximately 40%, from 14.1 to 8.4 uM. Changes of similar magnitude have been shown to reduce acetylcholine release from the neuromuscular junction in vivo. Thus, the reductions in plasma choline associated with strenuous exercise may reduce acetylcholine release, and could thereby affect endurance or performance.

Disengaging from Conflict Cycles

ERIC Educational Resources Information Center

Long, Nicholas J.

2014-01-01

Youth in pain often show self-defeating and destructive patterns of behavior which should be seen as calls for help and positive support. Instead, deep-seated brain programs and cultural beliefs about discipline can trigger angry or avoidant behavior by adults who deal with these young people. This brief introduction to the Conflict Cycle…

Oscillatory Dynamics Related to the Unagreement Pattern in Spanish

ERIC Educational Resources Information Center

Perez, Alejandro; Molinaro, Nicola; Mancini, Simona; Barraza, Paulo; Carreiras, Manuel

2012-01-01

Unagreement patterns consist in a person feature mismatch between subject and verb that is nonetheless grammatical in Spanish. The processing of this type of construction gives new insights into the understanding of agreement processes during language comprehension. Here, we contrasted oscillatory brain activity triggered by Unagreement in…

The Foot Engine: A Learning Styles Approach to Teaching History through Technology.

ERIC Educational Resources Information Center

Benson, Bernard W.; Eaves, Judith Y.

1985-01-01

This minicourse can be used in secondary U.S. history courses to teach about the social, economic, industrial, and technological changes that can be triggered by a single technological innovation. The lesson contains sequenced activities that alternatively stress right and left brain modes of learning. (RM)

Effect of blueberries and insulin on glucose induced neurotoxicity in brain cells in vitro

USDA-ARS?s Scientific Manuscript database

Introduction Literature had shown that disruption in glucose metabolism seen in metabolic syndrome maybe responsible for neuronal cell-death. Oxidative stress (OS) and inflammation (INF) triggered by the impaired metabolic process are considered to be the primary factors for the toxic neuronal atmos...

Excessive sugar consumption may be a difficult habit to break: a view from the brain and body

USDA-ARS?s Scientific Manuscript database

Importance: Sugar overconsumption and chronic stress are growing health concerns because they both may increase risk for obesity and related disease. Psychological or emotional stress may trigger habitual overconsumption of sugar and amplify the detrimental health effects of sugar consumption. The...

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.

Clearance of amyloid-β peptide across the choroid plexus in Alzheimer's disease.

PubMed

Alvira-Botero, Ximena; Carro, Eva M

2010-12-01

Aging and several neurodegenerative diseases bring about changes in the anatomy and physiology of the choroid plexus. The identification of specific membrane receptors that bind and internalize extracellular ligands has revolutionized the traditional roles of this tissue. Amyloid beta peptide (Aβ), the major constituent of the amyloid core of senile plaques in patients with Alzheimer's disease (AD) is known to contribute to disease neuropathology and progression. Recent emphasis on comorbidity of AD and a deficient clearance of Aβ across the blood-brain barrier and blood-cerebrospinal fluid barrier have highlighted the importance of brain Aβ clearance in AD. The megalin receptor has also been implicated in the pathogenesis of AD. Faulty Aβ clearance from the brain across the choroid plexus epithelium by megalin appears to mediate focal Aβ accumulation in AD. Patients with AD have reduced levels of megalin at the choroid plexus, which in turn seem to increase brain levels of Aβ through a decreased efflux of brain Aβ. Therapies that increase megalin expression at the choroid plexus could potentially control accumulation of brain Aβ. This review covers in depth the anatomy and function of the choroid plexus, focusing on the brain barrier at the choroid plexus, as it actively participates in Aβ clearance. In addition, we describe the role of the choroid plexus in brain functions, aging and AD, as well as the role of megalin in the process of Aβ clearance. Finally, we present current data on the use of choroid plexus cells to repair the damaged brain.

Brain imaging in the context of food perception and eating.

PubMed

Hollmann, Maurice; Pleger, Burkhard; Villringer, Arno; Horstmann, Annette

2013-02-01

Eating behavior depends heavily on brain function. In recent years, brain imaging has proved to be a powerful tool to elucidate brain function and brain structure in the context of eating. In this review, we summarize recent findings in the fast growing body of literature in the field and provide an overview of technical aspects as well as the basic brain mechanisms identified with imaging. Furthermore, we highlight findings linking neural processing of eating-related stimuli with obesity. The consumption of food is based on a complex interplay between homeostatic and hedonic mechanisms. Several hormones influence brain activity to regulate food intake and interact with the brain's reward circuitry, which is partly mediated by dopamine signaling. Additionally, it was shown that food stimuli trigger cognitive control mechanisms that incorporate internal goals into food choice. The brain mechanisms observed in this context are strongly influenced by genetic factors, sex and personality traits. Overall, a complex picture arises from brain-imaging findings, because a multitude of factors influence human food choice. Although several key mechanisms have been identified, there is no comprehensive model that is able to explain the behavioral observations to date. Especially a careful characterization of patients according to genotypes and phenotypes could help to better understand the current and future findings in neuroimaging studies.

Adenosine Kinase Deficiency in the Brain Results in Maladaptive Synaptic Plasticity.

PubMed

Sandau, Ursula S; Colino-Oliveira, Mariana; Jones, Abbie; Saleumvong, Bounmy; Coffman, Shayla Q; Liu, Long; Miranda-Lourenço, Catarina; Palminha, Cátia; Batalha, Vânia L; Xu, Yiming; Huo, Yuqing; Diógenes, Maria J; Sebastião, Ana M; Boison, Detlev

2016-11-30

Adenosine kinase (ADK) deficiency in human patients (OMIM:614300) disrupts the methionine cycle and triggers hypermethioninemia, hepatic encephalopathy, cognitive impairment, and seizures. To identify whether this neurological phenotype is intrinsically based on ADK deficiency in the brain or if it is secondary to liver dysfunction, we generated a mouse model with a brain-wide deletion of ADK by introducing a Nestin-Cre transgene into a line of conditional ADK deficient Adk fl/fl mice. These Adk Δbrain mice developed a progressive stress-induced seizure phenotype associated with spontaneous convulsive seizures and profound deficits in hippocampus-dependent learning and memory. Pharmacological, biochemical, and electrophysiological studies suggest enhanced adenosine levels around synapses resulting in an enhanced adenosine A 1 receptor (A 1 R)-dependent protective tone despite lower expression levels of the receptor. Theta-burst-induced LTP was enhanced in the mutants and this was dependent on adenosine A 2A receptor (A 2A R) and tropomyosin-related kinase B signaling, suggesting increased activation of these receptors in synaptic plasticity phenomena. Accordingly, reducing adenosine A 2A receptor activity in Adk Δbrain mice restored normal associative learning and contextual memory and attenuated seizure risk. We conclude that ADK deficiency in the brain triggers neuronal adaptation processes that lead to dysregulated synaptic plasticity, cognitive deficits, and increased seizure risk. Therefore, ADK mutations have an intrinsic effect on brain physiology and may present a genetic risk factor for the development of seizures and learning impairments. Furthermore, our data show that blocking A 2A R activity therapeutically can attenuate neurological symptoms in ADK deficiency. A novel human genetic condition (OMIM #614300) that is based on mutations in the adenosine kinase (Adk) gene has been discovered recently. Affected patients develop hepatic encephalopathy, seizures, and severe cognitive impairment. To model and understand the neurological phenotype of the human mutation, we generated a new conditional knock-out mouse with a brain-specific deletion of Adk (Adk Δbrain ). Similar to ADK-deficient patients, Adk Δbrain mice develop seizures and cognitive deficits. We identified increased basal synaptic transmission and enhanced adenosine A 2A receptor (A 2A R)-dependent synaptic plasticity as the underlying mechanisms that govern these phenotypes. Our data show that neurological phenotypes in ADK-deficient patients are intrinsic to ADK deficiency in the brain and that blocking A 2A R activity therapeutically can attenuate neurological symptoms in ADK deficiency. Copyright © 2016 the authors 0270-6474/16/3612118-12$15.00/0.

Increased calcineurin expression after pilocarpine-induced status epilepticus is associated with brain focal edema and astrogliosis.

PubMed

Liu, Jinzhi; Li, Xiaolin; Chen, Liguang; Xue, Ping; Yang, Qianqian; Wang, Aihua

2015-07-28

Calcineurin plays an important role in the development of neuronal excitability, modulation of receptor's function and induction of apoptosis in neurons. It has been established in kindling models that status epilepticus induces brain focal edema and astrocyte activation. However, the role of calcineurin in brain focal edema and astrocyte activation in status epilepticus has not been fully understood. In this study, we employed a model of lithium-pilocarpine-induced status epilepticus and detected calcineurin expression in hippocampus by immunoblotting, brain focal edema by non-invasive magnetic resonance imaging (MRI-7T) and astrocyte expression by immunohistochemistry. We found that the brain focal edema was seen at 24 h after status epilepticus, and astrocyte expression was obviously seen at 7 d after status epilepticus. Meanwhile, calcineurin expression was seen at24 h and retained to 7 d after status epilepticus. A FK506, a calcineurin inhibitor, remarkably suppressed the status epilepticus-induced brain focal edema and astrocyte expression. Our data suggested that calcineurin overexpression plays a very important role in brain focal edema and astrocyte expression. Therefore, calcineurin may be a novel candidate for brain focal edema occurring and intracellular trigger of astrogliosis in status epilepticus.

Photoperiodic Modulation of Circadian Clock and Reproductive Axis Gene Expression in the Pre-Pubertal European Sea Bass Brain

PubMed Central

Martins, Rute S. T.; Gomez, Ana; Zanuy, Silvia; Carrillo, Manuel; Canário, Adelino V. M.

2015-01-01

The acquisition of reproductive competence requires the activation of the brain-pituitary-gonad (BPG) axis, which in most vertebrates, including fishes, is initiated by changes in photoperiod. In the European sea bass long-term exposure to continuous light (LL) alters the rhythm of reproductive hormones, delays spermatogenesis and reduces the incidence of precocious males. In contrast, an early shift from long to short photoperiod (AP) accelerates spermatogenesis. However, how photoperiod affects key genes in the brain to trigger the onset of puberty is still largely unknown. Here, we investigated if the integration of the light stimulus by clock proteins is sufficient to activate key genes that trigger the BPG axis in the European sea bass. We found that the clock genes clock, npas2, bmal1 and the BPG genes gnrh, kiss and kissr share conserved transcription factor frameworks in their promoters, suggesting co-regulation. Other gene promoters of the BGP axis were also predicted to be co-regulated by the same frameworks. Co-regulation was confirmed through gene expression analysis of brains from males exposed to LL or AP photoperiod compared to natural conditions: LL fish had suppressed gnrh1, kiss2, galr1b and esr1, while AP fish had stimulated npas2, gnrh1, gnrh2, kiss2, kiss1rb and galr1b compared to NP. It is concluded that fish exposed to different photoperiods present significant expression differences in some clock and reproductive axis related genes well before the first detectable endocrine and morphological responses of the BPG axis. PMID:26641263

Gulf war syndrome: could it be triggered by biological warfare-vaccines using pertussis as an adjuvant?

PubMed

Tournier, J-N; Jouan, A; Mathieu, J; Drouet, E

2002-04-01

Several recent epidemiological studies have shown that vaccinations against biological warfare using pertussis as an adjuvant were associated with the Gulf war syndrome. If such epidemiological findings are confirmed, we propose that the use of pertussis as an adjuvant could trigger neurodegeneration through induction of interleukin-1beta secretion in the brain. In turn, neuronal lesions may be sustained by stress or neurotoxic chemical combinations. Particular susceptibility for IL-1beta secretion and potential distant neuronal damage could provide an explanation for the diversity of the symptoms observed on veterans. Copyright 2002 Elsevier Science Ltd. All rights reserved.

An anatomically comprehensive atlas of the adult human brain transcriptome

PubMed Central

Guillozet-Bongaarts, Angela L.; Shen, Elaine H.; Ng, Lydia; Miller, Jeremy A.; van de Lagemaat, Louie N.; Smith, Kimberly A.; Ebbert, Amanda; Riley, Zackery L.; Abajian, Chris; Beckmann, Christian F.; Bernard, Amy; Bertagnolli, Darren; Boe, Andrew F.; Cartagena, Preston M.; Chakravarty, M. Mallar; Chapin, Mike; Chong, Jimmy; Dalley, Rachel A.; David Daly, Barry; Dang, Chinh; Datta, Suvro; Dee, Nick; Dolbeare, Tim A.; Faber, Vance; Feng, David; Fowler, David R.; Goldy, Jeff; Gregor, Benjamin W.; Haradon, Zeb; Haynor, David R.; Hohmann, John G.; Horvath, Steve; Howard, Robert E.; Jeromin, Andreas; Jochim, Jayson M.; Kinnunen, Marty; Lau, Christopher; Lazarz, Evan T.; Lee, Changkyu; Lemon, Tracy A.; Li, Ling; Li, Yang; Morris, John A.; Overly, Caroline C.; Parker, Patrick D.; Parry, Sheana E.; Reding, Melissa; Royall, Joshua J.; Schulkin, Jay; Sequeira, Pedro Adolfo; Slaughterbeck, Clifford R.; Smith, Simon C.; Sodt, Andy J.; Sunkin, Susan M.; Swanson, Beryl E.; Vawter, Marquis P.; Williams, Derric; Wohnoutka, Paul; Zielke, H. Ronald; Geschwind, Daniel H.; Hof, Patrick R.; Smith, Stephen M.; Koch, Christof; Grant, Seth G. N.; Jones, Allan R.

2014-01-01

Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of ~900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography— the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function. PMID:22996553

Identification of novel antibody-reactive detection sites for comprehensive gluten monitoring.

PubMed

Röckendorf, Niels; Meckelein, Barbara; Scherf, Katharina A; Schalk, Kathrin; Koehler, Peter; Frey, Andreas

2017-01-01

Certain cereals like wheat, rye or barley contain gluten, a protein mixture that can trigger celiac disease (CD). To make gluten-free diets available for affected individuals the gluten content of foodstuff must be monitored. For this purpose, antibody-based assays exist which rely on the recognition of certain linear gluten sequence motifs. Yet, not all CD-active gluten constituents and fragments formed during food processing/fermentation may be covered by those tests. In this study, we therefore assayed the coverage of reportedly CD-active gluten components by currently available detection antibodies and determined the antibody-inducing capacity of wheat gluten constituents in order to provide novel diagnostic targets for comprehensive gluten quantitation. Immunizations of outbred mice with purified gliadins and glutenins were conducted and the linear target recognition profile of the sera was recorded using synthetic peptide arrays that covered the sequence space of gluten constituents present in those preparations. The resulting murine immunorecognition profile of gluten demonstrated that further linear binding sites beyond those recognized by the monoclonal antibodies α20, R5 and G12 exist and may be exploitable as diagnostic targets. We conclude that the safety of foodstuffs for CD patients can be further improved by complementing current tests with antibodies directed against additional CD-active gluten components. Currently unrepresented linear gluten detection sites in glutenins and α-gliadins suggest sequences QQQYPS, PQQSFP, QPGQGQQG and QQPPFS as novel targets for antibody generation.

Identification of novel antibody-reactive detection sites for comprehensive gluten monitoring

PubMed Central

Röckendorf, Niels; Meckelein, Barbara; Scherf, Katharina A.; Schalk, Kathrin; Koehler, Peter

2017-01-01

Certain cereals like wheat, rye or barley contain gluten, a protein mixture that can trigger celiac disease (CD). To make gluten-free diets available for affected individuals the gluten content of foodstuff must be monitored. For this purpose, antibody-based assays exist which rely on the recognition of certain linear gluten sequence motifs. Yet, not all CD-active gluten constituents and fragments formed during food processing/fermentation may be covered by those tests. In this study, we therefore assayed the coverage of reportedly CD-active gluten components by currently available detection antibodies and determined the antibody-inducing capacity of wheat gluten constituents in order to provide novel diagnostic targets for comprehensive gluten quantitation. Immunizations of outbred mice with purified gliadins and glutenins were conducted and the linear target recognition profile of the sera was recorded using synthetic peptide arrays that covered the sequence space of gluten constituents present in those preparations. The resulting murine immunorecognition profile of gluten demonstrated that further linear binding sites beyond those recognized by the monoclonal antibodies α20, R5 and G12 exist and may be exploitable as diagnostic targets. We conclude that the safety of foodstuffs for CD patients can be further improved by complementing current tests with antibodies directed against additional CD-active gluten components. Currently unrepresented linear gluten detection sites in glutenins and α-gliadins suggest sequences QQQYPS, PQQSFP, QPGQGQQG and QQPPFS as novel targets for antibody generation. PMID:28759621

Biosynthesis and expression of ependymin homologous sequences in zebrafish brain.

PubMed

Sterrer, S; Königstorfer, A; Hoffmann, W

1990-01-01

Ependymins are unique, brain specific glycoproteins, which are major constituents of the cerebrospinal fluid. Originally, they were discovered in goldfish and are thought to be involved in synaptic plasticity. In the present study two transcripts were characterized in Brachydanio rerio originating from a single gene possibly by alternative splicing. These transcripts differ only in the length of their 3'-non-coding-regions and the encoded protein shares 90 and 88% homology with the two corresponding goldfish proteins, respectively. In situ hybridization revealed the expression of ependymins exclusively in the leptomeninx including its invaginations but not at all in the ependymal layer surrounding the ventricles. An initial developmental profile showed that ependymins first appear before hatching, i.e. between 48 and 72 h postfertilization.

Perceptual grouping in the human brain: common processing of different cues.

PubMed

Seymour, Kiley; Karnath, Hans-Otto; Himmelbach, Marc

2008-12-03

The perception of global scenes and objects consisting of multiple constituents is based on the integration of local elements or features. Gestalt grouping cues, such as proximity or similarity, can aid this process. Using functional MRI we investigated whether grouping guided by different gestalt cues rely on distinct networks in the brain or share a common network. Our study revealed that gestalt grouping involved the inferior parietal cortex, middle temporal gyrus and prefrontal cortex irrespective of the specific cue used. These findings agree with observations in neurological patients, which suggest that inferior parietal regions may aid the integration of local features into a global gestalt. Damage to this region results in simultanagnosia, a deficit in perceiving multiple objects and global scenes.

Functional neuroanatomy of disorders of consciousness.

PubMed

Di Perri, Carol; Stender, Johan; Laureys, Steven; Gosseries, Olivia

2014-01-01

Our understanding of the mechanisms of loss and recovery of consciousness, following severe brain injury or during anesthesia, is changing rapidly. Recent neuroimaging studies have shown that patients with chronic disorders of consciousness and subjects undergoing general anesthesia present a complex dysfunctionality in the architecture of brain connectivity. At present, the global hallmark of impaired consciousness appears to be a multifaceted dysfunctional connectivity pattern with both within-network loss of connectivity in a widespread frontoparietal network and between-network hyperconnectivity involving other regions such as the insula and ventral tegmental area. Despite ongoing efforts, the mechanisms underlying the emergence of consciousness after severe brain injury are not thoroughly understood. Important questions remain unanswered: What triggers the connectivity impairment leading to disorders of consciousness? Why do some patients recover from coma, while others with apparently similar brain injuries do not? Understanding these mechanisms could lead to a better comprehension of brain function and, hopefully, lead to new therapeutic strategies in this challenging patient population. © 2013.

Two hands, one brain, and aging.

PubMed

Maes, Celine; Gooijers, Jolien; Orban de Xivry, Jean-Jacques; Swinnen, Stephan P; Boisgontier, Matthieu P

2017-04-01

Many activities of daily living require moving both hands in an organized manner in space and time. Therefore, understanding the impact of aging on bimanual coordination is essential for prolonging functional independence and well-being in older adults. Here we investigated the behavioral and neural determinants of bimanual coordination in aging. The studies surveyed in this review reveal that aging is associated with cortical hyper-activity (but also subcortical hypo-activity) during performance of bimanual tasks. In addition to changes in activation in local areas, the interaction between distributed brain areas also exhibits age-related effects, i.e., functional connectivity is increased in the resting brain as well as during task performance. The mechanisms and triggers underlying these functional activation and connectivity changes remain to be investigated. This requires further research investment into the detailed study of interactions between brain structure, function and connectivity. This will also provide the foundation for interventional research programs towards preservation of brain health and behavioral performance by maximizing neuroplasticity potential in older adults. Copyright © 2017 Elsevier Ltd. All rights reserved.

The brain-computer interface cycle.

PubMed

van Gerven, Marcel; Farquhar, Jason; Schaefer, Rebecca; Vlek, Rutger; Geuze, Jeroen; Nijholt, Anton; Ramsey, Nick; Haselager, Pim; Vuurpijl, Louis; Gielen, Stan; Desain, Peter

2009-08-01

Brain-computer interfaces (BCIs) have attracted much attention recently, triggered by new scientific progress in understanding brain function and by impressive applications. The aim of this review is to give an overview of the various steps in the BCI cycle, i.e., the loop from the measurement of brain activity, classification of data, feedback to the subject and the effect of feedback on brain activity. In this article we will review the critical steps of the BCI cycle, the present issues and state-of-the-art results. Moreover, we will develop a vision on how recently obtained results may contribute to new insights in neurocognition and, in particular, in the neural representation of perceived stimuli, intended actions and emotions. Now is the right time to explore what can be gained by embracing real-time, online BCI and by adding it to the set of experimental tools already available to the cognitive neuroscientist. We close by pointing out some unresolved issues and present our view on how BCI could become an important new tool for probing human cognition.

Brain mast cells link the immune system to anxiety-like behavior

PubMed Central

Nautiyal, Katherine M.; Ribeiro, Ana C.; Pfaff, Donald W.; Silver, Rae

2008-01-01

Mast cells are resident in the brain and contain numerous mediators, including neurotransmitters, cytokines, and chemokines, that are released in response to a variety of natural and pharmacological triggers. The number of mast cells in the brain fluctuates with stress and various behavioral and endocrine states. These properties suggest that mast cells are poised to influence neural systems underlying behavior. Using genetic and pharmacological loss-of-function models we performed a behavioral screen for arousal responses including emotionality, locomotor, and sensory components. We found that mast cell deficient KitW−sh/W−sh (sash−/−) mice had a greater anxiety-like phenotype than WT and heterozygote littermate control animals in the open field arena and elevated plus maze. Second, we show that blockade of brain, but not peripheral, mast cell activation increased anxiety-like behavior. Taken together, the data implicate brain mast cells in the modulation of anxiety-like behavior and provide evidence for the behavioral importance of neuroimmune links. PMID:19004805

Brain mast cells link the immune system to anxiety-like behavior.

PubMed

Nautiyal, Katherine M; Ribeiro, Ana C; Pfaff, Donald W; Silver, Rae

2008-11-18

Mast cells are resident in the brain and contain numerous mediators, including neurotransmitters, cytokines, and chemokines, that are released in response to a variety of natural and pharmacological triggers. The number of mast cells in the brain fluctuates with stress and various behavioral and endocrine states. These properties suggest that mast cells are poised to influence neural systems underlying behavior. Using genetic and pharmacological loss-of-function models we performed a behavioral screen for arousal responses including emotionality, locomotor, and sensory components. We found that mast cell deficient Kit(W-sh/W-sh) (sash(-/-)) mice had a greater anxiety-like phenotype than WT and heterozygote littermate control animals in the open field arena and elevated plus maze. Second, we show that blockade of brain, but not peripheral, mast cell activation increased anxiety-like behavior. Taken together, the data implicate brain mast cells in the modulation of anxiety-like behavior and provide evidence for the behavioral importance of neuroimmune links.

Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model.

PubMed

Tagge, Chad A; Fisher, Andrew M; Minaeva, Olga V; Gaudreau-Balderrama, Amanda; Moncaster, Juliet A; Zhang, Xiao-Lei; Wojnarowicz, Mark W; Casey, Noel; Lu, Haiyan; Kokiko-Cochran, Olga N; Saman, Sudad; Ericsson, Maria; Onos, Kristen D; Veksler, Ronel; Senatorov, Vladimir V; Kondo, Asami; Zhou, Xiao Z; Miry, Omid; Vose, Linnea R; Gopaul, Katisha R; Upreti, Chirag; Nowinski, Christopher J; Cantu, Robert C; Alvarez, Victor E; Hildebrandt, Audrey M; Franz, Erich S; Konrad, Janusz; Hamilton, James A; Hua, Ning; Tripodis, Yorghos; Anderson, Andrew T; Howell, Gareth R; Kaufer, Daniela; Hall, Garth F; Lu, Kun P; Ransohoff, Richard M; Cleveland, Robin O; Kowall, Neil W; Stein, Thor D; Lamb, Bruce T; Huber, Bertrand R; Moss, William C; Friedman, Alon; Stanton, Patric K; McKee, Ann C; Goldstein, Lee E

2018-02-01

The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.awx350media15713427811001. © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.

Multimodal Imaging of Alzheimer Pathophysiology in the Brain's Default Mode Network

DOE PAGES

Shin, Jonghan; Kepe, Vladimir; Small, Gary W.; ...

2011-01-01

The spatial correlations between the brain's default mode network (DMN) and the brain regions known to develop pathophysiology in Alzheimer's disease (AD) have recently attracted much attention. In this paper, we compare results of different functional and structural imaging modalities, including MRI and PET, and highlight different patterns of anomalies observed within the DMN. Multitracer PET imaging in subjects with and without dementia has demonstrated that [C-11]PIB- and [F-18]FDDNP-binding patterns in patients with AD overlap within nodes of the brain's default network including the prefrontal, lateral parietal, lateral temporal, and posterior cingulate cortices, with the exception of the medial temporalmore » cortex (especially, the hippocampus) where significant discrepancy between increased [F-18]FDDNP binding and negligible [C-11]PIB-binding was observed. [F-18]FDDNP binding in the medial temporal cortex—a key constituent of the DMN—coincides with both the presence of amyloid and tau pathology, and also with cortical areas with maximal atrophy as demonstrated by T1-weighted MR imaging of AD patients.« less

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).

Control of abdominal muscles by brain stem respiratory neurons in the cat

NASA Technical Reports Server (NTRS)

Miller, Alan D.; Ezure, Kazuhisa; Suzuki, Ichiro

1985-01-01

The nature of the control of abdominal muscles by the brain stem respiratory neurons was investigated in decerebrate unanesthetized cats. First, it was determined which of the brain stem respiratory neurons project to the lumbar cord (from which the abdominal muscles receive part of their innervation), by stimulating the neurons monopolarly. In a second part of the study, it was determined if lumbar-projecting respiratory neurons make monosynaptic connections with abdominal motoneurons; in these experiments, discriminate spontaneous spikes of antidromically acivated expiratory (E) neurons were used to trigger activity from both L1 and L2 nerves. A large projection was observed from E neurons in the caudal ventral respiratory group to the contralateral upper lumber cord. However, cross-correlation experiments found only two (out of 47 neuron pairs tested) strong monosynaptic connections between brain stem neurons and abdominal motoneurons.

Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation

PubMed Central

Alia, Claudia; Spalletti, Cristina; Lai, Stefano; Panarese, Alessandro; Lamola, Giuseppe; Bertolucci, Federica; Vallone, Fabio; Di Garbo, Angelo; Chisari, Carmelo; Micera, Silvestro; Caleo, Matteo

2017-01-01

Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration. PMID:28360842

Essential role for zinc-triggered p75NTR activation in preconditioning neuroprotection.

PubMed

Lee, Jin-Yeon; Kim, Yu-Jin; Kim, Tae-Youn; Koh, Jae-Young; Kim, Yang-Hee

2008-10-22

Ischemic preconditioning (PC) of the brain is a phenomenon by which mild ischemic insults render neurons resistant to subsequent strong insults. Key steps in ischemic PC of the brain include caspase-3 activation and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, but upstream events have not been clearly elucidated. We have tested whether endogenous zinc is required for ischemic PC of the brain in rats. Mild, transient zinc accumulation was observed in certain neurons after ischemic PC. Moreover, intraventricular administration of CaEDTA during ischemic PC abrogated both zinc accumulation and the protective effect against subsequent full ischemia. To elucidate the mechanism of the zinc-triggered PC (Zn PC) effect, cortical cultures were exposed to sublethal levels of zinc, and 18 h later to lethal levels of zinc or NMDA. Zn PC exhibited the characteristic features of ischemic PC, including caspase-3 activation, PARP-1 cleavage, and HSP70 induction, all of which are crucial for subsequent neuroprotection against NMDA or zinc toxicity. HSP70 induction was necessary for protection, as it halted caspase-3 activation before apoptosis. Interestingly, in both Zn PC in vitro and ischemic PC in vivo, p75(NTR) was necessary for neuroprotection. These results suggest that caspase-3 activation during ischemic PC, a necessary event for subsequent neuroprotection, may result from mild zinc accumulation and the consequent p75(NTR) activation in neurons.

Olfactory modulation by dopamine in the context of aversive learning

PubMed Central

Riffell, Jeffrey A.; Martin, Joshua P.; Gage, Stephanie L.; Nighorn, Alan J.

2012-01-01

The need to detect and process sensory cues varies in different behavioral contexts. Plasticity in sensory coding can be achieved by the context-specific release of neuromodulators in restricted brain areas. The context of aversion triggers the release of dopamine in the insect brain, yet the effects of dopamine on sensory coding are unknown. In this study, we characterize the morphology of dopaminergic neurons that innervate each of the antennal lobes (ALs; the first synaptic neuropils of the olfactory system) of the moth Manduca sexta and demonstrate with electrophysiology that dopamine enhances odor-evoked responses of the majority of AL neurons while reducing the responses of a small minority. Because dopamine release in higher brain areas mediates aversive learning we developed a naturalistic, ecologically inspired aversive learning paradigm in which an innately appetitive host plant floral odor is paired with a mimic of the aversive nectar of herbivorized host plants. This pairing resulted in a decrease in feeding behavior that was blocked when dopamine receptor antagonists were injected directly into the ALs. These results suggest that a transient dopaminergic enhancement of sensory output from the AL contributes to the formation of aversive memories. We propose a model of olfactory modulation in which specific contexts trigger the release of different neuromodulators in the AL to increase olfactory output to downstream areas of processing. PMID:22552185

Hello from the Other Side: How Autoantibodies Circumvent the Blood-Brain Barrier in Autoimmune Encephalitis.

PubMed

Platt, Maryann P; Agalliu, Dritan; Cutforth, Tyler

2017-01-01

Antibodies against neuronal receptors and synaptic proteins are associated with autoimmune encephalitides (AE) that produce movement and psychiatric disorders. In order to exert their pathological effects on neural circuits, autoantibodies against central nervous system (CNS) targets must gain access to the brain and spinal cord by crossing the blood-brain barrier (BBB), a tightly regulated gateway formed by endothelial cells lining CNS blood vessels. To date, the pathogenic mechanisms that underlie autoantibody-triggered encephalitic syndromes are poorly understood, and how autoantibodies breach the barrier remains obscure for almost all AE syndromes. The relative importance of cellular versus humoral immune mechanisms for disease pathogenesis also remains largely unexplored. Here, we review the proposed triggers for various autoimmune encephalopathies and their animal models, as well as basic structural features of the BBB and how they differ among various CNS regions, a feature that likely underlies some regional aspects of autoimmune encephalitis pathogenesis. We then discuss the routes that antibodies and immune cells employ to enter the CNS and their implications for AE. Finally, we explore future therapeutic strategies that may either preserve or restore barrier function and thereby limit immune cell and autoantibody infiltration into the CNS. Recent mechanistic insights into CNS autoantibody entry indicate promising future directions for therapeutic intervention beyond current, short-lived therapies that eliminate circulating autoantibodies.

Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis

PubMed Central

Platt, Maryann P.; Agalliu, Dritan; Cutforth, Tyler

2017-01-01

Antibodies against neuronal receptors and synaptic proteins are associated with autoimmune encephalitides (AE) that produce movement and psychiatric disorders. In order to exert their pathological effects on neural circuits, autoantibodies against central nervous system (CNS) targets must gain access to the brain and spinal cord by crossing the blood–brain barrier (BBB), a tightly regulated gateway formed by endothelial cells lining CNS blood vessels. To date, the pathogenic mechanisms that underlie autoantibody-triggered encephalitic syndromes are poorly understood, and how autoantibodies breach the barrier remains obscure for almost all AE syndromes. The relative importance of cellular versus humoral immune mechanisms for disease pathogenesis also remains largely unexplored. Here, we review the proposed triggers for various autoimmune encephalopathies and their animal models, as well as basic structural features of the BBB and how they differ among various CNS regions, a feature that likely underlies some regional aspects of autoimmune encephalitis pathogenesis. We then discuss the routes that antibodies and immune cells employ to enter the CNS and their implications for AE. Finally, we explore future therapeutic strategies that may either preserve or restore barrier function and thereby limit immune cell and autoantibody infiltration into the CNS. Recent mechanistic insights into CNS autoantibody entry indicate promising future directions for therapeutic intervention beyond current, short-lived therapies that eliminate circulating autoantibodies. PMID:28484451

Facial Speech Gestures: The Relation between Visual Speech Processing, Phonological Awareness, and Developmental Dyslexia in 10-Year-Olds

ERIC Educational Resources Information Center

Schaadt, Gesa; Männel, Claudia; van der Meer, Elke; Pannekamp, Ann; Friederici, Angela D.

2016-01-01

Successful communication in everyday life crucially involves the processing of auditory and visual components of speech. Viewing our interlocutor and processing visual components of speech facilitates speech processing by triggering auditory processing. Auditory phoneme processing, analyzed by event-related brain potentials (ERP), has been shown…

Infant diet-related changes in syllable processing between 4 and 5 months: Implications for developing native language sensitivity

USDA-ARS?s Scientific Manuscript database

Since maturational processes triggering increased attunement to native language features in early infancy are sensitive to dietary factors, infant-diet related differences in brain processing of native-language speech stimuli might indicate variations in onset of this tuning process. We measured cor...

Incorporating Movement with Fluency Instruction: A Motivation for Struggling Readers

ERIC Educational Resources Information Center

Peebles, Jodi L.

2007-01-01

This article discusses two activities--Readers Theatre and Rhythm Walks--that encourage students to "get moving" with fluency instruction. Movement can be a motivating factor for struggling students, as well as a kinesthetic tool for conceptualizing the rhythm and flow of fluent reading while triggering brain function for optimal learning. Also…

Norepinephrine Triggers Metaplasticity of LTP by Increasing Translation of Specific mRNAs

ERIC Educational Resources Information Center

Maity, Sabyasachi; Rah, Sean; Sonenberg, Nahum; Gkogkas, Christos G.; Nguyen, Peter V.

2015-01-01

Norepinephrine (NE) is a key modulator of synaptic plasticity in the hippocampus, a brain structure crucially involved in memory formation. NE boosts synaptic plasticity mostly through initiation of signaling cascades downstream from beta (ß)-adrenergic receptors (ß-ARs). Previous studies demonstrated that a ß-adrenergic receptor agonist,…

Neurolinguistics of Linguistic Perseveration: Evidences from Clinical Population

ERIC Educational Resources Information Center

Rao, Prema K. S.

2007-01-01

It is generally well known that linguistic perseveration is a common symptom in individuals with brain damage and that its manifestation may be at the phonological, syntactic and/or semantic levels. The influence of perseveratory behavior on a subject's response to test stimuli and in therapeutic process has triggered the interests of the speech…

Inflammation in Alzheimer's disease: amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors.

PubMed

Salminen, Antero; Ojala, Johanna; Kauppinen, Anu; Kaarniranta, Kai; Suuronen, Tiina

2009-02-01

The inflammatory process has a fundamental role in the pathogenesis of Alzheimer's disease (AD). Recent studies indicate that inflammation is not merely a bystander in neurodegeneration but a powerful pathogenetic force in the disease process. Increased production of amyloid-beta peptide species can activate the innate immunity system via pattern recognition receptors (PRRs) and evoke Alzheimer's pathology. We will focus on the role of innate immunity system of brain in the initiation and the propagation of inflammatory process in AD. We examine here in detail the significance of amyloid-beta oligomers and fibrils as danger-associated molecular patterns (DAMPs) in the activation of a wide array of PRRs in glial cells and neurons, such as Toll-like, NOD-like, formyl peptide, RAGE and scavenger receptors along with complement and pentraxin systems. We also characterize the signaling pathways triggered by different PRRs in evoking inflammatory responses. In addition, we will discuss whether AD pathology could be the outcome of chronic activation of the innate immunity defence in the brain of AD patients.

Headache Following Occipital Brain Lesion: A Case of Migraine Triggered by Occipital Spikes?

PubMed

Vollono, Catello; Mariotti, Paolo; Losurdo, Anna; Giannantoni, Nadia Mariagrazia; Mazzucchi, Edoardo; Valentini, Piero; De Rose, Paola; Della Marca, Giacomo

2015-10-01

This study describes the case of an 8-year-old boy who developed a genuine migraine after the surgical excision, from the right occipital lobe, of brain abscesses due to selective infestation of the cerebrum by Entamoeba histolytica. After the surgical treatment, the boy presented daily headaches with typical migraine features, including right-side parieto-temporal pain, nausea, vomiting, and photophobia. Electroencephalography (EEG) showed epileptiform discharges in the right occipital lobe, although he never presented seizures. Clinical and neurophysiological observations were performed, including video-EEG and polygraphic recordings. EEG showed "interictal" epileptiform discharges in the right occipital lobe. A prolonged video-EEG recording performed before, during, and after an acute attack ruled out ictal or postictal migraine. In this boy, an occipital lesion caused occipital epileptiform EEG discharges without seizures, probably prevented by the treatment. We speculate that occipital spikes, in turn, could have caused a chronic headache with features of migraine without aura. Occipital epileptiform discharges, even in absence of seizures, may trigger a genuine migraine, probably by means of either the trigeminovascular or brainstem system. © EEG and Clinical Neuroscience Society (ECNS) 2014.

An implantable bolus infusion pump for use in freely moving, nontethered rats

PubMed Central

HOLSCHNEIDER, D. P.; MAAREK, J.-M. I.; HARIMOTO, J.; YANG, J.; SCREMIN, O. U.

2014-01-01

One of the current constraints on functional neuroimaging in animals is that to avoid movement artifacts during data acquisition, subjects need to be immobilized, sedated, or anesthetized. Such measures limit the behaviors that can be examined, and introduce the additional variables of stress or anesthetic agents that may confound meaningful interpretation. This study provides a description of the design and characteristics of a self-contained, implantable microbolus infusion pump (MIP) that allows triggering of a bolus injection at a distance in conscious, behaving rats that are not restrained or tethered. The MIP is externally triggered by a pulse of infrared light and allows in vivo bolus drug delivery. We describe application of this technology to the intravenous bolus delivery of iodo[14C]antipyrine in a freely moving animal, followed immediately by lethal injection, rapid removal of the brain, and analysis of regional cerebral blood flow tissue radioactivity with the use of autoradiography. The ability to investigate changes in brain activation in nonrestrained animals makes the MIP a powerful tool for evaluation of complex behaviors. PMID:12234827

Brain-Heart Interaction: Cardiac Complications After Stroke.

PubMed

Chen, Zhili; Venkat, Poornima; Seyfried, Don; Chopp, Michael; Yan, Tao; Chen, Jieli

2017-08-04

Neurocardiology is an emerging specialty that addresses the interaction between the brain and the heart, that is, the effects of cardiac injury on the brain and the effects of brain injury on the heart. This review article focuses on cardiac dysfunction in the setting of stroke such as ischemic stroke, brain hemorrhage, and subarachnoid hemorrhage. The majority of post-stroke deaths are attributed to neurological damage, and cardiovascular complications are the second leading cause of post-stroke mortality. Accumulating clinical and experimental evidence suggests a causal relationship between brain damage and heart dysfunction. Thus, it is important to determine whether cardiac dysfunction is triggered by stroke, is an unrelated complication, or is the underlying cause of stroke. Stroke-induced cardiac damage may lead to fatality or potentially lifelong cardiac problems (such as heart failure), or to mild and recoverable damage such as neurogenic stress cardiomyopathy and Takotsubo cardiomyopathy. The role of location and lateralization of brain lesions after stroke in brain-heart interaction; clinical biomarkers and manifestations of cardiac complications; and underlying mechanisms of brain-heart interaction after stroke, such as the hypothalamic-pituitary-adrenal axis; catecholamine surge; sympathetic and parasympathetic regulation; microvesicles; microRNAs; gut microbiome, immunoresponse, and systemic inflammation, are discussed. © 2017 American Heart Association, Inc.

Elucidating the underlying components of food valuation in the human orbitofrontal cortex.

PubMed

Suzuki, Shinsuke; Cross, Logan; O'Doherty, John P

2017-12-01

The valuation of food is a fundamental component of our decision-making. Yet little is known about how value signals for food and other rewards are constructed by the brain. Using a food-based decision task in human participants, we found that subjective values can be predicted from beliefs about constituent nutritive attributes of food: protein, fat, carbohydrates and vitamin content. Multivariate analyses of functional MRI data demonstrated that, while food value is represented in patterns of neural activity in both medial and lateral parts of the orbitofrontal cortex (OFC), only the lateral OFC represents the elemental nutritive attributes. Effective connectivity analyses further indicate that information about the nutritive attributes represented in the lateral OFC is integrated within the medial OFC to compute an overall value. These findings provide a mechanistic account for the construction of food value from its constituent nutrients.

Inhibition of MAO by fractions and constituents of hypericum extract.

PubMed

Bladt, S; Wagner, H

1994-10-01

The inhibition of monoamine oxidase (MAO) by six fractions from hypericum extract and three characteristic constituents (as pure substances) were analyzed in vitro and ex vivo to study the antidepressive mechanism of action. Rat brain homogenates were used as the in vitro model, while the ex vivo analysis was performed after intraperitoneal application of the test substances to albino rats. Massive inhibition of MAO-A could be shown with the total extract and all fractions only at the concentration of 10(-3) mol/L. At 10(-4) mol/L, one fraction rich in flavonoides showed an inhibition of 39%, and all other fractions demonstrated less than 25% inhibition. Using pure hypericin as well as in all ex vivo experiments, no relevant inhibiting effects could be shown. From the results it can be concluded that the clinically proven antidepressive effect of hypericum extract cannot be explained in terms of MAO inhibition.

Brain-Computer Interface Controlled Cyborg: Establishing a Functional Information Transfer Pathway from Human Brain to Cockroach Brain

PubMed Central

2016-01-01

An all-chain-wireless brain-to-brain system (BTBS), which enabled motion control of a cyborg cockroach via human brain, was developed in this work. Steady-state visual evoked potential (SSVEP) based brain-computer interface (BCI) was used in this system for recognizing human motion intention and an optimization algorithm was proposed in SSVEP to improve online performance of the BCI. The cyborg cockroach was developed by surgically integrating a portable microstimulator that could generate invasive electrical nerve stimulation. Through Bluetooth communication, specific electrical pulse trains could be triggered from the microstimulator by BCI commands and were sent through the antenna nerve to stimulate the brain of cockroach. Serial experiments were designed and conducted to test overall performance of the BTBS with six human subjects and three cockroaches. The experimental results showed that the online classification accuracy of three-mode BCI increased from 72.86% to 78.56% by 5.70% using the optimization algorithm and the mean response accuracy of the cyborgs using this system reached 89.5%. Moreover, the results also showed that the cyborg could be navigated by the human brain to complete walking along an S-shape track with the success rate of about 20%, suggesting the proposed BTBS established a feasible functional information transfer pathway from the human brain to the cockroach brain. PMID:26982717

Brain-Computer Interface Controlled Cyborg: Establishing a Functional Information Transfer Pathway from Human Brain to Cockroach Brain.

