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Sample records for cortex reveals altered

  1. A Mouse Model of Visual Perceptual Learning Reveals Alterations in Neuronal Coding and Dendritic Spine Density in the Visual Cortex

    PubMed Central

    Wang, Yan; Wu, Wei; Zhang, Xian; Hu, Xu; Li, Yue; Lou, Shihao; Ma, Xiao; An, Xu; Liu, Hui; Peng, Jing; Ma, Danyi; Zhou, Yifeng; Yang, Yupeng

    2016-01-01

    Visual perceptual learning (VPL) can improve spatial vision in normally sighted and visually impaired individuals. Although previous studies of humans and large animals have explored the neural basis of VPL, elucidation of the underlying cellular and molecular mechanisms remains a challenge. Owing to the advantages of molecular genetic and optogenetic manipulations, the mouse is a promising model for providing a mechanistic understanding of VPL. Here, we thoroughly evaluated the effects and properties of VPL on spatial vision in C57BL/6J mice using a two-alternative, forced-choice visual water task. Briefly, the mice underwent prolonged training at near the individual threshold of contrast or spatial frequency (SF) for pattern discrimination or visual detection for 35 consecutive days. Following training, the contrast-threshold trained mice showed an 87% improvement in contrast sensitivity (CS) and a 55% gain in visual acuity (VA). Similarly, the SF-threshold trained mice exhibited comparable and long-lasting improvements in VA and significant gains in CS over a wide range of SFs. Furthermore, learning largely transferred across eyes and stimulus orientations. Interestingly, learning could transfer from a pattern discrimination task to a visual detection task, but not vice versa. We validated that this VPL fully restored VA in adult amblyopic mice and old mice. Taken together, these data indicate that mice, as a species, exhibit reliable VPL. Intrinsic signal optical imaging revealed that mice with perceptual training had higher cut-off SFs in primary visual cortex (V1) than those without perceptual training. Moreover, perceptual training induced an increase in the dendritic spine density in layer 2/3 pyramidal neurons of V1. These results indicated functional and structural alterations in V1 during VPL. Overall, our VPL mouse model will provide a platform for investigating the neurobiological basis of VPL. PMID:27014004

  2. A combined cumulative threshold spectra and digital reconstruction analysis reveal structural alterations of microglia within the prefrontal cortex following low-dose LPS administration.

    PubMed

    Kongsui, R; Johnson, S J; Graham, B A; Nilsson, M; Walker, F R

    2015-12-01

    Sickness behaviors have become the focus of great interest in recent years as they represent a clear case of how peripheral disturbances in immune signaling can disrupt quite complex behaviors. In the current study, we were interested in examining whether we could identify any significant morphological disturbances in microglia associated with these sickness-like behaviors in adult male Sprague-Dawley rats. We chose lipopolysaccharide (LPS 100 μg/kg/i.p.), to induce sickness-like behaviors as it is the most well-validated approach to do so in rodents and humans. We were particularly interested in examining changes in microglia within the prefrontal cortex (PFC) as several recent neuroimaging studies have highlighted significant functional changes in this region following peripheral LPS administration. Paraformaldehyde-fixed tissue was collected from animals 24h post LPS administration and labeled immunohistochemically with an antibody directed to bind to Iba-1, a protein known to be involved in the structural remodeling of microglia. To analyze changes, we have made use of two recently described image analysis procedures. The first is known as cumulative threshold spectra (CTS) analysis. The second involves the unsupervised digital reconstruction of microglia. We undertook these complementary analysis of microglial cells in the both the pre- and infralimbic divisions of the PFC. Our results indicated that microglial soma size was significantly enlarged, while cell processes had contracted slightly following LPS administration. To our knowledge this study is to first to definitely demonstrate substantial microglial disturbances within the PFC following LPS delivered at a dose that was sufficient to induce significant sickness-like behavior. PMID:26440295

  3. A combined cumulative threshold spectra and digital reconstruction analysis reveal structural alterations of microglia within the prefrontal cortex following low-dose LPS administration.

    PubMed

    Kongsui, R; Johnson, S J; Graham, B A; Nilsson, M; Walker, F R

    2015-12-01

    Sickness behaviors have become the focus of great interest in recent years as they represent a clear case of how peripheral disturbances in immune signaling can disrupt quite complex behaviors. In the current study, we were interested in examining whether we could identify any significant morphological disturbances in microglia associated with these sickness-like behaviors in adult male Sprague-Dawley rats. We chose lipopolysaccharide (LPS 100 μg/kg/i.p.), to induce sickness-like behaviors as it is the most well-validated approach to do so in rodents and humans. We were particularly interested in examining changes in microglia within the prefrontal cortex (PFC) as several recent neuroimaging studies have highlighted significant functional changes in this region following peripheral LPS administration. Paraformaldehyde-fixed tissue was collected from animals 24h post LPS administration and labeled immunohistochemically with an antibody directed to bind to Iba-1, a protein known to be involved in the structural remodeling of microglia. To analyze changes, we have made use of two recently described image analysis procedures. The first is known as cumulative threshold spectra (CTS) analysis. The second involves the unsupervised digital reconstruction of microglia. We undertook these complementary analysis of microglial cells in the both the pre- and infralimbic divisions of the PFC. Our results indicated that microglial soma size was significantly enlarged, while cell processes had contracted slightly following LPS administration. To our knowledge this study is to first to definitely demonstrate substantial microglial disturbances within the PFC following LPS delivered at a dose that was sufficient to induce significant sickness-like behavior.