PubMed

Li, Guangye; Zhang, Dingguo

2016-01-01

An all-chain-wireless brain-to-brain system (BTBS), which enabled motion control of a cyborg cockroach via human brain, was developed in this work. Steady-state visual evoked potential (SSVEP) based brain-computer interface (BCI) was used in this system for recognizing human motion intention and an optimization algorithm was proposed in SSVEP to improve online performance of the BCI. The cyborg cockroach was developed by surgically integrating a portable microstimulator that could generate invasive electrical nerve stimulation. Through Bluetooth communication, specific electrical pulse trains could be triggered from the microstimulator by BCI commands and were sent through the antenna nerve to stimulate the brain of cockroach. Serial experiments were designed and conducted to test overall performance of the BTBS with six human subjects and three cockroaches. The experimental results showed that the online classification accuracy of three-mode BCI increased from 72.86% to 78.56% by 5.70% using the optimization algorithm and the mean response accuracy of the cyborgs using this system reached 89.5%. Moreover, the results also showed that the cyborg could be navigated by the human brain to complete walking along an S-shape track with the success rate of about 20%, suggesting the proposed BTBS established a feasible functional information transfer pathway from the human brain to the cockroach brain.

Characterization of long-range functional connectivity in epileptic networks by neuronal spike-triggered local field potentials

NASA Astrophysics Data System (ADS)

Lopour, Beth A.; Staba, Richard J.; Stern, John M.; Fried, Itzhak; Ringach, Dario L.

2016-04-01

Objective. Quantifying the relationship between microelectrode-recorded multi-unit activity (MUA) and local field potentials (LFPs) in distinct brain regions can provide detailed information on the extent of functional connectivity in spatially widespread networks. These methods are common in studies of cognition using non-human animal models, but are rare in humans. Here we applied a neuronal spike-triggered impulse response to electrophysiological recordings from the human epileptic brain for the first time, and we evaluate functional connectivity in relation to brain areas supporting the generation of seizures. Approach. Broadband interictal electrophysiological data were recorded from microwires adapted to clinical depth electrodes that were implanted bilaterally using stereotactic techniques in six presurgical patients with medically refractory epilepsy. MUA and LFPs were isolated in each microwire, and we calculated the impulse response between the MUA on one microwire and the LFPs on a second microwire for all possible MUA/LFP pairs. Results were compared to clinical seizure localization, including sites of seizure onset and interictal epileptiform discharges. Main results. We detected significant interictal long-range functional connections in each subject, in some cases across hemispheres. Results were consistent between two independent datasets, and the timing and location of significant impulse responses reflected anatomical connectivity. However, within individual subjects, the spatial distribution of impulse responses was unique. In two subjects with clear seizure localization and successful surgery, the epileptogenic zone was associated with significant impulse responses. Significance. The results suggest that the spike-triggered impulse response can provide valuable information about the neuronal networks that contribute to seizures using only interictal data. This technique will enable testing of specific hypotheses regarding functional connectivity in epilepsy and the relationship between functional properties and imaging findings. Beyond epilepsy, we expect that the impulse response could be more broadly applied as a measure of long-range functional connectivity in studies of cognition.

Characterization of long-range functional connectivity in epileptic networks by neuronal spike-triggered local field potentials

PubMed Central

Lopour, Beth A; Staba, Richard J; Stern, John M; Fried, Itzhak; Ringach, Dario L

2017-01-01

Objective Quantifying the relationship between microelectrode-recorded multi-unit activity (MUA) and local field potentials (LFPs) in distinct brain regions can provide detailed information on the extent of functional connectivity in spatially widespread networks. These methods are common in studies of cognition using non-human animal models, but are rare in humans. Here we applied a neuronal spike-triggered impulse response to electrophysiological recordings from the human epileptic brain for the first time, and we evaluate functional connectivity in relation to brain areas supporting the generation of seizures. Approach Broadband interictal electrophysiological data were recorded from microwires adapted to clinical depth electrodes that were implanted bilaterally using stereotactic techniques in six presurgical patients with medically refractory epilepsy. MUA and LFPs were isolated in each microwire, and we calculated the impulse response between the MUA on one microwire and the LFPs on a second microwire for all possible MUA/LFP pairs. Results were compared to clinical seizure localization, including sites of seizure onset and interictal epileptiform discharges. Main results We detected significant interictal long-range functional connections in each subject, in some cases across hemispheres. Results were consistent between two independent datasets, and the timing and location of significant impulse responses reflected anatomical connectivity. However, within individual subjects, the spatial distribution of impulse responses was unique. In two subjects with clear seizure localization and successful surgery, the epileptogenic zone was associated with significant impulse responses. Significance The results suggest that the spike-triggered impulse response can provide valuable information about the neuronal networks that contribute to seizures using only interictal data. This technique will enable testing of specific hypotheses regarding functional connectivity in epilepsy and the relationship between functional properties and imaging findings. Beyond epilepsy, we expect that the impulse response could be more broadly applied as a measure of long-range functional connectivity in studies of cognition. PMID:26975603

Dopamine or opioid stimulation of nucleus accumbens similarly amplify cue-triggered 'wanting' for reward: entire core and medial shell mapped as substrates for PIT enhancement.

PubMed

Peciña, Susana; Berridge, Kent C

2013-05-01

Pavlovian cues [conditioned stimulus (CS+)] often trigger intense motivation to pursue and consume related reward [unconditioned stimulus (UCS)]. But cues do not always trigger the same intensity of motivation. Encountering a reward cue can be more tempting on some occasions than on others. What makes the same cue trigger more intense motivation to pursue reward on a particular encounter? The answer may be the level of incentive salience ('wanting') that is dynamically generated by mesocorticolimbic brain systems, influenced especially by dopamine and opioid neurotransmission in the nucleus accumbens (NAc) at that moment. We tested the ability of dopamine stimulation (by amphetamine microinjection) vs. mu opioid stimulation [by d-Ala, nMe-Phe, Glyol-enkephalin (DAMGO) microinjection] of either the core or shell of the NAc to amplify cue-triggered levels of motivation to pursue sucrose reward, measured with a Pavlovian-Instrumental Transfer (PIT) procedure, a relatively pure assay of incentive salience. Cue-triggered 'wanting' in PIT was enhanced by amphetamine or DAMGO microinjections equally, and also equally at nearly all sites throughout the entire core and medial shell (except for a small far-rostral strip of shell). NAc dopamine/opioid stimulations specifically enhanced CS+ ability to trigger phasic peaks of 'wanting' to obtain UCS, without altering baseline efforts when CS+ was absent. We conclude that dopamine/opioid stimulation throughout nearly the entire NAc can causally amplify the reactivity of mesocorticolimbic circuits, and so magnify incentive salience or phasic UCS 'wanting' peaks triggered by a CS+. Mesolimbic amplification of incentive salience may explain why a particular cue encounter can become irresistibly tempting, even when previous encounters were successfully resisted before. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Induction of specific micro RNA (miRNA) species by ROS-generating metal sulfates in primary human brain cells

PubMed Central

Lukiw, Walter J.; Pogue, Aileen I.

2007-01-01

Iron- and aluminum-sulfate together, at nanomolar concentrations, trigger the production of reactive oxygen species (ROS) in cultures of human brain cells. Previous studies have shown that following ROS induction, a family of pathogenic brain genes that promote inflammatory signalling, cellular apoptosis and brain cell death is significantly over-expressed. Notably, iron- and aluminum-sulfate induce genes in cultured human brain cells that exhibit expression patterns similar to those observed to be up-regulated in moderate- to late-stage Alzheimer's disease (AD). In this study we have extended our investigations to analyze the expression of micro RNA (miRNA) populations in iron- and aluminum-sulfate treated human neural cells in primary culture. The main finding was that these ROS-generating neurotoxic metal sulfates also up-regulate a specific set of miRNAs that includes miR-9, miR-125b and miR-128. Notably, these same miRNAs are up-regulated in AD brain. These findings further support the idea that iron- and aluminum-sulfates induce genotoxicity via a ROS-mediated up-regulation of specific regulatory elements and pathogenic genes that redirect brain cell fate towards progressive dysfunction and apoptotic cell death. PMID:17629564

Central nervous system regulation of intestinal lipid and lipoprotein metabolism.

PubMed

Farr, Sarah; Taher, Jennifer; Adeli, Khosrow

2016-02-01

In response to nutrient availability, the small intestine and brain closely communicate to modulate energy homeostasis and metabolism. The gut-brain axis involves complex nutrient sensing mechanisms and an integration of neuronal and hormonal signaling. This review summarizes recent evidence implicating the gut-brain axis in regulating lipoprotein metabolism, with potential implications for the dyslipidemia of insulin resistant states. The intestine and brain possess distinct mechanisms for sensing lipid availability, which triggers subsequent regulation of feeding, glucose homeostasis, and adipose tissue metabolism. More recently, central receptors, neuropeptides, and gut hormones that communicate with the brain have been shown to modulate hepatic and intestinal lipoprotein metabolism via parasympathetic and sympathetic signaling. Gut-derived glucagon-like peptides appear to be particularly important in modulating the intestinal secretion of chylomicron particles via a novel brain-gut axis. Dysregulation of these pathways may contribute to postprandial diabetic dyslipidemia. Emerging evidence implicates the central and enteric nervous systems in controlling many aspects of lipid and lipoprotein metabolism. Bidirectional communication between the gut and brain involving neuronal pathways and gut peptides is critical for regulating feeding and metabolism, and forms a neuroendocrine circuit to modulate dietary fat absorption and intestinal production of atherogenic chylomicron particles.

MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis.

PubMed

Baker, E H; Levin, S W; Zhang, Z; Mukherjee, A B

2017-02-01

Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase 1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood death. As part of a project studying the treatment benefits of a combination of cysteamine bitartrate and N -acetyl cysteine, we made serial measurements of patients' brain volumes with MR imaging. Ten patients with infantile neuronal ceroid lipofuscinosis participating in a treatment/follow-up study underwent brain MR imaging that included high-resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum-likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brain stem, and thalamus. Patients' brain volumes were compared with those of a healthy population. Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss and may never have been normal postnatally. The thalamus dropped out of the normal range around 6 months of age; the cerebellum, around 2 years of age; and the brain stem, around 3 years of age. Rapid cerebral volume loss was expected on the basis of previous qualitative reports. Because our study did not include a nontreatment arm and because progression of brain volumes in infantile neuronal ceroid lipofuscinosis has not been previously quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions. © 2017 by American Journal of Neuroradiology.

Diterpenoids and flavonoids from the fruits of Vitex agnus-castus and antioxidant activity of the fruit extracts and their constituents.

PubMed

Hajdú, Zsuzsanna; Hohmann, Judit; Forgo, Peter; Martinek, Tamás; Dervarics, Máté; Zupkó, István; Falkay, György; Cossuta, Daniel; Máthé, Imre

2007-04-01

From the n-hexane fraction of the fruits of Vitex agnus-castus, two labdane-type diterpenes, vitetrifolin B and C, were isolated by means of multiple chromatographic separations, together with the previously identified rotundifuran, vitexilactone and the sesquiterpene spathulenol. From the EtOAc fraction, eupatorin was identified for the first time, besides the known casticin, penduletin, vitexin and orientin. The n-hexane, EtOAc and MeOH-H(2)O fractions of the MeOH extract of Agni-casti fructus were subjected to in vitro antioxidant assays. The EtOAc extract displayed a significant concentration-dependent effect when tested by 1,1-diphenyl-2-picrylhydrasyl (DPPH) free radical assay (IC(50) = 68 microg/mL) and against the autooxidation of a standard rat brain homogenate (IC(50) = 14 microg/mL). The MeOH-H(2)O fraction was less active with 3643 microg/mL (DPPH test) and IC(50) = 125 microg/mL (rat brain homogenate), while the n-hexane phase proved to be inactive. The main flavonoid constituents of the EtOAc extract, casticin, vitexin and orientin were assayed for antioxidant activity and found that only casticin possesses a marked lipid peroxidation inhibitory effect (IC(50) = 0.049 mm) compared with that of the positive control ascorbic acid (IC(50) = 0.703 mm).

Effect of phospholipid-based formulations of Boswellia serrata extract on the solubility, permeability, and absorption of the individual boswellic acid constituents present.

PubMed

Hüsch, Jan; Gerbeth, Kathleen; Fricker, Gert; Setzer, Constanze; Zirkel, Jürgen; Rebmann, Herbert; Schubert-Zsilavecz, Manfred; Abdel-Tawab, Mona

2012-10-26

Boswellia serrata gum resin extracts are used widely for the treatment of inflammatory diseases. However, very low concentrations in the plasma and brain were observed for the boswellic acids (1-6, the active constituents of B. serrata). The present study investigated the effect of phospholipids alone and in combination with common co-surfactants (e.g., Tween 80, vitamin E-TPGS, pluronic f127) on the solubility of 1-6 in physiologically relevant media and on the permeability in the Caco-2 cell model. Because of the high lipophilicity of 1-6, the permeability experiments were adapted to physiological conditions using modified fasted state simulated intestinal fluid as apical (donor) medium and 4% bovine serum albumin in the basolateral (receiver) compartment. A formulation composed of extract/phospholipid/pluronic f127 (1:1:1 w/w/w) increased the solubility of 1-6 up to 54 times compared with the nonformulated extract and exhibited the highest mass net flux in the permeability tests. The oral administration of this formulation to rats (240 mg/kg) resulted in 26 and 14 times higher plasma levels for 11-keto-β-boswellic acid (1) and acetyl-11-keto-β-boswellic acid (2), respectively. In the brain, five times higher levels for 2 compared to the nonformulated extract were determined 8 h after oral administration.

MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis

PubMed Central

Baker, Eva H.; Levin, Sondra W.; Zhang, Zhongjian; Mukherjee, Anil B.

2016-01-01

Background Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. PPT1 deficiency impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood demise. As part of a project studying treatment benefits of a combination of cysteamine bitartrate and N-acetylcysteine, we made serial measurements of patients’ brain volumes using MRI. Methods Ten INCL patients participating in a treatment/follow-up study underwent brain MRI that included high resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum-likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brainstem, and thalamus. Patients’ brain volumes were compared to those of a normal population. Results Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss, and may never have been normal postnatally. The thalamus dropped out of the normal range around age 6 months, cerebellum around age 2 years, and brainstem around age 3 years. Discussion Rapid cerebral volume loss was expected based upon previous qualitative reports. Because our study did not include a non-treatment arm, and because progression of brain volumes in INCL has not previously been quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions. PMID:27765741

Morphology and physiology of the olfactory system of blood-feeding insects.

PubMed

Guidobaldi, F; May-Concha, I J; Guerenstein, P G

2014-01-01

Several blood-feeding (hematophagous) insects are vectors of a number of diseases including dengue, Chagas disease and leishmaniasis which persistently affect public health throughout Latin America. The vectors of those diseases include mosquitoes, triatomine bugs and sandflies. As vector control is an efficient way to prevent these illnesses it is important to understand the sensory biology of those harmful insects. We study the physiology of the olfactory system of those insects and apply that knowledge on the development of methods to manipulate their behavior. Here we review some of the latest information on insect olfaction with emphasis on hematophagous insects. The insect olfactory sensory neurons are housed inside hair-like organs called sensilla which are mainly distributed on the antenna and mouthparts. The identity of many of the odor compounds that those neurons detect are already known in hematophagous insects. They include several constituents of host (vertebrate) odor, sex, aggregation and alarm pheromones, and compounds related to egg-deposition behavior. Recent work has contributed significant knowledge on how odor information is processed in the insect first odor-processing center in the brain, the antennal lobe. The quality, quantity, and temporal features of the odor stimuli are encoded by the neural networks of the antennal lobe. Information regarding odor mixtures is also encoded. While natural mixtures evoke strong responses, synthetic mixtures that deviate from their natural counterparts in terms of key constituents or proportions of those constituents evoke weaker responses. The processing of olfactory information is largely unexplored in hematophagous insects. However, many aspects of their olfactory behavior are known. As in other insects, responses to relevant single odor compounds are weak while natural mixtures evoke strong responses. Future challenges include studying how information about odor mixtures is processed in their brain. This could help develop highly attractive synthetic odor blends to lure them into traps. Copyright © 2014 Elsevier Ltd. All rights reserved.

Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy?

PubMed

Washington, Patricia M; Villapol, Sonia; Burns, Mark P

2016-01-01

Neuropathological studies of human traumatic brain injury (TBI) cases have described amyloid plaques acutely after a single severe TBI, and tau pathology after repeat mild TBI (mTBI). This has helped drive the hypothesis that a single moderate to severe TBI increases the risk of developing late-onset Alzheimer's disease (AD), while repeat mTBI increases the risk of developing chronic traumatic encephalopathy (CTE). In this review we critically assess this position-examining epidemiological and case control human studies, neuropathological evidence, and preclinical data. Epidemiological studies emphasize that TBI is associated with the increased risk of developing multiple types of dementia, not just AD-type dementia, and that TBI can also trigger other neurodegenerative conditions such as Parkinson's disease. Further, human post-mortem studies on both single TBI and repeat mTBI can show combinations of amyloid, tau, TDP-43, and Lewy body pathology indicating that the neuropathology of TBI is best described as a 'polypathology'. Preclinical studies confirm that multiple proteins associated with the development of neurodegenerative disease accumulate in the brain after TBI. The chronic sequelae of both single TBI and repeat mTBI share common neuropathological features and clinical symptoms of classically defined neurodegenerative disorders. However, while the spectrum of chronic cognitive and neurobehavioral disorders that occur following repeat mTBI is viewed as the symptoms of CTE, the spectrum of chronic cognitive and neurobehavioral symptoms that occur after a single TBI is considered to represent distinct neurodegenerative diseases such as AD. These data support the suggestion that the multiple manifestations of TBI-induced neurodegenerative disorders be classified together as traumatic encephalopathy or trauma-induced neurodegeneration, regardless of the nature or frequency of the precipitating TBI. Copyright © 2015 Elsevier Inc. All rights reserved.

Opening of mitochondrial ATP-sensitive potassium channels is a trigger of 3-nitropropionic acid-induced tolerance to transient focal cerebral ischemia in rats.

PubMed

Horiguchi, Takashi; Kis, Bela; Rajapakse, Nishadi; Shimizu, Katsuyoshi; Busija, David W

2003-04-01

The role of mitochondrial ATP-sensitive potassium channels (mitoK(ATP)) in ischemic tolerance has been well documented in heart, but little work has been done in brain. To investigate the involvement of mitoK(ATP) activation in chemical preconditioning in brain, we examined the effect of 5-hydroxydecanoate (5-HD), a selective mitoK(ATP) blocker, on neurotoxin 3-nitropropionic acid (3-NPA)-induced ischemic tolerance to transient focal cerebral ischemia in rats. Male Wistar rats were administrated 3-NPA (20 mg/kg IP; n=16) or vehicle (saline; n=16) 3 days before temporary occlusion (120 minutes) of the middle cerebral artery; 5-HD (40 mg/kg IP; n=16) was injected 20 minutes before 3-NPA administration. Infarct volumes were measured 4 days after reperfusion. To directly investigate whether chemical preconditioning activates mitoK(ATP), we tested the effect of prior incubation with 1 mmol/L 5-HD on 300 micromol/L 3-NPA-induced alterations of mitochondrial membrane potential (Delta(Psi)m) in cultured neurons and astrocytes using the fluorescent dye tetramethylrhodamine ethyl ester. Treatment with 3-NPA exhibited a 16% reduction (P<0.05) and 23% reduction in infarct volume (P<0.01) for total brain and cortex, respectively. Pretreatment with 5-HD completely abolished the neuroprotective effect of chemical preconditioning. In cultured cells, 3-NPA resulted in mitochondrial depolarization. This change of Delta(Psi)m was completely blocked by 5-HD pretreatment. These results strongly suggest that opening of mitoK(ATP) plays a key role as the trigger in the development of 3-NPA-induced ischemic tolerance in brain.

Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should it be classified together as traumatic encephalopathy?

PubMed Central

Washington, Patricia M.; Villapol, Sonia; Burns, Mark P.

2015-01-01

Neuropathological studies of human traumatic brain injury (TBI) cases have described amyloid plaques acutely after a single severe TBI, and tau pathology after repeat mild TBI (mTBI). This has helped drive the hypothesis that a single moderate to severe TBI increases the risk of developing late-onset Alzheimer’s disease (AD), while mTBI increases the risk of developing chronic traumatic encephalopathy (CTE). In this review we critically assess this position—examining epidemiological and case-control human studies, neuropathological evidence, and preclinical studies. Epidemiological studies emphasize that TBI is associated with the increased risk of developing multiple types of dementia, not just AD-type dementia, and that TBI can also trigger other neurodegenerative conditions such as Parkinson’s disease. Further, human post-mortem studies on either single TBI and repeat mTBI can show combinations of amyloid, tau, TDP-43, and Lewy body pathology indicating that the neuropathology of TBI is best described as a ‘polypathology’. Preclinical studies confirm that multiple proteins associated with the development of neurodegenerative disease accumulate in the brain after TBI. The chronic sequelae of both single TBI and repeat mTBI share common neuropathological features and clinical symptoms of classically defined neurodegenerative disorders. However, while the spectrum of chronic cognitive and neurobehavioral disorders that occur following repeat mTBI are viewed as the symptoms of CTE, the spectrum of chronic cognitive and neurobehavioral symptoms that occur after a single TBI is considered to represent distinct neurodegenerative diseases such as AD. These data support the suggestion that the multiple manifestations of TBI-induced neurodegenerative disorders be classified together as traumatic encephalopathy or trauma-induced neurodegeneration, regardless of the nature or frequency of the precipitating TBI. PMID:26091850

How Does the Sparse Memory “Engram” Neurons Encode the Memory of a Spatial–Temporal Event?

PubMed Central

Guan, Ji-Song; Jiang, Jun; Xie, Hong; Liu, Kai-Yuan

2016-01-01

Episodic memory in human brain is not a fixed 2-D picture but a highly dynamic movie serial, integrating information at both the temporal and the spatial domains. Recent studies in neuroscience reveal that memory storage and recall are closely related to the activities in discrete memory engram (trace) neurons within the dentate gyrus region of hippocampus and the layer 2/3 of neocortex. More strikingly, optogenetic reactivation of those memory trace neurons is able to trigger the recall of naturally encoded memory. It is still unknown how the discrete memory traces encode and reactivate the memory. Considering a particular memory normally represents a natural event, which consists of information at both the temporal and spatial domains, it is unknown how the discrete trace neurons could reconstitute such enriched information in the brain. Furthermore, as the optogenetic-stimuli induced recall of memory did not depend on firing pattern of the memory traces, it is most likely that the spatial activation pattern, but not the temporal activation pattern of the discrete memory trace neurons encodes the memory in the brain. How does the neural circuit convert the activities in the spatial domain into the temporal domain to reconstitute memory of a natural event? By reviewing the literature, here we present how the memory engram (trace) neurons are selected and consolidated in the brain. Then, we will discuss the main challenges in the memory trace theory. In the end, we will provide a plausible model of memory trace cell network, underlying the conversion of neural activities between the spatial domain and the temporal domain. We will also discuss on how the activation of sparse memory trace neurons might trigger the replay of neural activities in specific temporal patterns. PMID:27601979

How Does the Sparse Memory "Engram" Neurons Encode the Memory of a Spatial-Temporal Event?

PubMed

Guan, Ji-Song; Jiang, Jun; Xie, Hong; Liu, Kai-Yuan

2016-01-01

Episodic memory in human brain is not a fixed 2-D picture but a highly dynamic movie serial, integrating information at both the temporal and the spatial domains. Recent studies in neuroscience reveal that memory storage and recall are closely related to the activities in discrete memory engram (trace) neurons within the dentate gyrus region of hippocampus and the layer 2/3 of neocortex. More strikingly, optogenetic reactivation of those memory trace neurons is able to trigger the recall of naturally encoded memory. It is still unknown how the discrete memory traces encode and reactivate the memory. Considering a particular memory normally represents a natural event, which consists of information at both the temporal and spatial domains, it is unknown how the discrete trace neurons could reconstitute such enriched information in the brain. Furthermore, as the optogenetic-stimuli induced recall of memory did not depend on firing pattern of the memory traces, it is most likely that the spatial activation pattern, but not the temporal activation pattern of the discrete memory trace neurons encodes the memory in the brain. How does the neural circuit convert the activities in the spatial domain into the temporal domain to reconstitute memory of a natural event? By reviewing the literature, here we present how the memory engram (trace) neurons are selected and consolidated in the brain. Then, we will discuss the main challenges in the memory trace theory. In the end, we will provide a plausible model of memory trace cell network, underlying the conversion of neural activities between the spatial domain and the temporal domain. We will also discuss on how the activation of sparse memory trace neurons might trigger the replay of neural activities in specific temporal patterns.

Dehydration triggers differential microRNA expression in Xenopus laevis brain.

PubMed

Luu, Bryan E; Storey, Kenneth B

2015-11-15

African clawed frogs, Xenopus laevis, although primarily aquatic, have a high tolerance for dehydration, being capable of withstanding the loss of up to 32-35% of total water body water. Recent studies have shown that microRNAs play a role in the response to dehydration by the liver, kidney and ventral skin of X. laevis. MicroRNAs act by modulating the expression of mRNA transcripts, thereby affecting diverse biochemical pathways. In this study, 43 microRNAs were assessed in frog brains comparing control and dehydrated (31.2±0.83% of total body water lost) conditions. MicroRNAs of interest were measured using a modified protocol which employs polyadenylation of microRNAs prior to reverse transcription and qPCR. Twelve microRNAs that showed a significant decrease in expression (to 41-77% of control levels) in brains from dehydrated frogs (xla-miR-15a, -150, -181a, -191, -211, -218, -219b, -30c, -30e, -31, -34a, and -34b) were identified. Genomic analysis showed that the sequences of these dehydration-responsive microRNAs were highly conserved as compared with the comparable microRNAs of mice (91-100%). Suppression of these microRNAs implies that translation of the mRNA transcripts under their control could be enhanced in response to dehydration. Bioinformatic analysis using the DIANA miRPath program (v.2.0) predicted the top two KEGG pathways that these microRNAs collectively regulate: 1. Axon guidance, and 2. Long-term potentiation. Previous studies indicated that suppression of these microRNAs promotes neuroprotective pathways by increasing the expression of brain-derived neurotrophic factor and activating anti-apoptotic pathways. This suggests that similar actions may be triggered in X. laevis brains as a protective response to dehydration. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

Brain-computer interface training combined with transcranial direct current stimulation in patients with chronic severe hemiparesis: Proof of concept study.

PubMed

Kasashima-Shindo, Yuko; Fujiwara, Toshiyuki; Ushiba, Junichi; Matsushika, Yayoi; Kamatani, Daiki; Oto, Misa; Ono, Takashi; Nishimoto, Atsuko; Shindo, Keiichiro; Kawakami, Michiyuki; Tsuji, Tetsuya; Liu, Meigen

2015-04-01

Brain-computer interface technology has been applied to stroke patients to improve their motor function. Event-related desynchronization during motor imagery, which is used as a brain-computer interface trigger, is sometimes difficult to detect in stroke patients. Anodal transcranial direct current stimulation (tDCS) is known to increase event-related desynchronization. This study investigated the adjunctive effect of anodal tDCS for brain-computer interface training in patients with severe hemiparesis. Eighteen patients with chronic stroke. A non-randomized controlled study. Subjects were divided between a brain-computer interface group and a tDCS- brain-computer interface group and participated in a 10-day brain-computer interface training. Event-related desynchronization was detected in the affected hemisphere during motor imagery of the affected fingers. The tDCS-brain-computer interface group received anodal tDCS before brain-computer interface training. Event-related desynchronization was evaluated before and after the intervention. The Fugl-Meyer Assessment upper extremity motor score (FM-U) was assessed before, immediately after, and 3 months after, the intervention. Event-related desynchronization was significantly increased in the tDCS- brain-computer interface group. The FM-U was significantly increased in both groups. The FM-U improvement was maintained at 3 months in the tDCS-brain-computer interface group. Anodal tDCS can be a conditioning tool for brain-computer interface training in patients with severe hemiparetic stroke.

Suppression of Brain Mast Cells Degranulation Inhibits Microglial Activation and Central Nervous System Inflammation.

PubMed

Dong, Hongquan; Zhang, Xiang; Wang, Yiming; Zhou, Xiqiao; Qian, Yanning; Zhang, Shu

2017-03-01

Brain inflammation has a critical role in the pathophysiology of brain diseases. Microglia, the resident immune cells in the brain, play an important role in brain inflammation, while brain mast cells are the "first responder" in the injury rather than microglia. Functional aspects of mast cell-microglia interactions remain poorly understood. Our results demonstrated that site-directed injection of the "mast cell degranulator" compound 48/80 (C48/80) in the hypothalamus induced mast cell degranulation, microglial activation, and inflammatory factor production, which initiated the acute brain inflammatory response. "Mast cell stabilizer" disodium cromoglycate (cromolyn) inhibited this effect, including decrease of inflammatory cytokines, reduced microglial activation, inhibition of MAPK and AKT pathways, and repression of protein expression of histamine receptor 1 (H 1 R), histamine receptor 4 (H 4 R), protease-activated receptor 2 (PAR2), and toll-like receptor 4 (TLR4) in microglia. We also demonstrated that C48/80 had no effect on microglial activation in mast cell-deficient Kit W-sh/W-sh mice. These results implicate that activated brain mast cells trigger microglial activation and stabilization of mast cell inhibits microglial activation-induced central nervous system (CNS) inflammation. Interactions between mast cells and microglia could constitute a new and unique therapeutic target for CNS immune inflammation-related diseases.

Left Hemisphere Regions Are Critical for Language in the Face of Early Left Focal Brain Injury

ERIC Educational Resources Information Center

Beharelle, Anjali Raja; Dick, Anthony Steven; Josse, Goulven; Solodkin, Ana; Huttenlocher, Peter R.; Levine, Susan C.; Small, Steven L.

2010-01-01

A predominant theory regarding early stroke and its effect on language development, is that early left hemisphere lesions trigger compensatory processes that allow the right hemisphere to assume dominant language functions, and this is thought to underlie the near normal language development observed after early stroke. To test this theory, we…

Assessment and the Learning Brain: What the Research Tells Us

ERIC Educational Resources Information Center

Hardiman, Mariale; Whitman, Glenn

2014-01-01

If you really want to see how innovative a school is, inquire about its thinking and practices regarding assessment. For the students, does the mere thought of assessment trigger stress? Do the teachers rely heavily on high-stakes, multiple-choice, Bell Curve-generating tests? Or do the students seem relaxed and engaged as teachers experiment with…

"Does Broca's Area Exist?:" Christofredo Jakob's 1906 Response to Pierre Marie's Holistic Stance

ERIC Educational Resources Information Center

Tsapkini, Kyrana; Vivas, Ana B.; Triarhou, Lazaros C.

2008-01-01

In 1906, Pierre Marie triggered a heated controversy and an exchange of articles with Jules Dejerine over the localization of language functions in the human brain. The debate spread internationally. One of the timeliest responses, that appeared in print 1 month after Marie's paper, came from Christofredo Jakob, a Bavarian-born neuropathologist…

Endogenous Cannabinoids Trigger the Depolarization-Induced Suppression of Excitation in the Lateral Amygdala

ERIC Educational Resources Information Center

Kodirov, Sodikdjon A.; Jasiewicz, Julia; Amirmahani, Parisa; Psyrakis, Dimitrios; Bonni, Kathrin; Wehrmeister, Michael; Lutz, Beat

2010-01-01

The amygdala is a key area of the brain where the emotional memories are stored throughout the lifespan. It is well established that synapses in the lateral nucleus of amygdala (LA) can undergo long-term potentiation, a putative cellular correlate of learning and memory. However, a type of short-term synaptic plasticity, known as…

Social Isolation Co-opts Fear and Aggression Circuits.

PubMed

Rodriguez-Romaguera, Jose; Stuber, Garret D

2018-05-17

Social isolation is a stressful condition that often leads to maladaptive behaviors. In this issue of Cell, Zelikowsky et al. find that chronic social isolation stress triggers an increase in neuronal tachykinin signaling across distinct brain regions that mediate fear and aggression, elucidating the neural basis of these maladaptive responses. Copyright © 2018. Published by Elsevier Inc.

Involvement of reactive oxygen species/c-Jun NH{sub 2}-terminal kinase pathway in kotomolide A induces apoptosis in human breast cancer cells

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

Kuo, P.-L.; Chen, C.-Y.; Tzeng, T.-F.

2008-06-01

The anticancer effects of kotomolide A (KTA), a new butanolide constituent isolated from the leaves of Cinnamomum kotoense (Lauraceae), on the two human breast cancer cell lines MCF-7 and MDA-MB-231, were first investigated in our study. KTA exhibited selectively antiproliferative effects in cancer cell lines without showing any toxicity in normal mammary epithelial cells. Treatment of cancer cells with KTA to trigger G2/M phase arrest was associated with increased p21/WAF1 levels and reduced amounts of cyclin A, cyclin B1, cdc2 and cdc25C. KTA induced cancer cell death treatment by triggering mitochondrial and death receptor 5 (DR5) apoptotic pathways, but didmore » not act on the Fas receptor. Exposure of MCF-7 and MDA-MB-231 cells to KTA resulted in cellular glutathione reduction and ROS generation, accompanied by JNK activation and apoptosis. Both antioxidants, NAC and catalase, significantly decreased apoptosis by inhibiting the phosphorylation of JNK and subsequently triggering DR5 cell death pathways. The reduction of JNK expression by siRNA decreased KTA-mediated Bim cleavage, DR5 upregulation and apoptosis. Furthermore, daily KTA i.p. injections in nude mice with MDA-MB-231 s.c. tumors resulted in a 50% decrease of mean tumor volume, compared with vehicle-treated controls. Taken together, the data show that cell death of breast cancer cells in response to KTA is dependent upon ROS generation and JNK activation, triggering intrinsic and extrinsic apoptotic pathways. The ROS/JNK pathway could be a useful target for novel approaches in breast cancer chemotherapy.« less

Wild-type rabies virus induces autophagy in human and mouse neuroblastoma cell lines.

PubMed

Peng, Jiaojiao; Zhu, Shenghe; Hu, Lili; Ye, Pingping; Wang, Yifei; Tian, Qin; Mei, Mingzhu; Chen, Hao; Guo, Xiaofeng

2016-10-02

Different rabies virus (RABV) strains have their own biological characteristics, but little is known about their respective impact on autophagy. Therefore, we evaluated whether attenuated RABV HEP-Flury and wild-type RABV GD-SH-01 strains triggered autophagy. We found that GD-SH-01 infection significantly increased the number of autophagy-like vesicles, the accumulation of enhanced green fluorescent protein (EGFP)-LC3 fluorescence puncta and the conversion of LC3-I to LC3-II, while HEP-Flury was not able to induce this phenomenon. When evaluating autophagic flux, we found that GD-SH-01 infection triggers a complete autophagic response in the human neuroblastoma cell line (SK), while autophagosome fusion with lysosomes was inhibited in a mouse neuroblastoma cell line (NA). In these cells, GD-SH-01 led to apoptosis and mitochondrial dysfunction while triggering autophagy, and apoptosis could be decreased by enhancing autophagy. To further identify the virus constituent causing autophagy, 5 chimeric recombinant viruses carrying single genes of HEP-Flury instead of those of GD-SH-01 were rescued. While the HEP-Flury virus carrying the wild-type matrix protein (M) gene of RABV triggered LC3-I to LC3-II conversion in SK and NA cells, replacement of genes of nucleoprotein (N), phosphoprotein (P) and glycoprotein (G) produced only minor autophagy. But no one single structural protein of GD-SH-01 induced autophagy. Moreover, the AMPK signaling pathway was activated by GD-SH-01 in SK. Therefore, our data provide strong evidence that autophagy is induced by GD-SH-01 and can decrease apoptosis in vitro. Furthermore, the M gene of GD-SH-01 may cooperatively induce autophagy.

Physiology and molecular biology of barrier mechanisms in the fetal and neonatal brain.

PubMed

Saunders, Norman R; Dziegielewska, Katarzyna M; Møllgård, Kjeld; Habgood, Mark D

2018-05-17

Properties of the local internal environment of the adult brain are tightly controlled providing a stable milieu essential for its normal function. The mechanisms involved in this complex control are structural, molecular and physiological (influx and efflux transporters) frequently referred to as the "blood-brain barrier". These mechanisms include regulation of ion levels in brain interstitial fluid essential for normal neuronal function, supply of nutrients, removal of metabolic products and prevention of entry or elimination of toxic agents. A key feature is cerebrospinal fluid secretion and turnover. This is much less during development, allowing greater accumulation of permeating molecules. The overall effect of these mechanisms is to tightly control the exchange of molecules into and out of the brain. This review presents experimental evidence currently available on the status of these mechanisms in developing brain. It has been frequently stated for over nearly a century that the blood-brain barrier is not present or at least is functionally deficient in the embryo, fetus and newborn. We suggest the alternative hypothesis that the barrier mechanisms in developing brain are likely to be appropriately matched to each stage of its development. The contributions of different barrier mechanisms, such as changes in constituents of cerebrospinal fluid in relation to specific features of brain development, for example neurogenesis, are only beginning to be studied. The evidence on this previously neglected aspect of brain barrier function is outlined. We also suggest future directions this field could follow with special emphasis on potential applications in a clinical setting. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

[Molecular logic of alcohol and taste].

PubMed

Matsumoto, Ichiro; Abe, Keiko; Arai, Soichi

2006-10-01

Ethanol, a main constituent of every alcohol beverage, has long been calling our attention to its gustatory effect. Recent molecular dynamics studies have suggested that ethanol as well as other tastants in foods, when taken in the oral cavity, gives rise to a taste signal which is expressed via reception at taste cells in the taste bud, intracellular signal transduction in collaboration with G proteins and effecters, and signal transmission to synapsed taste neurons, and/or simultaneous reception at and signal transduction in somatosensory neurons. The taste of ethanol and its acceptability are then recognized and judged at the higher center, with generation of various physiological phenomena in the body. We have tried to make an all-inclusive DNA microarray analysis, demonstrating that when a rat tongue is stimulated with a drop of aqueous ethanol in vivo, several particular genes are specifically up- or down-regulated in trigeminal ganglions. These initial gene expression changes at peripheral neurocytes might in whole or in part trigger some of the ethanol-associated gustatory and bodily response. The importance of defining a related molecular logic is emphasized to understand academic and industrial significances of this unique food constituent, ethanol.

First Quantification of Imidazoles in Ambient Aerosol Particles: Potential Photosensitizers, Brown Carbon Constituents, and Hazardous Components.

PubMed

Teich, Monique; van Pinxteren, Dominik; Kecorius, Simonas; Wang, Zhibin; Herrmann, Hartmut

2016-02-02

Imidazoles are widely discussed in recent literature. They have been studied as a secondary product of the reaction of dicarbonyls with nitrogen containing compounds in a number of laboratory studies, potentially acting as photosensitizers triggering secondary organic aerosol growth and are forming constituents of light absorbing brown carbon. Despite the knowledge from laboratory studies, no quantitative information about imidazoles in ambient aerosol particles is available. Within the present study, five imidazoles (1-butylimidazole, 1-ethylimidazole, 2-ethylimidazole, imidazol-2-carboxaldehyde, and 4(5)-methylimidazole) were successfully identified and quantified for the first time in ambient aerosol samples from different environments in Europe and China. Their concentrations range between 0.2 and 14 ng/m(3). 4(5)-Methylimidazole was found to be the most abundant imidazole. The occurrence of imidazoles seems to be favored at sites with strong biomass burning influence or connected to more polluted air masses. No connection was found between aerosol particle pH and imidazole concentration. Our work corroborates the laboratory studies by showing that imidazoles are present in ambient aerosol samples in measurable amounts. Moreover, it further motivates to explore the potential photosensitizing properties of small alkyl-substituted imidazoles.

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

PubMed Central

Matsui, Takashi; Omuro, Hideki; Liu, Yu-Fan; Soya, Mariko; Shima, Takeru; McEwen, Bruce S.; Soya, Hideaki

2017-01-01

Brain glycogen stored in astrocytes provides lactate as an energy source to neurons through monocarboxylate transporters (MCTs) to maintain neuronal functions such as hippocampus-regulated memory formation. Although prolonged exhaustive exercise decreases brain glycogen, the role of this decrease and lactate transport in the exercising brain remains less clear. Because muscle glycogen fuels exercising muscles, we hypothesized that astrocytic glycogen plays an energetic role in the prolonged-exercising brain to maintain endurance capacity through lactate transport. To test this hypothesis, we used a rat model of exhaustive exercise and capillary electrophoresis-mass spectrometry–based metabolomics to observe comprehensive energetics of the brain (cortex and hippocampus) and muscle (plantaris). At exhaustion, muscle glycogen was depleted but brain glycogen was only decreased. The levels of MCT2, which takes up lactate in neurons, increased in the brain, as did muscle MCTs. Metabolomics revealed that brain, but not muscle, ATP was maintained with lactate and other glycogenolytic/glycolytic sources. Intracerebroventricular injection of the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol did not affect peripheral glycemic conditions but suppressed brain lactate production and decreased hippocampal ATP levels at exhaustion. An MCT2 inhibitor, α-cyano-4-hydroxy-cinnamate, triggered a similar response that resulted in lower endurance capacity. These findings provide direct evidence for the energetic role of astrocytic glycogen-derived lactate in the exhaustive-exercising brain, implicating the significance of brain glycogen level in endurance capacity. Glycogen-maintained ATP in the brain is a possible defense mechanism for neurons in the exhausted brain. PMID:28515312

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity.