  4. Immunoprofiling of Rice Root Cortex Reveals Two Cortical Subdomains

    PubMed Central

    Henry, Sophia; Divol, Fanchon; Bettembourg, Mathilde; Bureau, Charlotte; Guiderdoni, Emmanuel; Périn, Christophe; Diévart, Anne

    2016-01-01

    The formation and differentiation of aerenchyma, i.e., air-containing cavities that are critical for flooding tolerance, take place exclusively in the cortex. The understanding of development and differentiation of the cortex is thus an important issue; however, studies on this tissue are limited, partly because of the lack of available molecular tools. We screened a commercially available library of cell wall antibodies to identify markers of cortical tissue in rice roots. Out of the 174 antibodies screened, eight were cortex-specific. Our analysis revealed that two types of cortical tissues are present in rice root seedlings. We named these cell layers “inner” and “outer” based on their location relative to the stele. We then used the antibodies to clarify cell identity in lateral roots. Without these markers, previous studies could not distinguish between the cortex and sclerenchyma in small lateral roots. By immunostaining lateral root sections, we showed that the internal ground tissue in small lateral roots has outer cortical identity. PMID:26779208

  5. Disrupting the right prefrontal cortex alters moral judgement

    PubMed Central

    Tassy, Sébastien; Oullier, Olivier; Duclos, Yann; Coulon, Olivier; Mancini, Julien; Deruelle, Christine; Attarian, Sharam; Felician, Olivier

    2012-01-01

    Humans daily face social situations involving conflicts between competing moral decision. Despite a substantial amount of studies published over the past 10 years, the respective role of emotions and reason, their possible interaction, and their behavioural expression during moral evaluation remains an unresolved issue. A dualistic approach to moral evaluation proposes that the right dorsolateral prefrontal cortex (rDLPFc) controls emotional impulses. However, recent findings raise the possibility that the right DLPFc processes emotional information during moral decision making. We used repetitive transcranial magnetic stimulation (rTMS) to transiently disrupt rDLPFc activity before measuring decision making in the context of moral dilemmas. Results reveal an increase of the probability of utilitarian responses during objective evaluation of moral dilemmas in the rTMS group (compared to a SHAM one). This suggests that the right DLPFc function not only participates to a rational cognitive control process, but also integrates emotions generated by contextual information appraisal, which are decisive for response selection in moral judgements. PMID:21515641

  6. Disrupting the right prefrontal cortex alters moral judgement.

    PubMed

    Tassy, Sébastien; Oullier, Olivier; Duclos, Yann; Coulon, Olivier; Mancini, Julien; Deruelle, Christine; Attarian, Sharam; Felician, Olivier; Wicker, Bruno

    2012-03-01

    Humans daily face social situations involving conflicts between competing moral decision. Despite a substantial amount of studies published over the past 10 years, the respective role of emotions and reason, their possible interaction, and their behavioural expression during moral evaluation remains an unresolved issue. A dualistic approach to moral evaluation proposes that the right dorsolateral prefrontal cortex (rDLPFc) controls emotional impulses. However, recent findings raise the possibility that the right DLPFc processes emotional information during moral decision making. We used repetitive transcranial magnetic stimulation (rTMS) to transiently disrupt rDLPFc activity before measuring decision making in the context of moral dilemmas. Results reveal an increase of the probability of utilitarian responses during objective evaluation of moral dilemmas in the rTMS group (compared to a SHAM one). This suggests that the right DLPFc function not only participates to a rational cognitive control process, but also integrates emotions generated by contextual information appraisal, which are decisive for response selection in moral judgements.

  7. Respiratory, metabolic and cardiac functions are altered by disinhibition of subregions of the medial prefrontal cortex

    PubMed Central

    Hassan, Sarah F; Cornish, Jennifer L; Goodchild, Ann K

    2013-01-01

    The prefrontal cortex (PFC) is referred to as the visceral motor cortex; however, little is known about whether this region influences respiratory or metabolic outflows. The aim of this study was to describe simultaneous changes in respiratory, metabolic and cardiovascular functions evoked by disinhibition of the medial PFC (mPFC) and adjacent lateral septal nucleus (LSN). In urethane-anaesthetized rats, bicuculline methiodide was microinjected (2 mm; GABA-A receptor antagonist) into 90 sites in the mPFC at 0.72–4.00 mm from bregma. Phrenic nerve amplitude and frequency, arterial pressure, heart rate, splanchnic and lumbar sympathetic nerve activities (SNA), expired CO2, and core and brown adipose tissue temperatures were measured. Novel findings included disturbances to respiratory rhythm evoked from all subregions of the mPFC. Injections into the cingulate cortex evoked reductions in central respiratory function exclusively, whereas in ventral sites, particularly the infralimbic region, increases in respiratory drive and frequency, and metabolic and cardiac outflows were evoked. Disinhibition of sites in surrounding regions revealed that the LSN could evoke cardiovascular changes accompanied by distinct oscillations in SNA, as well as increases in respiratory amplitude. We show that activation of neurons within the mPFC and LSN influence respiratory, metabolic and cardiac outflows in a site-dependent manner. This study has implications with respect to the altered PFC neuronal activity seen in stress-related and mental health disorders, and suggests how basic physiological systems may be affected. PMID:24042503

  8. Manganese-enhanced MRI reveals structural and functional changes in the cortex of Bassoon mutant mice.

    PubMed

    Angenstein, Frank; Niessen, Heiko G; Goldschmidt, Jürgen; Lison, Holger; Altrock, Wilko D; Gundelfinger, Eckart D; Scheich, Henning

    2007-01-01

    Manganese-enhanced magnetic resonance imaging (ME-MRI) was used to analyze the brain architecture in mice lacking the functional presynaptic active zone protein Bassoon. Anatomical characterization revealed a significant increase in the total brain volume in Bassoon mutants as compared with wild-type mice, which is mainly caused by changes in cortex and hippocampus volume. The measured enlargement in cortical volume coincides with an altered Mn2+ distribution within cortical layers as visualized by T1-weighted magnetic resonance imaging. Two days after manganese application, the cortex of Bassoon mutant mice appeared more laminated in ME-MRI, with an enhanced accumulation of manganese in deep, central, and superficial cortical cell layers. Whereas morphologically the cortical lamination is not affected by the absence of a functional Bassoon, an altered basal activation pattern was found in the cortex of the mutant mice both by metabolic labeling with [14C]-2-deoxyglucose and histochemical detection of the potassium analogue thallium uptake. Consequently, the results indicate that the absence of the functional presynaptic protein Bassoon causes disturbance in the formation of normal basal cortical activation patterns and thereby in the functional cortical architecture. Furthermore, this study shows that ME-MRI can become a valuable tool for a structural characterization of genetically modified mice.

  9. Enhancement of extinction learning attenuates ethanol-seeking behavior and alters plasticity in the prefrontal cortex.

    PubMed

    Gass, Justin T; Trantham-Davidson, Heather; Kassab, Amanda S; Glen, William B; Olive, M Foster; Chandler, L Judson

    2014-05-28

    Addiction is a chronic relapsing disorder in which relapse is often initiated by exposure to drug-related cues. The present study examined the effects of mGluR5 activation on extinction of ethanol-cue-maintained responding, relapse-like behavior, and neuronal plasticity. Rats were trained to self-administer ethanol and then exposed to extinction training during which they were administered either vehicle or the mGluR5 positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) or CDPPB. CDPPB treatment reduced active lever responding during extinction, decreased the total number of extinction sessions required to meet criteria, and attenuated cue-induced reinstatement of ethanol seeking. CDPPB facilitation of extinction was blocked by the local infusion of the mGluR5 antagonist 3-((2-methyl-4-thiazolyl)ethynyl) pyridine into the infralimbic (IfL) cortex, but had no effect when infused into the prelimbic (PrL) cortex. Analysis of dendritic spines revealed alterations in structural plasticity, whereas electrophysiological recordings demonstrated differential alterations in glutamatergic neurotransmission in the PrL and IfL cortex. Extinction was associated with increased amplitude of evoked synaptic PrL and IfL NMDA currents but reduced amplitude of PrL AMPA currents. Treatment with CDPPB prevented the extinction-induced enhancement of NMDA currents in PrL without affecting NMDA currents in the IfL. Whereas CDPPB treatment did not alter the amplitude of PrL or IfL AMPA currents, it did promote the expression of IfL calcium-permeable GluR2-lacking receptors in both abstinence- and extinction-trained rats, but had no effect in ethanol-naive rats. These results confirm changes in the PrL and IfL cortex in glutamatergic neurotransmission during extinction learning and demonstrate that manipulation of mGluR5 facilitates extinction of ethanol cues in association with neuronal plasticity.

  10. Altered magnesium transport in slices of kidney cortex from chemically-induced diabetic rats

    SciTech Connect

    Hoskins, B.

    1981-10-01

    The uptake of magnesium-28 was measured in slices of kidney cortex from rats with alloxan-diabetes and from rats with streptozotocin-diabetes of increasing durations. In both forms of chemically-induced diabetes, magnesium-28 uptake by kidney cortex slices was significantly increased over uptake measured in kidney cortex slices from control rats. Immediate institution of daily insulin therapy to the diabetic rats prevented the diabetes-induced elevated uptake of magnesium without controlling blood glucose levels. Late institution of daily insulin therapy was ineffective in restoring the magnesium uptake to control values. These alterations in magnesium uptake occurred prior to any evidence of nephropathy (via the classic indices of proteinuria and increased BUN levels). The implications of these findings, together with our earlier demonstrations of altered calcium transport by kidney cortex slices from chemically-induced diabetic rats, are discussed in terms of disordered divalent cation transport being at least part of the basic pathogenesis underlying diabetic nephropathy.

  11. Altering risky decision-making: Influence of impulsivity on the neuromodulation of prefrontal cortex.

    PubMed

    Cheng, Gordon L F; Lee, Tatia M C

    2016-01-01

    The prefrontal cortex (PFC) subserves complex cognitive abilities, including risky decision-making; the modulation of this brain area is shown to alter the way people take risks. Yet, neuromodulation of the PFC in relation to risk-taking behavior remains relatively less well-studied. Moreover, the psychological variables that influence such neuromodulation remain poorly understood. To address these issues, 16 participants took part in 3 experimental sessions on separate days. They received: (i) left anodal-right cathodal transcranial direct current stimulation (tDCS); (ii) left cathodal-right anodal stimulation; or (iii) sham stimulation while they completed two risk-taking tasks. They also measured on several cognitive-affective abilities and personality traits. It was revealed that left cathodal-right anodal stimulation led to significantly reduced risk-taking under a context of haste. The reduction of risk-taking (relative to sham) correlated with state and trait impulsivity, such that the effect was larger in more impulsive individuals. For these individuals, the tDCS effect size was considered to be large (generalized partial η(2) > .17). The effect of prefrontal-neuromodulation in reducing risk-taking was influenced by baseline impulsivity, reflecting a state-dependent effect of neuromodulation on the PFC. The results of this study carry important insights into the use of neuromodulation to alter higher cognition.