PubMed

Matsui, Takashi; Omuro, Hideki; Liu, Yu-Fan; Soya, Mariko; Shima, Takeru; McEwen, Bruce S; Soya, Hideaki

2017-06-13

Brain glycogen stored in astrocytes provides lactate as an energy source to neurons through monocarboxylate transporters (MCTs) to maintain neuronal functions such as hippocampus-regulated memory formation. Although prolonged exhaustive exercise decreases brain glycogen, the role of this decrease and lactate transport in the exercising brain remains less clear. Because muscle glycogen fuels exercising muscles, we hypothesized that astrocytic glycogen plays an energetic role in the prolonged-exercising brain to maintain endurance capacity through lactate transport. To test this hypothesis, we used a rat model of exhaustive exercise and capillary electrophoresis-mass spectrometry-based metabolomics to observe comprehensive energetics of the brain (cortex and hippocampus) and muscle (plantaris). At exhaustion, muscle glycogen was depleted but brain glycogen was only decreased. The levels of MCT2, which takes up lactate in neurons, increased in the brain, as did muscle MCTs. Metabolomics revealed that brain, but not muscle, ATP was maintained with lactate and other glycogenolytic/glycolytic sources. Intracerebroventricular injection of the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol did not affect peripheral glycemic conditions but suppressed brain lactate production and decreased hippocampal ATP levels at exhaustion. An MCT2 inhibitor, α-cyano-4-hydroxy-cinnamate, triggered a similar response that resulted in lower endurance capacity. These findings provide direct evidence for the energetic role of astrocytic glycogen-derived lactate in the exhaustive-exercising brain, implicating the significance of brain glycogen level in endurance capacity. Glycogen-maintained ATP in the brain is a possible defense mechanism for neurons in the exhausted brain.

Translational potential of astrocytes in brain disorders

PubMed Central

Verkhratsky, Alexei; Steardo, Luca; Montana, Vedrana

2015-01-01

Fundamentally, all brain disorders can be broadly defined as the homeostatic failure of this organ. As the brain is composed of many different cells types, including but not limited to neurons and glia, it is only logical that all the cell types/constituents could play a role in health and disease. Yet, for a long time the sole conceptualization of brain pathology was focused on the well-being of neurons. Here, we challenge this neuron-centric view and present neuroglia as a key element in neuropathology, a process that has a toll on astrocytes, which undergo complex morpho-functional changes that can in turn affect the course of the disorder. Such changes can be grossly identified as reactivity, atrophy with loss of function and pathological remodeling. We outline the pathogenic potential of astrocytes in variety of disorders, ranging from neurotrauma, infection, toxic damage, stroke, epilepsy, neurodevelopmental, neurodegenerative and psychiatric disorders, Alexander disease to neoplastic changes seen in gliomas. We hope that in near future we would witness glial-based translational medicine with generation of deliverables for the containment and cure of disorders. We point out that such as a task will require a holistic and multi-disciplinary approach that will take in consideration the concerted operation of all the cell types in the brain. PMID:26386136

Marijuana and cannabinoid regulation of brain reward circuits.

PubMed

Lupica, Carl R; Riegel, Arthur C; Hoffman, Alexander F

2004-09-01

The reward circuitry of the brain consists of neurons that synaptically connect a wide variety of nuclei. Of these brain regions, the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play central roles in the processing of rewarding environmental stimuli and in drug addiction. The psychoactive properties of marijuana are mediated by the active constituent, Delta(9)-THC, interacting primarily with CB1 cannabinoid receptors in a large number of brain areas. However, it is the activation of these receptors located within the central brain reward circuits that is thought to play an important role in sustaining the self-administration of marijuana in humans, and in mediating the anxiolytic and pleasurable effects of the drug. Here we describe the cellular circuitry of the VTA and the NAc, define the sites within these areas at which cannabinoids alter synaptic processes, and discuss the relevance of these actions to the regulation of reinforcement and reward. In addition, we compare the effects of Delta(9)-THC with those of other commonly abused drugs on these reward circuits, and we discuss the roles that endogenous cannabinoids may play within these brain pathways, and their possible involvement in regulating ongoing brain function, independently of marijuana consumption. We conclude that, whereas Delta(9)-THC alters the activity of these central reward pathways in a manner that is consistent with other abused drugs, the cellular mechanism through which this occurs is likely different, relying upon the combined regulation of several afferent pathways to the VTA.

Brain region-dependent differential expression of alpha-synuclein.

PubMed

Taguchi, Katsutoshi; Watanabe, Yoshihisa; Tsujimura, Atsushi; Tanaka, Masaki

2016-04-15

α-Synuclein, the major constituent of Lewy bodies (LBs), is normally expressed in presynapses and is involved in synaptic function. Abnormal intracellular aggregation of α-synuclein is observed as LBs and Lewy neurites in neurodegenerative disorders, such as Parkinson's disease (PD) or dementia with Lewy bodies. Accumulated evidence suggests that abundant intracellular expression of α-synuclein is one of the risk factors for pathological aggregation. Recently, we reported differential expression patterns of α-synuclein between excitatory and inhibitory hippocampal neurons. Here we further investigated the precise expression profile in the adult mouse brain with special reference to vulnerable regions along the progression of idiopathic PD. The results show that α-synuclein was highly expressed in the neuronal cell bodies of some early PD-affected brain regions, such as the olfactory bulb, dorsal motor nucleus of the vagus, and substantia nigra pars compacta. Synaptic expression of α-synuclein was mostly accompanied by expression of vesicular glutamate transporter-1, an excitatory presynaptic marker. In contrast, expression of α-synuclein in the GABAergic inhibitory synapses was different among brain regions. α-Synuclein was clearly expressed in inhibitory synapses in the external plexiform layer of the olfactory bulb, globus pallidus, and substantia nigra pars reticulata, but not in the cerebral cortex, subthalamic nucleus, or thalamus. These results suggest that some neurons in early PD-affected human brain regions express high levels of perikaryal α-synuclein, as happens in the mouse brain. Additionally, synaptic profiles expressing α-synuclein are different in various brain regions. © 2015 Wiley Periodicals, Inc.

Identification of multiple constituents in Chinese medicinal prescription Shensong Yangxin capsule by ultra-fast liquid chromatography combined with quadrupole time-of-flight mass spectrometry.

PubMed

Liu, Minyan; Zhao, Shaohua; Wang, Yufeng; Liu, Ting; Li, Song; Wang, Hongtao; Tu, Pengfei

2015-02-01

A practical method using ultra-fast liquid chromatography in tandem with quadrupole time-of-flight mass spectrometry combined with dynamic background subtraction technology was developed for the rapid separation and identification of the complicated constituents in the Shensong Yangxin capsule (SSYX). The chromatographic separation was performed on a C18 column (2.1 × 100 mm, 2.6 μm) with a gradient elution program using methanol and 0.1% formic acid aqueous solution as the mobile phase at a flow rate of 0.4 mL min(-1). Accurate mass measurements of the molecular ions in the full scan and the characteristic fragment ions triggered by information-dependent acquisition provided reliable identification criteria. Thus, 99 compounds, including saponins, phenolic acids, tanshinones, lignans, terpenoids, alkaloids and flavonoids, were unambiguously or tentatively identified in 40 min by comparing their retention times and accurate mass measurements for each molecular ion and its subsequent fragment ions with those of authentic standards or literature data. Simultaneously, all the compounds were further assigned to the individual raw materials. In conclusion, these results will provide a basis for quality control and further study of SSYX, and the proposed technique based on high-resolution mass spectrometry would be expected to be adaptable to the analysis of complicated constituents in various complex matrices. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Reflex epilepsy and reflex seizures of the visual system: a clinical review.

PubMed

Zifkin, B G; Kasteleijn-Nolst Trenité, D

2000-09-01

Reflex epilepsy of the visual system is charecterised by seizures precipitated by visual stimuli. EEG responses to intermittent photic stimulation depend on the age and sex of the subject and on how stimulation is performed: abnormalities are commonest in children and adolescents, especially girls. Only generalised paroxysmal epileptiform discharges are clearly linked to epilepsy. Abnormal responses may occur in asymptomatic subjects, especially children. Photosensitivity has an important genetic component. Some patients are sensitive to patterns, suggesting an occipital trigger for these events. Myoclonus and generalised convulsive and nonconvulsive seizures may be triggered by visual stimuli. Partial seizures occur less often and can be confused with migraine. Although usually idiopathic, photosensitive epilepsy may occur in degenerative diseases and some patients with photosensitive partial seizures have brain lesions. Sunlight and video screens, including television, video games, and computer displays, are the commonest environmental triggers of photosensitive seizures. Outbreaks of triggered seizures have occurred when certain flashing or patterned images have been broadcast. There are regulations to prevent this in some countries only. Pure photosensitive epilepsy has a good prognosis. There is a role for treatment with and without antiepileptic drugs, but photosensitivity usually does not disappear spontaneously, and then typically in the third decade.

Internal versus external features in triggering the brain waveforms for conjunction and feature faces in recognition.

PubMed

Nie, Aiqing; Jiang, Jingguo; Fu, Qiao

2014-08-20

Previous research has found that conjunction faces (whose internal features, e.g. eyes, nose, and mouth, and external features, e.g. hairstyle and ears, are from separate studied faces) and feature faces (partial features of these are studied) can produce higher false alarms than both old and new faces (i.e. those that are exactly the same as the studied faces and those that have not been previously presented) in recognition. The event-related potentials (ERPs) that relate to conjunction and feature faces at recognition, however, have not been described as yet; in addition, the contributions of different facial features toward ERPs have not been differentiated. To address these issues, the present study compared the ERPs elicited by old faces, conjunction faces (the internal and the external features were from two studied faces), old internal feature faces (whose internal features were studied), and old external feature faces (whose external features were studied) with those of new faces separately. The results showed that old faces not only elicited an early familiarity-related FN400, but a more anterior distributed late old/new effect that reflected recollection. Conjunction faces evoked similar late brain waveforms as old internal feature faces, but not to old external feature faces. These results suggest that, at recognition, old faces hold higher familiarity than compound faces in the profiles of ERPs and internal facial features are more crucial than external ones in triggering the brain waveforms that are characterized as reflecting the result of familiarity.

Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation.

PubMed

Diógenes, Maria José; Dias, Raquel B; Rombo, Diogo M; Vicente Miranda, Hugo; Maiolino, Francesca; Guerreiro, Patrícia; Näsström, Thomas; Franquelim, Henri G; Oliveira, Luís M A; Castanho, Miguel A R B; Lannfelt, Lars; Bergström, Joakim; Ingelsson, Martin; Quintas, Alexandre; Sebastião, Ana M; Lopes, Luísa V; Outeiro, Tiago Fleming

2012-08-22

Parkinson's disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of α-synuclein (a-syn) in various brain regions is the major pathological hallmark. Indeed, the motor symptoms in PD are caused by a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus. Here, we investigated the impact of a-syn aggregation on AMPA and NMDA receptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposure to a-syn oligomers drives the increase of glutamatergic synaptic transmission, preventing further potentiation by physiological stimuli. Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies.

Quantum aspects of brain activity and the role of consciousness.

PubMed Central

Beck, F; Eccles, J C

1992-01-01

The relationship of brain activity to conscious intentions is considered on the basis of the functional microstructure of the cerebral cortex. Each incoming nerve impulse causes the emission of transmitter molecules by the process of exocytosis. Since exocytosis is a quantal phenomenon of the presynaptic vesicular grid with a probability much less than 1, we present a quantum mechanical model for it based on a tunneling process of the trigger mechanism. Consciousness manifests itself in mental intentions. The consequent voluntary actions become effective by momentary increases of the probability of vesicular emission in the thousands of synapses on each pyramidal cell by quantal selection. PMID:1333607

Mind and Language Architecture

PubMed Central

Logan, Robert K

2010-01-01

A distinction is made between the brain and the mind. The architecture of the mind and language is then described within a neo-dualistic framework. A model for the origin of language based on emergence theory is presented. The complexity of hominid existence due to tool making, the control of fire and the social cooperation that fire required gave rise to a new level of order in mental activity and triggered the simultaneous emergence of language and conceptual thought. The mind is shown to have emerged as a bifurcation of the brain with the emergence of language. The role of language in the evolution of human culture is also described. PMID:20922045

Chronic Traumatic Encephalopathy: Known Causes, Unknown Effects.

PubMed

Iacono, Diego; Shively, Sharon B; Edlow, Brian L; Perl, Daniel P

2017-05-01

Chronic traumatic encephalopathy (CTE) is a neuropathologic diagnosis typically made in human brains with a history of repetitive traumatic brain injury (rTBI). It remains unknown whether CTE occurs exclusively after rTBI, or whether a single TBI (sTBI) can cause CTE. Similarly, it is unclear whether impact (eg, motor vehicle accidents) and non-impact (eg, blasts) types of energy transfer trigger divergent or common pathologies. While it is established that a history of rTBI increases the risk of multiple neurodegenerative diseases (eg, dementia, parkinsonism, and CTE), the possible pathophysiologic and molecular mechanisms underlying these risks have yet to be elucidated. Published by Elsevier Inc.

Sentence processing in anterior superior temporal cortex shows a social-emotional bias.

PubMed

Mellem, Monika S; Jasmin, Kyle M; Peng, Cynthia; Martin, Alex

2016-08-01

The anterior region of the left superior temporal gyrus/superior temporal sulcus (aSTG/STS) has been implicated in two very different cognitive functions: sentence processing and social-emotional processing. However, the vast majority of the sentence stimuli in previous reports have been of a social or social-emotional nature suggesting that sentence processing may be confounded with semantic content. To evaluate this possibility we had subjects read word lists that differed in phrase/constituent size (single words, 3-word phrases, 6-word sentences) and semantic content (social-emotional, social, and inanimate objects) while scanned in a 7T environment. This allowed us to investigate if the aSTG/STS responded to increasing constituent structure (with increased activity as a function of constituent size) with or without regard to a specific domain of concepts, i.e., social and/or social-emotional content. Activity in the left aSTG/STS was found to increase with constituent size. This region was also modulated by content, however, such that social-emotional concepts were preferred over social and object stimuli. Reading also induced content type effects in domain-specific semantic regions. Those preferring social-emotional content included aSTG/STS, inferior frontal gyrus, posterior STS, lateral fusiform, ventromedial prefrontal cortex, and amygdala, regions included in the "social brain", while those preferring object content included parahippocampal gyrus, retrosplenial cortex, and caudate, regions involved in object processing. These results suggest that semantic content affects higher-level linguistic processing and should be taken into account in future studies. Copyright © 2016. Published by Elsevier Ltd.

Oral uridine-5'-monophosphate (UMP) increases brain CDP-choline levels in gerbils.

PubMed

Cansev, Mehmet; Watkins, Carol J; van der Beek, Eline M; Wurtman, Richard J

2005-10-05

We examined the biochemical pathways whereby oral uridine-5'-monophosphate (UMP) increases membrane phosphatide synthesis in brains of gerbils. We previously showed that supplementing PC12 cells with uridine caused concentration-related increases in CDP-choline levels, and that this effect was mediated by elevations in intracellular uridine triphosphate (UTP) and cytidine triphosphate (CTP). In the present study, adult gerbils received UMP (1 mmol/kg), a constituent of human breast milk and infant formulas, by gavage, and plasma samples and brains were collected for assay between 5 min and 8 h thereafter. Thirty minutes after gavage, plasma uridine levels were increased from 6.6 +/- 0.58 to 32.7 +/- 1.85 microM (P < 0.001), and brain uridine from 22.6 +/- 2.9 to 89.1 +/- 8.82 pmol/mg tissue (P < 0.001). UMP also significantly increased plasma and brain cytidine levels; however, both basally and following UMP, these levels were much lower than those of uridine. Brain UTP, CTP, and CDP-choline were all elevated 15 min after UMP (from 254 +/- 31.9 to 417 +/- 50.2, [P < 0.05]; 56.8 +/- 1.8 to 71.7 +/- 1.8, [P < 0.001]; and 11.3 +/- 0.5 to 16.4 +/- 1, [P < 0.001] pmol/mg tissue, respectively), returning to basal levels after 20 and 30 min. The smallest UMP dose that significantly increased brain CDP-choline was 0.05 mmol/kg. These results show that oral UMP, a uridine source, enhances the synthesis of CDP-choline, the immediate precursor of PC, in gerbil brain.

Loss of proteostasis induced by amyloid beta peptide in brain endothelial cells.

PubMed

Fonseca, Ana Catarina; Oliveira, Catarina R; Pereira, Cláudia F; Cardoso, Sandra M

2014-06-01

Abnormal accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer's disease (AD). In addition to neurotoxic effects, Aβ also damages brain endothelial cells (ECs) and may thus contribute to the degeneration of cerebral vasculature, which has been proposed as an early pathogenic event in the course of AD and is able to trigger and/or potentiate the neurodegenerative process and cognitive decline. However, the mechanisms underlying Aβ-induced endothelial dysfunction are not completely understood. Here we hypothesized that Aβ impairs protein quality control mechanisms both in the secretory pathway and in the cytosol in brain ECs, leading cells to death. In rat brain RBE4 cells, we demonstrated that Aβ1-40 induces the failure of the ER stress-adaptive unfolded protein response (UPR), deregulates the ubiquitin-proteasome system (UPS) decreasing overall proteasome activity with accumulation of ubiquitinated proteins and impairs the autophagic protein degradation pathway due to failure in the autophagic flux, which culminates in cell demise. In conclusion, Aβ deregulates proteostasis in brain ECs and, as a consequence, these cells die by apoptosis. Copyright © 2014 Elsevier B.V. All rights reserved.

Nanoformulation of Brain-Derived Neurotrophic Factor with Target Receptor-Triggered-Release in the Central Nervous System.

PubMed

Jiang, Yuhang; Fay, James M; Poon, Chi-Duen; Vinod, Natasha; Zhao, Yuling; Bullock, Kristin; Qin, Si; Manickam, Devika S; Yi, Xiang; Banks, William A; Kabanov, Alexander V

2018-02-07

Brain-derived neurotrophic factor (BDNF) is identified as a potent neuroprotective and neuroregenerative agent for many neurological diseases. Regrettably, its delivery to the brain is hampered by poor serum stability and rapid brain clearance. Here, a novel nanoformulation is reported composed of a bio-compatible polymer, poly(ethylene glycol)- b -poly(L-glutamic acid) (PEG-PLE), that hosts the BDNF molecule in a nanoscale complex, termed here Nano-BDNF. Upon simple mixture, Nano-BDNF spontaneously forms uniform spherical particles with a core-shell structure. Molecular dynamics simulations suggest that binding between BDNF and PEG-PLE is mediated through electrostatic coupling as well as transient hydrogen bonding. The formation of Nano-BDNF complex stabilizes BDNF and protects it from nonspecific binding with common proteins in the body fluid, while allowing it to associate with its receptors. Following intranasal administration, the nanoformulation improves BDNF delivery throughout the brain and displays a more preferable regional distribution pattern than the native protein. Furthermore, intranasally delivered Nano-BDNF results in superior neuroprotective effects in the mouse brain with lipopolysaccharides-induced inflammation, indicating promise for further evaluation of this agent for the therapy of neurologic diseases.

Effect of dexamethasone on gliosis, ischemia, and dopamine extraction during microdialysis sampling in brain tissue.

PubMed

Jaquins-Gerstl, Andrea; Shu, Zhan; Zhang, Jing; Liu, Yansheng; Weber, Stephen G; Michael, Adrian C

2011-10-15

Microdialysis sampling of the brain is an analytical technique with numerous applications in neuroscience and the neurointensive care of brain-injured human patients. Even so, implanting microdialysis probes into brain tissue causes a penetration injury that triggers gliosis (the activation and proliferation of glial cells) and ischemia (the interruption of blood flow). Thus, the probe samples injured tissue. Mitigating the effects of the penetration injury might refine the technique. The synthetic glucocorticoid dexamethasone is a potent anti-inflammatory and immunosuppressant substance. We performed microdialysis in the rat brain for 5 days, with and without dexamethasone in the perfusion fluid (10 μM for the first 24 h and 2 μM thereafter). On the first and fourth day of the perfusion, we performed dopamine no-net-flux measurements. On the fifth day, we sectioned and stained the brain tissue and examined it by fluorescence microscopy. Although dexamethasone profoundly inhibited gliosis and ischemia around the probe tracks it had only modest effects on dopamine no-net-flux results. These findings show that dexamethasone is highly effective at suppressing gliosis and ischemia but is limited in its neuroprotective activity. © 2011 American Chemical Society

Cholesterol overload impairing cerebellar function: the promise of natural products.

PubMed

El-Sayyad, Hassan I H

2015-05-01

The cerebellum is the part of the brain most involved in controlling motor and cognitive function. The surface becomes convoluted, forming folia that have a characteristic internal structure of three layers including molecular, Purkinje cell, and granular layer. This complex neural network gives rise to a massive signal-processing capability. Cholesterol is a major constituent, derived by de novo synthesis and the blood-brain barrier. Cholesterol is tightly regulated between neurons and glia-that is, astrocytes, microglia, and oligodendrocytes-and is essential for normal brain development. The axon is wrapped by myelin (cholesterol, phospholipids, and glycosphingolipids) and made up of membranes of oligodendrocytes, separated by periodic gaps in the myelin sheath, called nodes of Ranvier. Hypercholesterolemia is associated with increased oxidative stress and the development of neurotoxicity and Alzheimer's disease. Treatment with natural products has been found to support improved brain function and reduce low-density-lipoprotein cholesterol level. Fish oil is one such product; among the many plant products are: Morus alba leaves, fruit, and bark; pomegranate fruit and peel; Barley β - glucans; date palm; and Allium sativum. The therapeutic potential was discussed in relation with the antilipidemic drugs, statins (HMG-CoA reductase inhibitors). Copyright © 2015 Elsevier Inc. All rights reserved.

Application of spatially modulated near-infrared structured light to study changes in optical properties of mouse brain tissue during heatstress.

PubMed

Shaul, Oren; Fanrazi-Kahana, Michal; Meitav, Omri; Pinhasi, Gad A; Abookasis, David

2017-11-10

Heat stress (HS) is a medical emergency defined by abnormally elevated body temperature that causes biochemical, physiological, and hematological changes. The goal of the present research was to detect variations in optical properties (absorption, reduced scattering, and refractive index coefficients) of mouse brain tissue during HS by using near-infrared (NIR) spatial light modulation. NIR spatial patterns with different spatial phases were used to differentiate the effects of tissue scattering from those of absorption. Decoupling optical scattering from absorption enabled the quantification of a tissue's chemical constituents (related to light absorption) and structural properties (related to light scattering). Technically, structured light patterns at low and high spatial frequencies of six wavelengths ranging between 690 and 970 nm were projected onto the mouse scalp surface while diffuse reflected light was recorded by a CCD camera positioned perpendicular to the mouse scalp. Concurrently to pattern projection, brain temperature was measured with a thermal camera positioned slightly off angle from the mouse head while core body temperature was monitored by thermocouple probe. Data analysis demonstrated variations from baseline measurements in a battery of intrinsic brain properties following HS.

Semisupervised learning using denoising autoencoders for brain lesion detection and segmentation.

PubMed

Alex, Varghese; Vaidhya, Kiran; Thirunavukkarasu, Subramaniam; Kesavadas, Chandrasekharan; Krishnamurthi, Ganapathy

2017-10-01

The work explores the use of denoising autoencoders (DAEs) for brain lesion detection, segmentation, and false-positive reduction. Stacked denoising autoencoders (SDAEs) were pretrained using a large number of unlabeled patient volumes and fine-tuned with patches drawn from a limited number of patients ([Formula: see text], 40, 65). The results show negligible loss in performance even when SDAE was fine-tuned using 20 labeled patients. Low grade glioma (LGG) segmentation was achieved using a transfer learning approach in which a network pretrained with high grade glioma data was fine-tuned using LGG image patches. The networks were also shown to generalize well and provide good segmentation on unseen BraTS 2013 and BraTS 2015 test data. The manuscript also includes the use of a single layer DAE, referred to as novelty detector (ND). ND was trained to accurately reconstruct nonlesion patches. The reconstruction error maps of test data were used to localize lesions. The error maps were shown to assign unique error distributions to various constituents of the glioma, enabling localization. The ND learns the nonlesion brain accurately as it was also shown to provide good segmentation performance on ischemic brain lesions in images from a different database.

Influence of Inflammation on Poststroke Plasticity

PubMed Central

Kossut, Malgorzata

2013-01-01

Age-related brain injuries including stroke are a leading cause of morbidity and mental disability worldwide. Most patients who survive stroke experience some degree of recovery. The restoration of lost functions can be explained by neuronal plasticity, understood as brain ability to reorganize and remodel itself in response to changed environmental requirements. However, stroke triggers a cascade of events which may prevent the normal development of the plastic changes. One of them may be inflammatory response initiated immediately after stroke, which has been found to contribute to neuronal injury. Some recent evidence though has suggested that inflammatory reaction can be also neuroprotective. This paper attempts to discuss the influence of poststroke inflammatory response on brain plasticity and stroke outcome. We also describe the recent anti-inflammatory strategies that have been effective for recovery in experimental stroke. PMID:23533818

Severe blood-brain barrier disruption and surrounding tissue injury.

PubMed

Chen, Bo; Friedman, Beth; Cheng, Qun; Tsai, Phil; Schim, Erica; Kleinfeld, David; Lyden, Patrick D

2009-12-01

Blood-brain barrier opening during ischemia follows a biphasic time course, may be partially reversible, and allows plasma constituents to enter brain and possibly damage cells. In contrast, severe vascular disruption after ischemia is unlikely to be reversible and allows even further extravasation of potentially harmful plasma constituents. We sought to use simple fluorescent tracers to allow wide-scale visualization of severely damaged vessels and determine whether such vascular disruption colocalized with regions of severe parenchymal injury. Severe vascular disruption and ischemic injury was produced in adult Sprague Dawley rats by transient occlusion of the middle cerebral artery for 1, 2, 4, or 8 hours, followed by 30 minutes of reperfusion. Fluorescein isothiocyanate-dextran (2 MDa) was injected intravenously before occlusion. After perfusion-fixation, brain sections were processed for ultrastructure or fluorescence imaging. We identified early evidence of tissue damage with Fluoro-Jade staining of dying cells. With increasing ischemia duration, greater quantities of high molecular weight dextran-fluorescein isothiocyanate invaded and marked ischemic regions in a characteristic pattern, appearing first in the medial striatum, spreading to the lateral striatum, and finally involving cortex; maximal injury was seen in the mid-parietal areas, consistent with the known ischemic zone in this model. The regional distribution of the severe vascular disruption correlated with the distribution of 24-hour 2,3,5-triphenyltetrazolium chloride pallor (r=0.75; P<0.05) and the cell death marker Fluoro-Jade (r=0.86; P<0.05). Ultrastructural examination showed significantly increased areas of swollen astrocytic foot process and swollen mitochondria in regions of high compared to low leakage, and compared to contralateral homologous regions (ANOVA P<0.01). Dextran extravasation into the basement membrane and surrounding tissue increased significantly from 2 to 8 hours of occlusion duration (Independent samples t test, P<0.05). Severe vascular disruption, as labeled with high-molecular-weight dextran-fluorescein isothiocyanate leakage, is associated with severe tissue injury. This marker of severe vascular disruption may be useful in further studies of the pathoanatomic mechanisms of vascular disruption-mediated tissue injury.

Processing of emotional information in the human subthalamic nucleus.

PubMed

Buot, Anne; Welter, Marie-Laure; Karachi, Carine; Pochon, Jean-Baptiste; Bardinet, Eric; Yelnik, Jérôme; Mallet, Luc

2013-12-01

The subthalamic nucleus (STN) is an efficient target for treating patients with Parkinson's disease as well as patients with obsessive-compulsive disorder (OCD) using high frequency stimulation (HFS). In both Parkinson's disease and OCD patients, STN-HFS can trigger abnormal behaviours, such as hypomania and impulsivity. To investigate if this structure processes emotional information, and whether it depends on motor demands, we recorded subthalamic local field potentials in 16 patients with Parkinson's disease using deep brain stimulation electrodes. Recordings were made with and without dopaminergic treatment while patients performed an emotional categorisation paradigm in which the response varied according to stimulus valence (pleasant, unpleasant and neutral) and to the instruction given (motor, non-motor and passive). Pleasant, unpleasant and neutral stimuli evoked an event related potential (ERP). Without dopamine medication, ERP amplitudes were significantly larger for unpleasant compared with neutral pictures, whatever the response triggered by the stimuli; and the magnitude of this effect was maximal in the ventral part of the STN. No significant difference in ERP amplitude was observed for pleasant pictures. With dopamine medication, ERP amplitudes were significantly increased for pleasant compared with neutral pictures whatever the response triggered by the stimuli, while ERP amplitudes to unpleasant pictures were not modified. These results demonstrate that the ventral part of the STN processes the emotional valence of stimuli independently of the motor context and that dopamine enhances processing of pleasant information. These findings confirm the specific involvement of the STN in emotional processes in human, which may underlie the behavioural changes observed in patients with deep brain stimulation.

Closing the gap between glia and neuroblast proliferation.

PubMed

Limmer, Stefanie; Klämbt, Christian

2014-08-11

Reporting in this issue of Developmental Cell, Spéder and Brand (2014) show that gap junctions are required in blood-brain barrier glial cells to reactivate proliferation of quiescent neuroblasts. Gap junctions allow synchronous Ca(2+) waves and control insulin-like protein Dipl6 expression and secretion to trigger neuroblast division. Copyright © 2014 Elsevier Inc. All rights reserved.

Assessing the Minimum Number of Synchronization Triggers Necessary for Temporal Variance Compensation in Commercial Electroencephalography (EEG) Systems

DTIC Science & Technology

2012-09-01

by the ARL Translational Neuroscience Branch. It covers the Emotiv EPOC,6 Advanced Brain Monitoring (ABM) B-Alert X10,7 Quasar 8 DSI helmet-based...Systems; ARL-TR-5945; U.S. Army Research Laboratory: Aberdeen Proving Ground, MD, 2012 4 Ibid. 5 Ibid. 6 EPOC is a trademark of Emotiv . 7 B

Mapping Brain Metals to Evaluate Therapies for Neurodegenerative Disease

PubMed Central

Popescu, Bogdan Florin Gh; Nichol, Helen

2013-01-01

The brain is rich in metals and has a high metabolic rate, making it acutely vulnerable to the toxic effects of endogenously produced free radicals. The abundant metals, iron and copper, transfer single electrons as they cycle between their reduced (Fe2+, Cu1+) and oxidized (Fe3+, Cu2+) states making them powerful catalysts of reactive oxygen species (ROS) production. Even redox inert zinc, if present in excess, can trigger ROS production indirectly by altering mitochondrial function. While metal chelators seem to improve the clinical outcome of several neurodegenerative diseases, their mechanisms of action remain obscure and the effects of long-term use are largely unknown. Most chelators are not specific to a single metal and could alter the distribution of multiple metals in the brain, leading to unexpected consequences over the long-term. We show here how X-ray fluorescence will be a valuable tool to examine the effect of chelators on the distribution and amount of metals in the brain. PMID:20553312

Putting the brain to work: neuroergonomics past, present, and future.

PubMed

Parasuraman, Raja; Wilson, Glenn F

2008-06-01

The authors describe research and applications in prominent areas of neuroergonomics. Because human factors/ergonomics examines behavior and mind at work, it should include the study of brain mechanisms underlying human performance. Neuroergonomic studies are reviewed in four areas: workload and vigilance, adaptive automation, neuroengineering, and molecular genetics and individual differences. Neuroimaging studies have helped identify the components of mental workload, workload assessment in complex tasks, and resource depletion in vigilance. Furthermore, real-time neurocognitive assessment of workload can trigger adaptive automation. Neural measures can also drive brain-computer interfaces to provide disabled users new communication channels. Finally, variants of particular genes can be associated with individual differences in specific cognitive functions. Neuroergonomics shows that considering what makes work possible - the human brain - can enrich understanding of the use of technology by humans and can inform technological design. Applications of neuroergonomics include the assessment of operator workload and vigilance, implementation of real-time adaptive automation, neuroengineering for people with disabilities, and design of selection and training methods.

Evidence that a synthetic amyloid-ß oligomer-binding peptide (ABP) targets amyloid-ß deposits in transgenic mouse brain and human Alzheimer's disease brain.

PubMed

Chakravarthy, Balu; Ito, Shingo; Atkinson, Trevor; Gaudet, Chantal; Ménard, Michel; Brown, Leslie; Whitfield, James

2014-03-14

The synthetic ~5 kDa ABP (amyloid-ß binding peptide) consists of a region of the 228 kDa human pericentrioloar material-1 (PCM-1) protein that selectively and avidly binds in vitro Aβ1-42 oligomers, believed to be key co-drivers of Alzheimer's disease (AD), but not monomers (Chakravarthy et al., (2013) [3]). ABP also prevents Aß1-42 from triggering the apoptotic death of cultured human SHSY5Y neuroblasts, likely by sequestering Aß oligomers, suggesting that it might be a potential AD therapeutic. Here we support this possibility by showing that ABP also recognizes and binds Aβ1-42 aggregates in sections of cortices and hippocampi from brains of AD transgenic mice and human AD patients. More importantly, ABP targets Aβ1-42 aggregates when microinjected into the hippocampi of the brains of live AD transgenic mice. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

Postischemic dementia with Alzheimer phenotype: selectively vulnerable versus resistant areas of the brain and neurodegeneration versus β-amyloid peptide.

PubMed

Pluta, Ryszard; Jabłoński, Mirosław; Czuczwar, Stanisław J

2012-01-01

The road to clarity for postischemic dementia mechanisms has been one fraught with a wide range of complications and numerous revisions with a lack of a final solution. Importantly, brain ischemia is a leading cause of death and cognitive impairment worldwide. However, the mechanisms of progressive cognitive decline following brain ischemia are not yet certain. Data from animal models and clinical pioneering studies of brain ischemia have demonstrated an increase in expression and processing of amyloid precursor protein to a neurotoxin oligomeric β-amyloid peptide. Functional and memory brain restoration after ischemic brain injury is delayed and incomplete due to a lesion related increase in the amount of the neurotoxin amyloid protein. Moreover, ischemic injury is strongly accelerated by aging, too. In this review, we will present our current thinking about biogenesis of amyloid from the amyloid precursor protein in ischemic brain injury, and how this factor presents etiological, therapeutic and diagnostic targets that are now under consideration. Progressive injury of the ischemic brain parenchyma may be caused not only by degeneration of selectively vulnerable neurons destroyed during ischemia but also by acute and chronic damage of resistant areas of the brain and progressive damage in the blood-brain barrier. We propose that in postischemic dementia an initial ischemic injury precedes the cerebrovascular and brain parenchyma accumulation of Alzheimer disease related neurotoxin β-amyloid peptide, which in turn amplifies the neurovascular dysfunction triggering focal ischemic episodes as a vicious cycle preceding final neurodegenerative pathology. Persistent ischemic blood-brain barrier insufficiency with accumulation of neurotoxin β-amyloid protein in the brain tissue, especially in extracellular perivascular space and blood-brain barrier microvessels, may gradually, over a lifetime, progress to brain atrophy and to full-blown ischemic dementia with Alzheimer phenotype.

Neurological basis of AMP-dependent thermoregulation and its relevance to central and peripheral hyperthermia

PubMed Central

Muzzi, Mirko; Blasi, Francesco; Masi, Alessio; Coppi, Elisabetta; Traini, Chiara; Felici, Roberta; Pittelli, Maria; Cavone, Leonardo; Pugliese, Anna Maria; Moroni, Flavio; Chiarugi, Alberto

2013-01-01

Therapeutic hypothermia is of relevance to treatment of increased body temperature and brain injury, but drugs inducing selective, rapid, and safe cooling in humans are not available. Here, we show that injections of adenosine 5′-monophosphate (AMP), an endogenous nucleotide, promptly triggers hypothermia in mice by directly activating adenosine A1 receptors (A1R) within the preoptic area (POA) of the hypothalamus. Inhibition of constitutive degradation of brain extracellular AMP by targeting ecto 5′-nucleotidase, also suffices to prompt hypothermia in rodents. Accordingly, sensitivity of mice and rats to the hypothermic effect of AMP is inversely related to their hypothalamic 5′-nucleotidase activity. Single-cell electrophysiological recording indicates that AMP reduces spontaneous firing activity of temperature-insensitive neurons of the mouse POA, thereby retuning the hypothalamic thermoregulatory set point towards lower temperatures. Adenosine 5′-monophosphate also suppresses prostaglandin E2-induced fever in mice, having no effects on peripheral hyperthermia triggered by dioxymetamphetamine (ecstasy) overdose. Together, data disclose the role of AMP, 5′-nucleotidase, and A1R in hypothalamic thermoregulation, as well and their therapeutic relevance to treatment of febrile illness. PMID:23093068

The Role of Hypoxia in Glioblastoma Invasion

PubMed Central

Monteiro, Ana Rita; Pilkington, Geoffrey J.

2017-01-01

Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most common and deadly type of primary malignant brain tumor, with a patient’s median survival rate ranging from 15 to 17 months. The current treatment for GBM involves tumor resection surgery based on MRI image analysis, followed by radiotherapy and treatment with temozolomide. However, the gradual development of tumor resistance to temozolomide is frequent in GBM patients leading to subsequent tumor regrowth/relapse. For this reason, the development of more effective therapeutic approaches for GBM is of critical importance. Low tumor oxygenation, also known as hypoxia, constitutes a major concern for GBM patients, since it promotes cancer cell spreading (invasion) into the healthy brain tissue in order to evade this adverse microenvironment. Tumor invasion not only constitutes a major obstacle to surgery, radiotherapy, and chemotherapy, but it is also the main cause of death in GBM patients. Understanding how hypoxia triggers the GBM cells to become invasive is paramount to developing novel and more effective therapies against this devastating disease. In this review, we will present a comprehensive examination of the available literature focused on investigating how GBM hypoxia triggers an invasive cancer cell phenotype and the role of these invasive proteins in GBM progression. PMID:29165393

Relational dimension of irritability following traumatic brain injury: a qualitative analysis.

PubMed

Hammond, Flora M; Davis, Christine S; Cook, James R; Philbrick, Peggy; Hirsch, Mark A

2012-01-01

Irritability is a common long-term sequelae of traumatic brain injury (TBI). In a prior study on TBI irritability, relational interactions were one of four dimensions of irritability occurrence and precipitation. This present analysis examines these same data in greater detail. Fifty focus group transcripts from a study on irritability were re-analysed to examine: (1) irritability in spousal relationships following TBI, (2) retrospective accounts of spousal interactions contributing to irritability and (3) impact of irritability on marital relationships. Grounded Theory was used to develop themes, metacodes and theories. Several theories emerged regarding irritability with respect to spousal relations, all based on the overarching theory that irritability in people with TBI has a strong relational component involved in triggering, experiencing and preventing irritability. Sub-theories supporting this include: (1) irritability breeds further irritability, (2) spousal responses can trigger irritability among persons with TBI and vice versa, (3) difficulties making emotional connections may incite negative interactions, (4) expectations of others may contribute to irritable behaviour, and (5) communication breakdowns may provoke irritability. Irritability associated with TBI resides in the family system as well as the individual. In treating irritability one should include comprehensive assessment and assistance to improve interpersonal interactions.

Gain-of-function somatic mutations contribute to inflammation and blood vessel damage that lead to Alzheimer dementia: a hypothesis.

PubMed

Marchesi, Vincent T

2016-02-01

Amyloid deposits are a characteristic feature of advanced Alzheimer dementia (AD), but whether they initiate the disease or are a consequence of it remains an unsettled question. To explore an alternative pathogenic mechanism, I propose that the triggering events that begin the pathogenic cascade are not amyloid deposits but damaged blood vessels caused by inflammatory reactions that lead to ischemia, amyloid accumulation, axonal degeneration, synaptic loss, and eventually irreversible neuronal cell death. Inflammation and blood vessel damage are well recognized complications of AD, but what causes them and why the cerebral microvasculature is affected have never been adequately addressed. Because heritable autosomal dominant mutations of NLRP3, APP, TREX1, NOTCH3, and Col4A1 are known to provoke inflammatory reactions and damage the brain in a wide variety of diseases, I propose that one or more low abundant, gain-of-function somatic mutations of the same 5 gene families damage the microvasculature of the brain that leads to dementia. This implies that the pathogenic triggers that lead to AD are derived not from external invaders or amyloid but from oxidative damage of our own genes. © FASEB.

Rapid and efficient crossing blood-brain barrier: Hydrophobic drug delivery system based on propionylated amylose helix nanoclusters.

PubMed

Gao, Wei; Liu, Yongchun; Jing, Guixia; Li, Ke; Zhao, Yuan; Sha, Baoyong; Wang, Qiang; Wu, Daocheng

2017-01-01

A novel strategy of rapid transport across the blood-brain barrier (BBB) via phosphatidylethanolamine-triggered release is developed through both molecular dynamics (MD) simulation and experiments. Hydrophobic drugs, namely, propofol, iodine, and 1,1'-dioctadecyltetramethyl indotricarbocyanine iodide, were loaded with propionylated amylose helix (HLPAH) nanoclusters to form PLPAH, ILPAH, and DLPAH nanoclusters, respectively. These clusters were subjected to MD simulation, structure measurement, in vitro triggered study, in vivo DLPAH imaging, and analysis of PLPAH sedative effects on rabbits. Results indicated that HLPAH nanoclusters were initially located on the BBB, and the helix was unfolded to release the loaded hydrophobic drugs. The released drugs crossed the BBB and performed their functions in the central nervous system (CNS) through concentration gradient and hydrophobicity. This mechanism of HLPAH across the BBB featured high membrane permeability and specificity, rapid onset, short maintenance, rapid recovery, and lower dosage of drugs. Hence, this novel strategy is very meaningful for the development of CNS drug carriers and the proposed system could be used to improve the therapeutic effects of CNS diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

JAK2-binding long noncoding RNA promotes breast cancer brain metastasis

PubMed Central

Wang, Shouyu; Liang, Ke; Hu, Qingsong; Li, Ping; Song, Jian; Yang, Yuedong; Yao, Jun; Mangala, Lingegowda Selanere; Li, Chunlai; Park, Peter K.; Hawke, David H.; Zhou, Jianwei; Zhou, Yan; Xia, Weiya; Hung, Mien-Chie; Marks, Jeffrey R.; Gallick, Gary E.; Lopez-Berestein, Gabriel; Flores, Elsa R.; Sood, Anil K.; Huang, Suyun; Yu, Dihua; Yang, Liuqing

2017-01-01

Conventional therapies for breast cancer brain metastases (BCBMs) have been largely ineffective because of chemoresistance and impermeability of the blood-brain barrier. A comprehensive understanding of the underlying mechanism that allows breast cancer cells to infiltrate the brain is necessary to circumvent treatment resistance of BCBMs. Here, we determined that expression of a long noncoding RNA (lncRNA) that we have named lncRNA associated with BCBM (Lnc-BM) is prognostic of the progression of brain metastasis in breast cancer patients. In preclinical murine models, elevated Lnc-BM expression drove BCBM, while depletion of Lnc-BM with nanoparticle-encapsulated siRNAs effectively treated BCBM. Lnc-BM increased JAK2 kinase activity to mediate oncostatin M– and IL-6–triggered STAT3 phosphorylation. In breast cancer cells, Lnc-BM promoted STAT3-dependent expression of ICAM1 and CCL2, which mediated vascular co-option and recruitment of macrophages in the brain, respectively. Recruited macrophages in turn produced oncostatin M and IL-6, thereby further activating the Lnc-BM/JAK2/STAT3 pathway and enhancing BCBM. Collectively, our results show that Lnc-BM and JAK2 promote BCBMs by mediating communication between breast cancer cells and the brain microenvironment. Moreover, these results suggest targeting Lnc-BM as a potential strategy for fighting this difficult disease. PMID:29130936

Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat.