  12. Altered Value Coding in the Ventromedial Prefrontal Cortex in Healthy Older Adults

    PubMed Central

    Yu, Jing; Mamerow, Loreen; Lei, Xu; Fang, Lei; Mata, Rui

    2016-01-01

    Previous work suggests that aging is associated with changes in risk taking but less is known about their underlying neural basis, such as the potential age differences in the neural processing of value and risk. The goal of the present study was to investigate adult age differences in functional neural responses in a naturalistic risk-taking task. Twenty-six young adults and 27 healthy older adults completed the Balloon Analogue Risk Task while undergoing functional magnetic resonance imaging. Young and older adults showed similar overt risk-taking behavior. Group comparison of neural activity in response to risky vs. control stimuli revealed similar patterns of activation in the bilateral striatum, anterior insula (AI) and ventromedial prefrontal cortex (vmPFC). Group comparison of parametrically modulated activity in response to continued pumping similarly revealed comparable results for both age groups in the AI and, potentially, the striatum, yet differences emerged for regional activity in the vmPFC. At whole brain level, insular, striatal and vmPFC activation was predictive of behavioral risk taking for young but not older adults. The current results are interpreted and discussed as preserved neural tracking of risk and reward in the AI and striatum, respectively, but altered value coding in the vmPFC in the two age groups. The latter finding points toward older adults exhibiting differential vmPFC-related integration and value coding. Furthermore, neural activation holds differential predictive validity for behavioral risk taking in young and older adults.

  13. Altered Value Coding in the Ventromedial Prefrontal Cortex in Healthy Older Adults

    PubMed Central

    Yu, Jing; Mamerow, Loreen; Lei, Xu; Fang, Lei; Mata, Rui

    2016-01-01

    Previous work suggests that aging is associated with changes in risk taking but less is known about their underlying neural basis, such as the potential age differences in the neural processing of value and risk. The goal of the present study was to investigate adult age differences in functional neural responses in a naturalistic risk-taking task. Twenty-six young adults and 27 healthy older adults completed the Balloon Analogue Risk Task while undergoing functional magnetic resonance imaging. Young and older adults showed similar overt risk-taking behavior. Group comparison of neural activity in response to risky vs. control stimuli revealed similar patterns of activation in the bilateral striatum, anterior insula (AI) and ventromedial prefrontal cortex (vmPFC). Group comparison of parametrically modulated activity in response to continued pumping similarly revealed comparable results for both age groups in the AI and, potentially, the striatum, yet differences emerged for regional activity in the vmPFC. At whole brain level, insular, striatal and vmPFC activation was predictive of behavioral risk taking for young but not older adults. The current results are interpreted and discussed as preserved neural tracking of risk and reward in the AI and striatum, respectively, but altered value coding in the vmPFC in the two age groups. The latter finding points toward older adults exhibiting differential vmPFC-related integration and value coding. Furthermore, neural activation holds differential predictive validity for behavioral risk taking in young and older adults. PMID:27630561

  14. Altered Value Coding in the Ventromedial Prefrontal Cortex in Healthy Older Adults.

    PubMed

    Yu, Jing; Mamerow, Loreen; Lei, Xu; Fang, Lei; Mata, Rui

    2016-01-01

    Previous work suggests that aging is associated with changes in risk taking but less is known about their underlying neural basis, such as the potential age differences in the neural processing of value and risk. The goal of the present study was to investigate adult age differences in functional neural responses in a naturalistic risk-taking task. Twenty-six young adults and 27 healthy older adults completed the Balloon Analogue Risk Task while undergoing functional magnetic resonance imaging. Young and older adults showed similar overt risk-taking behavior. Group comparison of neural activity in response to risky vs. control stimuli revealed similar patterns of activation in the bilateral striatum, anterior insula (AI) and ventromedial prefrontal cortex (vmPFC). Group comparison of parametrically modulated activity in response to continued pumping similarly revealed comparable results for both age groups in the AI and, potentially, the striatum, yet differences emerged for regional activity in the vmPFC. At whole brain level, insular, striatal and vmPFC activation was predictive of behavioral risk taking for young but not older adults. The current results are interpreted and discussed as preserved neural tracking of risk and reward in the AI and striatum, respectively, but altered value coding in the vmPFC in the two age groups. The latter finding points toward older adults exhibiting differential vmPFC-related integration and value coding. Furthermore, neural activation holds differential predictive validity for behavioral risk taking in young and older adults. PMID:27630561

  15. Chronic stress alters inhibitory networks in the medial prefrontal cortex of adult mice.

    PubMed

    Gilabert-Juan, Javier; Castillo-Gomez, Esther; Guirado, Ramón; Moltó, Maria Dolores; Nacher, Juan

    2013-11-01

    Chronic stress in experimental animals induces dendritic atrophy and decreases spine density in principal neurons of the medial prefrontal cortex (mPFC). This structural plasticity may play a neuroprotective role and underlie stress-induced behavioral changes. Different evidences indicate that the prefrontocortical GABA system is also altered by stress and in major depression patients. In the amygdala, chronic stress induces dendritic remodeling both in principal neurons and in interneurons. However, it is not known whether similar structural changes occur in mPFC interneurons. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) may mediate these changes, because it is known to influence the dendritic organization of adult cortical interneurons. We have analyzed the dendritic arborization and spine density of mPFC interneurons in adult mice after 21 days of restraint stress and have found dendritic hypertrophy in a subpopulation of interneurons identified mainly as Martinotti cells. This aversive experience also decreases the number of glutamate decarboxylase enzyme, 67 kDa isoform (GAD67) expressing somata, without affecting different parameters related to apoptosis, but does not alter the number of interneurons expressing PSA-NCAM. Quantitative retrotranscription-polymerase chain reaction (qRT-PCR) analysis of genes related to general and inhibitory neurotransmission and of PSA synthesizing enzymes reveals increases in the expression of NCAM, synaptophysin and GABA(A)α1. Together these results show that mPFC inhibitory networks are affected by chronic stress and suggest that structural plasticity may be an important feature of stress-related psychiatric disorders where this cortical region, specially their GABAergic system, is altered.

  16. Altered Neural Responses to Sounds in Primate Primary Auditory Cortex during Slow-Wave Sleep

    PubMed Central

    Issa, Elias B.