PubMed

Cadet, Jean Lud; Brannock, Christie; Jayanthi, Subramaniam; Krasnova, Irina N

2015-04-01

Methamphetamine use disorder is a chronic neuropsychiatric disorder characterized by recurrent binge episodes, intervals of abstinence, and relapses to drug use. Humans addicted to methamphetamine experience various degrees of cognitive deficits and other neurological abnormalities that complicate their activities of daily living and their participation in treatment programs. Importantly, models of methamphetamine addiction in rodents have shown that animals will readily learn to give themselves methamphetamine. Rats also accelerate their intake over time. Microarray studies have also shown that methamphetamine taking is associated with major transcriptional changes in the striatum measured within a short or longer time after cessation of drug taking. After a 2-h withdrawal time, there was increased expression of genes that participate in transcription regulation. These included cyclic AMP response element binding (CREB), ETS domain-containing protein (ELK1), and members of the FOS family of transcription factors. Other genes of interest include brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor, type 2 (TrkB), and synaptophysin. Methamphetamine-induced transcription was found to be regulated via phosphorylated CREB-dependent events. After a 30-day withdrawal from methamphetamine self-administration, however, there was mostly decreased expression of transcription factors including junD. There was also downregulation of genes whose protein products are constituents of chromatin-remodeling complexes. Altogether, these genome-wide results show that methamphetamine abuse might be associated with altered regulation of a diversity of gene networks that impact cellular and synaptic functions. These transcriptional changes might serve as triggers for the neuropsychiatric presentations of humans who abuse this drug. Better understanding of the way that gene products interact to cause methamphetamine addiction will help to develop better pharmacological treatment of methamphetamine addicts.

Elevation of GM2 ganglioside during ethanol-induced apoptotic neurodegeneration in the developing mouse brain

PubMed Central

Saito, Mitsuo; Chakraborty, Goutam; Shah, Relish; Mao, Rui-Fen; Kumar, Asok; Yang, Dun-Sheng; Dobrenis, Kostantin; Saito, Mariko

2012-01-01

GM2 ganglioside in the brain increased during ethanol-induced acute apoptotic neurodegeneration in 7-day-old mice. A small but a significant increase observed 2 h after ethanol exposure was followed by a marked increase around 24 h. Subcellular fractionation of the brain 24 h after ethanol treatment indicated that GM2 increased in synaptic and non-synaptic mitochondrial fractions as well as in a lysosome-enriched fraction characteristic to the ethanol-exposed brain. Immunohistochemical staining of GM2 in the ethanol-treated brain showed strong punctate staining mainly in activated microglia, in which it partially overlapped with staining for LAMP1, a late endosomal/lysosomal marker. Also, there was weaker neuronal staining, which partially co-localized with complex IV, a mitochondrial marker, and was augmented in cleaved caspase-3-positive neurons. In contrast, the control brain showed only faint and diffuse GM2 staining in neurons. Incubation of isolated brain mitochondria with GM2 in vitro induced cytochrome c release in a manner similar to that of GD3 ganglioside. Because ethanol is known to trigger mitochondria-mediated apoptosis with cytochrome c release and caspase-3 activation in the 7-day–old mouse brain, the GM2 elevation in mitochondria may be relevant to neuroapoptosis. Subsequently, activated microglia accumulated GM2, indicating a close relationship between GM2 and ethanol-induced neurodegeneration. PMID:22372857

New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain

PubMed Central

Venkat, Poornima; Chopp, Michael; Chen, Jieli

2016-01-01

The brain has high metabolic and energy needs and requires continuous cerebral blood flow (CBF), which is facilitated by a tight coupling between neuronal activity, CBF, and metabolism. Upon neuronal activation, there is an increase in energy demand, which is then met by a hemodynamic response that increases CBF. Such regional CBF increase in response to neuronal activation is observed using neuroimaging techniques such as functional magnetic resonance imaging and positron emission tomography. The mechanisms and mediators (eg, nitric oxide, astrocytes, and ion channels) that regulate CBF-metabolism coupling have been extensively studied. The neurovascular unit is a conceptual model encompassing the anatomical and metabolic interactions between the neurons, vascular components, and glial cells in the brain. It is compromised under disease states such as stroke, diabetes, hypertension, dementias, and with aging, all of which trigger a cascade of inflammatory responses that exacerbate brain damage. Hence, tight regulation and maintenance of neurovascular coupling is central for brain homeostasis. This review article also discusses the waste clearance pathways in the brain such as the glymphatic system. The glymphatic system is a functional waste clearance pathway that removes metabolic wastes and neurotoxins from the brain along paravascular channels. Disruption of the glymphatic system burdens the brain with accumulating waste and has been reported in aging as well as several neurological diseases. PMID:27374823

New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain.

PubMed

Venkat, Poornima; Chopp, Michael; Chen, Jieli

2016-06-30

The brain has high metabolic and energy needs and requires continuous cerebral blood flow (CBF), which is facilitated by a tight coupling between neuronal activity, CBF, and metabolism. Upon neuronal activation, there is an increase in energy demand, which is then met by a hemodynamic response that increases CBF. Such regional CBF increase in response to neuronal activation is observed using neuroimaging techniques such as functional magnetic resonance imaging and positron emission tomography. The mechanisms and mediators (eg, nitric oxide, astrocytes, and ion channels) that regulate CBF-metabolism coupling have been extensively studied. The neurovascular unit is a conceptual model encompassing the anatomical and metabolic interactions between the neurons, vascular components, and glial cells in the brain. It is compromised under disease states such as stroke, diabetes, hypertension, dementias, and with aging, all of which trigger a cascade of inflammatory responses that exacerbate brain damage. Hence, tight regulation and maintenance of neurovascular coupling is central for brain homeostasis. This review article also discusses the waste clearance pathways in the brain such as the glymphatic system. The glymphatic system is a functional waste clearance pathway that removes metabolic wastes and neurotoxins from the brain along paravascular channels. Disruption of the glymphatic system burdens the brain with accumulating waste and has been reported in aging as well as several neurological diseases.

Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology.

PubMed

Wijdicks, Eelco F M; Varelas, Panayiotis N; Gronseth, Gary S; Greer, David M

2010-06-08

To provide an update of the 1995 American Academy of Neurology guideline with regard to the following questions: Are there patients who fulfill the clinical criteria of brain death who recover neurologic function? What is an adequate observation period to ensure that cessation of neurologic function is permanent? Are complex motor movements that falsely suggest retained brain function sometimes observed in brain death? What is the comparative safety of techniques for determining apnea? Are there new ancillary tests that accurately identify patients with brain death? A systematic literature search was conducted and included a review of MEDLINE and EMBASE from January 1996 to May 2009. Studies were limited to adults. In adults, there are no published reports of recovery of neurologic function after a diagnosis of brain death using the criteria reviewed in the 1995 American Academy of Neurology practice parameter. Complex-spontaneous motor movements and false-positive triggering of the ventilator may occur in patients who are brain dead. There is insufficient evidence to determine the minimally acceptable observation period to ensure that neurologic functions have ceased irreversibly. Apneic oxygenation diffusion to determine apnea is safe, but there is insufficient evidence to determine the comparative safety of techniques used for apnea testing. There is insufficient evidence to determine if newer ancillary tests accurately confirm the cessation of function of the entire brain.

Structural study of Purkinje cell axonal torpedoes in essential tremor.

PubMed

Louis, Elan D; Yi, Hong; Erickson-Davis, Cordelia; Vonsattel, Jean-Paul G; Faust, Phyllis L

2009-02-06

Essential tremor (ET) is one of the most common neurological diseases. A basic understanding of its neuropathology is now emerging. Aside from Purkinje cell loss, a prominent finding is an abundance of torpedoes (rounded swellings of Purkinje cell axons). Such swellings often result from the mis-accumulation of cell constituents. Identifying the basic nature of these accumulations is an important step in understanding the underlying disease process. Torpedoes, only recently identified in ET, have not yet been characterized ultrastructurally. Light and electron microscopy were used to characterize the structural constituents of torpedoes in ET. Formalin-fixed cerebellar cortical tissue from four prospectively collected ET brains was sectioned and immunostained with a monoclonal phosphorylated neurofilament antibody (SMI-31, Covance, Emeryville, CA). Using additional sections from three ET brains, torpedoes were assessed using electron microscopy. Immunoreactivity for phosphorylated neurofilament protein revealed clear labeling of torpedoes in each case. Torpedoes were strongly immunoreactive; in many instances, two or more torpedoes were noted in close proximity to one another. On electron microscopy, torpedoes were packed with randomly arranged 10-12nm neurofilaments. Mitochondria and smooth endoplasmic reticulum were abundant as well, particularly at the periphery of the torpedo. We demonstrated that the torpedoes in ET represent the mis-accumulation of disorganized neurofilaments and other organelles. It is not known where in the pathogenic cascade these accumulations occur (i.e., whether these accumulations are the primary event or a secondary/downstream event) and this deserves further study.

Blood-brain barrier specific permeability assay reveals N-methylated tyramine derivatives in standardised leaf extracts and herbal products of Ginkgo biloba.

PubMed

Könczöl, Árpád; Rendes, Kata; Dékány, Miklós; Müller, Judit; Riethmüller, Eszter; Balogh, György Tibor

2016-11-30

The linkage between the central nervous system availability and neuropharmacological activity of the constituents of Ginkgo biloba L. extracts (GBE) is still incomplete. In this study, the in vitro blood-brain barrier (BBB) permeability profile of the standardised GBE was investigated by the parallel artificial membrane permeability assay (PAMPA). Biomarkers, such as terpene trilactones, flavonoid aglycones and ginkgotoxin exerted moderate or good BBB-permeability potential (BBB+), while glycosides and biflavones were predicted as unable to pass the BBB. N-methyltyramine (NMT) and N,N-dimethyltyramine or hordenine (Hor) were identified among BBB+ compounds, while subsequent direct HRMS analysis revealed tyramine (Tyr) and N,N,N-trimethyltyramine or candicine (Can) in GBE as trace constituents. Distribution of Tyr, NMT, Hor and Can was determined by a validated ion-exchange mechanism-based liquid chromatography-electrospray ionisation-mass spectrometry (LC-ESI-MS) method in G. biloba samples, such as herbal drugs and dietary supplements. The total content of the four tyramine derivatives in various GBEs ranged from 7.3 up to 6357μg/g dry extract with NMT and Hor as most abundant ones. Considering the pharmacological activities and the revealed fluctuation in the concentration of the analysed adrenergic protoalkaloids, the presented rapid LC-ESI-MS method is proposed for monitoring of the levels of Tyr, NMT, Hor and Can in G. biloba products. Copyright © 2016 Elsevier B.V. All rights reserved.

Identification of Unstable Network Modules Reveals Disease Modules Associated with the Progression of Alzheimer’s Disease

PubMed Central

Kikuchi, Masataka; Ogishima, Soichi; Miyamoto, Tadashi; Miyashita, Akinori; Kuwano, Ryozo; Nakaya, Jun; Tanaka, Hiroshi

2013-01-01

Alzheimer’s disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system. PMID:24348898

Danshen diversity defeating dementia.

PubMed

Hügel, Helmut M; Jackson, Neale

2014-02-01

Salvia miltiorrhiza (danshen) is widely used for the clinical treatment of cerebral ischemia and cardiovascular diseases. Its diverse molecular makeup of simple and poly hydroxycinnamic acids and diterpenoid quinones are also associated with its beneficial health effects such as improved cognitive deficits in mice, protection of neuronal cells, prevention of amyloid fibril formation and preformed amyloid fibril disaggregation related to Alzheimer's disease. Whilst the in vitro studies have therapeutic promise, the anti-dementia effect/impact of danshen however depends on its absorbed constituents and pharmacokinetic properties. Both the water and lipid danshen fractions have been shown to have low oral bioavailability and at physiological pH, the polyphenolic carboxylate anions are not brain permeable. To tap into the many neuroprotective and other biological benefits of danshen, the key challenge resides in developing danshen nanopharmaceuticals, semi-synthetic pro-drug forms of its constituents to improve its biocompatability, that is, absorption, circulation in bloodstream and optimization of BBB permeability. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Control of Aβ release from human neurons by differentiation status and RET signaling.

PubMed

Scholz, Diana; Chernyshova, Yana; Leist, Marcel

2013-01-01

Few studies have compared the processing of endogenous human amyloid precursor protein (APP) in younger and older neurons. Here, we characterized LUHMES cells as a human model to study Alzheimer's disease-related processes during neuronal maturation and aging. Differentiated LUHMES expressed and spontaneously processed APP via the secretase pathways, and they secreted amyloid β (Aβ) peptide. This was inhibited by cholesterol depletion or secretase inhibition, but not by block of tau phosphorylation. In vitro aged cells increased Aβ secretion without upregulation of APP or secretases. We identified the medium constituent glial cell line-derived neurotrophic factor (GDNF) as responsible for this effect. GDNF-triggered Aβ release was associated with rapid upregulation of the GDNF coreceptor "rearranged during transfection" (RET). Other direct (neurturin) or indirect (nerve growth factor) RET activators also increased Aβ, whereas different neurotrophins were ineffective. Downstream of RET, we found activation of protein kinase B (AKT) to be involved. Accordingly, inhibitors of the AKT regulator phosphatidylinositol-3-kinase completely blocked GDNF-triggered AKT phosphorylation and Aβ increase. This suggests that RET signaling affects Aβ release from aging neurons. Copyright © 2013 Elsevier Inc. All rights reserved.

Oxytocin, brain physiology, and functional connectivity: a review of intranasal oxytocin fMRI studies.

PubMed

Bethlehem, Richard A I; van Honk, Jack; Auyeung, Bonnie; Baron-Cohen, Simon

2013-07-01

In recent years the neuropeptide oxytocin (OT) has become one of the most studied peptides of the human neuroendocrine system. Research has shown widespread behavioural effects and numerous potential therapeutic benefits. However, little is known about how OT triggers these effects in the brain. Here, we discuss some of the physiological properties of OT in the human brain including the long half-life of neuropeptides, the diffuse projections of OT throughout the brain and interactions with other systems such as the dopaminergic system. These properties indicate that OT acts without clear spatial and temporal specificity. Therefore, it is likely to have widespread effects on the brain's intrinsic functioning. Additionally, we review studies that have used functional magnetic resonance imaging (fMRI) concurrently with OT administration. These studies reveal a specific set of 'social' brain regions that are likely to be the strongest targets for OT's potential to influence human behaviour. On the basis of the fMRI literature and the physiological properties of the neuropeptide, we argue that OT has the potential to not only modulate activity in a set of specific brain regions, but also the functional connectivity between these regions. In light of the increasing knowledge of the behavioural effects of OT in humans, studies of the effects of OT administration on brain function can contribute to our understanding of the neural networks in the social brain. Copyright © 2012 Elsevier Ltd. All rights reserved.

What Does Their Saliva Say? Salivary Cortisol Levels in Children Exposed to Severe Stressors

ERIC Educational Resources Information Center

McCabe, Paul C.; Schneider, Marissa

2009-01-01

Stress is an unavoidable aspect of the human experience. When the brain interprets a situation as stressful, it triggers the release of a hormone called cortisol that acts as a catalyst of the body's "fight or flight" response system. In small amounts this hormone can provide the body with the necessary tools to escape a stressful situation.…

Endotoxins in Environmental and Clinical Samples Assessed by GC-Tandem MS

NASA Astrophysics Data System (ADS)

Szponar, Bogumila

Bacteria appeared on the Earth millions years before us and human evolution was triggered by the constant presence of pathogenic and symbiotic microorganisms in our surroundings. Interplay occurred between higher organism and microbial consortia residing in the host organs and on the epithelial surfaces; another natural space of bacteria-human interaction is the indoor environment where we spend the majority of our lifetime. Indoor microbial exposure affects our well-being and can result in respiratory symptoms, such as allergies and asthma, since both dead and live microorganisms and their cell constituents, including lipopolysaccharides (LPS, endotoxins), interact with our immune system. Thus, there is a demand for robust tools for qualitative and quantitative determination of the microbial communities that we are exposed to.

Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice

PubMed Central

Avraham, Y; Grigoriadis, NC; Poutahidis, T; Vorobiev, L; Magen, I; Ilan, Y; Mechoulam, R; Berry, EM

2011-01-01

BACKGROUND AND PURPOSE Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT1A, on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. EXPERIMENTAL APPROACH Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. KEY RESULTS Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. CONCLUSIONS AND IMPLICATIONS Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. PMID:21182490

Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice.

PubMed

Avraham, Y; Grigoriadis, Nc; Poutahidis, T; Vorobiev, L; Magen, I; Ilan, Y; Mechoulam, R; Berry, Em

2011-04-01

Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT(1A) , on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Cooling treatment transiently increases the permeability of brain capillary endothelial cells through translocation of claudin-5.

PubMed

Inamura, Akinori; Adachi, Yasuhiro; Inoue, Takao; He, Yeting; Tokuda, Nobuko; Nawata, Takashi; Shirao, Satoshi; Nomura, Sadahiro; Fujii, Masami; Ikeda, Eiji; Owada, Yuji; Suzuki, Michiyasu

2013-08-01

The blood-brain-barrier (BBB) is formed by different cell types, of which brain microvascular endothelial cells are major structural constituents. The goal of this study was to examine the effects of cooling on the permeability of the BBB with reference to tight junction formation of brain microendothelial cells. The sensorimotor cortex above the dura mater in adult male Wistar rats was focally cooled to a temperature of 5 °C for 1 h, then immunostaining for immunoglobulin G (IgG) was performed to evaluate the permeability of the BBB. Permeability produced by cooling was also evaluated in cultured murine brain endothelial cells (bEnd3) based on measurement of trans-epithelial electric resistance (TEER). Immunocytochemistry and Western blotting of proteins associated with tight junctions in bEnd3 were performed to determine protein distribution before and after cooling. After focal cooling of the rat brain cortex, diffuse immunostaining for IgG was observed primarily around the small vasculature and in the extracellular spaces of parenchyma of the cortex. In cultured bEnd3, TEER significantly decreased during cooling (15 °C) and recovered to normal levels after rewarming to 37 °C. Immunocytochemistry and Western blotting showed that claudin-5, a critical regulatory protein for tight junctions, was translocated from the membrane to the cytoplasm after cooling in cultured bEnd3 cells. These results suggest that focal brain cooling may open the BBB transiently through an effect on tight junctions of brain microendothelial cells, and that therapeutically this approach may allow control of BBB function and drug delivery through the BBB.

Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils.

PubMed

Cansev, M; Wurtman, R J

2007-08-24

Synthesis of phosphatidylcholine, the most abundant brain membrane phosphatide, requires three circulating precursors: choline; a pyrimidine (e.g. uridine); and a polyunsaturated fatty acid. Supplementing a choline-containing diet with the uridine source uridine-5'-monophosphate (UMP) or, especially, with UMP plus the omega-3 fatty acid docosahexaenoic acid (given by gavage), produces substantial increases in membrane phosphatide and synaptic protein levels within gerbil brain. We now compare the effects of various polyunsaturated fatty acids, given alone or with UMP, on these synaptic membrane constituents. Gerbils received, daily for 4 weeks, a diet containing choline chloride with or without UMP and/or, by gavage, an omega-3 (docosahexaenoic or eicosapentaenoic acid) or omega-6 (arachidonic acid) fatty acid. Both of the omega-3 fatty acids elevated major brain phosphatide levels (by 18-28%, and 21-27%) and giving UMP along with them enhanced their effects significantly. Arachidonic acid, given alone or with UMP, was without effect. After UMP plus docosahexaenoic acid treatment, total brain phospholipid levels and those of each individual phosphatide increased significantly in all brain regions examined (cortex, striatum, hippocampus, brain stem, and cerebellum). The increases in brain phosphatides in gerbils receiving an omega-3 (but not omega-6) fatty acid, with or without UMP, were accompanied by parallel elevations in levels of pre- and post-synaptic proteins (syntaxin-3, PSD-95 and synapsin-1) but not in those of a ubiquitous structural protein, beta-tubulin. Hence administering omega-3 polyunsaturated fatty acids can enhance synaptic membrane levels in gerbils, and may do so in patients with neurodegenerative diseases, especially when given with a uridine source, while the omega-6 polyunsaturated fatty acid arachidonic acid is ineffective.

Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils

PubMed Central

Cansev, M.; Wurtman, R. J.

2007-01-01

Synthesis of phosphatidylcholine, the most abundant brain membrane phosphatide, requires three circulating precursors: choline; a pyrimidine (e.g., uridine); and a polyunsaturated fatty acid. Supplementing a choline-containing diet with the uridine source uridine-5′-monophosphate (UMP) or, especially, with UMP plus the omega-3 fatty acid docosahexaenoic acid (given by gavage), produces substantial increases in membrane phosphatide and synaptic protein levels within gerbil brain. We now compare the effects of various polyunsaturated fatty acids, given alone or with UMP, on these synaptic membrane constituents. Gerbils received, daily for 4 weeks, a diet containing choline chloride with or without UMP and/or, by gavage, an omega-3 (docosahexaenoic or eicosapentaenoic acid) or omega-6 (arachidonic acid) fatty acid. Both of the omega-3 fatty acids elevated major brain phosphatide levels (by 18-28%, and 21-27%) and giving UMP along with them enhanced their effects significantly. Arachidonic acid, given alone or with UMP, was without effect. After UMP plus docosahexaenoic acid treatment, total brain phospholipids levels and those of each individual phosphatide increased significantly in all brain regions examined (cortex, striatum, hippocampus, brain stem, and cerebellum). The increases in brain phosphatides in gerbils receiving an omega-3 (but not omega-6) fatty acid, with or without UMP, were accompanied by parallel elevations in levels of pre- and post-synaptic proteins (syntaxin-3, PSD-95 and Synapsin-1) but not in those of a ubiquitous structural protein, β-tubulin. Hence administering omega-3 polyunsaturated fatty acids can enhance synaptic membrane levels in gerbils, and may do so in patients with neurodegenerative diseases, especially when given with a uridine source, while the omega-6 polyunsaturated fatty acid arachidonic acid is ineffective. PMID:17683870

Imaging Neural Activity Using Thy1-GCaMP Transgenic mice

PubMed Central

Chen, Qian; Cichon, Joseph; Wang, Wenting; Qiu, Li; Lee, Seok-Jin R.; Campbell, Nolan R.; DeStefino, Nicholas; Goard, Michael J.; Fu, Zhanyan; Yasuda, Ryohei; Looger, Loren L.; Arenkiel, Benjamin R.; Gan, Wen-Biao; Feng, Guoping

2014-01-01

Summary The ability to chronically monitor neuronal activity in the living brain is essential for understanding the organization and function of the nervous system. The genetically encoded green fluorescent protein based calcium sensor GCaMP provides a powerful tool for detecting calcium transients in neuronal somata, processes, and synapses that are triggered by neuronal activities. Here we report the generation and characterization of transgenic mice that express improved GCaMPs in various neuronal subpopulations under the control of the Thy1 promoter. In vitro and in vivo studies show that calcium transients induced by spontaneous and stimulus-evoked neuronal activities can be readily detected at the level of individual cells and synapses in acute brain slices, as well as chronically in awake behaving animals. These GCaMP transgenic mice allow investigation of activity patterns in defined neuronal populations in the living brain, and will greatly facilitate dissecting complex structural and functional relationships of neural networks. PMID:23083733

Erotic and disgust-inducing pictures--differences in the hemodynamic responses of the brain.

PubMed

Stark, Rudolf; Schienle, Anne; Girod, Cornelia; Walter, Bertram; Kirsch, Peter; Blecker, Carlo; Ott, Ulrich; Schäfer, Axel; Sammer, Gebhard; Zimmermann, Mark; Vaitl, Dieter

2005-09-01

The aim of this fMRI study was to explore brain structures that are involved in the processing of erotic and disgust-inducing pictures. The stimuli were chosen to trigger approach and withdrawal tendencies, respectively. By adding sadomasochistic (SM) scenes to the design and examining 12 subjects with and 12 subjects without sadomasochistic preferences, we introduced a picture category that induced erotic pleasure in one sample and disgust in the other sample. Since we also presented neutral pictures, all subjects viewed pictures of four different categories: neutral, disgust-inducing, erotic, and SM erotic pictures. The analysis indicated that several brain structures are commonly involved in the processing of disgust-inducing and erotic pictures (occipital cortex, hippocampus, thalamus, and the amygdala). The ventral striatum was specifically activated when subjects saw highly sexually arousing pictures. This indicates the involvement of the human reward system during the processing of visual erotica.

Mammalian Target of Rapamycin: Its Role in Early Neural Development and in Adult and Aged Brain Function

PubMed Central

Garza-Lombó, Carla; Gonsebatt, María E.

2016-01-01

The kinase mammalian target of rapamycin (mTOR) integrates signals triggered by energy, stress, oxygen levels, and growth factors. It regulates ribosome biogenesis, mRNA translation, nutrient metabolism, and autophagy. mTOR participates in various functions of the brain, such as synaptic plasticity, adult neurogenesis, memory, and learning. mTOR is present during early neural development and participates in axon and dendrite development, neuron differentiation, and gliogenesis, among other processes. Furthermore, mTOR has been shown to modulate lifespan in multiple organisms. This protein is an important energy sensor that is present throughout our lifetime its role must be precisely described in order to develop therapeutic strategies and prevent diseases of the central nervous system. The aim of this review is to present our current understanding of the functions of mTOR in neural development, the adult brain and aging. PMID:27378854

The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives

PubMed Central

Swerdlow, Russell H.; Burns, Jeffrey M.; Khan, Shaharyar M.

2013-01-01

Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it. PMID:24071439

Heart-rate sensitive optical coherence angiography for measuring vascular changes due to posttraumatic brain injury in mice

NASA Astrophysics Data System (ADS)

Tremoleda, Jordi L.; Alvarez, Karl; Aden, Abdirahman; Donnan, Robert; Michael-Titus, Adina T.; Tomlins, Peter H.

2017-12-01

Traumatic brain injury (TBI) results in direct vascular disruption, triggering edema, and reduction in cerebral blood flow. Therefore, understanding the pathophysiology of brain microcirculation following TBI is important for the development of effective therapies. Optical coherence angiography (OCA) is a promising tool for evaluating TBI in rodent models. We develop an approach to OCA that uses the heart-rate frequency to discriminate between static tissue and vasculature. This method operates on intensity data and is therefore not phase sensitive. Furthermore, it does not require spatial overlap of voxels and thus can be applied to pre-existing datasets for which oversampling may not have been explicitly considered. Heart-rate sensitive OCA was developed for dynamic assessment of mouse microvasculature post-TBI. Results show changes occurring at 5-min intervals within the first 50 min of injury.

Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration.

PubMed

Spielman, Lindsay J; Little, Jonathan P; Klegeris, Andis

2014-08-15

Obesity is a growing epidemic that contributes to several brain disorders including Alzheimer's, Parkinson's, and Huntington's diseases. Obesity could promote these diseases through several different mechanisms. Here we review evidence supporting the involvement of two recently recognized factors linking obesity with neurodegeneration: the induction of pro-inflammatory cytokines and onset of insulin and insulin-like growth factor 1 (IGF-1) resistance. Excess peripheral pro-inflammatory mediators, some of which can cross the blood brain barrier, may trigger neuroinflammation, which subsequently exacerbates neurodegeneration. Insulin and IGF-1 resistance leads to weakening of neuroprotective signaling by these molecules and can contribute to onset of neurodegenerative diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

[Methods of brain stimulation based on weak electric current--future tool for the clinician?].

PubMed

Kotilainen, Tuukka; Lehto, Soili M

2016-01-01

Methods of brain stimulation based on a weak electric current are non-invasive neuromodulation techniques. They include transcranial direct current, alternating current and random noise stimulation. These methods modify the membrane potential of neurons without triggering the action potential, and have been successfully utilized to influence cognition and regulation of emotions in healthy experimental subjects. In clinical studies, indications of the efficacy of these techniques have been obtained in the treatment of depression, schizophrenia, memory disorders and pain as well as in stroke rehabilitation. It is hoped that these techniques will become established as part of the care and rehabilitation of psychiatric and neurologic patients in the future.

[Posterior reversible encephalopathy syndrome after neurosurgery: A literature review].

PubMed

Durán Paz, S; Moreno Casanova, I; Benatar-Haserfaty, J

2015-12-01

Posterior reversible encephalopathy syndrome is a clinical-radiological characterized by decreased level of consciousness, seizures, and visual disturbances, as well as radiologically ras brain edema, predominantly in parieto-occipital white matter regions. There are many situations that can trigger the disorder, including the administration of immunosuppressants, chemotherapy agents, hypertensive disorders, and sepsis. The case is described of a patient diagnosed with stage IV prostate adenocarcinoma, receiving chemotherapy, andundergoing a posterior reversible encephalopathy syndrome after surgery for resection of brain metastasis. Copyright © 2014 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

Molecular Mechanisms of Cannabis Signaling in the Brain.

PubMed

Ronan, Patrick J; Wongngamnit, Narin; Beresford, Thomas P

2016-01-01

Cannabis has been cultivated and used by humans for thousands of years. Research for decades was focused on understanding the mechanisms of an illegal/addictive drug. This led to the discovery of the vast endocannabinoid system. Research has now shifted to understanding fundamental biological questions related to one of the most widespread signaling systems in both the brain and the body. Our understanding of cannabinoid signaling has advanced significantly in the last two decades. In this review, we discuss the state of knowledge on mechanisms of Cannabis signaling in the brain and the modulation of key brain neurotransmitter systems involved in both brain reward/addiction and psychiatric disorders. It is highly probable that various cannabinoids will be found to be efficacious in the treatment of a number of psychiatric disorders. However, while there is clearly much potential, marijuana has not been properly vetted by the medical-scientific evaluation process and there are clearly a range of potentially adverse side-effects-including addiction. We are at crossroads for research on endocannabinoid function and therapeutics (including the use of exogenous treatments such as Cannabis). With over 100 cannabinoid constituents, the majority of which have not been studied, there is much Cannabis research yet to be done. With more states legalizing both the medicinal and recreational use of marijuana the rigorous scientific investigation into cannabinoid signaling is imperative. Copyright © 2016. Published by Elsevier Inc.

Reinforcing and neural activating effects of norharmane, a non-nicotine tobacco constituent, alone and in combination with nicotine.

PubMed

Arnold, Monica M; Loughlin, Sandra E; Belluzzi, James D; Leslie, Frances M

2014-10-01

Tobacco use is the leading cause of preventable death. Although the health risks are well known, cessation rates remain low. Whereas behavioral and neuroanatomical studies on tobacco addiction conventionally use nicotine, there is evidence that other constituents, such as monoamine oxidase inhibitors, may be important factors for modeling smoking. The aims of the present study were therefore to determine whether norharmane, a tobacco constituent and monoamine oxidase inhibitor, is self-administered alone and/or in combination with nicotine, and to evaluate the neural mechanisms underlying acquisition of self-administration of the two drugs. Sprague-Dawley rats were catheterized and allowed to intravenously self-administer either saline, nicotine (7.5 μg/kg/inj), norharmane (0.25 or 2.5 μg/kg/inj), alone or combined together (7.5+2.5 μg/kg/inj) for five days at fixed ratio (FR)1, two days each at FR2 and FR5, and one day at progressive ratio. Animals acquired self-administration of norharmane alone (2.5 μg/kg/inj), and the reinforcing effects of nicotine and norharmane were additive. For neuroanatomical analyses, rats self-administered the same treatments for six days at FR1, then brains were collected and processed by in situ hybridization for cfos mRNA expression. Treatment-specific profiles of regional cfos expression and correlations between cfos mRNA levels and behavioral responding were observed. Thus, not only was norharmane behaviorally reinforcing but, when combined with nicotine, resulted in patterns of neural activation distinct from that of norharmane or nicotine alone. This suggests that non-nicotine constituents can have central activating effects independent of nicotine, further substantiating the need for their inclusion in preclinical investigations of tobacco dependence. Copyright © 2014 Elsevier Ltd. All rights reserved.

Boron Neutron Capture Therapy for Malignant Brain Tumors

PubMed Central

MIYATAKE, Shin-Ichi; KAWABATA, Shinji; HIRAMATSU, Ryo; KUROIWA, Toshihiko; SUZUKI, Minoru; KONDO, Natsuko; ONO, Koji

2016-01-01

Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Therefore, BNCT enables the application of a high dose of particle radiation selectively to tumor cells in which boron-10 compound has been accumulated. We applied BNCT using nuclear reactors for 167 cases of malignant brain tumors, including recurrent malignant gliomas, newly diagnosed malignant gliomas, and recurrent high-grade meningiomas from January 2002 to May 2014. Here, we review the principle and history of BNCT. In addition, we introduce fluoride-18-labeled boronophenylalanine positron emission tomography and the clinical results of BNCT for the above-mentioned malignant brain tumors. Finally, we discuss the recent development of accelerators producing epithermal neutron beams. This development could provide an alternative to the current use of specially modified nuclear reactors as a neutron source, and could allow BNCT to be performed in a hospital setting. PMID:27250576

Boron Neutron Capture Therapy for Malignant Brain Tumors.

PubMed

Miyatake, Shin-Ichi; Kawabata, Shinji; Hiramatsu, Ryo; Kuroiwa, Toshihiko; Suzuki, Minoru; Kondo, Natsuko; Ono, Koji

2016-07-15

Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Therefore, BNCT enables the application of a high dose of particle radiation selectively to tumor cells in which boron-10 compound has been accumulated. We applied BNCT using nuclear reactors for 167 cases of malignant brain tumors, including recurrent malignant gliomas, newly diagnosed malignant gliomas, and recurrent high-grade meningiomas from January 2002 to May 2014. Here, we review the principle and history of BNCT. In addition, we introduce fluoride-18-labeled boronophenylalanine positron emission tomography and the clinical results of BNCT for the above-mentioned malignant brain tumors. Finally, we discuss the recent development of accelerators producing epithermal neutron beams. This development could provide an alternative to the current use of specially modified nuclear reactors as a neutron source, and could allow BNCT to be performed in a hospital setting.

Measuring the labeling efficiency of pseudocontinuous arterial spin labeling.

PubMed

Chen, Zhensen; Zhang, Xingxing; Yuan, Chun; Zhao, Xihai; van Osch, Matthias J P

2017-05-01

Optimization and validation of a sequence for measuring the labeling efficiency of pseudocontinuous arterial spin labeling (pCASL) perfusion MRI. The proposed sequence consists of a labeling module and a single slice Look-Locker echo planar imaging readout. A model-based algorithm was used to calculate labeling efficiency from the signal acquired from the main brain-feeding arteries. Stability of the labeling efficiency measurement was evaluated with regard to the use of cardiac triggering, flow compensation and vein signal suppression. Accuracy of the measurement was assessed by comparing the measured labeling efficiency to mean brain pCASL signal intensity over a wide range of flip angles as applied in the pCASL labeling. Simulations show that the proposed algorithm can effectively calculate labeling efficiency when correcting for T1 relaxation of the blood spins. Use of cardiac triggering and vein signal suppression improved stability of the labeling efficiency measurement, while flow compensation resulted in little improvement. The measured labeling efficiency was found to be linearly (R = 0.973; P < 0.001) related to brain pCASL signal intensity over a wide range of pCASL flip angles. The optimized labeling efficiency sequence provides robust artery-specific labeling efficiency measurement within a short acquisition time (∼30 s), thereby enabling improved accuracy of pCASL CBF quantification. Magn Reson Med 77:1841-1852, 2017. © 2016 International Society for Magnetic Resonance in Medicine Magn Reson Med 77:1841-1852, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

Computational neuroanatomy: mapping cell-type densities in the mouse brain, simulations from the Allen Brain Atlas

NASA Astrophysics Data System (ADS)

Grange, Pascal

2015-09-01

The Allen Brain Atlas of the adult mouse (ABA) consists of digitized expression profiles of thousands of genes in the mouse brain, co-registered to a common three-dimensional template (the Allen Reference Atlas).This brain-wide, genome-wide data set has triggered a renaissance in neuroanatomy. Its voxelized version (with cubic voxels of side 200 microns) is available for desktop computation in MATLAB. On the other hand, brain cells exhibit a great phenotypic diversity (in terms of size, shape and electrophysiological activity), which has inspired the names of some well-studied cell types, such as granule cells and medium spiny neurons. However, no exhaustive taxonomy of brain cell is available. A genetic classification of brain cells is being undertaken, and some cell types have been chraracterized by their transcriptome profiles. However, given a cell type characterized by its transcriptome, it is not clear where else in the brain similar cells can be found. The ABA can been used to solve this region-specificity problem in a data-driven way: rewriting the brain-wide expression profiles of all genes in the atlas as a sum of cell-type-specific transcriptome profiles is equivalent to solving a quadratic optimization problem at each voxel in the brain. However, the estimated brain-wide densities of 64 cell types published recently were based on one series of co-registered coronal in situ hybridization (ISH) images per gene, whereas the online ABA contains several image series per gene, including sagittal ones. In the presented work, we simulate the variability of cell-type densities in a Monte Carlo way by repeatedly drawing a random image series for each gene and solving the optimization problem. This yields error bars on the region-specificity of cell types.

Matrix Metalloproteinase-Mediated Blood-Brain Barrier Dysfunction in Epilepsy.

PubMed

Rempe, Ralf G; Hartz, Anika M S; Soldner, Emma L B; Sokola, Brent S; Alluri, Satya R; Abner, Erin L; Kryscio, Richard J; Pekcec, Anton; Schlichtiger, Juli; Bauer, Björn

2018-05-02

The blood-brain barrier is dysfunctional in epilepsy, thereby contributing to seizure genesis and resistance to antiseizure drugs. Previously, several groups reported that seizures increase brain glutamate levels, which leads to barrier dysfunction. One critical component of barrier dysfunction is brain capillary leakage. Based on our preliminary data, we hypothesized that glutamate released during seizures mediates an increase in matrix-metalloproteinase (MMP) expression and activity levels, thereby contributing to barrier leakage. To test this hypothesis, we exposed isolated brain capillaries from male Sprague Dawley rats to glutamate ex vivo and used an in vivo / ex vivo approach of isolated brain capillaries from female Wistar rats that experienced status epilepticus as an acute seizure model. We found that exposing isolated rat brain capillaries to glutamate increased MMP-2 and MMP-9 protein and activity levels, and decreased tight junction protein levels, which resulted in barrier leakage. We confirmed these findings in vivo in rats after status epilepticus and in brain capillaries from male mice lacking cytosolic phospholipase A 2 Together, our data support the hypothesis that glutamate released during seizures signals an increase in MMP-2 and MMP-9 protein expression and activity levels, resulting in blood-brain barrier leakage. SIGNIFICANCE STATEMENT The mechanism leading to seizure-mediated blood-brain barrier dysfunction in epilepsy is poorly understood. In the present study, we focused on defining this mechanism in the brain capillary endothelium. We demonstrate that seizures trigger a pathway that involves glutamate signaling through cytosolic phospholipase A 2 , which increases MMP levels and decreases tight junction protein expression levels, resulting in barrier leakage. These findings may provide potential therapeutic avenues within the blood-brain barrier to limit barrier dysfunction in epilepsy and decrease seizure burden. Copyright © 2018 the authors 0270-6474/18/384301-15$15.00/0.

Rapid Morphological Brain Abnormalities during Acute Methamphetamine Intoxication in the Rat. An Experimental study using Light and Electron Microscopy

PubMed Central

Sharma, Hari S.; Kiyatkin, Eugene A.

2009-01-01

This study describes morphological abnormalities of brain cells during acute methamphetamine (METH) intoxication in the rat and demonstrates the role of hyperthermia, disruption of the blood-brain barrier (BBB) and edema in their development. Rats with chronically implanted brain, muscle and skin temperature probes and an intravenous (iv) catheter were exposed to METH (9 mg/kg) at standard (23°C) and warm (29°C) ambient temperatures, allowing for the observation of hyperthermia ranging from mild to pathological levels (38–42°C). When brain temperature peaked or reached a level suggestive of possible lethality (>41.5°C), rats were injected with Evans blue (EB), rapidly anesthetized, perfused, and their brains were taken for further analyses. Four brain areas (cortex, hippocampus, thalamus and hypothalamus) were analyzed for EB extravasation, water and electrolyte (Na+, K+, Cl−) contents, immunostained for albumin and glial fibrillary acidic protein, and examined for neuronal, glial and axonal alterations using standard light and electron microscopy. These examinations revealed profound abnormalities in neuronal, glial, and endothelial cells, which were stronger with METH administered at 29°C than 23°C and tightly correlated with brain and body hyperthermia. These changes had some structural specificity, but in each structure they tightly correlated with increases in EB levels, the numbers of albumin-positive cells, and water and ion contents, suggesting leakage of the BBB, acutely developing brain edema, and serious shifts in brain ion homeostasis as leading factors underlying brain abnormalities. While most of these acute structural and functional abnormalities appear to be reversible, they could trigger subsequent cellular alterations in the brain and accelerate neurodegeneration—the most dangerous complication of chronic amphetamine-like drug abuse. PMID:18773954

An on-line analysis of syntactic processing in Broca's and Wernicke's aphasia.

PubMed

Zurif, E; Swinney, D; Prather, P; Solomon, J; Bushell, C

1993-10-01

This paper is about syntactic processing in aphasia. Specifically, we present data concerning the ability of Broca's and Wernicke's aphasic patients to link moved constituents and empty elements in real time. We show that Wernicke's aphasic patients carry out this syntactic analysis in a normal fashion, but that Broca's aphasic patients do not. We discuss these data in the context of some current grammar-based theories of comprehension limitations in aphasia and in terms of the different functional commitments of the brain regions implicated in Broca's and Wernicke's aphasia, respectively.

A trombosis story and PRES

PubMed Central

Kartal, Vural; Zara, Zeynep; Yilmaz, Sema; Ayhan, Aylin; Yoruk, Asim; Timur, Cetin

2014-01-01

Trombosis is seen in children with acute lymphoblastic leukemia during or after L-asparaginase treatment. Posterior reversible encephalopathy syndrome (PRES) is a complex syndrome characterized with sudden hypertension, headache, nausea, vomiting, alteration in the state of consciousness, vision defect and seizures. The cases related to this syndrome have been reportedly seen after eclampsia, organ transplantation, immunsuppressive treatments, autoimmune diseases and chemotherapy. Vasogenic edema occuring in the brain parencyhma constitues the basic pathophysiology. We present a case who developed seizures during treatment for B-cell acute lymphoblastic leukemia and diagnosed as posterior reversible encephalopathy. PMID:28058302

A trombosis story and PRES.

PubMed

Kartal, Vural; Zara, Zeynep; Yilmaz, Sema; Ayhan, Aylin; Yoruk, Asim; Timur, Cetin

2014-01-01

Trombosis is seen in children with acute lymphoblastic leukemia during or after L-asparaginase treatment. Posterior reversible encephalopathy syndrome (PRES) is a complex syndrome characterized with sudden hypertension, headache, nausea, vomiting, alteration in the state of consciousness, vision defect and seizures. The cases related to this syndrome have been reportedly seen after eclampsia, organ transplantation, immunsuppressive treatments, autoimmune diseases and chemotherapy. Vasogenic edema occuring in the brain parencyhma constitues the basic pathophysiology. We present a case who developed seizures during treatment for B-cell acute lymphoblastic leukemia and diagnosed as posterior reversible encephalopathy.

[New pharmacological activities of garlic and its constituents].

PubMed

Sumiyoshi, H

1997-10-01

According to the recent pharmacological findings, garlic is a preventive rather than therapeutic. Epidemiological studies in China, Italy and USA showed the inverse relationship between stomach and colon cancer incidences and dietary garlic intake. Anti-carcinogenic activities of garlic and its constituents including sulfides and S-allyl cysteine, have been demonstrated using several animal models. Garlic preparations has been also shown to lower serum cholesterol and triglyceride levels, which are major risk factors of cardiovascular diseases, through inhibition of their bio-synthesis in the liver, and to inhibit oxidation of low density lipoprotein. Furthermore, in vitro and in vivo studies have revealed that aged garlic extract stimulated immune functions, such as proliferation of lymphocyte, cytokine release, NK activity and phagocytosis. More recently, aged garlic extract has been demonstrated to prolong life span of senescence accelerated mice and prevent brain atrophy. Manufacturing processes significantly affect chemical constituents in garlic preparations. Different forms contain different phytochemicals and may have different effects and toxicities. For example, aged garlic extract inhibited t-BuOOH-induced oxidation, whereas raw garlic stimulated the oxidation. Although garlic has been used as a condiment and folklore for a long time, it has been noted to cause adverse reactions, such as stomach ulcer and anemia. Among the garlic preparations, only aged garlic extract has been proven to be safe through toxicological studies. Thus, aged garlic extract could be the most promising garlic preparation for disease prevention.

Concepts and strategies for clinical management of blast-induced traumatic brain injury and posttraumatic stress disorder.

PubMed

Chen, Yun; Huang, Wei; Constantini, Shlomi

2013-01-01

After exposure of the human body to blast, kinetic energy of the blast shock waves might be transferred into hydraulic energy in the cardiovascular system to cause a rapid physical movement or displacement of blood (a volumetric blood surge). The volumetric blood surge moves through blood vessels from the high-pressure body cavity to the low-pressure cranial cavity, causing damage to tiny cerebral blood vessels and the blood-brain barrier (BBB). Large-scale cerebrovascular insults and BBB damage that occur globally throughout the brain may be the main causes of non-impact, blast-induced brain injuries, including the spectrum of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD). The volumetric blood surge may be a major contributor not only to blast-induced brain injuries resulting from physical trauma, but may also be the trigger to psychiatric disorders resulting from emotional and psychological trauma. Clinical imaging technologies, which are able to detect tiny cerebrovascular insults, changes in blood flow, and cerebral edema, may help diagnose both TBI and PTSD in the victims exposed to blasts. Potentially, prompt medical treatment aiming at prevention of secondary neuronal damage may slow down or even block the cascade of events that lead to progressive neuronal damage and subsequent long-term neurological and psychiatric impairment.

Gut Microbiota Dysfunction as Reliable Non-invasive Early Diagnostic Biomarkers in the Pathophysiology of Parkinson’s Disease: A Critical Review

PubMed Central

Nair, Arun T; Ramachandran, Vadivelan; Joghee, Nanjan M; Antony, Shanish; Ramalingam, Gopalakrishnan

2018-01-01

Recent investigations suggest that gut microbiota affects the brain activity through the microbiota-gut-brain axis under both physiological and pathological disease conditions like Parkinson’s disease. Further dopamine synthesis in the brain is induced by dopamine producing enzymes that are controlled by gut microbiota via the microbiota-gut-brain axis. Also alpha synuclein deposition and the associated neurodegeneration in the enteric nervous system that increase intestinal permeability, oxidative stress, and local inflammation, accounts for constipation in Parkinson’s disease patients. The trigger that causes blood brain barrier leakage, immune cell activation and inflammation, and ultimately neuroinflammation in the central nervous system is believed to be due to the chronic low-grade inflammation in the gut. The non-motor symptoms that appear years before motor symptoms could be reliable early biomarkers, if they could be correlated with the established and reliable neuroimaging techniques or behavioral indices. The future directions should therefore, focus on the exploration of newer investigational techniques to identify these reliable early biomarkers and define the specific gut microbes that contribute to the development of Parkinson’s disease. This ultimately should pave the way to safer and novel therapeutic approaches that avoid the complications of the drugs delivered today to the brain of Parkinson’s disease patients. PMID:29291606

Anti-high mobility group box-1 antibody therapy for traumatic brain injury.

PubMed

Okuma, Yu; Liu, Keyue; Wake, Hidenori; Zhang, Jiyong; Maruo, Tomoko; Date, Isao; Yoshino, Tadashi; Ohtsuka, Aiji; Otani, Naoki; Tomura, Satoshi; Shima, Katsuji; Yamamoto, Yasuhiko; Yamamoto, Hiroshi; Takahashi, Hideo K; Mori, Shuji; Nishibori, Masahiro

2012-09-01

High mobility group box-1 (HMGB1) plays an important role in triggering inflammatory responses in many types of diseases. In this study, we examined the involvement of HMGB1 in traumatic brain injury (TBI) and evaluated the ability of intravenously administered neutralizing anti-HMGB1 monoclonal antibody (mAb) to attenuate brain injury. Traumatic brain injury was induced in rats or mice by fluid percussion. Anti-HMGB1 mAb or control mAb was administered intravenously after TBI. Anti-HMGB1 mAb remarkably inhibited fluid percussion-induced brain edema in rats, as detected by T2-weighted magnetic resonance imaging; this was associated with inhibition of HMGB1 translocation, protection of blood-brain barrier (BBB) integrity, suppression of inflammatory molecule expression, and improvement of motor function. In contrast, intravenous injection of recombinant HMGB1 dose-dependently produced the opposite effects. Experiments using receptor for advanced glycation end product (RAGE)(-/-) , toll-like receptor-4 (TLR4)(-/-) , and TLR2(-/-) mice suggested the involvement of RAGE as the predominant receptor for HMGB1. Anti-HMGB1 mAb may provide a novel and effective therapy for TBI by protecting against BBB disruption and reducing the inflammatory responses induced by HMGB1. Copyright © 2012 American Neurological Association.

Altered blood-brain barrier permeability in rats with prehepatic portal hypertension turns to normal when portal pressure is lowered

PubMed Central

Eizayaga, Francisco; Scorticati, Camila; Prestifilippo, Juan P; Romay, Salvador; Fernandez, Maria A; Castro, José L; Lemberg, Abraham; Perazzo, Juan C

2006-01-01

AIM: To study the blood-brain barrier integrity in prehepatic portal hypertensive rats induced by partial portal vein ligation, at 14 and 40 d after ligation when portal pressure is spontaneously normalized. METHODS: Adult male Wistar rats were divided into four groups: Group I: Sham14d , sham operated; Group II: PH14d , portal vein stenosis; (both groups were used 14 days after surgery); Group III: Sham40d, Sham operated and Group IV: PH40d Portal vein stenosis (Groups II and IV used 40 d after surgery). Plasma ammonia, plasma and cerebrospinal fluid protein and liver enzymes concentrations were determined. Trypan and Evans blue dyes, systemically injected, were investigated in hippocampus to study blood-brain barrier integrity. Portal pressure was periodically recorded. RESULTS: Forty days after stricture, portal pressure was normalized, plasma ammonia was moderately high, and both dyes were absent in central nervous system parenchyma. All other parameters were reestablished. When portal pressure was normalized and ammonia level was lowered, but not normal, the altered integrity of blood-brain barrier becomes reestablished. CONCLUSION: The impairment of blood-brain barrier and subsequent normalization could be a mechanism involved in hepatic encephalopathy reversibility. Hemodynamic changes and ammonia could trigger blood-brain barrier alterations and its reestablishment. PMID:16552803

Pathophysiology and neuroprotection of global and focal perinatal brain injury: lessons from animal models

PubMed Central

Manganozzi, Lucilla; Moretti, Raffaella; Vexler, Zinaida S.; Gressens, Pierre

2016-01-01

BACKGROUND Arterial ischemic stroke occurs most frequently in term newborns than in the elderly, and brain immaturity affects mechanisms of ischemic injury and recovery. The susceptibility to injury of the brain was assumed to be lower in the perinatal period as compared to childhood. This concept was recently challenged by clinical studies showing marked motor disabilities after stroke in neonates, with the severity of motor and cortical sensory deficits similar in both perinatal and childhood ischemic stroke. The understanding of the triggers and the pathophysiological mechanisms of perinatal stroke has greatly improved in recent years, but many aspects remain still unclear. METHODS In this review, we will focus on the pathophysiology of perinatal stroke and on therapeutic strategies that can protect the immature brain from the consequences of stroke by targeting inflammation and brain microenvironment. RESULTS Studies in neonatal rodent models of cerebral ischemia have shown a potential role for soluble inflammatory molecules as important modulators of injury and recovery. A great effort has been made and is still in act to try neuroprotective molecules based on the new physiopatological acquisition. CONCLUSION In this review we aim to give a comprehensive view of new insights concerning pathophysiological mechanism of focal and global perinatal brain injury and its new therapeutic approaches. PMID:26002050

Blocking Lymphocyte Trafficking with FTY720 Prevents Inflammation-Sensitized Hypoxic–Ischemic Brain Injury in Newborns

PubMed Central

Yang, Dianer; Sun, Yu-Yo; Bhaumik, Siddhartha Kumar; Li, Yikun; Baumann, Jessica M.; Lin, Xiaoyi; Zhang, Yujin; Lin, Shang-Hsuan; Dunn, R. Scott; Liu, Chia-Yang; Shie, Feng-Shiun; Lee, Yi-Hsuan; Wills-Karp, Marsha; Chougnet, Claire A.; Kallapur, Suhas G.; Lewkowich, Ian P.; Lindquist, Diana M.; Murali-Krishna, Kaja

2014-01-01

Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic–ischemic (HI) brain injury, but the mechanisms linking systemic inflammation to the CNS damage remain uncertain. Here we report evidence for brain influx of T-helper 17 (TH17)-like lymphocytes to coordinate neuroinflammatory responses in lipopolysaccharide (LPS)-sensitized HI injury in neonates. We found that both infants with histological chorioamnionitis and rat pups challenged by LPS/HI have elevated expression of the interleukin-23 (IL-23) receptor, a marker of early TH17 lymphocytes, in the peripheral blood mononuclear cells. Post-LPS/HI administration of FTY720 (fingolimod), a sphingosine-1-phosphate receptor agonist that blocks lymphocyte trafficking, mitigated the influx of leukocytes through the choroid plexus and acute induction of nuclear factor-κB signaling in the brain. Subsequently, the FTY720 treatment led to attenuated blood–brain barrier damage, fewer cluster of differentiation 4-positive, IL-17A-positive T-cells in the brain, less proinflammatory cytokine, and better preservation of growth and white matter functions. The FTY720 treatment also provided dose-dependent reduction of brain atrophy, rescuing >90% of LPS/HI-induced brain tissue loss. Interestingly, FTY720 neither opposed pure-HI brain injury nor directly inhibited microglia in both in vivo and in vitro models, highlighting its unique mechanism against inflammation-sensitized HI injury. Together, these results suggest that the dual hit of systemic inflammation and neonatal HI injury triggers early onset of the TH17/IL-17-mediated immunity, which causes severe brain destruction but responds remarkably to the therapeutic blockade of lymphocyte trafficking. PMID:25471584

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus.

PubMed

Varvel, Nicholas H; Neher, Jonas J; Bosch, Andrea; Wang, Wenyi; Ransohoff, Richard M; Miller, Richard J; Dingledine, Raymond

2016-09-20

The generalized seizures of status epilepticus (SE) trigger a series of molecular and cellular events that produce cognitive deficits and can culminate in the development of epilepsy. Known early events include opening of the blood-brain barrier (BBB) and astrocytosis accompanied by activation of brain microglia. Whereas circulating monocytes do not infiltrate the healthy CNS, monocytes can enter the brain in response to injury and contribute to the immune response. We examined the cellular components of innate immune inflammation in the days following SE by discriminating microglia vs. brain-infiltrating monocytes. Chemokine receptor 2 (CCR2(+)) monocytes invade the hippocampus between 1 and 3 d after SE. In contrast, only an occasional CD3(+) T lymphocyte was encountered 3 d after SE. The initial cellular sources of the chemokine CCL2, a ligand for CCR2, included perivascular macrophages and microglia. The induction of the proinflammatory cytokine IL-1β was greater in FACS-isolated microglia than in brain-invading monocytes. However, Ccr2 knockout mice displayed greatly reduced monocyte recruitment into brain and reduced levels of the proinflammatory cytokine IL-1β in hippocampus after SE, which was explained by higher expression of the cytokine in circulating and brain monocytes in wild-type mice. Importantly, preventing monocyte recruitment accelerated weight regain, reduced BBB degradation, and attenuated neuronal damage. Our findings identify brain-infiltrating monocytes as a myeloid-cell subclass that contributes to neuroinflammation and morbidity after SE. Inhibiting brain invasion of CCR2(+) monocytes could represent a viable method for alleviating the deleterious consequences of SE.

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

PubMed Central

Varvel, Nicholas H.; Neher, Jonas J.; Bosch, Andrea; Wang, Wenyi; Ransohoff, Richard M.; Miller, Richard J.; Dingledine, Raymond

2016-01-01

The generalized seizures of status epilepticus (SE) trigger a series of molecular and cellular events that produce cognitive deficits and can culminate in the development of epilepsy. Known early events include opening of the blood–brain barrier (BBB) and astrocytosis accompanied by activation of brain microglia. Whereas circulating monocytes do not infiltrate the healthy CNS, monocytes can enter the brain in response to injury and contribute to the immune response. We examined the cellular components of innate immune inflammation in the days following SE by discriminating microglia vs. brain-infiltrating monocytes. Chemokine receptor 2 (CCR2+) monocytes invade the hippocampus between 1 and 3 d after SE. In contrast, only an occasional CD3+ T lymphocyte was encountered 3 d after SE. The initial cellular sources of the chemokine CCL2, a ligand for CCR2, included perivascular macrophages and microglia. The induction of the proinflammatory cytokine IL-1β was greater in FACS-isolated microglia than in brain-invading monocytes. However, Ccr2 knockout mice displayed greatly reduced monocyte recruitment into brain and reduced levels of the proinflammatory cytokine IL-1β in hippocampus after SE, which was explained by higher expression of the cytokine in circulating and brain monocytes in wild-type mice. Importantly, preventing monocyte recruitment accelerated weight regain, reduced BBB degradation, and attenuated neuronal damage. Our findings identify brain-infiltrating monocytes as a myeloid-cell subclass that contributes to neuroinflammation and morbidity after SE. Inhibiting brain invasion of CCR2+ monocytes could represent a viable method for alleviating the deleterious consequences of SE. PMID:27601660

Caffeine Augments Anesthesia Neurotoxicity in the Fetal Macaque Brain.

PubMed

Noguchi, Kevin K; Johnson, Stephen A; Manzella, Francesca M; Masuoka, Kobe L; Williams, Sasha L; Martin, Lauren D; Dissen, Gregory A; Ikonomidou, Chrysanthy; Schenning, Katie J; Olney, John W; Brambrink, Ansgar M

2018-03-28

Caffeine is the most frequently used medication in premature infants. It is the respiratory stimulant of choice for apnea associated with prematurity and has been called the silver bullet in neonatology because of many proven benefits and few known risks. Research has revealed that sedative/anesthetic drugs trigger apoptotic death of neurons and oligodendrocytes in developing mammalian brains. Here we evaluated the influence of caffeine on the neurotoxicity of anesthesia in developing nonhuman primate brains. Fetal macaques (n = 7-8/group), at a neurodevelopmental age comparable to premature human infants, were exposed in utero for 5 hours to no drug (control), isoflurane, or isoflurane + caffeine and examined for evidence of apoptosis. Isoflurane exposure increased apoptosis 3.3 fold for neurons and 3.4 fold for oligodendrocytes compared to control brains. Isoflurane + caffeine caused neuronal apoptosis to increase 8.0 fold compared to control levels but did not augment oligoapoptosis. Neuronal death was particularly pronounced in the basal ganglia and cerebellum. Higher blood levels of caffeine within the range considered therapeutic and safe for human infants correlated with increased neuroapoptosis. Caffeine markedly augments neurotoxicity of isoflurane in the fetal macaque brain and challenges the assumption that caffeine is safe for premature infants.

The Case for Musical Instrument Training in Cerebral Palsy for Neurorehabilitation

PubMed Central

2016-01-01

Recent imaging studies in cerebral palsy (CP) have described several brain structural changes, functional alterations, and neuroplastic processes that take place after brain injury during early development. These changes affect motor pathways as well as sensorimotor networks. Several of these changes correlate with behavioral measures of motor and sensory disability. It is now widely acknowledged that management of sensory deficits is relevant for rehabilitation in CP. Playing a musical instrument demands the coordination of hand movements with integrated auditory, visual, and tactile feedback, in a process that recruits multiple brain regions. These multiple demands during instrument playing, together with the entertaining character of music, have led to the development and investigation of music-supported therapies, especially for rehabilitation with motor disorders resulting from brain damage. We review scientific evidence that supports the use of musical instrument playing for rehabilitation in CP. We propose that active musical instrument playing may be an efficient means for triggering neuroplastic processes necessary for the development of sensorimotor skills in patients with early brain damage. We encourage experimental research on neuroplasticity and on its impact on the physical and personal development of individuals with CP. PMID:27867664

Traumatic Brain Injury: At the Crossroads of Neuropathology and Common Metabolic Endocrinopathies

PubMed Central

Li, Melanie

2018-01-01

Building on the seminal work by Geoffrey Harris in the 1970s, the neuroendocrinology field, having undergone spectacular growth, has endeavored to understand the mechanisms of hormonal connectivity between the brain and the rest of the body. Given the fundamental role of the brain in the orchestration of endocrine processes through interactions among neurohormones, it is thus not surprising that the structural and/or functional alterations following traumatic brain injury (TBI) can lead to endocrine changes affecting the whole organism. Taking into account that systemic hormones also act on the brain, modifying its structure and biochemistry, and can acutely and chronically affect several neurophysiological endpoints, the question is to what extent preexisting endocrine dysfunction may set the stage for an adverse outcome after TBI. In this review, we provide an overview of some aspects of three common metabolic endocrinopathies, e.g., diabetes mellitus, obesity, and thyroid dysfunction, and how these could be triggered by TBI. In addition, we discuss how the complex endocrine networks are woven into the responses to sudden changes after TBI, as well as some of the potential mechanisms that, separately or synergistically, can influence outcomes after TBI. PMID:29538298

Evidence of CCR2-independent transmigration of Ly6C(hi) monocytes into the brain after permanent cerebral ischemia in mice.

PubMed

Chu, Hannah X; Kim, Hyun Ah; Lee, Seyoung; Broughton, Brad R S; Drummond, Grant R; Sobey, Christopher G

2016-04-15

Previously we showed that INCB3344, a CCR2 antagonist, inhibits transmigration of Ly6C(hi) monocytes into the brain after ischemia-reperfusion. Here we tested the effect of CCR2 inhibition during permanent cerebral ischemia. Mice were administered either vehicle (dimethyl sulfoxide/carboxymethylcellulose) or INCB3344 (30 or 100mg/kg IP) 1h before middle cerebral artery occlusion and at 2 and 6h after the initiation of ischemia. After 24h, we assessed functional outcome, infarct volume and quantified immune cells in blood and brain. The increase in circulating bone marrow-derived Ly6C(hi) monocytes, but not the infiltration of those cells into the brain, was blocked by the CCR2 antagonist. INCB3344 had no effect on either neurological deficit or infarct volume. Our data confirm that cerebral ischemia triggers a CCR2-dependent increase in circulating Ly6C(hi) monocytes, but suggest that in the absence of reperfusion these cells may transmigrate into the ischemic brain in a CCR2-independent manner. Copyright © 2016 Elsevier B.V. All rights reserved.

Designing and testing a wearable, wireless fNIRS patch.

PubMed

Abtahi, Mohammadreza; Cay, Gozde; Saikia, Manob Jyoti; Mankodiya, Kunal

2016-08-01

Optical brain monitoring using near infrared (NIR) light has got a lot of attention in order to study the complexity of the brain due to several advantages as oppose to other methods such as EEG, fMRI and PET. There are a few commercially available functional NIR spectroscopy (fNIRS) brain monitoring systems, but they are still non-wearable and pose difficulties in scanning the brain while the participants are in motion. In this work, we present our endeavors to design and test a low-cost, wireless fNIRS patch using NIR light sources at wavelengths of 770 and 830nm, photodetectors and a microcontroller to trigger the light sources, read photodetector's output and transfer data wirelessly (via Bluetooth) to a smart-phone. The patch is essentially a 3-D printed wearable system, recording and displaying the brain hemodynamic responses on smartphone, also eliminates the need for complicated wiring of the electrodes. We have performed rigorous lab experiments on the presented system for its functionality. In a proof of concept experiment, the patch detected the NIR absorption on the arm. Another experiment revealed that the patch's battery could last up to several hours with continuous fNIRS recording with and without wireless data transfer.

Characterization of impaired processing of neuropeptides in the brains of endoprotease knockout mice.

PubMed

Beinfeld, Margery C

2011-01-01

With the development of mice in which individual proteolytic enzymes have been inactivated, it has been of great interest to see how loss of these enzymes alters the processing of neuropeptides. In the course of studying changes in the peptide cholecystokinin (CCK) and other neuropeptides in several of these knockout mice, it has become clear that neuropeptide processing is complex and regionally specific. The enzyme responsible for processing in one part of the brain may not be involved in other parts of the brain. It is essential to do a detailed dissection of the brain and analyze peptide levels in many brain regions to fully understand the role of the enzymes. Because loss of these proteases may trigger compensatory mechanisms which involve expression of the neuropeptides being studied or other proteases or accessory proteins, it is also important to examine how loss of an enzyme alters expression of the neuropeptides being studied as well as other proteins thought to be involved in neuropeptide processing. By determining how loss of an enzyme alters the molecular form(s) of the peptide that are made, additional mechanistic information can be obtained. This review will describe established methods to achieve these research goals.

The Case for Musical Instrument Training in Cerebral Palsy for Neurorehabilitation.

PubMed

Alves-Pinto, Ana; Turova, Varvara; Blumenstein, Tobias; Lampe, Renée

2016-01-01

Recent imaging studies in cerebral palsy (CP) have described several brain structural changes, functional alterations, and neuroplastic processes that take place after brain injury during early development. These changes affect motor pathways as well as sensorimotor networks. Several of these changes correlate with behavioral measures of motor and sensory disability. It is now widely acknowledged that management of sensory deficits is relevant for rehabilitation in CP. Playing a musical instrument demands the coordination of hand movements with integrated auditory, visual, and tactile feedback, in a process that recruits multiple brain regions. These multiple demands during instrument playing, together with the entertaining character of music, have led to the development and investigation of music-supported therapies, especially for rehabilitation with motor disorders resulting from brain damage. We review scientific evidence that supports the use of musical instrument playing for rehabilitation in CP. We propose that active musical instrument playing may be an efficient means for triggering neuroplastic processes necessary for the development of sensorimotor skills in patients with early brain damage. We encourage experimental research on neuroplasticity and on its impact on the physical and personal development of individuals with CP.

Variability of perceptual multistability: from brain state to individual trait

PubMed Central

Kleinschmidt, Andreas; Sterzer, Philipp; Rees, Geraint

2012-01-01

Few phenomena are as suitable as perceptual multistability to demonstrate that the brain constructively interprets sensory input. Several studies have outlined the neural circuitry involved in generating perceptual inference but only more recently has the individual variability of this inferential process been appreciated. Studies of the interaction of evoked and ongoing neural activity show that inference itself is not merely a stimulus-triggered process but is related to the context of the current brain state into which the processing of external stimulation is embedded. As brain states fluctuate, so does perception of a given sensory input. In multistability, perceptual fluctuation rates are consistent for a given individual but vary considerably between individuals. There has been some evidence for a genetic basis for these individual differences and recent morphometric studies of parietal lobe regions have identified neuroanatomical substrates for individual variability in spontaneous switching behaviour. Moreover, disrupting the function of these latter regions by transcranial magnetic stimulation yields systematic interference effects on switching behaviour, further arguing for a causal role of these regions in perceptual inference. Together, these studies have advanced our understanding of the biological mechanisms by which the brain constructs the contents of consciousness from sensory input. PMID:22371620

Programmable Self-Locking Origami Mechanical Metamaterials.

PubMed

Fang, Hongbin; Chu, Shih-Cheng A; Xia, Yutong; Wang, Kon-Well

2018-04-01

Developing mechanical metamaterials with programmable properties is an emerging topic receiving wide attention. While the programmability mainly originates from structural multistability in previously designed metamaterials, here it is shown that nonflat-foldable origami provides a new platform to achieve programmability via its intrinsic self-locking and reconfiguration capabilities. Working with the single-collinear degree-4 vertex origami tessellation, it is found that each unit cell can self-lock at a nonflat configuration and, therefore, possesses wide design space to program its foldability and relative density. Experiments and numerical analyses are combined to demonstrate that by switching the deformation modes of the constituent cell from prelocking folding to postlocking pressing, its stiffness experiences a sudden jump, implying a limiting-stopper effect. Such a stiffness jump is generalized to a multisegment piecewise stiffness profile in a multilayer model. Furthermore, it is revealed that via strategically switching the constituent cells' deformation modes through passive or active means, the n-layer metamaterial's stiffness is controllable among 2 n target stiffness values. Additionally, the piecewise stiffness can also trigger bistable responses dynamically under harmonic excitations, highlighting the metamaterial's rich dynamic performance. These unique characteristics of self-locking origami present new paths for creating programmable mechanical metamaterials with in situ controllable mechanical properties. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of fisetin on hyperhomocysteinemia-induced experimental endothelial dysfunction and vascular dementia.

PubMed

Hemanth Kumar, Boyina; Arun Reddy, Ravula; Mahesh Kumar, Jerald; Dinesh Kumar, B; Diwan, Prakash V

2017-01-01

This study was designed to investigate the effects of fisetin (FST) on hyperhomocysteinemia (HHcy)-induced experimental endothelial dysfunction (ED) and vascular dementia (VaD) in rats. Wistar rats were randomly divided into 8 groups: control, vehicle control, l-methionine, FST (5, 10, and 25 mg/kg, p.o.), FST-per se (25 mg/kg, p.o.), and donepezil (0.1 mg/kg, p.o.). l-Methionine administration (1.7 g/kg, p.o.) for 32 days induced HHcy. ED and VaD induced by HHcy were determined by vascular reactivity measurements, behavioral analysis using Morris water maze and Y-maze, along with a biochemical and histological evaluation of thoracic aorta and brain tissues. Administration of l-methionine developed behavioral deficits; triggered brain lipid peroxidation (LPO); compromised brain acetylcholinesterase activity (AChE); and reduced the levels of brain superoxide dismutase (SOD), brain catalase (CAT), brain reduced glutathione (GSH), and serum nitrite; and increased serum homocysteine and cholesterol levels. These effects were accompanied by decreased vascular NO bioavailability, marked intimal thickening of the aorta, and multiple necrotic foci in brain cortex. HHcy-induced alterations in the activities of SOD, CAT, GSH, AChE, LPO, behavioral deficits, ED, and histological aberrations were significantly attenuated by treatment with fisetin in a dose-dependent manner. Collectively, our results indicate that fisetin exerts endothelial and neuroprotective effects against HHcy-induced ED and VaD.

Epileptic rat brain tissue analyzed by 2D correlation Raman spectroscopy

NASA Astrophysics Data System (ADS)

Sacharz, Julia; Wesełucha-Birczyńska, Aleksandra; Zięba-Palus, Janina; Lewandowski, Marian H.; Kowalski, Rafał; Palus, Katarzyna; Chrobok, Łukasz; Moskal, Paulina; Birczyńska, Malwina; Sozańska, Agnieszka

2018-01-01

Absence epilepsy is the neurological disorder characterized by the pathological spike-and wave discharges present in the electroencephalogram, accompanying a sudden loss of consciousness. Experiments were performed on brain slices obtained from young male WAG/Rij rats (2-3 weeks old), so that they were sampled before the appearance of brain-damaging seizures symptoms. Two differing brain areas of the rats' brain tissue were studied: the somatosensory cortex (Sc) and the dorsal lateral geniculate nucleus of the thalamus (DLG). The Raman spectra of the fresh brain scraps, kept during measurements in artificial cerebrospinal fluid, were collected using as an excitation source 442 nm, 514.5 nm, 785 nm and 1064 nm laser line. The average spectra were analyzed by 2D correlation method regarding laser line as an external perturbation. In 2D synchronous spectra positive auto-peaks corresponding to the Cdbnd C stretching and amide I band vibrations show maxima at 1660 cm- 1 and 1662 cm- 1 for Sc and DLG, respectively. The prominent auto-peak at 2937 cm- 1, originated from the CH3 mode in DLG brain area, seems to indicate the importance of methylation, considered to be significant in epileptogenesis. Synchronous and asynchronous correlations peaks, glutamic acid and gamma-aminobutyric acid (GABA), appear in Sc and DLG, respectively. In the 1730-1600 cm- 1 range occur cross-peaks which appearance might be triggered by glial fibrillary acidic protein (GFAP) activation.

Automatic processing of political preferences in the human brain.

PubMed

Tusche, Anita; Kahnt, Thorsten; Wisniewski, David; Haynes, John-Dylan

2013-05-15

Individual political preferences as expressed, for instance, in votes or donations are fundamental to democratic societies. However, the relevance of deliberative processing for political preferences has been highly debated, putting automatic processes in the focus of attention. Based on this notion, the present study tested whether brain responses reflect participants' preferences for politicians and their associated political parties in the absence of explicit deliberation and attention. Participants were instructed to perform a demanding visual fixation task while their brain responses were measured using fMRI. Occasionally, task-irrelevant images of German politicians from two major competing parties were presented in the background while the distraction task was continued. Subsequent to scanning, participants' political preferences for these politicians and their affiliated parties were obtained. Brain responses in distinct brain areas predicted automatic political preferences at the different levels of abstraction: activation in the ventral striatum was positively correlated with preference ranks for unattended politicians, whereas participants' preferences for the affiliated political parties were reflected in activity in the insula and the cingulate cortex. Using an additional donation task, we showed that the automatic preference-related processing in the brain extended to real-world behavior that involved actual financial loss to participants. Together, these findings indicate that brain responses triggered by unattended and task-irrelevant political images reflect individual political preferences at different levels of abstraction. Copyright © 2013 Elsevier Inc. All rights reserved.

Vascular signaling abnormalities in Alzheimer disease.

PubMed

Grammas, Paula; Sanchez, Alma; Tripathy, Debjani; Luo, Ester; Martinez, Joseph

2011-08-01

Our laboratory has documented that brain microvessels derived from patients with Alzheimer disease (AD) express or release a myriad of factors that have been implicated in vascular activation and angiogenesis. In addition, we have documented that signaling cascades associated with vascular activation and angiogenesis are upregulated in AD-derived brain microvessels. These results are consistent with emerging data suggesting that factors and processes characteristic of vascular activation and angiogenesis are found in the AD brain. Despite increases in proangiogenic factors and signals in the AD brain, however, evidence for increased vascularity in AD is lacking. Cerebral hypoperfusion/hypoxia, a potent stimulus for vascular activation and angiogenesis, triggers hypometabolic, cognitive, and degenerative changes in the brain. In our working model, hypoxia stimulates the angiogenic process; yet, there is no new vessel growth. Therefore, there are no feedback signals to shut off vascular activation, and endothelial cells become irreversibly activated. This activation results in release of a large number of proteases, inflammatory proteins, and other gene products with biologic activity that can injure or kill neurons. Pathologic activation of brain vasculature may contribute noxious mediators that lead to neuronal injury and disease processes in AD brains. This concept is supported by preliminary experiments in our laboratory, which show that pharmacologic blockade of vascular activation improves cognitive function in an animal model of AD. Thus, "vascular activation" could be a novel, unexplored therapeutic target in AD.

Acupuncture inhibits cue-induced heroin craving and brain activation★

PubMed Central

Cai, Xinghui; Song, Xiaoge; Li, Chuanfu; Xu, Chunsheng; Li, Xiliang; Lu, Qi

2012-01-01

Previous research using functional MRI has shown that specific brain regions associated with drug dependence and cue-elicited heroin craving are activated by environmental cues. Craving is an important trigger of heroin relapse, and acupuncture may inhibit craving. In this study, we performed functional MRI in heroin addicts and control subjects. We compared differences in brain activation between the two groups during heroin cue exposure, heroin cue exposure plus acupuncture at the Zusanli point (ST36) without twirling of the needle, and heroin cue exposure plus acupuncture at the Zusanli point with twirling of the needle. Heroin cue exposure elicited significant activation in craving-related brain regions mainly in the frontal lobes and callosal gyri. Acupuncture without twirling did not significantly affect the range of brain activation induced by heroin cue exposure, but significantly changed the extent of the activation in the heroin addicts group. Acupuncture at the Zusanli point with twirling of the needle significantly decreased both the range and extent of activation induced by heroin cue exposure compared with heroin cue exposure plus acupuncture without twirling of the needle. These experimental findings indicate that presentation of heroin cues can induce activation in craving-related brain regions, which are involved in reward, learning and memory, cognition and emotion. Acupuncture at the Zusanli point can rapidly suppress the activation of specific brain regions related to craving, supporting its potential as an intervention for drug craving. PMID:25368637

Acupuncture inhibits cue-induced heroin craving and brain activation.

PubMed

Cai, Xinghui; Song, Xiaoge; Li, Chuanfu; Xu, Chunsheng; Li, Xiliang; Lu, Qi

2012-11-25

Previous research using functional MRI has shown that specific brain regions associated with drug dependence and cue-elicited heroin craving are activated by environmental cues. Craving is an important trigger of heroin relapse, and acupuncture may inhibit craving. In this study, we performed functional MRI in heroin addicts and control subjects. We compared differences in brain activation between the two groups during heroin cue exposure, heroin cue exposure plus acupuncture at the Zusanli point (ST36) without twirling of the needle, and heroin cue exposure plus acupuncture at the Zusanli point with twirling of the needle. Heroin cue exposure elicited significant activation in craving-related brain regions mainly in the frontal lobes and callosal gyri. Acupuncture without twirling did not significantly affect the range of brain activation induced by heroin cue exposure, but significantly changed the extent of the activation in the heroin addicts group. Acupuncture at the Zusanli point with twirling of the needle significantly decreased both the range and extent of activation induced by heroin cue exposure compared with heroin cue exposure plus acupuncture without twirling of the needle. These experimental findings indicate that presentation of heroin cues can induce activation in craving-related brain regions, which are involved in reward, learning and memory, cognition and emotion. Acupuncture at the Zusanli point can rapidly suppress the activation of specific brain regions related to craving, supporting its potential as an intervention for drug craving.

Splicing factor NSSR1 reduces neuronal injury after mouse transient global cerebral ischemia.

PubMed

Qi, Yao; Li, Ya; Cui, Shi-Chao; Zhao, Jing-Jing; Liu, Xiao-Yan; Ji, Chun-Xia; Sun, Feng-Yan; Xu, Ping; Chen, Xian-Hua

2015-05-01

This study focuses on the function of NSSR1, a splicing factor, in neuronal injury in the ischemic mouse brain using the transient global cerebral ischemic mouse model and the cultured cells treated with oxygen-glucose deprivation (OGD). The results showed that the cerebral ischemia triggers the expression of NSSR1 in hippocampal astrocytes, predominantly the dephosphorylated NSSR1 proteins, and the Exon3 inclusive NCAM-L1 variant and the Exon4 inclusive CREB variant. While in the hippocampus of astrocyte-specific NSSR1 conditional knockdown (cKD) mice, where cerebral ischemia no longer triggers NSSR1 expression in astrocytes, the expression of Exon3 inclusive NCAM-L1 variant and Exon4 inclusive CREB variant were no longer triggered as well. In addition, the injury of hippocampal neurons was more severe in astrocyte-specific NSSR1 cKD mice compared with in wild-type mice after brain ischemia. Of note, the culture media harvested from the astrocytes with overexpression of NSSR1 or the Exon3 inclusive NCAM-L1 variant, or Exon4 inclusive CREB variant were all able to reduce the neuronal injury induced by OGD. The results provide the evidence demonstrating that: (1) Splicing factor NSSR1 is a new factor involved in reducing ischemic injury. (2) Ischemia induces NSSR1 expression in astrocytes, not in neurons. (3) NSSR1-mediated pathway in astrocytes is required for reducing ischemic neuronal injury. (4) NCAM-L1 and CREB are probably mediators in NSSR1-mediated pathway. In conclusion, our results suggest for the first time that NSSR1 may provide a novel mechanism for reducing neuronal injury after ischemia, probably through regulation on alternative splicing of NCAM-L1 and CREB in astrocytes. © 2014 Wiley Periodicals, Inc.

Oligomers of Amyloid β Prevent Physiological Activation of the Cellular Prion Protein-Metabotropic Glutamate Receptor 5 Complex by Glutamate in Alzheimer Disease.

PubMed

Haas, Laura T; Strittmatter, Stephen M

2016-08-12

The dysfunction and loss of synapses in Alzheimer disease are central to dementia symptoms. We have recently demonstrated that pathological Amyloid β oligomer (Aβo) regulates the association between intracellular protein mediators and the synaptic receptor complex composed of cellular prion protein (PrP(C)) and metabotropic glutamate receptor 5 (mGluR5). Here we sought to determine whether Aβo alters the physiological signaling of the PrP(C)-mGluR5 complex upon glutamate activation. We provide evidence that acute exposure to Aβo as well as chronic expression of familial Alzheimer disease mutant transgenes in model mice prevents protein-protein interaction changes of the complex induced by the glutamate analog 3,5-dihydroxyphenylglycine. We further show that 3,5-dihydroxyphenylglycine triggers the phosphorylation and activation of protein-tyrosine kinase 2-β (PTK2B, also referred to as Pyk2) and of calcium/calmodulin-dependent protein kinase II in wild-type brain slices but not in Alzheimer disease transgenic brain slices or wild-type slices incubated with Aβo. This study further distinguishes two separate Aβo-dependent signaling cascades, one dependent on extracellular Ca(2+) and Fyn kinase activation and the other dependent on the release of Ca(2+) from intracellular stores. Thus, Aβo triggers multiple distinct PrP(C)-mGluR5-dependent events implicated in neurodegeneration and dementia. We propose that targeting the PrP(C)-mGluR5 complex will reverse aberrant Aβo-triggered states of the complex to allow physiological fluctuations of glutamate signaling. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Low-level laser irradiation modulates brain-derived neurotrophic factor mRNA transcription through calcium-dependent activation of the ERK/CREB pathway.

PubMed

Yan, Xiaodong; Liu, Juanfang; Zhang, Zhengping; Li, Wenhao; Sun, Siguo; Zhao, Jian; Dong, Xin; Qian, Jixian; Sun, Honghui

2017-01-01

Low-level laser (LLL) irradiation has been reported to promote neuronal differentiation, but the mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) has been confirmed to be one of the most important neurotrophic factors because it is critical for the differentiation and survival of neurons during development. Thus, this study aimed to investigate the effects of LLL irradiation on Bdnf messenger RNA (mRNA) transcription and the molecular pathway involved in LLL-induced Bdnf mRNA transcription in cultured dorsal root ganglion neurons (DRGNs) using Ca 2+ imaging, pharmacological detections, RNA interference, immunocytochemistry assay, Western blot, and qPCR analysis. We show here that LLL induced increases in the [Ca 2+ ] i level, Bdnf mRNA transcription, cAMP-response element-binding protein (CREB) phosphorylation, and extracellular signal-regulated kinase (ERK) phosphorylation, mediated by Ca 2+ release via inositol triphosphate receptor (IP3R)-sensitive calcium (Ca 2+ ) stores. Blockade of Ca 2+ increase suppressed Bdnf mRNA transcription, CREB phosphorylation, and ERK phosphorylation. Downregulation of phosphorylated (p)-CREB reduced Bdnf mRNA transcription triggered by LLL. Furthermore, blockade of ERK using PD98059 inhibitor reduced p-CREB and Bdnf mRNA transcription induced by LLL. Taken together, these findings establish the Ca 2+ -ERK-CREB cascade as a potential signaling pathway involved in LLL-induced Bdnf mRNA transcription. To our knowledge, this is the first report of the mechanisms of Ca 2+ -dependent Bdnf mRNA transcription triggered by LLL. These findings may help further explore the complex molecular signaling networks in LLL-triggered nerve regeneration in vivo and may also provide experimental evidence for the development of LLL for clinical applications.

Source Reconstruction of Brain Potentials Using Bayesian Model Averaging to Analyze Face Intra-Domain vs. Face-Occupation Cross-Domain Processing.

PubMed

Olivares, Ela I; Lage-Castellanos, Agustín; Bobes, María A; Iglesias, Jaime

2018-01-01

We investigated the neural correlates of the access to and retrieval of face structure information in contrast to those concerning the access to and retrieval of person-related verbal information, triggered by faces. We experimentally induced stimulus familiarity via a systematic learning procedure including faces with and without associated verbal information. Then, we recorded event-related potentials (ERPs) in both intra-domain (face-feature) and cross-domain (face-occupation) matching tasks while N400-like responses were elicited by incorrect eyes-eyebrows completions and occupations, respectively. A novel Bayesian source reconstruction approach plus conjunction analysis of group effects revealed that in both cases the generated N170s were of similar amplitude but had different neural origin. Thus, whereas the N170 of faces was associated predominantly to right fusiform and occipital regions (the so-called "Fusiform Face Area", "FFA" and "Occipital Face Area", "OFA", respectively), the N170 of occupations was associated to a bilateral very posterior activity, suggestive of basic perceptual processes. Importantly, the right-sided perceptual P200 and the face-related N250 were evoked exclusively in the intra-domain task, with sources in OFA and extensively in the fusiform region, respectively. Regarding later latencies, the intra-domain N400 seemed to be generated in right posterior brain regions encompassing mainly OFA and, to some extent, the FFA, likely reflecting neural operations triggered by structural incongruities. In turn, the cross-domain N400 was related to more anterior left-sided fusiform and temporal inferior sources, paralleling those described previously for the classic verbal N400. These results support the existence of differentiated neural streams for face structure and person-related verbal processing triggered by faces, which can be activated differentially according to specific task demands.

CaMKII-dependent endoplasmic reticulum fission by whisker stimulation and during cortical spreading depolarization.