    2011-01-01

    How sounds are processed by the brain during sleep is an important question for understanding how we perceive the sensory environment in this unique behavioral state. While human behavioral data have indicated selective impairments of sound processing during sleep, brain imaging and neurophysiology studies have reported that overall neural activity in auditory cortex during sleep is surprisingly similar to that during wakefulness. This responsiveness to external stimuli leaves open the question of how neural responses during sleep differ, if at all, from wakefulness. Using extracellular neural recordings in the primary auditory cortex of naturally sleeping common marmosets, we show that slow-wave sleep (SWS) alters neural responses in the primate auditory cortex in two specific ways. SWS reduced the sensitivity of auditory cortex such that quiet sounds elicited weak responses in SWS compared with wakefulness, while loud sounds evoked similar responses in SWS and wakefulness. Furthermore, SWS reduced the extent of sound-evoked response suppression. This pattern of alterations was not observed during rapid eye movement sleep and could not be easily explained by the presence of slow rhythms in SWS. The alteration of excitatory and inhibitory responses during SWS suggests limitations in auditory processing and provides novel insights for understanding why certain sounds are processed while others are missed during deep sleep. PMID:21414918

  17. Sphingolipid profiles are altered in prefrontal cortex of rats under acute hyperglycemia.

    PubMed

    Fiedorowicz, A; Prokopiuk, S; Zendzian-Piotrowska, M; Chabowski, A; Car, H

    2014-01-01

    Diabetes type 1 is a common autoimmune disease manifesting by insulin deficiency and hyperglycemia, which can lead to dementia-like brain dysfunctions. The factors triggering the pathological processes in hyperglycemic brain remain unknown. We reported in this study that brain areas with different susceptibility to diabetes (prefrontal cortex (PFC), hippocampus, striatum and cerebellum) revealed differential alterations in ceramide (Cer) and sphingomyelin (SM) profiles in rats with streptozotocin-induced hyperglycemia. Employing gas-liquid chromatography, we found that level of total Cer increased significantly only in the PFC of diabetic animals, which also exhibited a broad spectrum of sphingolipid (SLs) changes, such as elevations of Cer-C16:0, -C18:0, -C20:0, -C22:0, -C18:1, -C24:1 and SM-C16:0 and -C18:1. In opposite, only minor changes were noted in other examined structures. In addition, de novo synthesis pathway could play a role in generation of Cer containing monounsaturated fatty acids in PFC during hyperglycemia. In turn, simultaneous accumulation of Cers and their SM counterparts may suggest that overproduced Cers are converted to SMs to avoid excessive Cer-mediated cytotoxicity. We conclude that broad changes in SLs compositions in PFC induced by hyperglycemia may provoke membrane rearrangements in some cell populations, which can disturb cellular signaling and cause tissue damage.

  18. Optical tweezers reveal how proteins alter replication

    NASA Astrophysics Data System (ADS)

    Chaurasiya, Kathy

    Single molecule force spectroscopy is a powerful method that explores the DNA interaction properties of proteins involved in a wide range of fundamental biological processes such as DNA replication, transcription, and repair. We use optical tweezers to capture and stretch a single DNA molecule in the presence of proteins that bind DNA and alter its mechanical properties. We quantitatively characterize the DNA binding mechanisms of proteins in order to provide a detailed understanding of their function. In this work, we focus on proteins involved in replication of Escherichia coli (E. coli ), endogenous eukaryotic retrotransposons Ty3 and LINE-1, and human immunodeficiency virus (HIV). DNA polymerases replicate the entire genome of the cell, and bind both double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA) during DNA replication. The replicative DNA polymerase in the widely-studied model system E. coli is the DNA polymerase III subunit alpha (DNA pol III alpha). We use optical tweezers to determine that UmuD, a protein that regulates bacterial mutagenesis through its interactions with DNA polymerases, specifically disrupts alpha binding to ssDNA. This suggests that UmuD removes alpha from its ssDNA template to allow DNA repair proteins access to the damaged DNA, and to facilitate exchange of the replicative polymerase for an error-prone translesion synthesis (TLS) polymerase that inserts nucleotides opposite the lesions, so that bacterial DNA replication may proceed. This work demonstrates a biophysical mechanism by which E. coli cells tolerate DNA damage. Retroviruses and retrotransposons reproduce by copying their RNA genome into the nuclear DNA of their eukaryotic hosts. Retroelements encode proteins called nucleic acid chaperones, which rearrange nucleic acid secondary structure and are therefore required for successful replication. The chaperone activity of these proteins requires strong binding affinity for both single- and double-stranded nucleic

  19. Renal cortex taurine content regulates renal adaptive response to altered dietary intake of sulfur amino acids.

    PubMed Central

    Chesney, R W; Gusowski, N; Dabbagh, S

    1985-01-01

    Rats fed a reduced sulfur amino acid diet (LTD) or a high-taurine diet (HTD) demonstrate a renal adaptive response. The LTD results in hypotaurinuria and enhanced brush border membrane vesicle (BBMV) accumulation of taurine. The HTD causes hypertaurinuria and reduced BBMV uptake. This adaptation may relate to changes in plasma or renal cortex taurine concentration. Rats were fed a normal-taurine diet (NTD), LTD, or HTD for 14 d or they underwent: (a) 3% beta-alanine for the last 8 d of each diet; (b) 3 d of fasting; or (c) a combination of 3% beta-alanine added for 8 d and 3 d of fasting. Each maneuver lowered the cortex taurine concentration, but did not significantly lower plasma taurine values compared with controls. Increased BBMV taurine uptake occurred after each manipulation. Feeding 3% glycine did not alter the plasma, renal cortex, or urinary taurine concentrations, or BBMV uptake of taurine. Feeding 3% methionine raised plasma and urinary taurine excretion but renal tissue taurine was unchanged, as was initial BBMV uptake. Hence, nonsulfur-containing alpha-amino acids did not change beta-amino acid transport. The increase in BBMV uptake correlates with the decline in renal cortex and plasma taurine content. However, since 3% methionine changed plasma taurine without altering BBMV uptake, it is more likely that the change in BBMV uptake and the adaptive response expressed at the brush border surface relate to changes in renal cortex taurine concentrations. Finally, despite changes in urine and renal cortex taurine content, brain taurine values were unchanged, which suggests that this renal adaptive response maintains stable taurine concentrations where taurine serves as a neuromodulator. PMID:3935668