PubMed

Kucharz, Krzysztof; Lauritzen, Martin

2018-04-01

Cortical spreading depolarization waves, the cause underlying migraine aura, are also the markers and mechanism of pathology in the acutely injured human brain. Propagation of spreading depolarization wave uniquely depends on the interaction between presynaptic and postsynaptic glutamate N-methyl-d-aspartate receptors (NMDARs). In the normally perfused brain, even a single wave causes a massive depolarization of neurons and glia, which results in transient loss of neuronal function and depression of the ongoing electrocorticographic activity. Endoplasmic reticulum is the cellular organelle of particular importance for modulation of neurotransmission. Neuronal endoplasmic reticulum structure is assumed to be persistently continuous in neurons, but is rapidly lost within 1 to 2 min of global cerebral ischaemia, i.e. the organelle disintegrates by fission. This phenomenon appears to be timed with the cardiac arrest-induced cortical spreading depolarizations, rather than ensuing cell death. To what extent NMDAR-dependent processes may trigger neuronal endoplasmic reticulum fission and whether fission is reversible in the normally perfused brain is unknown. We used two-photon microscopy to examine neuronal endoplasmic reticulum structural dynamics during whisker stimulation and cortical spreading depolarizations in vivo. Somatosensory stimulation triggered loss of endoplasmic reticulum continuity, a likely outcome of constriction and fission, in dendritic spines within less than 10 s of stimulation, which was spontaneously reversible and recovery to normal took 5 min. The endoplasmic reticulum fission was inhibited by blockade of NMDAR and Ca2+/calmodulin-dependent protein kinase II (CaMKII) activated downstream of the NMDARs, whereas inhibition of guanosine triphosphate hydrolases hindered regain of endoplasmic reticulum continuity, i.e. fusion. In contrast to somatosensory stimulation, endoplasmic reticulum fission during spreading depolarization was widespread and present in dendrites and spines, and was preceded by dramatic rise in intracellular Ca2+. The endoplasmic reticulum fission during spreading depolarization was more persistent, as 1 h after the depolarization cortical neurons still exhibited loss of endoplasmic reticulum continuity. Notably, endoplasmic reticulum fission was accompanied with loss of electrocorticographic activity, whereas subsequent regain of synaptic function paralleled the organelle fusion. Furthermore, blocking CaMKII activity partly rescued endoplasmic reticulum fission and markedly shortened the recovery time of brain spontaneous activity. Thus, prevention of endoplasmic reticulum fission with CaMKII inhibitors may be a novel strategy to rescue brain function in patients with migraine and a promising therapeutic avenue in the acutely injured brain.

Cortical changes after mental imagery training combined with electromyography-triggered electrical stimulation in patients with chronic stroke.

PubMed

Hong, Il Ki; Choi, Jong Bae; Lee, Jong Ha

2012-09-01

Paresis of the upper extremity after stroke is not effectively solved by existing therapies. We investigated whether mental imagery training combined with electromyogram-triggered electric stimulation improved motor function of the paretic upper extremity in patients with chronic stroke and induced cortical changes. Fourteen subjects with chronic stroke (≥12 months) were randomly allocated to receive mental imagery training combined with electromyogram-triggered electric stimulation (n=7) or generalized functional electric stimulation (n=7) on the forearm extensor muscles of the paretic extremity in 2 20-minute daily sessions 5 days a week for 4 weeks. The upper extremity component of the Fugl-Meyer Motor Assessment, the Motor Activity Log, the modified Barthel Index, and (18)F-fluorodeoxyglucose brain positron emission tomography were measured before and after the intervention. The group receiving mental imagery training combined with electromyogram-triggered electric stimulation exhibited significant improvements in the upper extremity component of the Fugl-Meyer Motor Assessment after intervention (median, 7; interquartile range, 5-8; P<0.05), but the group receiving functional electric stimulation did not (median, 0; interquartile range, 0-3). Differences in score changes between the 2 groups were significant. The mental imagery training combined with electromyogram-triggered electric stimulation group showed significantly increased metabolism in the contralesional supplementary motor, precentral, and postcentral gyri (P(uncorrected)<0.001) after the intervention, but the functional electric stimulation group showed no significant differences. Mental imagery training combined with electromyogram-triggered electric stimulation improved motor function of the paretic extremity in patients with chronic stroke. The intervention increased metabolism in the contralesional motor-sensory cortex. Clinical Trial Registration- URL: https://e-irb.khmccri.or.kr/eirb/receipt/index.html?code=02&status=5. Unique identifier: KHUHMDIRB 1008-02.

A brain-computer interface for potential non-verbal facial communication based on EEG signals related to specific emotions

PubMed Central

Kashihara, Koji

2014-01-01

Unlike assistive technology for verbal communication, the brain-machine or brain-computer interface (BMI/BCI) has not been established as a non-verbal communication tool for amyotrophic lateral sclerosis (ALS) patients. Face-to-face communication enables access to rich emotional information, but individuals suffering from neurological disorders, such as ALS and autism, may not express their emotions or communicate their negative feelings. Although emotions may be inferred by looking at facial expressions, emotional prediction for neutral faces necessitates advanced judgment. The process that underlies brain neuronal responses to neutral faces and causes emotional changes remains unknown. To address this problem, therefore, this study attempted to decode conditioned emotional reactions to neutral face stimuli. This direction was motivated by the assumption that if electroencephalogram (EEG) signals can be used to detect patients' emotional responses to specific inexpressive faces, the results could be incorporated into the design and development of BMI/BCI-based non-verbal communication tools. To these ends, this study investigated how a neutral face associated with a negative emotion modulates rapid central responses in face processing and then identified cortical activities. The conditioned neutral face-triggered event-related potentials that originated from the posterior temporal lobe statistically significantly changed during late face processing (600–700 ms) after stimulus, rather than in early face processing activities, such as P1 and N170 responses. Source localization revealed that the conditioned neutral faces increased activity in the right fusiform gyrus (FG). This study also developed an efficient method for detecting implicit negative emotional responses to specific faces by using EEG signals. A classification method based on a support vector machine enables the easy classification of neutral faces that trigger specific individual emotions. In accordance with this classification, a face on a computer morphs into a sad or displeased countenance. The proposed method could be incorporated as a part of non-verbal communication tools to enable emotional expression. PMID:25206321

EG-05COMBINATION OF GENE COPY GAIN AND EPIGENETIC DEREGULATION ARE ASSOCIATED WITH THE ABERRANT EXPRESSION OF A STEM CELL RELATED HOX-SIGNATURE IN GLIOBLASTOMA

PubMed Central

Kurscheid, Sebastian; Bady, Pierre; Sciuscio, Davide; Samarzija, Ivana; Shay, Tal; Vassallo, Irene; Van Criekinge, Wim; Domany, Eytan; Stupp, Roger; Delorenzi, Mauro; Hegi, Monika

2014-01-01

We previously reported a stem cell related HOX gene signature associated with resistance to chemo-radiotherapy (TMZ/RT- > TMZ) in glioblastoma. However, underlying mechanisms triggering overexpression remain mostly elusive. Interestingly, HOX genes are neither involved in the developing brain, nor expressed in normal brain, suggestive of an acquired gene expression signature during gliomagenesis. HOXA genes are located on CHR 7 that displays trisomy in most glioblastoma which strongly impacts gene expression on this chromosome, modulated by local regulatory elements. Furthermore we observed more pronounced DNA methylation across the HOXA locus as compared to non-tumoral brain (Human methylation 450K BeadChip Illumina; 59 glioblastoma, 5 non-tumoral brain sampes). CpG probes annotated for HOX-signature genes, contributing most to the variability, served as input into the analysis of DNA methylation and expression to identify key regulatory regions. The structural similarity of the observed correlation matrices between DNA methylation and gene expression in our cohort and an independent data-set from TCGA (106 glioblastoma) was remarkable (RV-coefficient, 0.84; p-value < 0.0001). We identified a CpG located in the promoter region of the HOXA10 locus exerting the strongest mean negative correlation between methylation and expression of the whole HOX-signature. Applying this analysis the same CpG emerged in the external set. We then determined the contribution of both, gene copy aberration (CNA) and methylation at the selected probe to explain expression of the HOX-signature using a linear model. Statistically significant results suggested an additive effect between gene dosage and methylation at the key CpG identified. Similarly, such an additive effect was also observed in the external data-set. Taken together, we hypothesize that overexpression of the stem-cell related HOX signature is triggered by gain of trisomy 7 and escape from compensatory DNA methylation at positions controlling the effect of enhanced gene dose on expression.

A brain-computer interface for potential non-verbal facial communication based on EEG signals related to specific emotions.

PubMed

Kashihara, Koji

2014-01-01

Unlike assistive technology for verbal communication, the brain-machine or brain-computer interface (BMI/BCI) has not been established as a non-verbal communication tool for amyotrophic lateral sclerosis (ALS) patients. Face-to-face communication enables access to rich emotional information, but individuals suffering from neurological disorders, such as ALS and autism, may not express their emotions or communicate their negative feelings. Although emotions may be inferred by looking at facial expressions, emotional prediction for neutral faces necessitates advanced judgment. The process that underlies brain neuronal responses to neutral faces and causes emotional changes remains unknown. To address this problem, therefore, this study attempted to decode conditioned emotional reactions to neutral face stimuli. This direction was motivated by the assumption that if electroencephalogram (EEG) signals can be used to detect patients' emotional responses to specific inexpressive faces, the results could be incorporated into the design and development of BMI/BCI-based non-verbal communication tools. To these ends, this study investigated how a neutral face associated with a negative emotion modulates rapid central responses in face processing and then identified cortical activities. The conditioned neutral face-triggered event-related potentials that originated from the posterior temporal lobe statistically significantly changed during late face processing (600-700 ms) after stimulus, rather than in early face processing activities, such as P1 and N170 responses. Source localization revealed that the conditioned neutral faces increased activity in the right fusiform gyrus (FG). This study also developed an efficient method for detecting implicit negative emotional responses to specific faces by using EEG signals. A classification method based on a support vector machine enables the easy classification of neutral faces that trigger specific individual emotions. In accordance with this classification, a face on a computer morphs into a sad or displeased countenance. The proposed method could be incorporated as a part of non-verbal communication tools to enable emotional expression.

Impact of breast milk on IQ, brain size and white matter development

PubMed Central

Isaacs, Elizabeth B.; Fischl, Bruce R.; Quinn, Brian T.; Chong, Wui K.; Gadian, David G.; Lucas, Alan

2010-01-01

Although observational findings linking breast milk to higher scores on cognitive tests may be confounded by factors associated with mothers’ choice to breastfeed, it has been suggested that one or more constituents of breast milk facilitate cognitive development, particularly in preterms. Because cognitive scores are related to head size, we hypothesised that breast milk mediates cognitive effects by affecting brain growth. We used detailed data from a randomized feeding trial to calculate percentage of breast milk (%EBM) in the infant diet of 50 adolescents. MRI scans were obtained (mean age=15y9m), allowing volumes of total brain (TBV), white and grey matter (WMV, GMV) to be calculated. In the total group %EBM correlated significantly with Verbal IQ (VIQ); in boys, with all IQ scores, TBV and WMV. VIQ was, in turn, correlated with WMV and, in boys only, additionally with TBV. No significant relationships were seen in girls or with grey matter. These data support the hypothesis that breast milk promotes brain development, particularly white matter growth. The selective effect in males accords with animal and human evidence regarding gender effects of early diet. Our data have important neurobiological and public health implications and identify areas for future mechanistic study. PMID:20035247

Impact of breast milk on intelligence quotient, brain size, and white matter development.

PubMed

Isaacs, Elizabeth B; Fischl, Bruce R; Quinn, Brian T; Chong, Wui K; Gadian, David G; Lucas, Alan

2010-04-01

Although observational findings linking breast milk to higher scores on cognitive tests may be confounded by factors associated with mothers' choice to breastfeed, it has been suggested that one or more constituents of breast milk facilitate cognitive development, particularly in preterms. Because cognitive scores are related to head size, we hypothesized that breast milk mediates cognitive effects by affecting brain growth. We used detailed data from a randomized feeding trial to calculate percentage of expressed maternal breast milk (%EBM) in the infant diet of 50 adolescents. MRI scans were obtained (mean age=15 y 9 mo), allowing volumes of total brain (TBV) and white and gray matter (WMV, GMV) to be calculated. In the total group, %EBM correlated significantly with verbal intelligence quotient (VIQ); in boys, with all IQ scores, TBV and WMV. VIQ was, in turn, correlated with WMV and, in boys only, additionally with TBV. No significant relationships were seen in girls or with gray matter. These data support the hypothesis that breast milk promotes brain development, particularly white matter growth. The selective effect in males accords with animal and human evidence regarding gender effects of early diet. Our data have important neurobiological and public health implications and identify areas for future mechanistic study.

Computation of pattern invariance in brain-like structures.

PubMed

Ullman, S; Soloviev, S

1999-10-01

A fundamental capacity of the perceptual systems and the brain in general is to deal with the novel and the unexpected. In vision, we can effortlessly recognize a familiar object under novel viewing conditions, or recognize a new object as a member of a familiar class, such as a house, a face, or a car. This ability to generalize and deal efficiently with novel stimuli has long been considered a challenging example of brain-like computation that proved extremely difficult to replicate in artificial systems. In this paper we present an approach to generalization and invariant recognition. We focus our discussion on the problem of invariance to position in the visual field, but also sketch how similar principles could apply to other domains.The approach is based on the use of a large repertoire of partial generalizations that are built upon past experience. In the case of shift invariance, visual patterns are described as the conjunction of multiple overlapping image fragments. The invariance to the more primitive fragments is built into the system by past experience. Shift invariance of complex shapes is obtained from the invariance of their constituent fragments. We study by simulations aspects of this shift invariance method and then consider its extensions to invariant perception and classification by brain-like structures.

Effects of endogenous pyrogen and prostaglandin E2 on hypothalamic neurons in rat brain slices.

PubMed

Watanabe, T; Morimoto, A; Murakami, N

1987-06-01

We investigated the effects of endogenous pyrogen and prostaglandin E2 (PGE2) on the preoptic and anterior hypothalamic (POAH) neurons using brain slice preparations from the rat. Partially purified endogenous pyrogen did not change the activities of most of the neurons in the POAH region when applied locally through a micropipette attached to the recording electrode in proximity to the neurons. This indicates that partially purified endogenous pyrogen does not act directly on the neuronal activity in the POAH region. The partially purified endogenous pyrogen, applied into a culture chamber containing a brain slice, facilitated the activities in 24% of the total neurons tested, regardless of the thermal specificity of the neurons. Moreover, PGE2 added to the culture chamber facilitated 48% of the warm-responsive, 33% of the cold-responsive, and 29% of the thermally insensitive neurons. The direction of change in neuronal activity induced by partially purified endogenous pyrogen appears to be almost the same as that induced by PGE2 when these substances were applied by perfusion to the same neuron in the culture chamber. These results suggest that partially purified pyrogen applied to the perfusate of the culture chamber stimulates some constituents of brain tissue to synthesize and release prostaglandin, which in turn affects the neuronal activity of the POAH region.

Identification of potential novel interaction partners of the sodium-activated potassium channels Slick and Slack in mouse brain.

PubMed

Rizzi, Sandra; Schwarzer, Christoph; Kremser, Leopold; Lindner, Herbert H; Knaus, Hans-Günther

2015-12-01

The sodium-activated potassium channels Slick (Slo2.1, KCNT2) and Slack (Slo2.2, KCNT1) are paralogous channels of the Slo family of high-conductance potassium channels. Slick and Slack channels are widely distributed in the mammalian CNS and they play a role in slow afterhyperpolarization, generation of depolarizing afterpotentials and in setting and stabilizing the resting potential. In the present study we used a combined approach of (co)-immunoprecipitation studies, Western blot analysis, double immunofluorescence and mass spectrometric sequencing in order to investigate protein-protein interactions of the Slick and Slack channels. The data strongly suggest that Slick and Slack channels co-assemble into identical cellular complexes. Double immunofluorescence experiments revealed that Slick and Slack channels co-localize in distinct mouse brain regions. Moreover, we identified the small cytoplasmic protein beta-synuclein and the transmembrane protein 263 (TMEM 263) as novel interaction partners of both, native Slick and Slack channels. In addition, the inactive dipeptidyl-peptidase (DPP 10) and the synapse associated protein 102 (SAP 102) were identified as constituents of the native Slick and Slack channel complexes in the mouse brain. This study presents new insights into protein-protein interactions of native Slick and Slack channels in the mouse brain.

Influence of sex steroid hormones on the adolescent brain and behavior: An update

PubMed Central

Vigil, Pilar; del Río, Juan Pablo; Carrera, BÁrbara; ArÁnguiz, Florencia C.

2016-01-01

This review explains the main effects exerted by sex steroids and other hormones on the adolescent brain. During the transition from puberty to adolescence, these hormones participate in the organizational phenomena that structurally shape some brain circuits. In adulthood, this will propitiate some specific behavior as responses to the hormones now activating those neural circuits. Adolescence is, then, a critical “organizational window” for the brain to develop adequately, since steroid hormones perform important functions at this stage. For this reason, the adolescent years are very important for future behaviors in human beings. Changes that occur or fail to occur during adolescence will determine behaviors for the rest of one's lifetime. Consequently, understanding the link between adolescent behavior and brain development as influenced by sex steroids and other hormones and compounds is very important in order to interpret various psycho-affective pathologies. Lay Summary: The effect of steroid hormones on the development of the adolescent brain, and therefore, on adolescent behavior, is noticeable. This review presents their main activational and organizational effects. During the transition from puberty to adolescence, organizational phenomena triggered by steroids structurally affect the remodeling of brain circuits. Later in adulthood, these changes will be reflected in behavioral responses to such hormones. Adolescence can then be seen as a fundamental “organizational window” during which sex steroids and other hormones and compounds play relevant roles. The understanding of the relationship between adolescent behavior and the way hormones influence brain development help understand some psychological disorders. PMID:27833209

Methamphetamine abuse affects gene expression in brain-derived microglia of SIV-infected macaques to enhance inflammation and promote virus targets.

PubMed

Najera, Julia A; Bustamante, Eduardo A; Bortell, Nikki; Morsey, Brenda; Fox, Howard S; Ravasi, Timothy; Marcondes, Maria Cecilia Garibaldi

2016-04-23

Methamphetamine (Meth) abuse is a major health problem linked to the aggravation of HIV- associated complications, especially within the Central Nervous System (CNS). Within the CNS, Meth has the ability to modify the activity/function of innate immune cells and increase brain viral loads. Here, we examined changes in the gene expression profile of neuron-free microglial cell preparations isolated from the brain of macaques infected with the Simian Immunodeficiency Virus (SIV), a model of neuroAIDS, and exposed to Meth. We aimed to identify molecular patterns triggered by Meth that could explain the detection of higher brain viral loads and the development of a pro-inflammatory CNS environment in the brain of infected drug abusers. We found that Meth alone has a strong effect on the transcription of genes associated with immune pathways, particularly inflammation and chemotaxis. Systems analysis led to a strong correlation between Meth exposure and enhancement of molecules associated with chemokines and chemokine receptors, especially CXCR4 and CCR5, which function as co-receptors for viral entry. The increase in CCR5 expression was confirmed in the brain in correlation with increased brain viral load. Meth enhances the availability of CCR5-expressing cells for SIV in the brain, in correlation with increased viral load. This suggests that Meth is an important factor in the susceptibility to the infection and to the aggravated CNS inflammatory pathology associated with SIV in macaques and HIV in humans.

Elevation of GM2 ganglioside during ethanol-induced apoptotic neurodegeneration in the developing mouse brain.

PubMed

Saito, Mitsuo; Chakraborty, Goutam; Shah, Relish; Mao, Rui-Fen; Kumar, Asok; Yang, Dun-Sheng; Dobrenis, Kostantin; Saito, Mariko

2012-05-01

GM2 ganglioside in the brain increased during ethanol-induced acute apoptotic neurodegeneration in 7-day-old mice. A small but a significant increase observed 2 h after ethanol exposure was followed by a marked increase around 24 h. Subcellular fractionation of the brain 24 h after ethanol treatment indicated that GM2 increased in synaptic and non-synaptic mitochondrial fractions as well as in a lysosome-enriched fraction characteristic to the ethanol-exposed brain. Immunohistochemical staining of GM2 in the ethanol-treated brain showed strong punctate staining mainly in activated microglia, in which it partially overlapped with staining for LAMP1, a late endosomal/lysosomal marker. Also, there was weaker neuronal staining, which partially co-localized with complex IV, a mitochondrial marker, and was augmented in cleaved caspase 3-positive neurons. In contrast, the control brain showed only faint and diffuse GM2 staining in neurons. Incubation of isolated brain mitochondria with GM2 in vitro induced cytochrome c release in a manner similar to that of GD3 ganglioside. Because ethanol is known to trigger mitochondria-mediated apoptosis with cytochrome c release and caspase 3 activation in the 7-day-old mouse brain, the GM2 elevation in mitochondria may be relevant to neuroapoptosis. Subsequently, activated microglia accumulated GM2, indicating a close relationship between GM2 and ethanol-induced neurodegeneration. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Levels of word processing and incidental memory: dissociable mechanisms in the temporal lobe.

PubMed

Castillo, E M; Simos, P G; Davis, R N; Breier, J; Fitzgerald, M E; Papanicolaou, A C

2001-11-16

Word recall is facilitated when deep (e.g. semantic) processing is applied during encoding. This fact raises the question of the existence of specific brain mechanisms supporting different levels of information processing that can modulate incidental memory performance. In this study we obtained spatiotemporal brain activation profiles, using magnetic source imaging, from 10 adult volunteers as they performed a shallow (phonological) processing task and a deep (semantic) processing task. When phonological analysis of the word stimuli into their constituent phonemes was required, activation was largely restricted to the posterior portion of the left superior temporal gyrus (area 22). Conversely, when access to lexical/semantic representations was required, activation was found predominantly in the left middle temporal gyrus and medial temporal cortex. The differential engagement of each mechanism during word encoding was associated with dramatic changes in subsequent incidental memory performance.

Distinct neuronal coding schemes in memory revealed by selective erasure of fast synchronous synaptic transmission.

PubMed

Xu, Wei; Morishita, Wade; Buckmaster, Paul S; Pang, Zhiping P; Malenka, Robert C; Südhof, Thomas C

2012-03-08

Neurons encode information by firing spikes in isolation or bursts and propagate information by spike-triggered neurotransmitter release that initiates synaptic transmission. Isolated spikes trigger neurotransmitter release unreliably but with high temporal precision. In contrast, bursts of spikes trigger neurotransmission reliably (i.e., boost transmission fidelity), but the resulting synaptic responses are temporally imprecise. However, the relative physiological importance of different spike-firing modes remains unclear. Here, we show that knockdown of synaptotagmin-1, the major Ca(2+) sensor for neurotransmitter release, abrogated neurotransmission evoked by isolated spikes but only delayed, without abolishing, neurotransmission evoked by bursts of spikes. Nevertheless, knockdown of synaptotagmin-1 in the hippocampal CA1 region did not impede acquisition of recent contextual fear memories, although it did impair the precision of such memories. In contrast, knockdown of synaptotagmin-1 in the prefrontal cortex impaired all remote fear memories. These results indicate that different brain circuits and types of memory employ distinct spike-coding schemes to encode and transmit information. Copyright © 2012 Elsevier Inc. All rights reserved.

ENA/VASP downregulation triggers cell death by impairing axonal maintenance in hippocampal neurons.

PubMed

Franco, D Lorena; Rezával, Carolina; Cáceres, Alfredo; Schinder, Alejandro F; Ceriani, M Fernanda

2010-06-01

Neurodegenerative diseases encompass a broad variety of motor and cognitive disorders that are accompanied by death of specific neuronal populations or brain regions. Cellular and molecular mechanisms underlying these complex disorders remain largely unknown. In a previous work we searched for novel Drosophila genes relevant for neurodegeneration and singled out enabled (ena), which encodes a protein involved in cytoskeleton remodeling. To extend our understanding on the mechanisms of ENA-triggered degeneration we now investigated the effect of silencing ena ortholog genes in mouse hippocampal neurons. We found that ENA/VASP downregulation led to neurite retraction and concomitant neuronal cell death through an apoptotic pathway. Remarkably, this retraction initially affected the axonal structure, showing no effect on dendrites. Reduction in ENA/VASP levels blocked the neuritogenic effect of a specific RhoA kinase (ROCK) inhibitor, thus suggesting that these proteins could participate in the Rho-signaling pathway. Altogether these observations demonstrate that ENA/VASP proteins are implicated in the establishment and maintenance of the axonal structure and that a change on their expression levels triggers neuronal degeneration. 2010 Elsevier Inc. All rights reserved.

Prying into the Prion Hypothesis for Parkinson's Disease.

PubMed

Brundin, Patrik; Melki, Ronald

2017-10-11

In Parkinson's disease, intracellular α-synuclein inclusions form in neurons. We suggest that prion-like behavior of α-synuclein is a key component in Parkinson's disease pathogenesis. Although multiple molecular changes are involved in the triggering of the disease process, we propose that neuron-to-neuron transfer is a crucial event that is essential for Lewy pathology to spread from one brain region to another. In this review, we describe key findings in human postmortem brains, cultured cells, and animal models of disease that support the idea that α-synuclein can act as a prion. We consider potential triggers of the α-synuclein misfolding and why the aggregates escape cellular degradation under disease conditions. We also discuss whether different strains of α-synuclein fibrils can underlie differences in cellular and regional distribution of aggregates in different synucleinopathies. Our conclusion is that α-synuclein probably acts as a prion in human diseases, and a deeper understanding of this step in the pathogenesis of Parkinson's disease can facilitate the development of disease-modifying therapies in the future. Dual Perspectives Companion Paper: Parkinson's Disease Is Not Simply a Prion Disorder, by D. James Surmeier, José A. Obeso, and Glenda M. Halliday. Copyright © 2017 the authors 0270-6474/17/379808-11$15.00/0.

Influences of unconscious priming on voluntary actions: Role of the rostral cingulate zone.

PubMed

Teuchies, Martyn; Demanet, Jelle; Sidarus, Nura; Haggard, Patrick; Stevens, Michaël A; Brass, Marcel

2016-07-15

The ability to make voluntary, free choices is fundamental to what it means to be human. A key brain region that is involved in free choices is the rostral cingulate zone (RCZ), which is part of the medial frontal cortex. Previous research has shown that activity in this brain region can be modulated by bottom-up information while making free choices. The current study extends those findings, and shows, for the first time, that activation in the RCZ can also be modulated by subliminal information. We used a subliminal response priming paradigm to bias free and cued choices. We observed more activation in the RCZ when participants made a choice that went against the prime's suggestion, compared to when they chose according to the prime. This shows that the RCZ plays an important role in overcoming externally-triggered conflict between different response options, even when the stimuli triggering this conflict are not consciously perceived. Our results suggest that an important mechanism of endogenous action in the RCZ may therefore involve exerting an internally-generated action choice against conflicting influences, such as external sensory evidence. We further found that subliminal information also modulated activity in the anterior insula and the supramarginal gyrus. Copyright © 2016 Elsevier Inc. All rights reserved.

The Mechanism of Extracellular Stimulation of Nerve Cells on an Electrolyte-Oxide-Semiconductor Capacitor

PubMed Central

Schoen, Ingmar; Fromherz, Peter

2007-01-01

Extracellular excitation of neurons is applied in studies of cultured networks and brain tissue, as well as in neuroprosthetics. We elucidate its mechanism in an electrophysiological approach by comparing voltage-clamp and current-clamp recordings of individual neurons on an insulated planar electrode. Noninvasive stimulation of neurons from pedal ganglia of Lymnaea stagnalis is achieved by defined voltage ramps applied to an electrolyte/HfO2/silicon capacitor. Effects on the smaller attached cell membrane and the larger free membrane are distinguished in a two-domain-stimulation model. Under current-clamp, we study the polarization that is induced for closed ion channels. Under voltage-clamp, we determine the capacitive gating of ion channels in the attached membrane by falling voltage ramps and for comparison also the gating of all channels by conventional variation of the intracellular voltage. Neuronal excitation is elicited under current-clamp by two mechanisms: Rising voltage ramps depolarize the free membrane such that an action potential is triggered. Falling voltage ramps depolarize the attached membrane such that local ion currents are activated that depolarize the free membrane and trigger an action potential. The electrophysiological analysis of extracellular stimulation in the simple model system is a basis for its systematic optimization in neuronal networks and brain tissue. PMID:17098803

Imbalance in Fatty-Acid-Chain Length of Gangliosides Triggers Alzheimer Amyloid Deposition in the Precuneus

PubMed Central

Oikawa, Naoto; Matsubara, Teruhiko; Fukuda, Ryoto; Yasumori, Hanaki; Hatsuta, Hiroyuki; Murayama, Shigeo; Sato, Toshinori; Suzuki, Akemi; Yanagisawa, Katsuhiko

2015-01-01

Amyloid deposition, a crucial event of Alzheimer’s disease (AD), emerges in distinct brain regions. A key question is what triggers the assembly of the monomeric amyloid ß-protein (Aß) into fibrils in the regions. On the basis of our previous findings that gangliosides facilitate the initiation of Aß assembly at presynaptic neuritic terminals, we investigated how lipids, including gangliosides, cholesterol and sphingomyelin, extracted from synaptic plasma membranes (SPMs) isolated from autopsy brains were involved in the Aß assembly. We focused on two regions of the cerebral cortex; precuneus and calcarine cortex, one of the most vulnerable and one of the most resistant regions to amyloid deposition, respectively. Here, we show that lipids extracted from SPMs isolated from the amyloid-bearing precuneus, but neither the amyloid-free precuneus nor the calcarine cortex, markedly accelerate the Aß assembly in vitro. Through liquid chromatography-mass spectrometry of the lipids, we identified an increase in the ratio of the level of GD1b-ganglioside containing C20:0 fatty acid to that containing C18:0 as a cause of the enhanced Aß assembly in the precuneus. Our results suggest that the local glycolipid environment play a critical role in the initiation of Alzheimer amyloid deposition. PMID:25798597

Excitotoxicity triggered by neonatal monosodium glutamate treatment and blood-brain barrier function.

PubMed

Gudiño-Cabrera, Graciela; Ureña-Guerrero, Monica E; Rivera-Cervantes, Martha C; Feria-Velasco, Alfredo I; Beas-Zárate, Carlos

2014-11-01

It is likely that monosodium glutamate (MSG) is the excitotoxin that has been most commonly employed to characterize the process of excitotoxicity and to improve understanding of the ways that this process is related to several pathological conditions of the central nervous system. Excitotoxicity triggered by neonatal MSG treatment produces a significant pathophysiological impact on adulthood, which could be due to modifications in the blood-brain barrier (BBB) permeability and vice versa. This mini-review analyzes this topic through brief descriptions about excitotoxicity, BBB structure and function, role of the BBB in the regulation of Glu extracellular levels, conditions that promote breakdown of the BBB, and modifications induced by neonatal MSG treatment that could alter the behavior of the BBB. In conclusion, additional studies to better characterize the effects of neonatal MSG treatment on excitatory amino acids transporters, ionic exchangers, and efflux transporters, as well as the role of the signaling pathways mediated by erythropoietin and vascular endothelial growth factor in the cellular elements of the BBB, should be performed to identify the mechanisms underlying the increase in neurovascular permeability associated with excitotoxicity observed in several diseases and studied using neonatal MSG treatment. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

Mechanical confinement triggers glioma linear migration dependent on formin FHOD3

PubMed Central

Monzo, Pascale; Chong, Yuk Kien; Guetta-Terrier, Charlotte; Krishnasamy, Anitha; Sathe, Sharvari R.; Yim, Evelyn K. F.; Ng, Wai Hoe; Ang, Beng Ti; Tang, Carol; Ladoux, Benoit; Gauthier, Nils C.; Sheetz, Michael P.

2016-01-01

Glioblastomas are extremely aggressive brain tumors with highly invasive properties. Brain linear tracks such as blood vessel walls constitute their main invasive routes. Here we analyze rat C6 and patient-derived glioma cell motility in vitro using micropatterned linear tracks to mimic blood vessels. On laminin-coated tracks (3–10 μm), these cells used an efficient saltatory mode of migration similar to their in vivo migration. This saltatory migration was also observed on larger tracks (50–400 μm in width) at high cell densities. In these cases, the mechanical constraints imposed by neighboring cells triggered this efficient mode of migration, resulting in the formation of remarkable antiparallel streams of cells along the tracks. This motility involved microtubule-dependent polarization, contractile actin bundles and dynamic paxillin-containing adhesions in the leading process and in the tail. Glioma linear migration was dramatically reduced by inhibiting formins but, surprisingly, accelerated by inhibiting Arp2/3. Protein expression and phenotypic analysis indicated that the formin FHOD3 played a role in this motility but not mDia1 or mDia2. We propose that glioma migration under confinement on laminin relies on formins, including FHOD3, but not Arp2/3 and that the low level of adhesion allows rapid antiparallel migration. PMID:26912794

A BMI-based occupational therapy assist suit: asynchronous control by SSVEP

PubMed Central

Sakurada, Takeshi; Kawase, Toshihiro; Takano, Kouji; Komatsu, Tomoaki; Kansaku, Kenji

2013-01-01

A brain-machine interface (BMI) is an interface technology that uses neurophysiological signals from the brain to control external machines. Recent invasive BMI technologies have succeeded in the asynchronous control of robot arms for a useful series of actions, such as reaching and grasping. In this study, we developed non-invasive BMI technologies aiming to make such useful movements using the subject's own hands by preparing a BMI-based occupational therapy assist suit (BOTAS). We prepared a pre-recorded series of useful actions—a grasping-a-ball movement and a carrying-the-ball movement—and added asynchronous control using steady-state visual evoked potential (SSVEP) signals. A SSVEP signal was used to trigger the grasping-a-ball movement and another SSVEP signal was used to trigger the carrying-the-ball movement. A support vector machine was used to classify EEG signals recorded from the visual cortex (Oz) in real time. Untrained, able-bodied participants (n = 12) operated the system successfully. Classification accuracy and time required for SSVEP detection were ~88% and 3 s, respectively. We further recruited three patients with upper cervical spinal cord injuries (SCIs); they also succeeded in operating the system without training. These data suggest that our BOTAS system is potentially useful in terms of rehabilitation of patients with upper limb disabilities. PMID:24068982

Long-Lasting Crossmodal Cortical Reorganization Triggered by Brief Postnatal Visual Deprivation.

PubMed

Collignon, Olivier; Dormal, Giulia; de Heering, Adelaide; Lepore, Franco; Lewis, Terri L; Maurer, Daphne

2015-09-21

Animal and human studies have demonstrated that transient visual deprivation early in life, even for a very short period, permanently alters the response properties of neurons in the visual cortex and leads to corresponding behavioral visual deficits. While it is acknowledged that early-onset and longstanding blindness leads the occipital cortex to respond to non-visual stimulation, it remains unknown whether a short and transient period of postnatal visual deprivation is sufficient to trigger crossmodal reorganization that persists after years of visual experience. In the present study, we characterized brain responses to auditory stimuli in 11 adults who had been deprived of all patterned vision at birth by congenital cataracts in both eyes until they were treated at 9 to 238 days of age. When compared to controls with typical visual experience, the cataract-reversal group showed enhanced auditory-driven activity in focal visual regions. A combination of dynamic causal modeling with Bayesian model selection indicated that this auditory-driven activity in the occipital cortex was better explained by direct cortico-cortical connections with the primary auditory cortex than by subcortical connections. Thus, a short and transient period of visual deprivation early in life leads to enduring large-scale crossmodal reorganization of the brain circuitry typically dedicated to vision. Copyright © 2015 Elsevier Ltd. All rights reserved.

The role of astrocytes in amyloid production and Alzheimer's disease

PubMed Central

Frost, Georgia R.

2017-01-01

Alzheimer's disease (AD) is marked by the presence of extracellular amyloid beta (Aβ) plaques, intracellular neurofibrillary tangles (NFTs) and gliosis, activated glial cells, in the brain. It is thought that Aβ plaques trigger NFT formation, neuronal cell death, neuroinflammation and gliosis and, ultimately, cognitive impairment. There are increased numbers of reactive astrocytes in AD, which surround amyloid plaques and secrete proinflammatory factors and can phagocytize and break down Aβ. It was thought that neuronal cells were the major source of Aβ. However, mounting evidence suggests that astrocytes may play an additional role in AD by secreting significant quantities of Aβ and contributing to overall amyloid burden in the brain. Astrocytes are the most numerous cell type in the brain, and therefore even minor quantities of amyloid secretion from individual astrocytes could prove to be substantial when taken across the whole brain. Reactive astrocytes have increased levels of the three necessary components for Aβ production: amyloid precursor protein, β-secretase (BACE1) and γ-secretase. The identification of environmental factors, such as neuroinflammation, that promote astrocytic Aβ production, could redefine how we think about developing therapeutics for AD. PMID:29237809

Probiotics drive gut microbiome triggering emotional brain signatures.

PubMed

Bagga, Deepika; Reichert, Johanna Louise; Koschutnig, Karl; Aigner, Christoph Stefan; Holzer, Peter; Koskinen, Kaisa; Eichinger, Christine Moissl; Schöpf, Veronika

2018-05-03

Experimental manipulation of the gut microbiome was found to modify emotional and cognitive behavior, neurotransmitter expression and brain function in rodents, but corresponding human data remain scarce. The present double-blind, placebo-controlled randomised study aimed at investigating the effects of 4 weeks' probiotic administration on behavior, brain function and gut microbial composition in healthy volunteers. Forty-five healthy participants divided equally into three groups (probiotic, placebo and no intervention) underwent functional MRI (emotional decision-making and emotional recognition memory tasks). In addition, stool samples were collected to investigate the gut microbial composition. Probiotic administration for 4 weeks was associated with changes in brain activation patterns in response to emotional memory and emotional decision-making tasks, which were also accompanied by subtle shifts in gut microbiome profile. Microbiome composition mirrored self-reported behavioral measures and memory performance. This is the first study reporting a distinct influence of probiotic administration at behavioral, neural, and microbiome levels at the same time in healthy volunteers. The findings provide a basis for future investigations into the role of the gut microbiota and potential therapeutic application of probiotics.

Resting state brain dynamics and its transients: a combined TMS-EEG study.

PubMed

Bonnard, Mireille; Chen, Sophie; Gaychet, Jérôme; Carrere, Marcel; Woodman, Marmaduke; Giusiano, Bernard; Jirsa, Viktor

2016-08-04

The brain at rest exhibits a spatio-temporally rich dynamics which adheres to systematic behaviours that persist in task paradigms but appear altered in disease. Despite this hypothesis, many rest state paradigms do not act directly upon the rest state and therefore cannot confirm hypotheses about its mechanisms. To address this challenge, we combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to study brain's relaxation toward rest following a transient perturbation. Specifically, TMS targeted either the medial prefrontal cortex (MPFC), i.e. part of the Default Mode Network (DMN) or the superior parietal lobule (SPL), involved in the Dorsal Attention Network. TMS was triggered by a given brain state, namely an increase in occipital alpha rhythm power. Following the initial TMS-Evoked Potential, TMS at MPFC enhances the induced occipital alpha rhythm, called Event Related Synchronisation, with a longer transient lifetime than TMS at SPL, and a higher amplitude. Our findings show a strong coupling between MPFC and the occipital alpha power. Although the rest state is organized around a core of resting state networks, the DMN functionally takes a special role among these resting state networks.

Self-Assembly of Gold Nanoparticles Shows Microenvironment-Mediated Dynamic Switching and Enhanced Brain Tumor Targeting

PubMed Central

Feng, Qishuai; Shen, Yajing; Fu, Yingjie; Muroski, Megan E.; Zhang, Peng; Wang, Qiaoyue; Xu, Chang; Lesniak, Maciej S.; Li, Gang; Cheng, Yu

2017-01-01

Inorganic nanoparticles with unique physical properties have been explored as nanomedicines for brain tumor treatment. However, the clinical applications of the inorganic formulations are often hindered by the biological barriers and failure to be bioeliminated. The size of the nanoparticle is an essential design parameter which plays a significant role to affect the tumor targeting and biodistribution. Here, we report a feasible approach for the assembly of gold nanoparticles into ~80 nm nanospheres as a drug delivery platform for enhanced retention in brain tumors with the ability to be dynamically switched into the single formulation for excretion. These nanoassemblies can target epidermal growth factor receptors on cancer cells and are responsive to tumor microenvironmental characteristics, including high vascular permeability and acidic and redox conditions. Anticancer drug release was controlled by a pH-responsive mechanism. Intracellular L-glutathione (GSH) triggered the complete breakdown of nanoassemblies to single gold nanoparticles. Furthermore, in vivo studies have shown that nanospheres display enhanced tumor-targeting efficiency and therapeutic effects relative to single-nanoparticle formulations. Hence, gold nanoassemblies present an effective targeting strategy for brain tumor treatment. PMID:28638474

[Acute brain expansion during emergency neck clipping surgery for cerebral aneurysms in a patient with dilated cardiomyopathy].

PubMed

Nakao, M; Kawaguchi, R; Nakatani, K; Niinai, H; Takezaki, T; Hanaki, C

1996-06-01

A 61-year-old male with coma and undiagnosed dilated cardiomyopathy received emergency cerebral aneurysm surgery. Anesthesia was induced with thiamylal, fentanyl and vecuronium and maintained with 66% N2O and 1.0% isoflurane. Five hundred ml of 20% mannitol was infused in 30 min. At the end of the infusion, hypotension occurred. Immediately after the injection of ephedrine, acute brain swelling was observed. The operation was switched to external decompression. Post-operative echocardiography revealed the presence of dilated cardiomyopathy (DCM). The ejection fraction was 34%. Two weeks later, the second operation was scheduled. The anesthesia was induced with fentanyl, midazolam and vecuronium and maintained with N2O and 0.7% isoflurane. Nitroglycerine, lidocaine, PGE1, dopamine and dobutamine were infused throughout the operation. Five hundred ml of 20% mannitol was infused in 60 min. There were no considerable hemodynamic changes and no episode of brain expansion during operation. We conclude that the rapid infusion of mannitol can trigger acute cardiac failure and brain edema in patients with DCM.

The intracellular angiotensin system buffers deleterious effects of the extracellular paracrine system

PubMed Central

Villar-Cheda, Begoña; Costa-Besada, Maria A; Valenzuela, Rita; Perez-Costas, Emma; Melendez-Ferro, Miguel; Labandeira-Garcia, Jose L

2017-01-01

The ‘classical’ renin–angiotensin system (RAS) is a circulating system that controls blood pressure. Local/paracrine RAS, identified in a variety of tissues, including the brain, is involved in different functions and diseases, and RAS blockers are commonly used in clinical practice. A third type of RAS (intracellular/intracrine RAS) has been observed in some types of cells, including neurons. However, its role is still unknown. The present results indicate that in brain cells the intracellular RAS counteracts the intracellular superoxide/H2O2 and oxidative stress induced by the extracellular/paracrine angiotensin II acting on plasma membrane receptors. Activation of nuclear receptors by intracellular or internalized angiotensin triggers a number of mechanisms that protect the cell, such as an increase in the levels of protective angiotensin type 2 receptors, intracellular angiotensin, PGC-1α and IGF-1/SIRT1. Interestingly, this protective mechanism is altered in isolated nuclei from brains of aged animals. The present results indicate that at least in the brain, AT1 receptor blockers acting only on the extracellular or paracrine RAS may offer better protection of cells. PMID:28880266

[Inflammation and oxidation: predictive and/or causative factors].

PubMed

Fernández-Viadero, Carlos; Jiménez-Sanz, Magdalena; Fernández-Pérez, Anzu; Verduga Vélez, Rosario; Crespo Santiago, Dámaso

2016-06-01

Brain ageing leads to a series of changes that reduce the processes of adaptation and response. These transformations can end in cognitive impairment and/or dementia. Although the cause of these changes is diverse, inflammation and oxidative stress explain some of the pathophysiological mechanisms of these anomalies of brain functioning. Neuroinflammation triggers neuronal injury through the presence of inflammatory cytokines and the activation of microglia through membrane receptors and nuclear activation factors. This neuroinflammatory phenomenon also affects neuron plasticity, altering the genesis and maintenance of long-term potentiation, leading to impairment of hippocampus-dependent memory. Oxidative stress and the production of free oxygen radicals also cause toxic effects in aged brains, largely due to lipid peroxidation and DNA damage. The identification of the molecular mechanisms involved in the pathogenesis of these events could shed new light on possible therapeutic targets and offer strategies for the prevention of diseases related to brain ageing, cognitive impairment and dementia. Copyright © 2016 Sociedad Española de Geriatría y Gerontología. Publicado por Elsevier España, S.L.U. All rights reserved.

Self-Assembly of Gold Nanoparticles Shows Microenvironment-Mediated Dynamic Switching and Enhanced Brain Tumor Targeting.

PubMed

Feng, Qishuai; Shen, Yajing; Fu, Yingjie; Muroski, Megan E; Zhang, Peng; Wang, Qiaoyue; Xu, Chang; Lesniak, Maciej S; Li, Gang; Cheng, Yu

2017-01-01

Inorganic nanoparticles with unique physical properties have been explored as nanomedicines for brain tumor treatment. However, the clinical applications of the inorganic formulations are often hindered by the biological barriers and failure to be bioeliminated. The size of the nanoparticle is an essential design parameter which plays a significant role to affect the tumor targeting and biodistribution. Here, we report a feasible approach for the assembly of gold nanoparticles into ~80 nm nanospheres as a drug delivery platform for enhanced retention in brain tumors with the ability to be dynamically switched into the single formulation for excretion. These nanoassemblies can target epidermal growth factor receptors on cancer cells and are responsive to tumor microenvironmental characteristics, including high vascular permeability and acidic and redox conditions. Anticancer drug release was controlled by a pH-responsive mechanism. Intracellular L-glutathione (GSH) triggered the complete breakdown of nanoassemblies to single gold nanoparticles. Furthermore, in vivo studies have shown that nanospheres display enhanced tumor-targeting efficiency and therapeutic effects relative to single-nanoparticle formulations. Hence, gold nanoassemblies present an effective targeting strategy for brain tumor treatment.

Short- and long-lasting consequences of novelty, deviance and surprise on brain and cognition.

PubMed

Schomaker, J; Meeter, M

2015-08-01

When one encounters a novel stimulus this sets off a cascade of brain responses, activating several neuromodulatory systems. As a consequence novelty has a wide range of effects on cognition; improving perception and action, increasing motivation, eliciting exploratory behavior, and promoting learning. Here, we review these benefits and how they may arise in the brain. We propose a framework that organizes novelty's effects on brain and cognition into three groups. First, novelty can transiently enhance perception. This effect is proposed to be mediated by novel stimuli activating the amygdala and enhancing early sensory processing. Second, novel stimuli can increase arousal, leading to short-lived effects on action in the first hundreds of milliseconds after presentation. We argue that these effects are related to deviance, rather than to novelty per se, and link them to activation of the locus-coeruleus norepinephrine system. Third, spatial novelty may trigger the dopaminergic mesolimbic system, promoting dopamine release in the hippocampus, having longer-lasting effects, up to tens of minutes, on motivation, reward processing, and learning and memory. Copyright © 2015 Elsevier Ltd. All rights reserved.

New World Tryptamine Hallucinogens and the Neuroscience of Ayahuasca.

PubMed

McKenna, Dennis; Riba, Jordi

2018-01-01

New World indigenous peoples are noted for their sophisticated use of psychedelic plants in shamanic and ethnomedical practices. The use of psychedelic plant preparations among New World tribes is far more prevalent than in the Old World. Yet, although these preparations are botanically diverse, almost all are chemically similar in that their active principles are tryptamine derivatives, either DMT or related constituents. Part 1 of this paper provides an ethnopharmacological overview of the major tryptamine-containing New World hallucinogens. Part 2 focuses on ayahuasca and its effects on the human brain. Using complementary neurophysiological and neuroimaging techniques, we have identified brain areas involved in the cognitive effects induced by this complex botanical preparation. Initial SPECT data showed that ayahuasca modulated activity in higher order association areas of the brain. Increased blood perfusion was observed mainly in anterior brain regions encompassing the frontomedial and anterior cingulate cortices of the frontal lobes, and in the medial regions of the temporal lobes. On the other hand, applying spectral analysis and source location techniques to cortical electrical signals, we found changes in neuronal activity that predominated in more posterior sensory-selective areas of the brain. Now, using functional connectivity analysis of brain oscillations we have been able to reconcile these seemingly contradictory findings. By measuring transfer entropy, a metric based on information theory, we have shown that ayahuasca temporarily modifies the ordinary flow of information within the brain. We propose a model in which ayahuasca reduces top-down constraints and facilitates bottom-up information transfer. By simultaneously enhancing endogenous cortical excitability and reducing higher-order cognitive control, ayahuasca temporarily disrupts neural hierarchies allowing inner exploration and a new outlook on reality.

Intrahippocampal Infusion of Crotamine Isolated from Crotalus durissus terrificus Alters Plasma and Brain Biochemical Parameters †

PubMed Central

Gonçalves, Rithiele; Vargas, Liane S.; Lara, Marcus V. S.; Güllich, Angélica; Mandredini, Vanusa; Ponce-Soto, Luis; Marangoni, Sergio; Dal Belo, Cháriston A.; Mello-Carpes, Pâmela B.

2014-01-01

Crotamine is one of the main constituents of the venom of the South American rattlesnake Crotalus durissus terrificus. Here we sought to investigate the inflammatory and toxicological effects induced by the intrahippocampal administration of crotamine isolated from Crotalus whole venom. Adult rats received an intrahippocampal infusion of crotamine or vehicle and were euthanized 24 h or 21 days after infusion. Plasma and brain tissue were collected for biochemical analysis. Complete blood count, creatinine, urea, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), creatine-kinase (CK), creatine kinase-muscle B (CK-MB) and oxidative parameters (assessed by DNA damage and micronucleus frequency in leukocytes, lipid peroxidation and protein carbonyls in plasma and brain) were quantified. Unpaired and paired t-tests were used for comparisons between saline and crotamine groups, and within groups (24 h vs. 21 days), respectively. After 24 h crotamine infusion promoted an increase of urea, GOT, GPT, CK, and platelets values (p ≤ 0.01), while red blood cells, hematocrit and leukocytes values decreased (p ≤ 0.01). Additionally, 21 days after infusion crotamine group showed increased creatinine, leukocytes, TBARS (plasma and brain), carbonyl (plasma and brain) and micronucleus compared to the saline-group (p ≤ 0.01). Our findings show that crotamine infusion alter hematological parameters and cardiac markers, as well as oxidative parameters, not only in the brain, but also in the blood, indicating a systemic pro-inflammatory and toxicological activity. A further scientific attempt in terms of preserving the beneficial activity over toxicity is required. PMID:25380458

Multi-brain fusion and applications to intelligence analysis

NASA Astrophysics Data System (ADS)

Stoica, A.; Matran-Fernandez, A.; Andreou, D.; Poli, R.; Cinel, C.; Iwashita, Y.; Padgett, C.

2013-05-01

In a rapid serial visual presentation (RSVP) images are shown at an extremely rapid pace. Yet, the images can still be parsed by the visual system to some extent. In fact, the detection of specific targets in a stream of pictures triggers a characteristic electroencephalography (EEG) response that can be recognized by a brain-computer interface (BCI) and exploited for automatic target detection. Research funded by DARPA's Neurotechnology for Intelligence Analysts program has achieved speed-ups in sifting through satellite images when adopting this approach. This paper extends the use of BCI technology from individual analysts to collaborative BCIs. We show that the integration of information in EEGs collected from multiple operators results in performance improvements compared to the single-operator case.

How schizophrenia develops: cognitive and brain mechanisms underlying onset of psychosis

PubMed Central

Cannon, Tyrone D.

2015-01-01

Identifying cognitive and neural mechanisms involved in the development of schizophrenia requires longitudinal observation of individuals prior to onset. Here recent studies of prodromal individuals who progress to full psychosis are briefly reviewed in relation to models of schizophrenia pathophysiology. Together, this body of work suggests that disruption in brain connectivity, driven primarily by a progressive reduction in dendritic spines on cortical pyramidal neurons, may represent a key triggering mechanism. The earliest disruptions appear to be in circuits involved in referencing experiences according to time, place, and agency, which may result in a failure to recognize particular cognitions as self-generated or to constrain interpretations of the meaning of events based on prior experiences, providing the scaffolding for faulty reality testing. PMID:26493362

The neurovascular unit - concept review.

PubMed

Muoio, V; Persson, P B; Sendeski, M M

2014-04-01

The cerebral hyperaemia is one of the fundamental mechanisms for the central nervous system homeostasis. Due also to this mechanism, oxygen and nutrients are maintained in satisfactory levels, through vasodilation and vasoconstriction. The brain hyperaemia, or coupling, is accomplished by a group of cells, closely related to each other; called neurovascular unit (NVU). The neurovascular unit is composed by neurones, astrocytes, endothelial cells of blood-brain barrier (BBB), myocytes, pericytes and extracellular matrix components. These cells, through their intimate anatomical and chemical relationship, detect the needs of neuronal supply and trigger necessary responses (vasodilation or vasoconstriction) for such demands. Here, we review the concepts of NVU, the coupling mechanisms and research strategies. © 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Manipulation of Length and Lexicality Localizes the Functional Neuroanatomy of Phonological Processing in Adult Readers

PubMed Central

Church, Jessica A.; Balota, David A.; Petersen, Steven E.; Schlaggar, Bradley L.

2010-01-01

In a previous study of single word reading, regions in the left supramarginal gyrus and left angular gyrus showed positive BOLD activity in children but significantly less activity in adults for high-frequency words. This developmental decrease may reflect decreased reliance on phonological processing for familiar stimuli in adults. Therefore, in the present study, variables thought to influence phonological demand (string length and lexicality) were manipulated. Length and lexicality effects in the brain were explored using both ROI and whole-brain approaches. In the ROI analysis, the supramarginal and angular regions from the previous study were applied to this study. The supramarginal region showed a significant positive effect of length, consistent with a role in phonological processing, whereas the angular region showed only negative deflections from baseline with a strong effect of lexicality and other weaker effects. At the whole-brain level, varying effects of length and lexicality and their interactions were observed in 85 regions throughout the brain. The application of hierarchical clustering analysis to the BOLD time course data derived from these regions revealed seven clusters, with potentially revealing anatomical locations. Of note, a left angular gyrus region was the sole constituent of one cluster. Taken together, these findings in adult readers (1) provide support for a widespread set of brain regions affected by lexical variables, (2) corroborate a role for phonological processing in the left supramarginal gyrus, and (3) do not support a strong role for phonological processing in the left angular gyrus. PMID:20433237

Refractory Causes of Kernicterus in Developed Countries: Can We Eradicate G6PD Deficiency Triggered and Low-Bilirubin Kernicterus?

PubMed

Watchko, Jon F

2017-01-01

Glucose-6-phosphate dehydrogenase (G6PD) deficiency triggered and low-bilirubin kernicterus persist despite current prevention strategies. Review efforts to eradicate bilirubin induced brain injury in these two conditions including novel approaches to risk assessment and hyperbilirubinemia evaluation. In the case of G6PD deficiency, a heightened awareness of populations at risk and an expanded kernicterus prevention strategy focused on intensified parental engagement, education and counselling on neonatal jaundice is needed. In the case of low-bilirubin kernicterus, a renewed focus on identifying infants with hypoalbuminemia and implementation of hyperbilirubinemia treatment thresholds based on the bilirubin/albumin ratio is needed. Bilirubin binding panels when commercially available will prove valuable. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Controlling an avatar by thought using real-time fMRI

NASA Astrophysics Data System (ADS)

Cohen, Ori; Koppel, Moshe; Malach, Rafael; Friedman, Doron

2014-06-01

Objective. We have developed a brain-computer interface (BCI) system based on real-time functional magnetic resonance imaging (fMRI) with virtual reality feedback. The advantage of fMRI is the relatively high spatial resolution and the coverage of the whole brain; thus we expect that it may be used to explore novel BCI strategies, based on new types of mental activities. However, fMRI suffers from a low temporal resolution and an inherent delay, since it is based on a hemodynamic response rather than electrical signals. Thus, our objective in this paper was to explore whether subjects could perform a BCI task in a virtual environment using our system, and how their performance was affected by the delay. Approach. The subjects controlled an avatar by left-hand, right-hand and leg motion or imagery. The BCI classification is based on locating the regions of interest (ROIs) related with each of the motor classes, and selecting the ROI with maximum average values online. The subjects performed a cue-based task and a free-choice task, and the analysis includes evaluation of the performance as well as subjective reports. Main results. Six subjects performed the task with high accuracy when allowed to move their fingers and toes, and three subjects achieved high accuracy using imagery alone. In the cue-based task the accuracy was highest 8-12 s after the trigger, whereas in the free-choice task the subjects performed best when the feedback was provided 6 s after the trigger. Significance. We show that subjects are able to perform a navigation task in a virtual environment using an fMRI-based BCI, despite the hemodynamic delay. The same approach can be extended to other mental tasks and other brain areas.

Short Chemical Ischemia Triggers Phosphorylation of eIF2α and Death of SH-SY5Y Cells but not Proteasome Stress and Heat Shock Protein Response in both SH-SY5Y and T98G Cells.

PubMed

Klacanova, Katarina; Pilchova, Ivana; Klikova, Katarina; Racay, Peter

2016-04-01

Both translation arrest and proteasome stress associated with accumulation of ubiquitin-conjugated protein aggregates were considered as a cause of delayed neuronal death after transient global brain ischemia; however, exact mechanisms as well as possible relationships are not fully understood. The aim of this study was to compare the effect of chemical ischemia and proteasome stress on cellular stress responses and viability of neuroblastoma SH-SY5Y and glioblastoma T98G cells. Chemical ischemia was induced by transient treatment of the cells with sodium azide in combination with 2-deoxyglucose. Proteasome stress was induced by treatment of the cells with bortezomib. Treatment of SH-SY5Y cells with sodium azide/2-deoxyglucose for 15 min was associated with cell death observed 24 h after treatment, while glioblastoma T98G cells were resistant to the same treatment. Treatment of both SH-SY5Y and T98G cells with bortezomib was associated with cell death, accumulation of ubiquitin-conjugated proteins, and increased expression of Hsp70. These typical cellular responses to proteasome stress, observed also after transient global brain ischemia, were not observed after chemical ischemia. Finally, chemical ischemia, but not proteasome stress, was in SH-SY5Y cells associated with increased phosphorylation of eIF2α, another typical cellular response triggered after transient global brain ischemia. Our results showed that short chemical ischemia of SH-SY5Y cells is not sufficient to induce both proteasome stress associated with accumulation of ubiquitin-conjugated proteins and stress response at the level of heat shock proteins despite induction of cell death and eIF2α phosphorylation.

Child abuse associates with an imbalance of oligodendrocyte-lineage cells in ventromedial prefrontal white matter.

PubMed

Tanti, A; Kim, J J; Wakid, M; Davoli, M-A; Turecki, G; Mechawar, N

2017-11-21

Child abuse (CA) is a major risk factor for depression, and strongly associates with suicidal behavior during adulthood. Neuroimaging studies have reported widespread changes in white matter integrity and brain connectivity in subjects with a history of CA. Although such observations could reflect changes in myelin and oligodendrocyte function, their cellular underpinnings have never been addressed. Using postmortem brain samples from depressed suicides with or without history of CA and matched controls (18 per group), we aimed to characterize the effects of CA on oligodendrocyte-lineage (OL) cells in the ventromedial prefrontal white matter. Using immunoblotting, double-labeling immunofluorescence and stereological estimates of stage-specific markers, we found that CA is associated with increased numbers of mature myelinating oligodendrocytes, accompanied by decreased numbers of more immature OL cells. This was paralleled by an increased expression of transcription factor MASH1, which is involved in the terminal differentiation of the OL, suggesting that CA may trigger an increased maturation, or bias the populations of OL cells toward a more mature phenotype. Some of these effects, which were absent in the brain of depressed suicides with no history of CA, were also found to recover with age, suggesting that changes in the balance of the OL may reflect a transient adaptive mechanism triggered by early-life adversity. In conclusion, our results indicate that CA in depressed suicides is associated with an imbalance of the OL in the ventromedial prefrontal white matter, an effect that could lead to myelin remodeling and long-term connectivity changes within the limbic network.Molecular Psychiatry advance online publication, 21 November 2017; doi:10.1038/mp.2017.231.

Evidence of bone marrow downregulation in brain-dead rats.

PubMed

Menegat, Laura; Simas, Rafael; Caliman, Julia M; Zanoni, Fernando L; Jacysyn, Jacqueline F; da Silva, Luiz Fernando F; Borelli, Primavera; Moreira, Luiz Felipe P; Sannomiya, Paulina

2017-06-01

Experimental findings support the evidence of a persistent leucopenia triggered by brain death (BD). This study aimed to investigate leucocyte behaviour in bone marrow and blood after BD in rats. BD was induced using intracranial balloon catheter inflation. Sham-operated (SH) rats were trepanned only. Thereafter bone marrow cells were harvested every six hours from the femoral cavity and used for total and differential counts. They were analysed further by flow cytometry to characterize lymphocyte subsets, granulocyte adhesion molecules expression and apoptosis/necrosis [annexin V/propidium iodide (PI) protocol]. BD rats exhibited a reduction in bone marrow cells due to a reduction in lymphocytes (40%) and segmented cells (45%). Bone marrow lymphocyte subsets were similar in BD and SH rats (CD3, P = 0.1; CD4, P = 0.4; CD3/CD4, P = 0.4; CD5, P = 0.4, CD3/CD5, P = 0.2; CD8, P = 0.8). Expression of L-selectin and beta 2 -integrins on granulocytes did not differ (CD11a, P = 0.9; CD11b/c, P = 0.7; CD62L, P = 0.1). There were no differences in the percentage of apoptosis and necrosis (Annexin V, P = 0.73; PI, P = 0.21; Annexin V/PI, P = 0.29). In conclusion, data presented suggest that the downregulation of the bone marrow is triggered by brain death itself, and it is not related to changes in lymphocyte subsets, granulocyte adhesion molecules expression or apoptosis and necrosis. © 2017 The Authors. International Journal of Experimental Pathology © 2017 International Journal of Experimental Pathology.

Social factors and aromatase gene expression during adult male-to-female sex change in captive leopard grouper Mycteroperca rosacea.

PubMed

Romo-Mendoza, Daniel; Campos-Ramos, Rafael; Vázquez-Islas, Grecia; Burgos-Aceves, Mario A; Esquivel-Gutiérrez, Edgar R; Guerrero-Tortolero, Danitzia A

2018-01-25

Social factors and aromatase gene expression in the leopard grouper Mycteroperca rosacea was studied when captive fish were separated by sex during the reproductive (April-June) and post-reproductive (July-September) seasons. Monosex females, monosex males, and mixed-sex, held in social sextet units were analyzed for sex steroids throughout confinement. At the end of the experiment, the gonad-sex was defined by histology, and gonad and brain aromatase gene expressions were quantified. Only males held in the monosex social units changed sex. Histology showed one male remained unchanged, six were found in a transitional sexual stage, in which two had intersex-predominantly-testes, and four had a more defined intersex ovo-testes pattern, and 11 were immature de novo females (neofemales). Neofemales and most intersex fish did not survive. In spring, 11-ketosterone showed a specific male profile, which suggests that male-to-female sex change was not triggered during the reproductive season. The low steroid levels in summer made it impossible to associate the sex change to a gonad hormonal shift; in September, gonad aromatase gene expression was not significantly different among groups. However, brain aromatase expression in intersex fish was significantly higher than monosex females, mixed-sex females, and neofemale groups. These results suggest that in the absence of female hormonal compounds, and at a time when male gonad steroidogenesis was diminished, the brain mediated male-to-male social-behavioral interactions, including stress, by increasing aromatization, resulting in derived intersex-male, which triggered more aromatization, followed by a sex change. Copyright © 2018 Elsevier Inc. All rights reserved.

Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles.

PubMed

Santos, Tiago; Ferreira, Raquel; Quartin, Emanuel; Boto, Carlos; Saraiva, Cláudia; Bragança, José; Peça, João; Rodrigues, Cecília; Ferreira, Lino; Bernardino, Liliana

2017-09-01

Neurogenic niches constitute a powerful endogenous source of new neurons that can be used for brain repair strategies. Neuronal differentiation of these cells can be regulated by molecules such as retinoic acid (RA) or by mild levels of reactive oxygen species (ROS) that are also known to upregulate RA receptor alpha (RARα) levels. Data showed that neural stem cells from the subventricular zone (SVZ) exposed to blue light (405nm laser) transiently induced NADPH oxidase-dependent ROS, resulting in β-catenin activation and neuronal differentiation, and increased RARα levels. Additionally, the same blue light stimulation was capable of triggering the release of RA from light-responsive nanoparticles (LR-NP). The synergy between blue light and LR-NP led to amplified neurogenesis both in vitro and in vivo, while offering a temporal and spatial control of RA release. In conclusion, this combinatory treatment offers great advantages to potentiate neuronal differentiation, and provides an innovative and efficient application for brain regenerative therapies. Controlling the differentiation of stem cells would support the development of promising brain regenerative therapies. Blue light transiently increased reactive oxygen species, resulting in neuronal differentiation and increased retinoic acid receptor (RARα) levels. Additionally, the same blue light stimulation was capable of triggering the release of RA from light-responsive nanoparticles (LR-NP). The synergy between blue light and LR-NP led to amplified neurogenesis, while offering a temporal and spatial control of RA release. In this sense, our approach relying on the modulation of endogenous stem cells for the generation of new neurons may support the development of novel clinical therapies. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Dissecting the Roles of Brain Injury and Combat-Related Stress in Post-Traumatic Headache

DTIC Science & Technology

2015-10-01

were the major goals of the project? Post-traumatic headache (PTH) is an epidemic in our military personnel. It is a chronic, migraine -like...and affective processing that lead to PTH. Cortical spreading depression (CSD) is the physiological correlate of the migraine aura, but it also...paradigm. NTG infusion triggers migraine without aura in human migraineurs and reduced mechanical allodynia threshold in rodents. This enables 11

Why does brain metabolism not favor burning of fatty acids to provide energy? - Reflections on disadvantages of the use of free fatty acids as fuel for brain

PubMed Central

Schönfeld, Peter; Reiser, Georg

2013-01-01

It is puzzling that hydrogen-rich fatty acids are used only poorly as fuel in the brain. The long-standing belief that a slow passage of fatty acids across the blood–brain barrier might be the reason. However, this has been corrected by experimental results. Otherwise, accumulated nonesterified fatty acids or their activated derivatives could exert detrimental activities on mitochondria, which might trigger the mitochondrial route of apoptosis. Here, we draw attention to three particular problems: (1) ATP generation linked to β-oxidation of fatty acids demands more oxygen than glucose, thereby enhancing the risk for neurons to become hypoxic; (2) β-oxidation of fatty acids generates superoxide, which, taken together with the poor anti-oxidative defense in neurons, causes severe oxidative stress; (3) the rate of ATP generation based on adipose tissue-derived fatty acids is slower than that using blood glucose as fuel. Thus, in periods of extended continuous and rapid neuronal firing, fatty acid oxidation cannot guarantee rapid ATP generation in neurons. We conjecture that the disadvantages connected with using fatty acids as fuel have created evolutionary pressure on lowering the expression of the β-oxidation enzyme equipment in brain mitochondria to avoid extensive fatty acid oxidation and to favor glucose oxidation in brain. PMID:23921897

Microstructural Abnormalities Were Found in Brain Gray Matter from Patients with Chronic Myofascial Pain

PubMed Central

Xie, Peng; Qin, Bangyong; Song, Ganjun; Zhang, Yi; Cao, Song; Yu, Jin; Wu, Jianjiang; Wang, Jiang; Zhang, Tijiang; Zhang, Xiaoming; Yu, Tian; Zheng, Hong

2016-01-01

Myofascial pain, presented as myofascial trigger points (MTrPs)-related pain, is a common, chronic disease involving skeletal muscle, but its underlying mechanisms have been poorly understood. Previous studies have revealed that chronic pain can induce microstructural abnormalities in the cerebral gray matter. However, it remains unclear whether the brain gray matters of patients with chronic MTrPs-related pain undergo alteration. In this study, we employed the Diffusion Kurtosis Imaging (DKI) technique, which is particularly sensitive to brain microstructural perturbation, to monitor the MTrPs-related microstructural alterations in brain gray matter of patients with chronic pain. Our results revealed that, in comparison with the healthy controls, patients with chronic myofascial pain exhibited microstructural abnormalities in the cerebral gray matter and these lesions were mainly distributed in the limbic system and the brain areas involved in the pain matrix. In addition, we showed that microstructural abnormalities in the right anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) had a significant negative correlation with the course of disease and pain intensity. The results of this study demonstrated for the first time that there are microstructural abnormalities in the brain gray matter of patients with MTrPs-related chronic pain. Our findings may provide new insights into the future development of appropriate therapeutic strategies to this disease. PMID:28066193

Diminished brain resilience syndrome: A modern day neurological pathology of increased susceptibility to mild brain trauma, concussion, and downstream neurodegeneration.

PubMed

Morley, Wendy A; Seneff, Stephanie

2014-01-01

The number of sports-related concussions has been steadily rising in recent years. Diminished brain resilience syndrome is a term coined by the lead author to describe a particular physiological state of nutrient functional deficiency and disrupted homeostatic mechanisms leading to increased susceptibility to previously considered innocuous concussion. We discuss how modern day environmental toxicant exposure, along with major changes in our food supply and lifestyle practices, profoundly reduce the bioavailability of neuro-critical nutrients such that the normal processes of homeostatic balance and resilience are no longer functional. Their diminished capacity triggers physiological and biochemical 'work around' processes that result in undesirable downstream consequences. Exposure to certain environmental chemicals, particularly glyphosate, the active ingredient in the herbicide, Roundup(®), may disrupt the body's innate switching mechanism, which normally turns off the immune response to brain injury once danger has been removed. Deficiencies in serotonin, due to disruption of the shikimate pathway, may lead to impaired melatonin supply, which reduces the resiliency of the brain through reduced antioxidant capacity and alterations in the cerebrospinal fluid, reducing critical protective buffering mechanisms in impact trauma. Depletion of certain rare minerals, overuse of sunscreen and/or overprotection from sun exposure, as well as overindulgence in heavily processed, nutrient deficient foods, further compromise the brain's resilience. Modifications to lifestyle practices, if widely implemented, could significantly reduce this trend of neurological damage.

Why does brain metabolism not favor burning of fatty acids to provide energy? Reflections on disadvantages of the use of free fatty acids as fuel for brain.

PubMed

Schönfeld, Peter; Reiser, Georg

2013-10-01

It is puzzling that hydrogen-rich fatty acids are used only poorly as fuel in the brain. The long-standing belief that a slow passage of fatty acids across the blood-brain barrier might be the reason. However, this has been corrected by experimental results. Otherwise, accumulated nonesterified fatty acids or their activated derivatives could exert detrimental activities on mitochondria, which might trigger the mitochondrial route of apoptosis. Here, we draw attention to three particular problems: (1) ATP generation linked to β-oxidation of fatty acids demands more oxygen than glucose, thereby enhancing the risk for neurons to become hypoxic; (2) β-oxidation of fatty acids generates superoxide, which, taken together with the poor anti-oxidative defense in neurons, causes severe oxidative stress; (3) the rate of ATP generation based on adipose tissue-derived fatty acids is slower than that using blood glucose as fuel. Thus, in periods of extended continuous and rapid neuronal firing, fatty acid oxidation cannot guarantee rapid ATP generation in neurons. We conjecture that the disadvantages connected with using fatty acids as fuel have created evolutionary pressure on lowering the expression of the β-oxidation enzyme equipment in brain mitochondria to avoid extensive fatty acid oxidation and to favor glucose oxidation in brain.

Stimuli and consequences of dendritic release of oxytocin within the brain.

PubMed

Neumann, I D

2007-11-01

The brain oxytocin system has served as a distinguished model system in neuroendocrinology to study detailed mechanisms of intracerebral release, in particular of somatodendritic release, and its behavioural and neuroendocrine consequences. It has been shown that oxytocin is released within various brain regions, but evidence for dendritic release is limited to the main sites of oxytocin synthesis, i.e. the hypothalamic SON (supraoptic nucleus) and PVN (paraventricular nucleus). In the present paper, stimuli of dendritic release of oxytocin and the related neuropeptide vasopressin are discussed, including parturition and suckling, i.e. the period of a highly activated brain oxytocin system. Also, exposure to various pharmacological, psychological or physical stressors triggers dendritic oxytocin release, as monitored by intracerebral microdialysis within the SON and PVN during ongoing behavioural testing. So far, dendritic release of the neuropeptide has only been demonstrated within the hypothalamus, but intracerebral oxytocin release has also been found within the central amygdala and the septum in response to various stimuli including stressor exposure. Such a locally released oxytocin modulates physiological and behavioural reproductive functions, emotionality and hormonal stress responses, as it exerts, for example, pro-social, anxiolytic and antistress actions within restricted brain regions. These discoveries make oxytocin a promising neuromodulator of the brain for psychotherapeutic intervention and treatment of numerous psychiatric illnesses, for example, anxiety-related diseases, social phobia, autism and postpartum depression.

Neuroprotective effects of NAP against excitotoxic brain damage in the newborn mice: implications for cerebral palsy.

PubMed

Sokolowska, P; Passemard, S; Mok, A; Schwendimann, L; Gozes, I; Gressens, P

2011-01-26

Activity-dependent neuroprotective protein (ADNP) was shown to be essential for embryogenesis and brain development while NAP, an active motif of ADNP, is neuroprotective in a broad range of neurodegenerative disorders. In the present study, we examined the protective potential of ADNP/NAP in a mouse model of excitotoxic brain lesion mimicking brain damage associated with cerebral palsy. We demonstrated that NAP had a potent neuroprotective effect against ibotenate-induced excitotoxic damage in the cortical plate and the white matter of P5 mice, and moderate against brain lesions of P0 mice. In contrast, endogenous ADNP appears not to be involved in the response to excitotoxic challenge in the studied model. Our findings further show that NAP reduced the number of apoptotic neurons through activation of PI-3K/Akt pathway in the cortical plate or both PI-3K/Akt and MAPK/MEK1 kinases in the white matter. In addition, NAP prevented ibotenate-induced loss of pre-oligodendrocytes without affecting the number of astrocytes or activated microglia around the site of injection. These findings indicate that protective actions of NAP are mediated by triggering transduction pathways that are crucial for neuronal and oligodendroglial survival, thus, NAP might be a promising therapeutic agent for treating developing brain damage. © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Phosphatidyl-Inositol-3 Kinase Inhibitors Regulate Peptidoglycan-Induced Myeloid Leukocyte Recruitment, Inflammation, and Neurotoxicity in Mouse Brain.

PubMed

Arroyo, Daniela S; Gaviglio, Emilia A; Peralta Ramos, Javier M; Bussi, Claudio; Avalos, Maria P; Cancela, Liliana M; Iribarren, Pablo

2018-01-01

Acute brain injury leads to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral myeloid cells (MC), which contribute to the inflammatory response involved in neuronal damage. We previously reported that TLR2 stimulation by peptidoglycan (PGN) from Staphylococcus aureus, in vitro and in vivo , induced microglial cell activation followed by autophagy induction. In this report, we evaluated if phosphatidyl-inositol-3 kinase (PI3K) pharmacological inhibitors LY294200 and 3-methyladenine (3-MA) can modulate the innate immune response to PGN in the central nervous system. We found that injection of PGN into the mouse brain parenchyma (caudate putamen) triggered an inflammatory reaction, which involved activation of microglial cells, recruitment of infiltrating MC to injection site, production of pro-inflammatory mediators, and neuronal injury. In addition, we observed the accumulation of LC3B + CD45 + cells and colocalization of LC3B and lysosomal-associated membrane protein 1 in brain cells. Besides, we found that pharmacological inhibitors of PI3K, including the classical autophagy inhibitor 3-MA, reduced the recruitment of MC, microglial cell activation, and neurotoxicity induced by brain PGN injection. Collectively, our results suggest that PI3K pathways and autophagic response may participate in the PGN-induced microglial activation and MC recruitment to the brain. Thus, inhibition of these pathways could be therapeutically targeted to control acute brain inflammatory conditions.

Cholecystokinin levels in prohormone convertase 2 knock-out mouse brain regions reveal a complex phenotype of region-specific alterations.

PubMed

Beinfeld, Margery C; Blum, Alissa; Vishnuvardhan, Daesety; Fanous, Sanya; Marchand, James E

2005-11-18

Prohormone convertase 2 is widely co-localized with cholecystokinin in rodent brain. To examine its role in cholecystokinin processing, cholecystokinin levels were measured in dissected brain regions from prohormone convertase 2 knock-out mice. Cholecystokinin levels were lower in hippocampus, septum, thalamus, mesencephalon, and pons in knock-out mice than wild-type mice. In cerebral cortex, cortex-related structures and olfactory bulb, cholecystokinin levels were higher than wild type. Female mice were more affected by the loss of prohormone convertase 2 than male mice. The decrease in cholecystokinin levels in these brain regions shows that prohormone convertase 2 is important for cholecystokinin processing. Quantitative polymerase chain reaction measurements were performed to examine the relationship between peptide levels and cholecystokinin and enzyme expression. They revealed that cholecystokinin and prohormone convertase 1 mRNA levels in cerebral cortex and olfactory bulb were actually lower in knock-out than wild type, whereas their expression in other brain regions of knock-out mouse brain was the same as wild type. Female mice frequently had higher expression of cholecystokinin and prohormone convertase 1, 2, and 5 mRNA than male mice. The loss of prohormone convertase 2 alters CCK processing in specific brain regions. This loss also appears to trigger compensatory mechanisms in cerebral cortex and olfactory bulb that produce elevated levels of cholecystokinin but do not involve increased expression of cholecystokinin, prohormone convertase 1 or 5 mRNA.

Phosphatidyl-Inositol-3 Kinase Inhibitors Regulate Peptidoglycan-Induced Myeloid Leukocyte Recruitment, Inflammation, and Neurotoxicity in Mouse Brain

PubMed Central

Arroyo, Daniela S.; Gaviglio, Emilia A.; Peralta Ramos, Javier M.; Bussi, Claudio; Avalos, Maria P.; Cancela, Liliana M.; Iribarren, Pablo

2018-01-01

Acute brain injury leads to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral myeloid cells (MC), which contribute to the inflammatory response involved in neuronal damage. We previously reported that TLR2 stimulation by peptidoglycan (PGN) from Staphylococcus aureus, in vitro and in vivo, induced microglial cell activation followed by autophagy induction. In this report, we evaluated if phosphatidyl-inositol-3 kinase (PI3K) pharmacological inhibitors LY294200 and 3-methyladenine (3-MA) can modulate the innate immune response to PGN in the central nervous system. We found that injection of PGN into the mouse brain parenchyma (caudate putamen) triggered an inflammatory reaction, which involved activation of microglial cells, recruitment of infiltrating MC to injection site, production of pro-inflammatory mediators, and neuronal injury. In addition, we observed the accumulation of LC3B+ CD45+ cells and colocalization of LC3B and lysosomal-associated membrane protein 1 in brain cells. Besides, we found that pharmacological inhibitors of PI3K, including the classical autophagy inhibitor 3-MA, reduced the recruitment of MC, microglial cell activation, and neurotoxicity induced by brain PGN injection. Collectively, our results suggest that PI3K pathways and autophagic response may participate in the PGN-induced microglial activation and MC recruitment to the brain. Thus, inhibition of these pathways could be therapeutically targeted to control acute brain inflammatory conditions. PMID:29719536

A comparative pharmacognostical and preliminary physico-chemical analysis of stem and leaf of Bacopa monnieri (L.) Pennel and Bacopa floribunda (R.BR.) Wettst.

PubMed

Gubbannavar, Jyoti S; Chandola, H M; Harisha, C R; Khanpara, Komal; Shukla, V J

2013-01-01

Brahmi is a well-known herbal drug having an effect on brain as a memory enhancer. Bacopa monnieri (L.) Pennel and Bacopa floribunda (R.Br.) Wettst are both marketed in the name of Brahmi. The present study differentiates Bacopa monnieri and Bacopa floribunda in morphology, transverse section (T.S.) of root and leaf, powder microscopy, and chemical constituents. Morphological characters show color difference in flower, stem and leaf and differences in microscopic study, organoleptic study, and powder characteristics. Morphologically, Bacopa monnieri leaf is fleshy and more succulent than Bacopa floribunda leaf. There is also a difference in the interval of the stem internodes of the two. Physico-chemical analysis revealed presence of 26% bacoside A in Bacopa floribunda leaf and 27% in Bacopa floribunda stem, which is higher than the bacoside A content in leaf (22%) and stem (18%) of Bacopa monnieri. However due to the hemolytic action of bacoside A, which is the toxic effect of the chemical constituent, it seems likely that Bacopa monnieri is more popular in regular use than Bacopa floribunda.

NMDA receptor-antagonistic properties of hyperforin, a constituent of St. John's Wort.

PubMed

Kumar, Vikas; Mdzinarishvili, Alexander; Kiewert, Cornelia; Abbruscato, Thomas; Bickel, Ulrich; van der Schyf, Cornelis J; Klein, Jochen

2006-09-01

Extracts of the medicinal plant St. John's wort (Hypericum perforatum) are widely used for the treatment of affective disorders. Hyperforin, a constituent of St. John's wort, is known to modulate the release and re-uptake of various neurotransmitters, an action that likely underlies its antidepressive activity. We now report that hyperforin also has N-methyl-D-aspartate (NMDA)-antagonistic effects. Hyperforin (10 microM) was found to inhibit the NMDA-induced calcium influx into cortical neurons. In rat hippocampal slices, hyperforin inhibited the NMDA-receptor-mediated release of choline from phospholipids. Hyperforin also antagonized the increase of water content in freshly isolated hippocampal slices, and it counteracted, at 3 and 10 microM, the increase of water content induced by NMDA. Hyperforin was inactive, however, in two in vivo models of brain edema formation, middle cerebral artery occlusion and water intoxication in mice. In conclusion, hyperforin has NMDA-receptor-antagonistic and potential neuroprotective effects in vitro. This effect may contribute to the therapeutic effectiveness of St. John's wort extracts in some situations, for example, for relapse prevention in alcoholism.

Inhibition of benzodiazepine binding in vitro by amentoflavone, a constituent of various species of Hypericum.

PubMed

Baureithel, K H; Büter, K B; Engesser, A; Burkard, W; Schaffner, W

1997-06-01

Flower extracts of Hypericum perforatum, Hypericum hirsutum, Hypericum patulum and Hypericum olympicum efficiently inhibited binding of [3H]flumazenil to rat brain benzodiazepine binding sites of the GABAA-receptor in vitro with IC50 values of 6.83, 6.97, 13.2 and 6.14 micrograms/ml, respectively. Single constituents of the extracts like hypericin, the flavones quercetin and luteolin, the glycosylated flavonoides rutin, hyperoside and quercitrin and the biflavone 13, II8-biapigenin did not inhibit binding up to concentrations of 1 microM. In contrast, amentoflavone revealed an IC50 = 14.9 +/- 1.9 nM on benzodiazepine binding in vitro. Comparative HPLC analyses of hypericin and amentoflavone in extracts of different Hypericum species revealed a possible correlation between the amentoflavone concentration and the inhibition of flumazenil binding. For hypericin no such correlation was observed. Our experimental data demonstrate that amentoflavone, in contrast to hypericin, presents a very active compound with regard to the inhibition of [3H]-flumazenil binding in vitro and thus might be involved in the antidepressant effects of Hypericum perforatum extracts.

Chemical constituents and antiproliferative effects of cultured Mougeotia nummuloides and Spirulina major against cancerous cell lines.

PubMed

Erenler, Ramazan; Pabuccu, Koksal; Yaglioglu, Ayse Sahin; Demirtas, Ibrahim; Gul, Fatih

2016-03-01

In this study, the effect of Mougeotia nummuloides and Spirulina major on Vero cells (African green monkey kidney), C6 cells (rat brain tumor cells) and HeLa cells (human uterus carcinoma) was investigated in vitro. The antiproliferative effect of the methanol extract of M. nummuloides and S. major compared with 5-fluorourasil (5-FU) and cisplatin was tested at various concentrations using the BrdU Cell Proliferation ELISA. Both M. nummuloides and S. major extracts significantly inhibited the proliferation of Vero, HeLa and C6 cancer cell lines with IC50 and IC75 values. The M. nummuloides extract exhibited higher activity than 5-FU and cisplatin on Vero and C6 cells at high concentrations. The S. major extract revealed better antifproliferative activity than standards against Vero cells at 500 μg/mL. The compounds of methanol extracts were determined by GC-MS after the silylation process. Trehalose, monostearin and 1-monopalmitin were detected as major products in the M. nummuloides extract where as in the S. major extract; monostearin, 1-monopalmitin and hexyl alcohol were the main constituents.

Saffron as an antidote or a protective agent against natural or chemical toxicities.

PubMed

Razavi, Bibi Marjan; Hosseinzadeh, Hossein

2015-05-01

Saffron (Crocus sativus) is an extensively used food additive for its color and taste. Since ancient times this plant has been introduced as a marvelous medicine throughout the world. The wide spectrum of saffron pharmacological activities is related to its major constituents including crocin, crocetin and safranal. Based on several studies, saffron and its active ingredients have been used as an antioxidant, antiinflammatory and antinociceptive, antidepressant, antitussive, anticonvulsant, memory enhancer, hypotensive and anticancer. According to the literatures, saffron has remarkable therapeutic effects. The protective effects of saffron and its main constituents in different tissues including brain, heart, liver, kidney and lung have been reported against some toxic materials either natural or chemical toxins in animal studies.In this review article, we have summarized different in vitro and animal studies in scientific databases which investigate the antidotal and protective effects of saffron and its major components against natural toxins and chemical-induced toxicities. Due to the lake of human studies, further investigations are required to ascertain the efficacy of saffron as an antidote or a protective agent in human intoxication.