  20. Adaptive Processes in Thalamus and Cortex Revealed by Silencing of Primary Visual Cortex during Contrast Adaptation.

    PubMed

    King, Jillian L; Lowe, Matthew P; Stover, Kurt R; Wong, Aimee A; Crowder, Nathan A

    2016-05-23

    Visual adaptation illusions indicate that our perception is influenced not only by the current stimulus but also by what we have seen in the recent past. Adaptation to stimulus contrast (the relative luminance created by edges or contours in a scene) induces the perception of the stimulus fading away and increases the contrast detection threshold in psychophysical tests [1, 2]. Neural correlates of contrast adaptation have been described throughout the visual system including the retina [3], dorsal lateral geniculate nucleus (dLGN) [4, 5], primary visual cortex (V1) [6], and parietal cortex [7]. The apparent ubiquity of adaptation at all stages raises the question of how this process cascades across brain regions [8]. Focusing on V1, adaptation could be inherited from pre-cortical stages, arise from synaptic depression at the thalamo-cortical synapse [9], or develop locally, but what is the weighting of these contributions? Because contrast adaptation in mouse V1 is similar to classical animal models [10, 11], we took advantage of the optogenetic tools available in mice to disentangle the processes contributing to adaptation in V1. We disrupted cortical adaptation by optogenetically silencing V1 and found that adaptation measured in V1 now resembled that observed in dLGN. Thus, the majority of adaptation seen in V1 neurons arises through local activity-dependent processes, with smaller contributions from dLGN inheritance and synaptic depression at the thalamo-cortical synapse. Furthermore, modeling indicates that divisive scaling of the weakly adapted dLGN input can predict some of the emerging features of V1 adaptation.

  1. Alteration of rat fetal cerebral cortex development after prenatal exposure to polychlorinated biphenyls.

    PubMed

    Naveau, Elise; Pinson, Anneline; Gérard, Arlette; Nguyen, Laurent; Charlier, Corinne; Thomé, Jean-Pierre; Zoeller, R Thomas; Bourguignon, Jean-Pierre; Parent, Anne-Simone

    2014-01-01

    Polychlorinated biphenyls (PCBs) are environmental contaminants that persist in environment and human tissues. Perinatal exposure to these endocrine disruptors causes cognitive deficits and learning disabilities in children. These effects may involve their ability to interfere with thyroid hormone (TH) action. We tested the hypothesis that developmental exposure to PCBs can concomitantly alter TH levels and TH-regulated events during cerebral cortex development: progenitor proliferation, cell cycle exit and neuron migration. Pregnant rats exposed to the commercial PCB mixture Aroclor 1254 ended gestation with reduced total and free serum thyroxine levels. Exposure to Aroclor 1254 increased cell cycle exit of the neuronal progenitors and delayed radial neuronal migration in the fetal cortex. Progenitor cell proliferation, cell death and differentiation rate were not altered by prenatal exposure to PCBs. Given that PCBs remain ubiquitous, though diminishing, contaminants in human systems, it is important that we further understand their deleterious effects in the brain.

  2. From Blame to Punishment: Disrupting Prefrontal Cortex Activity Reveals Norm Enforcement Mechanisms.

    PubMed

    Buckholtz, Joshua W; Martin, Justin W; Treadway, Michael T; Jan, Katherine; Zald, David H; Jones, Owen; Marois, René

    2015-09-23

    The social welfare provided by cooperation depends on the enforcement of social norms. Determining blameworthiness and assigning a deserved punishment are two cognitive cornerstones of norm enforcement. Although prior work has implicated the dorsolateral prefrontal cortex (DLPFC) in norm-based judgments, the relative contribution of this region to blameworthiness and punishment decisions remains poorly understood. Here, we used repetitive transcranial magnetic stimulation (rTMS) and fMRI to determine the specific role of DLPFC function in norm-enforcement behavior. DLPFC rTMS reduced punishment for wrongful acts without affecting blameworthiness ratings, and fMRI revealed punishment-selective DLPFC recruitment, suggesting that these two facets of norm-based decision making are neurobiologically dissociable. Finally, we show that DLPFC rTMS affects punishment decision making by altering the integration of information about culpability and harm. Together, these findings reveal a selective, causal role for DLPFC in norm enforcement: representational integration of the distinct information streams used to make punishment decisions. PMID:26386518

  3. From Blame to Punishment: Disrupting Prefrontal Cortex Activity Reveals Norm Enforcement Mechanisms.

    PubMed

    Buckholtz, Joshua W; Martin, Justin W; Treadway, Michael T; Jan, Katherine; Zald, David H; Jones, Owen; Marois, René

    2015-09-23

    The social welfare provided by cooperation depends on the enforcement of social norms. Determining blameworthiness and assigning a deserved punishment are two cognitive cornerstones of norm enforcement. Although prior work has implicated the dorsolateral prefrontal cortex (DLPFC) in norm-based judgments, the relative contribution of this region to blameworthiness and punishment decisions remains poorly understood. Here, we used repetitive transcranial magnetic stimulation (rTMS) and fMRI to determine the specific role of DLPFC function in norm-enforcement behavior. DLPFC rTMS reduced punishment for wrongful acts without affecting blameworthiness ratings, and fMRI revealed punishment-selective DLPFC recruitment, suggesting that these two facets of norm-based decision making are neurobiologically dissociable. Finally, we show that DLPFC rTMS affects punishment decision making by altering the integration of information about culpability and harm. Together, these findings reveal a selective, causal role for DLPFC in norm enforcement: representational integration of the distinct information streams used to make punishment decisions.

  4. Altered astrocytic swelling in the cortex of α-syntrophin-negative GFAP/EGFP mice.

    PubMed

    Anderova, Miroslava; Benesova, Jana; Mikesova, Michaela; Dzamba, David; Honsa, Pavel; Kriska, Jan; Butenko, Olena; Novosadova, Vendula; Valihrach, Lukas; Kubista, Mikael; Dmytrenko, Lesia; Cicanic, Michal; Vargova, Lydia

    2014-01-01

    Brain edema accompanying ischemic or traumatic brain injuries, originates from a disruption of ionic/neurotransmitter homeostasis that leads to accumulation of K(+) and glutamate in the extracellular space. Their increased uptake, predominantly provided by astrocytes, is associated with water influx via aquaporin-4 (AQP4). As the removal of perivascular AQP4 via the deletion of α-syntrophin was shown to delay edema formation and K(+) clearance, we aimed to elucidate the impact of α-syntrophin knockout on volume changes in individual astrocytes in situ evoked by pathological stimuli using three dimensional confocal morphometry and changes in the extracellular space volume fraction (α) in situ and in vivo in the mouse cortex employing the real-time iontophoretic method. RT-qPCR profiling was used to reveal possible differences in the expression of ion channels/transporters that participate in maintaining ionic/neurotransmitter homeostasis. To visualize individual astrocytes in mice lacking α-syntrophin we crossbred GFAP/EGFP mice, in which the astrocytes are labeled by the enhanced green fluorescent protein under the human glial fibrillary acidic protein promoter, with α-syntrophin knockout mice. Three-dimensional confocal morphometry revealed that α-syntrophin deletion results in significantly smaller astrocyte swelling when induced by severe hypoosmotic stress, oxygen glucose deprivation (OGD) or 50 mM K(+). As for the mild stimuli, such as mild hypoosmotic or hyperosmotic stress or 10 mM K(+), α-syntrophin deletion had no effect on astrocyte swelling. Similarly, evaluation of relative α changes showed a significantly smaller decrease in α-syntrophin knockout mice only during severe pathological conditions, but not during mild stimuli. In summary, the deletion of α-syntrophin markedly alters astrocyte swelling during severe hypoosmotic stress, OGD or high K(+). PMID:25426721

  5. Altered Astrocytic Swelling in the Cortex of α-Syntrophin-Negative GFAP/EGFP Mice

    PubMed Central

    Anderova, Miroslava; Benesova, Jana; Mikesova, Michaela; Dzamba, David; Honsa, Pavel; Kriska, Jan; Butenko, Olena; Novosadova, Vendula; Valihrach, Lukas; Kubista, Mikael; Dmytrenko, Lesia; Cicanic, Michal; Vargova, Lydia

    2014-01-01

    Brain edema accompanying ischemic or traumatic brain injuries, originates from a disruption of ionic/neurotransmitter homeostasis that leads to accumulation of K+ and glutamate in the extracellular space. Their increased uptake, predominantly provided by astrocytes, is associated with water influx via aquaporin-4 (AQP4). As the removal of perivascular AQP4 via the deletion of α-syntrophin was shown to delay edema formation and K+ clearance, we aimed to elucidate the impact of α-syntrophin knockout on volume changes in individual astrocytes in situ evoked by pathological stimuli using three dimensional confocal morphometry and changes in the extracellular space volume fraction (α) in situ and in vivo in the mouse cortex employing the real-time iontophoretic method. RT-qPCR profiling was used to reveal possible differences in the expression of ion channels/transporters that participate in maintaining ionic/neurotransmitter homeostasis. To visualize individual astrocytes in mice lacking α-syntrophin we crossbred GFAP/EGFP mice, in which the astrocytes are labeled by the enhanced green fluorescent protein under the human glial fibrillary acidic protein promoter, with α-syntrophin knockout mice. Three-dimensional confocal morphometry revealed that α-syntrophin deletion results in significantly smaller astrocyte swelling when induced by severe hypoosmotic stress, oxygen glucose deprivation (OGD) or 50 mM K+. As for the mild stimuli, such as mild hypoosmotic or hyperosmotic stress or 10 mM K+, α-syntrophin deletion had no effect on astrocyte swelling. Similarly, evaluation of relative α changes showed a significantly smaller decrease in α-syntrophin knockout mice only during severe pathological conditions, but not during mild stimuli. In summary, the deletion of α-syntrophin markedly alters astrocyte swelling during severe hypoosmotic stress, OGD or high K+. PMID:25426721

  6. Extinction reveals that primary sensory cortex predicts reinforcement outcome.

    PubMed

    Bieszczad, Kasia M; Weinberger, Norman M

    2012-02-01

    Primary sensory cortices are traditionally regarded as stimulus analysers. However, studies of associative learning-induced plasticity in the primary auditory cortex (A1) indicate involvement in learning, memory and other cognitive processes. For example, the area of representation of a tone becomes larger for stronger auditory memories and the magnitude of area gain is proportional to the degree that a tone becomes behaviorally important. Here, we used extinction to investigate whether 'behavioral importance' specifically reflects a sound's ability to predict reinforcement (reward or punishment) vs. to predict any significant change in the meaning of a sound. If the former, then extinction should reverse area gains as the signal no longer predicts reinforcement. Rats (n = 11) were trained to bar-press to a signal tone (5.0 kHz) for water-rewards, to induce signal-specific area gains in A1. After subsequent withdrawal of reward, A1 was mapped to determine representational areas. Signal-specific area gains, estimated from a previously established brain-behavior quantitative function, were reversed, supporting the 'reinforcement prediction' hypothesis. Area loss was specific to the signal tone vs. test tones, further indicating that withdrawal of reinforcement, rather than unreinforced tone presentation per se, was responsible for area loss. Importantly, the amount of area loss was correlated with the amount of extinction (r = 0.82, P < 0.01). These findings show that primary sensory cortical representation can encode behavioral importance as a signal's value to predict reinforcement, and that the number of cells tuned to a stimulus can dictate its ability to command behavior. PMID:22304434