Potassium efflux fires the canon: Potassium efflux as a common trigger for canonical and noncanonical NLRP3 pathways.

PubMed

Rivers-Auty, Jack; Brough, David

2015-10-01

Murine caspase-11 and its human orthologues, caspase-4 and caspase-5, activate an inflammatory response following cytoplasmic recognition of cell wall constituents from Gram-negative bacteria, such as LPS. This inflammatory response involves pyroptotic cell death and the concomitant release of IL-1α, as well as the production of IL-1β and IL-18 through the noncanonical NLR family, pyrin domain containing 3 (NLRP3) pathway. This commentary discusses three papers in this issue of the European Journal of Immunology that advance our understanding of the roles of caspase-11, -4, and -5 in the noncanonical pathway. By utilizing the new gene editing technique, clustered regularly interspaced short palindromic repeats (CRISPR), as well as sensitive cell imaging techniques, these papers establish that cytoplasmic LPS-dependent IL-1β production requires the NLRP3 inflammasome and that its activation is dependent on K(+) efflux, whereas IL-1α release and pyroptotic cell death pathways are NLRP3-independent. These findings expand on previous research implicating K(+) efflux as the principal trigger for NLRP3 activation and suggest that canonical and noncanonical NLRP3 pathways are not as dissimilar as first thought. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Decoding Pedophilia: Increased Anterior Insula Response to Infant Animal Pictures

PubMed Central

Ponseti, Jorge; Bruhn, Daniel; Nolting, Julia; Gerwinn, Hannah; Pohl, Alexander; Stirn, Aglaja; Granert, Oliver; Laufs, Helmut; Deuschl, Günther; Wolff, Stephan; Jansen, Olav; Siebner, Hartwig; Briken, Peer; Mohnke, Sebastian; Amelung, Till; Kneer, Jonas; Schiffer, Boris; Walter, Henrik; Kruger, Tillmann H. C.

2018-01-01

Previous research found increased brain responses of men with sexual interest in children (i.e., pedophiles) not only to pictures of naked children but also to pictures of child faces. This opens the possibly that pedophilia is linked (in addition to or instead of an aberrant sexual system) to an over-active nurturing system. To test this hypothesis we exposed pedophiles and healthy controls to pictures of infant and adult animals during functional magnetic resonance imaging of the brain. By using pictures of infant animals (instead of human infants), we aimed to elicit nurturing processing without triggering sexual processing. We hypothesized that elevated brain responses to nurturing stimuli will be found – in addition to other brain areas – in the anterior insula of pedophiles because this area was repeatedly found to be activated when adults see pictures of babies. Behavioral ratings confirmed that pictures of infant or adult animals were not perceived as sexually arousing neither by the pedophilic participants nor by the heathy controls. Statistical analysis was applied to the whole brain as well as to the anterior insula as region of interest. Only in pedophiles did infants relative to adult animals increase brain activity in the anterior insula, supplementary motor cortex, and dorsolateral prefrontal areas. Within-group analysis revealed an increased brain response to infant animals in the left anterior insular cortex of the pedophilic participants. Currently, pedophilia is considered the consequence of disturbed sexual or executive brain processing, but details are far from known. The present findings raise the question whether there is also an over-responsive nurturing system in pedophilia. PMID:29403367

Intravenous Heroin Induces Rapid Brain Hypoxia and Hyperglycemia that Precede Brain Metabolic Response.

PubMed

Solis, Ernesto; Cameron-Burr, Keaton T; Shaham, Yavin; Kiyatkin, Eugene A

2017-01-01

Heroin use and overdose have increased in recent years as people transition from abusing prescription opiates to using the cheaper street drug. Despite a long history of research, many physiological effects of heroin and their underlying mechanisms remain unknown. Here, we used high-speed amperometry to examine the effects of intravenous heroin on oxygen and glucose levels in the nucleus accumbens (NAc) in freely-moving rats. Heroin within the dose range of human drug use and rat self-administration (100-200 μg/kg) induced a rapid, strong, but transient drop in NAc oxygen that was followed by a slower and more prolonged rise in glucose. Using oxygen recordings in the subcutaneous space, a densely-vascularized site with no metabolic activity, we confirmed that heroin-induced brain hypoxia results from decreased blood oxygen, presumably due to drug-induced respiratory depression. Respiratory depression and the associated rise in CO 2 levels appear to drive tonic increases in NAc glucose via local vasodilation. Heroin-induced changes in oxygen and glucose were rapid and preceded the slow and prolonged increase in brain temperature and were independent of enhanced intra-brain heat production, an index of metabolic activation. A very high heroin dose (3.2 mg/kg), corresponding to doses used by experienced drug users in overdose conditions, caused strong and prolonged brain hypoxia and hyperglycemia coupled with robust initial hypothermia that preceded an extended hyperthermic response. Our data suggest heroin-induced respiratory depression as a trigger for brain hypoxia, which leads to hyperglycemia, both of which appear independent of subsequent changes in brain temperature and metabolic neural activity.

Decoding Pedophilia: Increased Anterior Insula Response to Infant Animal Pictures.

PubMed

Ponseti, Jorge; Bruhn, Daniel; Nolting, Julia; Gerwinn, Hannah; Pohl, Alexander; Stirn, Aglaja; Granert, Oliver; Laufs, Helmut; Deuschl, Günther; Wolff, Stephan; Jansen, Olav; Siebner, Hartwig; Briken, Peer; Mohnke, Sebastian; Amelung, Till; Kneer, Jonas; Schiffer, Boris; Walter, Henrik; Kruger, Tillmann H C

2017-01-01

Previous research found increased brain responses of men with sexual interest in children (i.e., pedophiles) not only to pictures of naked children but also to pictures of child faces. This opens the possibly that pedophilia is linked (in addition to or instead of an aberrant sexual system) to an over-active nurturing system. To test this hypothesis we exposed pedophiles and healthy controls to pictures of infant and adult animals during functional magnetic resonance imaging of the brain. By using pictures of infant animals (instead of human infants), we aimed to elicit nurturing processing without triggering sexual processing. We hypothesized that elevated brain responses to nurturing stimuli will be found - in addition to other brain areas - in the anterior insula of pedophiles because this area was repeatedly found to be activated when adults see pictures of babies. Behavioral ratings confirmed that pictures of infant or adult animals were not perceived as sexually arousing neither by the pedophilic participants nor by the heathy controls. Statistical analysis was applied to the whole brain as well as to the anterior insula as region of interest. Only in pedophiles did infants relative to adult animals increase brain activity in the anterior insula, supplementary motor cortex, and dorsolateral prefrontal areas. Within-group analysis revealed an increased brain response to infant animals in the left anterior insular cortex of the pedophilic participants. Currently, pedophilia is considered the consequence of disturbed sexual or executive brain processing, but details are far from known. The present findings raise the question whether there is also an over-responsive nurturing system in pedophilia.

CD11c- and CD11b-expressing mouse leukocytes transport single Toxoplasma gondii tachyzoites to the brain

PubMed Central

Courret, Nathalie; Darche, Sylvie; Sonigo, Pierre; Milon, Geneviève; Buzoni-Gâtel, Dominique; Tardieux, Isabelle

2006-01-01

The protozoan parasite Toxoplasma gondii enters hosts through the intestinal mucosa and colonizes distant tissues such as the brain, where its progeny persists for a lifetime. We investigated the role of CD11c- and CD11b-expressing leukocytes in T gondii transport during the early step of parasitism from the mouse small intestine and during subsequent parasite localization in the brain. Following intragastric inoculation of cyst-containing parasites in mice, CD11c+ dendritic cells from the intestinal lamina propria, the Peyer patches, and the mesenteric lymph nodes were parasitized while in the blood, parasites were associated with the CD11c- CD11b+ monocytes. Using adoptive transfer experiments, we demonstrated that these parasitized cells triggered a parasitic process in the brain of naive recipient mice. Ex vivo analysis of parasitized leukocytes showed that single tachyzoites remained at the cell periphery, often surrounded by the host cell plasma membrane, but did not divide. Using either a dye that labels circulating leukocytes or an antibody known to prevent CD11b+ circulating leukocytes from leaving the microvascular bed lumen, and chimeric mice in which the hematopoietic cells expressed the green fluorescent protein, we established that T gondii zoites hijacked CD11b+ leukocytes to reach the brain extravascular space. PMID:16051744

Transferrin-conjugated magnetic dextran-spermine nanoparticles for targeted drug transport across blood-brain barrier.

PubMed

Ghadiri, Maryam; Vasheghani-Farahani, Ebrahim; Atyabi, Fatemeh; Kobarfard, Farzad; Mohamadyar-Toupkanlou, Farzaneh; Hosseinkhani, Hossein

2017-10-01

Application of many vital hydrophilic medicines have been restricted by blood-brain barrier (BBB) for treatment of brain diseases. In this study, a targeted drug delivery system based on dextran-spermine biopolymer was developed for drug transport across BBB. Drug loaded magnetic dextran-spermine nanoparticles (DS-NPs) were prepared via ionic gelation followed by transferrin (Tf) conjugation as targeting moiety. The characteristics of Tf conjugated nanoparticles (TDS-NPs) were analyzed by different methods and their cytotoxicity effects on U87MG cells were tested. The superparamagnetic characteristic of TDS-NPs was verified by vibration simple magnetometer. Capecitabine loaded TDS-NPs exhibited pH-sensitive release behavior with enhanced cytotoxicity against U87MG cells, compared to DS-NPs and free capecitabine. Prussian-blue staining and TEM-imaging showed the significant cellular uptake of TDS-NPs. Furthermore, a remarkable increase of Fe concentrations in brain was observed following their biodistribution and histological studies in vivo, after 1 and 7 days of post-injection. Enhanced drug transport across BBB and pH-triggered cellular uptake of TDS-NPs indicated that these theranostic nanocarriers are promising candidate for the brain malignance treatment. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2851-2864, 2017. © 2017 Wiley Periodicals, Inc.

Ethanol-Induced Neurodegeneration and Glial Activation in the Developing Brain.

PubMed

Saito, Mariko; Chakraborty, Goutam; Hui, Maria; Masiello, Kurt; Saito, Mitsuo

2016-08-16

Ethanol induces neurodegeneration in the developing brain, which may partially explain the long-lasting adverse effects of prenatal ethanol exposure in fetal alcohol spectrum disorders (FASD). While animal models of FASD show that ethanol-induced neurodegeneration is associated with glial activation, the relationship between glial activation and neurodegeneration has not been clarified. This review focuses on the roles of activated microglia and astrocytes in neurodegeneration triggered by ethanol in rodents during the early postnatal period (equivalent to the third trimester of human pregnancy). Previous literature indicates that acute binge-like ethanol exposure in postnatal day 7 (P7) mice induces apoptotic neurodegeneration, transient activation of microglia resulting in phagocytosis of degenerating neurons, and a prolonged increase in glial fibrillary acidic protein-positive astrocytes. In our present study, systemic administration of a moderate dose of lipopolysaccharides, which causes glial activation, attenuates ethanol-induced neurodegeneration. These studies suggest that activation of microglia and astrocytes by acute ethanol in the neonatal brain may provide neuroprotection. However, repeated or chronic ethanol can induce significant proinflammatory glial reaction and neurotoxicity. Further studies are necessary to elucidate whether acute or sustained glial activation caused by ethanol exposure in the developing brain can affect long-lasting cellular and behavioral abnormalities observed in the adult brain.

Nutrients, Microglia Aging, and Brain Aging.

PubMed

Wu, Zhou; Yu, Janchun; Zhu, Aiqin; Nakanishi, Hiroshi

2016-01-01

As the life expectancy continues to increase, the cognitive decline associated with Alzheimer's disease (AD) becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of "microglia aging." This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging.

Nutrients, Microglia Aging, and Brain Aging

PubMed Central

Wu, Zhou; Yu, Janchun; Zhu, Aiqin; Nakanishi, Hiroshi

2016-01-01

As the life expectancy continues to increase, the cognitive decline associated with Alzheimer's disease (AD) becomes a big major issue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start to release proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challenges induce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even in middle-aged animals. We thus raise the concept of “microglia aging.” This concept is based on the fact that microglia are the key contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammation induces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types of cells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatory mediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. The intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive decline during aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We propose that a nutritional approach to controlling microglia aging will open a new window for healthy brain aging. PMID:26941889

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

Recombinant Human Sonic Hedgehog Protein Regulates the Expression of ZO-1 and Occludin by Activating Angiopoietin-1 in Stroke Damage

PubMed Central

Chen, Sheng-cai; Huang, Ming; Wang, Yong; Gao, Yuan; Huang, Yan; Wang, Meng-die; Mao, Ling; Hu, Bo

2013-01-01

This study examines the regulating effect of Sonic Hedgehog (Shh) on the permeability of the blood-brain barrier (BBB) in cerebral ischemia. By employing permanent middle cerebral artery occlusion (pMCAO) model, we find that Shh significantly decreases brain edema and preserves BBB permeability. Moreover, Shh increases zonula occludens-1 (ZO-1), occludin and angiopiotetin-1 (Ang-1) expression in the ischemic penumbra. Blockage of Shh with cyclopamine abolishes the effects of Shh on brain edema, BBB permeability and ZO-1, occludin, Ang-1 expression. Primary brain microvessel endothelial cells (BMECs) and astrocytes were pre-treated with Shh, cyclopamine, Ang-1-neutralizing antibody, and subjected to oxygen-glucose deprivation (OGD). Results show that the Ang-1 protein level in the culture medium of Shh-treated astrocytes is significantly higher. Shh also increased ZO-1, occludin and Ang-1 expression in BMECs, while cyclopamine and Ang-1-neutralizing antibody inhibited the effects of Shh on the ZO-1 and occludin expression, respectively. This study suggests that, under ischemic insults, Shh triggers Ang-1 production predominantly in astrocytes, and the secreted Ang-1 acts on BMECs, thereby upregulating ZO-1 and occludin to repair the tight junction and ameliorate the brain edema and BBB leakage. PMID:23894369

Clear signals or mixed messages: inter-individual emotion congruency modulates brain activity underlying affective body perception

PubMed Central

de Gelder, B.

2016-01-01

The neural basis of emotion perception has mostly been investigated with single face or body stimuli. However, in daily life one may also encounter affective expressions by groups, e.g. an angry mob or an exhilarated concert crowd. In what way is brain activity modulated when several individuals express similar rather than different emotions? We investigated this question using an experimental design in which we presented two stimuli simultaneously, with same or different emotional expressions. We hypothesized that, in the case of two same-emotion stimuli, brain activity would be enhanced, while in the case of two different emotions, one emotion would interfere with the effect of the other. The results showed that the simultaneous perception of different affective body expressions leads to a deactivation of the amygdala and a reduction of cortical activity. It was revealed that the processing of fearful bodies, compared with different-emotion bodies, relied more strongly on saliency and action triggering regions in inferior parietal lobe and insula, while happy bodies drove the occipito-temporal cortex more strongly. We showed that this design could be used to uncover important differences between brain networks underlying fearful and happy emotions. The enhancement of brain activity for unambiguous affective signals expressed by several people simultaneously supports adaptive behaviour in critical situations. PMID:27025242

NAD+ depletion or PAR polymer formation: which plays the role of executioner in ischaemic cell death?

PubMed

Siegel, C; McCullough, L D

2011-09-01

Multiple cell death pathways are activated in cerebral ischaemia. Much of the initial injury, especially in the core of the infarct where cerebral blood flow is severely reduced, is necrotic and secondary to severe energy failure. However, there is considerable evidence that delayed cell death continues for several days, primarily in the penumbral region. As reperfusion therapies grow in number and effectiveness, restoration of blood flow early after injury may lead to a shift towards apoptosis. It is important to elucidate what are the key mediators of apoptotic cell death after stroke, as inhibition of apoptosis may have therapeutic implications. There are two well described pathways that lead to apoptotic cell death; the caspase pathway and the more recently described caspase-independent pathway triggered by poly-ADP-ribose polymers (PARP) activation. Caspase-induced cell death is initiated by release of mitochondrial cytochrome c, formation of the cytosolic apoptosome, and activation of endonucleases leading to a multitude of small randomly cleaved DNA fragments. In contrast caspase-independent cell death is secondary to activation of apoptosis inducing factor (AIF). Mitochondrial AIF translocates to the nucleus, where it induces peripheral chromatin condensation, as well as characteristic high-molecular-weight (50 kbp) DNA fragmentation. Although caspase-independent cell death has been recognized for some time and is known to contribute to ischaemic injury, the upstream triggering events leading to activation of this pathway remain unclear. The two major theories are that ischaemia leads to nicotinamide adenine dinucleotide (NAD+) depletion and subsequent energy failure, or alternatively that cell death is directly triggered by a pro-apoptotic factor produced by activation of the DNA repair enzyme PARP. PARP activation is robust in the ischaemic brain producing variable lengths of poly-ADP-ribose (PAR) polymers as byproducts of PARP activation. PAR polymers may be directly toxic by triggering mitochondrial AIF release independently of NAD+ depletion. Recently, sex differences have been discovered that illustrate the importance of understanding these molecular pathways, especially as new therapeutics targeting apoptotic cell death are developed. Cell death in females proceeds primarily via caspase activation whereas caspase-independent mechanisms triggered by the activation of PARP predominate in the male brain. This review summarizes the current literature in an attempt to clarify the roles of NAD+ and PAR polymers in caspase-independent cell death, and discuss sex specific cell death to provide an example of the possible importance of these downstream mediators. © 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society.

Why language really is not a communication system: a cognitive view of language evolution

PubMed Central

Reboul, Anne C.

2015-01-01

While most evolutionary scenarios for language see it as a communication system with consequences on the language-ready brain, there are major difficulties for such a view. First, language has a core combination of features—semanticity, discrete infinity, and decoupling—that makes it unique among communication systems and that raise deep problems for the view that it evolved for communication. Second, extant models of communication systems—the code model of communication (Millikan, 2005) and the ostensive model of communication (Scott-Phillips, 2015) cannot account for language evolution. I propose an alternative view, according to which language first evolved as a cognitive tool, following Fodor’s (1975, 2008) Language of Thought Hypothesis, and was then exapted (externalized) for communication. On this view, a language-ready brain is a brain profoundly reorganized in terms of connectivity, allowing the human conceptual system to emerge, triggering the emergence of syntax. Language as used in communication inherited its core combination of features from the Language of Thought. PMID:26441802

Mind-controlled transgene expression by a wireless-powered optogenetic designer cell implant.

PubMed

Folcher, Marc; Oesterle, Sabine; Zwicky, Katharina; Thekkottil, Thushara; Heymoz, Julie; Hohmann, Muriel; Christen, Matthias; Daoud El-Baba, Marie; Buchmann, Peter; Fussenegger, Martin

2014-11-11

Synthetic devices for traceless remote control of gene expression may provide new treatment opportunities in future gene- and cell-based therapies. Here we report the design of a synthetic mind-controlled gene switch that enables human brain activities and mental states to wirelessly programme the transgene expression in human cells. An electroencephalography (EEG)-based brain-computer interface (BCI) processing mental state-specific brain waves programs an inductively linked wireless-powered optogenetic implant containing designer cells engineered for near-infrared (NIR) light-adjustable expression of the human glycoprotein SEAP (secreted alkaline phosphatase). The synthetic optogenetic signalling pathway interfacing the BCI with target gene expression consists of an engineered NIR light-activated bacterial diguanylate cyclase (DGCL) producing the orthogonal second messenger cyclic diguanosine monophosphate (c-di-GMP), which triggers the stimulator of interferon genes (STING)-dependent induction of synthetic interferon-β promoters. Humans generating different mental states (biofeedback control, concentration, meditation) can differentially control SEAP production of the designer cells in culture and of subcutaneous wireless-powered optogenetic implants in mice.

Thirst Driving and Suppressing Signals Encoded by Distinct Neural Populations in the Brain

PubMed Central

Oka, Yuki; Ye, Mingyu; Zuker, Charles S.

2014-01-01

Thirst is the basic instinct to drink water. Previously, it was shown that neurons in several circumventricular organs (CVO) of the hypothalamus are activated by thirst-inducing conditions 1. Here, we identify two distinct, genetically-separable neural populations in the subfornical organ (SFO) that trigger or suppress thirst. We show that optogenetic activation of SFO excitatory neurons, marked by the expression of the transcription factor ETV-1, evokes intense drinking behavior, and does so even in fully water-satiated animals. The light-induced response is highly specific for water, immediate, and strictly locked to the laser stimulus. In contrast, activation of a second population of SFO neurons, marked by expression of the vesicular GABA transporter VGAT, drastically suppressed drinking, even in water-craving thirsty animals. These results reveal an innate brain circuit that can turn on and off an animal’s water-drinking behavior, and likely functions as a center for thirst control in the mammalian brain. PMID:25624099

Neuroprotective effect of oral choline administration after global brain ischemia in rats.

PubMed

Borges, Andrea Aurélio; El-Batah, Philipe Nicolas; Yamashita, Lilia Fumie; Santana, Aline dos Santos; Lopes, Antonio Carlos; Freymuller-Haapalainen, Edna; Coimbra, Cicero Galli; Sinigaglia-Coimbra, Rita

2015-08-01

Choline - now recognized as an essential nutrient - is the most common polar group found in the outer leaflet of the plasma membrane bilayer. Brain ischemia-reperfusion causes lipid peroxidation triggering multiple cell death pathways involving necrosis and apoptosis. Membrane breakdown is, therefore, a major pathophysiologic event in brain ischemia. The ability to achieve membrane repair is a critical step for survival of ischemic neurons following reperfusion injury. The availability of choline is a rate-limiting factor in phospholipid synthesis and, therefore, may be important for timely membrane repair and cell survival. This work aimed at verifying the effects of 7-day oral administration with different doses of choline on survival of CA1 hippocampal neurons following transient global forebrain ischemia in rats. The administration of 400 mg/kg/day divided into two daily doses for 7 consecutive days significantly improved CA1 pyramidal cell survival, indicating that the local availability of this essential nutrient may limit postischemic neuronal survival.

Neurocomputational account of how the human brain decides when to have a break

PubMed Central

Meyniel, Florent; Sergent, Claire; Rigoux, Lionel; Daunizeau, Jean; Pessiglione, Mathias

2013-01-01

No pain, no gain: cost–benefit trade-off has been formalized in classical decision theory to account for how we choose whether to engage effort. However, how the brain decides when to have breaks in the course of effort production remains poorly understood. We propose that decisions to cease and resume work are triggered by a cost evidence accumulation signal reaching upper and lower bounds, respectively. We developed a task in which participants are free to exert a physical effort knowing that their payoff would be proportional to their effort duration. Functional MRI and magnetoencephalography recordings conjointly revealed that the theoretical cost evidence accumulation signal was expressed in proprioceptive regions (bilateral posterior insula). Furthermore, the slopes and bounds of the accumulation process were adapted to the difficulty of the task and the money at stake. Cost evidence accumulation might therefore provide a dynamical mechanistic account of how the human brain maximizes benefits while preventing exhaustion. PMID:23341598

Synaptic Mechanisms of Blast-Induced Brain Injury

PubMed Central

Przekwas, Andrzej; Somayaji, Mahadevabharath R.; Gupta, Raj K.

2016-01-01

Blast wave-induced traumatic brain injury (TBI) is one of the most common injuries to military personnel. Brain tissue compression/tension due to blast-induced cranial deformations and shear waves due to head rotation may generate diffuse micro-damage to neuro-axonal structures and trigger a cascade of neurobiological events culminating in cognitive and neurodegenerative disorders. Although diffuse axonal injury is regarded as a signature wound of mild TBI (mTBI), blast loads may also cause synaptic injury wherein neuronal synapses are stretched and sheared. This synaptic injury may result in temporary disconnect of the neural circuitry and transient loss in neuronal communication. We hypothesize that mTBI symptoms such as loss of consciousness or dizziness, which start immediately after the insult, could be attributed to synaptic injury. Although empirical evidence is beginning to emerge; the detailed mechanisms underlying synaptic injury are still elusive. Coordinated in vitro–in vivo experiments and mathematical modeling studies can shed light into the synaptic injury mechanisms and their role in the potentiation of mTBI symptoms. PMID:26834697

The dark side of high-frequency oscillations in the developing brain.

PubMed

Le Van Quyen, Michel; Khalilov, Ilgam; Ben-Ari, Yehezkel

2006-07-01

Adult brain networks generate a wide range of oscillations. Some of these are behaviourally relevant, whereas others occur during seizures and other pathological conditions. This raises the question of how physiological oscillations differ from pathogenic ones. In this review, this issue is discussed from a developmental standpoint. Indeed, both epileptic and physiological high-frequency oscillations (HFOs) appear progressively during maturation, and it is therefore possible to determine how this program corresponds to maturation of the neuronal populations that generate these oscillations. We review here important differences in the development of neuronal populations that might contribute to their different oscillatory properties. In particular, at an early stage, the density of glutamatergic synapses is too low for physiological HFOs but an additional drive can be provided by excitatory GABA, triggering epileptic HFOs and the cascades involved in long-lasting epileptogenic transformations. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).

Internally and externally generated emotions in people with acquired brain injury: preservation of emotional experience after right hemisphere lesions

PubMed Central

Salas Riquelme, Christian E.; Radovic, Darinka; Castro, Osvaldo; Turnbull, Oliver H.

2015-01-01

The study of emotional changes after brain injury has contributed enormously to the understanding of the neural basis of emotion. However, little attention has been placed on the methods used to elicit emotional responses in people with brain damage. Of particular interest are subjects with right hemisphere [RH] cortical lesions, who have been described as presenting impairment in emotional processing. In this article, an internal and external mood induction procedure [MIP] was used to trigger positive and negative emotions, in a sample of 10 participants with RH damage, and 15 healthy controls. Emotional experience was registered by using a self-report questionnaire. As observed in previous studies, internal and external MIPs were equally effective in eliciting the target emotion, but the internal procedure generated higher levels of intensity. Remarkably, participants with RH lesions were equally able to experience both positive and negative affect. The results are discussed in relation to the role of the RH in the capacity to experience negative emotions. PMID:25762951

CCSVI and MS: no meaning, no fact.

PubMed

Baracchini, Claudio; Atzori, Matteo; Gallo, Paolo

2013-03-01

A condition called "chronic cerebrospinal venous insufficiency" (CCSVI) has been postulated to play a role in the pathogenesis of multiple sclerosis (MS). This hypothesis implies that a complex pattern of extracranial venous stenosis determines a venous reflux into the brain of MS patients, followed by increased intravenous pressure, blood-brain barrier breakdown and iron deposition into the brain parenchyma, thus triggering a local inflammatory response. In this review, we critically analyze the scientific basis of CCSVI, the current literature on the relationship between CCSVI and MS, as well as the ultrasound methodology that has been claimed to provide evidence of impaired cerebral venous drainage. We show that no piece of the CCSVI theory has a solid supportive scientific evidence. The CCSVI appears to be a rather alien condition and its existence should be definitely questioned. Finally, no proven (i.e., based on strict scientific methodology and on the rules of evidence-based medicine) therapeutic effect of the "liberation" procedure (unblocking the extracranial venous obstruction using angioplasty) has been shown up to date.

Internally and externally generated emotions in people with acquired brain injury: preservation of emotional experience after right hemisphere lesions.

PubMed

Salas Riquelme, Christian E; Radovic, Darinka; Castro, Osvaldo; Turnbull, Oliver H

2015-01-01

The study of emotional changes after brain injury has contributed enormously to the understanding of the neural basis of emotion. However, little attention has been placed on the methods used to elicit emotional responses in people with brain damage. Of particular interest are subjects with right hemisphere [RH] cortical lesions, who have been described as presenting impairment in emotional processing. In this article, an internal and external mood induction procedure [MIP] was used to trigger positive and negative emotions, in a sample of 10 participants with RH damage, and 15 healthy controls. Emotional experience was registered by using a self-report questionnaire. As observed in previous studies, internal and external MIPs were equally effective in eliciting the target emotion, but the internal procedure generated higher levels of intensity. Remarkably, participants with RH lesions were equally able to experience both positive and negative affect. The results are discussed in relation to the role of the RH in the capacity to experience negative emotions.

Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer disease mice.

PubMed

Chen, Zu-Lin; Revenko, Alexey S; Singh, Pradeep; MacLeod, A Robert; Norris, Erin H; Strickland, Sidney

2017-05-04

Vascular abnormalities and inflammation are found in many Alzheimer disease (AD) patients, but whether these changes play a causative role in AD is not clear. The factor XII (FXII) -initiated contact system can trigger both vascular pathology and inflammation and is activated in AD patients and AD mice. We have investigated the role of the contact system in AD pathogenesis. Cleavage of high-molecular-weight kininogen (HK), a marker for activation of the inflammatory arm of the contact system, is increased in a mouse model of AD, and this cleavage is temporally correlated with the onset of brain inflammation. Depletion of FXII in AD mice inhibited HK cleavage in plasma and reduced neuroinflammation, fibrinogen deposition, and neurodegeneration in the brain. Moreover, FXII-depleted AD mice showed better cognitive function than untreated AD mice. These results indicate that FXII-mediated contact system activation contributes to AD pathogenesis, and therefore this system may offer novel targets for AD treatment. © 2017 by The American Society of Hematology.

How Shakespeare tempests the brain: neuroimaging insights.

PubMed

Keidel, James L; Davis, Philip M; Gonzalez-Diaz, Victorina; Martin, Clara D; Thierry, Guillaume

2013-04-01

Shakespeare made extensive use of the functional shift (FS), a rhetorical device involving a change in the grammatical status of words, e.g., using nouns as verbs. Previous work using event-related brain potentials showed how FS triggers a surprise effect inviting mental re-evaluation, seemingly independent of semantic processing. Here, we used functional magnetic resonance imaging to investigate brain activation in participants making judgements on the semantic relationship between sentences -some containing a Shakespearean FS- and subsequently presented words. Behavioural performance in the semantic decision task was high and unaffected by sentence type. However, neuroimaging results showed that sentences featuring FS elicited significant activation beyond regions classically activated by typical language tasks, including the left caudate nucleus, the right inferior frontal gyrus and the right inferior temporal gyrus. These findings show how Shakespeare's grammatical exploration forces the listener to take a more active role in integrating the meaning of what is said. Copyright © 2012 Elsevier Ltd. All rights reserved.

Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation.

PubMed

Saito, Takashi; Iwata, Nobuhisa; Tsubuki, Satoshi; Takaki, Yoshie; Takano, Jiro; Huang, Shu-Ming; Suemoto, Takahiro; Higuchi, Makoto; Saido, Takaomi C

2005-04-01

Expression of somatostatin in the brain declines during aging in various mammals including apes and humans. A prominent decrease in this neuropeptide also represents a pathological characteristic of Alzheimer disease. Using in vitro and in vivo paradigms, we show that somatostatin regulates the metabolism of amyloid beta peptide (Abeta), the primary pathogenic agent of Alzheimer disease, in the brain through modulating proteolytic degradation catalyzed by neprilysin. Among various effector candidates, only somatostatin upregulated neprilysin activity in primary cortical neurons. A genetic deficiency of somatostatin altered hippocampal neprilysin activity and localization, and increased the quantity of a hydrophobic 42-mer form of Abeta, Abeta(42), in a manner similar to presenilin gene mutations that cause familial Alzheimer disease. These results indicate that the aging-induced downregulation of somatostatin expression may be a trigger for Abeta accumulation leading to late-onset sporadic Alzheimer disease, and suggest that somatostatin receptors may be pharmacological-target candidates for prevention and treatment of Alzheimer disease.

Visual projection neurons in the Drosophila lobula link feature detection to distinct behavioral programs

PubMed Central

Wu, Ming; Nern, Aljoscha; Williamson, W Ryan; Morimoto, Mai M; Reiser, Michael B; Card, Gwyneth M; Rubin, Gerald M

2016-01-01

Visual projection neurons (VPNs) provide an anatomical connection between early visual processing and higher brain regions. Here we characterize lobula columnar (LC) cells, a class of Drosophila VPNs that project to distinct central brain structures called optic glomeruli. We anatomically describe 22 different LC types and show that, for several types, optogenetic activation in freely moving flies evokes specific behaviors. The activation phenotypes of two LC types closely resemble natural avoidance behaviors triggered by a visual loom. In vivo two-photon calcium imaging reveals that these LC types respond to looming stimuli, while another type does not, but instead responds to the motion of a small object. Activation of LC neurons on only one side of the brain can result in attractive or aversive turning behaviors depending on the cell type. Our results indicate that LC neurons convey information on the presence and location of visual features relevant for specific behaviors. DOI: http://dx.doi.org/10.7554/eLife.21022.001 PMID:28029094

Escherichia coli K1 utilizes host macropinocytic pathways for invasion of brain microvascular endothelial cells.

PubMed

Loh, Lip Nam; McCarthy, Elizabeth M C; Narang, Priyanka; Khan, Naveed A; Ward, Theresa H

2017-11-01

Eukaryotic cells utilize multiple endocytic pathways for specific uptake of ligands or molecules, and these pathways are commonly hijacked by pathogens to enable host cell invasion. Escherichia coli K1, a pathogenic bacterium that causes neonatal meningitis, invades the endothelium of the blood-brain barrier, but the entry route remains unclear. Here, we demonstrate that the bacteria trigger an actin-mediated uptake route, stimulating fluid phase uptake, membrane ruffling and macropinocytosis. The route of uptake requires intact lipid rafts as shown by cholesterol depletion. Using a variety of perturbants we demonstrate that small Rho GTPases and their downstream effectors have a significant effect on bacterial invasion. Furthermore, clathrin-mediated endocytosis appears to play an indirect role in E. coli K1 uptake. The data suggest that the bacteria effect a complex interplay between the Rho GTPases to increase their chances of uptake by macropinocytosis into human brain microvascular endothelial cells. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Diversity of sharp-wave-ripple LFP signatures reveals differentiated brain-wide dynamical events.

PubMed

Ramirez-Villegas, Juan F; Logothetis, Nikos K; Besserve, Michel

2015-11-17

Sharp-wave-ripple (SPW-R) complexes are believed to mediate memory reactivation, transfer, and consolidation. However, their underlying neuronal dynamics at multiple scales remains poorly understood. Using concurrent hippocampal local field potential (LFP) recordings and functional MRI (fMRI), we study local changes in neuronal activity during SPW-R episodes and their brain-wide correlates. Analysis of the temporal alignment between SPW and ripple components reveals well-differentiated SPW-R subtypes in the CA1 LFP. SPW-R-triggered fMRI maps show that ripples aligned to the positive peak of their SPWs have enhanced neocortical metabolic up-regulation. In contrast, ripples occurring at the trough of their SPWs relate to weaker neocortical up-regulation and absent subcortical down-regulation, indicating differentiated involvement of neuromodulatory pathways in the ripple phenomenon mediated by long-range interactions. To our knowledge, this study provides the first evidence for the existence of SPW-R subtypes with differentiated CA1 activity and metabolic correlates in related brain areas, possibly serving different memory functions.

Diversity of sharp-wave–ripple LFP signatures reveals differentiated brain-wide dynamical events

PubMed Central

Ramirez-Villegas, Juan F.; Logothetis, Nikos K.; Besserve, Michel

2015-01-01

Sharp-wave–ripple (SPW-R) complexes are believed to mediate memory reactivation, transfer, and consolidation. However, their underlying neuronal dynamics at multiple scales remains poorly understood. Using concurrent hippocampal local field potential (LFP) recordings and functional MRI (fMRI), we study local changes in neuronal activity during SPW-R episodes and their brain-wide correlates. Analysis of the temporal alignment between SPW and ripple components reveals well-differentiated SPW-R subtypes in the CA1 LFP. SPW-R–triggered fMRI maps show that ripples aligned to the positive peak of their SPWs have enhanced neocortical metabolic up-regulation. In contrast, ripples occurring at the trough of their SPWs relate to weaker neocortical up-regulation and absent subcortical down-regulation, indicating differentiated involvement of neuromodulatory pathways in the ripple phenomenon mediated by long-range interactions. To our knowledge, this study provides the first evidence for the existence of SPW-R subtypes with differentiated CA1 activity and metabolic correlates in related brain areas, possibly serving different memory functions. PMID:26540729

Neurocomputational account of how the human brain decides when to have a break.

PubMed

Meyniel, Florent; Sergent, Claire; Rigoux, Lionel; Daunizeau, Jean; Pessiglione, Mathias

2013-02-12

No pain, no gain: cost-benefit trade-off has been formalized in classical decision theory to account for how we choose whether to engage effort. However, how the brain decides when to have breaks in the course of effort production remains poorly understood. We propose that decisions to cease and resume work are triggered by a cost evidence accumulation signal reaching upper and lower bounds, respectively. We developed a task in which participants are free to exert a physical effort knowing that their payoff would be proportional to their effort duration. Functional MRI and magnetoencephalography recordings conjointly revealed that the theoretical cost evidence accumulation signal was expressed in proprioceptive regions (bilateral posterior insula). Furthermore, the slopes and bounds of the accumulation process were adapted to the difficulty of the task and the money at stake. Cost evidence accumulation might therefore provide a dynamical mechanistic account of how the human brain maximizes benefits while preventing exhaustion.

Behavioural and biochemical investigations of the influence of altered gravity on the CNS of aquatic vertebrates during ontogeny

NASA Astrophysics Data System (ADS)

Slenzka, K.; Appel, R.; Hilbig, R.; Kappel, Th.; Vetter, S.; Freischütz, B.; Rahmann, H.

1994-08-01

Quantitative data are presented on the influences of hyper-gravity (3+/-1g) and of simulated weightlessness (~0g) during early ontogeny of cichild fish (Oreochromis mossambicus) and clawed toad (Xenopus laevis, Daudin) demonstrating changes in the swimming behaviour and the brain energy and plasma membrane metabolism. After return to 1g conditions, hyper-g reared fish and toads express the well known ``loop-swimming'' behaviour. By means of a computer based video analyzing system different types of swimming movements and velocities were quantitatively determined. Analyses of the brain energy and plasma-membrane metabolism of hyper-g fish larvae demonstrated an increase in energy availability (glucose 6Pi dehydrogenase, G-6P-DH), a decrease of cellular energy transformation (creatine kinase activity, CK) but no changes in energy consumptive processes (e.g. ATPases) and cytochrome oxidase activity (Cyt.-Ox). In contrast hypo-g fish larvae showed a slight increase in brain CK activity. In addition, unlike 1g controls, hyper-g fish larvae showed pronounced variations in the composition (=polarity) of sialoglycosphingolipids (=gangliosides), typical constituents of the nerve cell membranes, and a slight increase in the activity of sialidase, the enzyme responsible for ganglioside degradation.

Neurotoxicants are in the air: convergence of human, animal, and in vitro studies on the effects of air pollution on the brain.

PubMed

Costa, Lucio G; Cole, Toby B; Coburn, Jacki; Chang, Yu-Chi; Dao, Khoi; Roque, Pamela

2014-01-01

In addition to increased morbidity and mortality caused by respiratory and cardiovascular diseases, air pollution may also negatively affect the brain and contribute to central nervous system diseases. Air pollution is a mixture comprised of several components, of which ultrafine particulate matter (UFPM; <100 nm) is of much concern, as these particles can enter the circulation and distribute to most organs, including the brain. A major constituent of ambient UFPM is represented by traffic-related air pollution, mostly ascribed to diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution may lead to neurotoxicity. In addition to a variety of behavioral abnormalities, two prominent effects caused by air pollution are oxidative stress and neuroinflammation, which are seen in both humans and animals and are confirmed by in vitro studies. Among factors which can affect neurotoxic outcomes, age is considered the most relevant. Human and animal studies suggest that air pollution (and DE) may cause developmental neurotoxicity and may contribute to the etiology of neurodevelopmental disorders, including autistic spectrum disorders. In addition, air pollution exposure has been associated with increased expression of markers of neurodegenerative disease pathologies.

Magnetic resonance spectroscopy of the human brain.

PubMed

Ross, B; Bluml, S

2001-04-01

Magnetic resonance (MR; synonymous with NMR = nuclear magnetic resonance) is a universal physical technique best known for non-invasive detection and anatomical mapping of water protons (H). MR-spectroscopy (MRS) records protons from tissue chemicals other than water, intrinsic phosphorus containing metabolites, sodium, potassium, carbon, nitrogen, and fluorine. MRS is therefore an imaging technique with the potential to record human and animal biochemistry in vivo. As a result of wide availability of MRI equipment in research laboratories and hospitals, MRS is a serious competitor with PET to define normal body composition and its perturbation by pharmacological and pathological events. This article describes practical aspects of in vivo MRS with particular emphasis on the brain, where novel metabolites have been described. A survey of these new aspects of neurochemistry emphasize their practical utility as neuronal and axonal markers, measures of energy status, membrane constituents, and osmolytes, as well as some xenobiotics, such as alcohol. The concept of multinuclear in vivo MRS is illustrated by diagnosis and therapeutic monitoring of several human brain disorders. Although these methods are currently most frequently encountered in human studies, as well as with transgenic and knockout mouse models, MRS adds a new dimension to anatomic and histopathologic descriptions. Copyright 2001 Wiley-Liss, Inc.

Cannabidiol in medical marijuana: Research vistas and potential opportunities.

PubMed

Rong, Carola; Lee, Yena; Carmona, Nicole E; Cha, Danielle S; Ragguett, Renee-Marie; Rosenblat, Joshua D; Mansur, Rodrigo B; Ho, Roger C; McIntyre, Roger S

2017-07-01

The high and increasing prevalence of medical marijuana consumption in the general population invites the need for quality evidence regarding its safety and efficacy. Herein, we synthesize extant literature pertaining to the phytocannabinoid cannabidiol (CBD) and its brain effects. The principle phytocannabinoid Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and CBD are the major pharmacologically active cannabinoids. The effect of CBD on brain systems as well as on phenomenological measures (e.g. cognitive function) are distinct and in many cases opposite to that of Δ 9 -THC. Cannabidiol is without euphoriant properties, and exerts antipsychotic, anxiolytic, anti-seizure, as well as anti-inflammatory properties. It is essential to parcellate phytocannabinoids into their constituent moieties as the most abundant cannabinoid have differential effects on physiologic systems in psychopathology measures. Disparate findings and reports related to effects of cannabis consumption reflect differential relative concentration of Δ 9 -THC and CBD. Existing literature, notwithstanding its deficiencies, provides empirical support for the hypothesis that CBD may exert beneficial effects on brain effector systems/substrates subserving domain-based phenomenology. Interventional studies with purified CBD are warranted with a call to target-engagement proof-of-principle studies using the research domain criteria (RDoC) framework. Copyright © 2017 Elsevier Ltd. All rights reserved.