  7. Extinction reveals that primary sensory cortex predicts reinforcement outcome.

    PubMed

    Bieszczad, Kasia M; Weinberger, Norman M

    2012-02-01

    Primary sensory cortices are traditionally regarded as stimulus analysers. However, studies of associative learning-induced plasticity in the primary auditory cortex (A1) indicate involvement in learning, memory and other cognitive processes. For example, the area of representation of a tone becomes larger for stronger auditory memories and the magnitude of area gain is proportional to the degree that a tone becomes behaviorally important. Here, we used extinction to investigate whether 'behavioral importance' specifically reflects a sound's ability to predict reinforcement (reward or punishment) vs. to predict any significant change in the meaning of a sound. If the former, then extinction should reverse area gains as the signal no longer predicts reinforcement. Rats (n = 11) were trained to bar-press to a signal tone (5.0 kHz) for water-rewards, to induce signal-specific area gains in A1. After subsequent withdrawal of reward, A1 was mapped to determine representational areas. Signal-specific area gains, estimated from a previously established brain-behavior quantitative function, were reversed, supporting the 'reinforcement prediction' hypothesis. Area loss was specific to the signal tone vs. test tones, further indicating that withdrawal of reinforcement, rather than unreinforced tone presentation per se, was responsible for area loss. Importantly, the amount of area loss was correlated with the amount of extinction (r = 0.82, P < 0.01). These findings show that primary sensory cortical representation can encode behavioral importance as a signal's value to predict reinforcement, and that the number of cells tuned to a stimulus can dictate its ability to command behavior.

  8. Alteration of digital representations in somatosensory cortex in focal hand dystonia.

    PubMed

    Elbert, T; Candia, V; Altenmüller, E; Rau, H; Sterr, A; Rockstroh, B; Pantev, C; Taub, E

    1998-11-16

    Focal hand dystonia involves a loss of motor control of one or more digits; it is associated with the repetitive, synchronous movements of the digits made by musicians over periods of many years. Magnetic source imaging revealed that there is a smaller distance (fusion) between the representations of the digits in somatosensory cortex for the affected hand of dystonic musicians than for the hands of non-musician control subjects. The data suggest that use-dependent susceptibility to digital representation fusion in cortex may be involved in the etiology of focal dystonia. A successful therapy for the condition has been developed based on this consideration.

  9. Altered information processing in the prefrontal cortex of Huntington's disease mouse models.

    PubMed

    Walker, Adam G; Miller, Benjamin R; Fritsch, Jenna N; Barton, Scott J; Rebec, George V

    2008-09-01

    Understanding cortical information processing in Huntington's disease (HD), a genetic neurological disorder characterized by prominent motor and cognitive abnormalities, is key to understanding the mechanisms underlying the HD behavioral phenotype. We recorded extracellular spike activity in two symptomatic, freely behaving mouse models: R6/2 transgenics, which are based on a CBA x C57BL/6 background and show robust behavioral symptoms, and HD knock-in (KI) mice, which have a 129sv background and express relatively mild behavioral signs. We focused on prefrontal cortex and assessed firing patterns of individually recorded neurons as well as the amount of synchrony between simultaneously recorded neuronal pairs. At the single-unit level, spike trains in R6/2 transgenics were less variable and had a faster rate than their corresponding wild-type (WT) littermates but showed significantly less bursting. In contrast, KI and WT firing patterns were closely matched. An assessment of both WTs revealed that the R6/2 and KI difference could not be explained by a difference in WT electrophysiology. Thus, the altered pattern of individual spike trains in R6/2 mice appears to parallel their aggressive form of symptom expression. Both WT lines, however, showed a high proportion of synchrony between neuronal pairs (>85%) that was significantly attenuated in both corresponding HD models (decreases of approximately 20% and approximately 30% in R6/2s and knock-ins, respectively). The loss of spike synchrony, regardless of symptom severity, suggests a population-level deficit in cortical information processing that underlies HD progression.

  10. Representational cortex in musicians. Plastic alterations in response to musical practice.

    PubMed

    Pantev, C; Engelien, A; Candia, V; Elbert, T

    2001-06-01

    The lifelong ability to adapt to environmental needs is based on the capacity of the central nervous system for plastic alterations. In a series of neurophysiological experiments, we studied the impact of music and musical training in musicians on the specific functional organization in auditory and somatosensory representational cortex. In one such study, subjects listened to music from which one specific spectral frequency was removed. This led to rapid and reversible adaptation of neuronal responses in auditory cortex. Further experimental evidence demonstrated that long years of practice and training by professional musicians to enable them to reach their capacity is associated with enlarged cortical representations in the somatosensory and auditory domains. This tuning of neuronal representations was specifically observed for musical tones and was absent when pure sinusoidal tones were used as stimuli. In the somatosensory cortex, plastic changes proved to be specific for the fingers frequently used and stimulated. These changes were not detected in the fingers of the hand that were not involved in playing the particular instrument. Neuroplastic alterations also may be driven into a domain where they may become maladaptive. The clinical syndrome of focal hand dystonia that may occur in musicians who engage in forceful practice may be one such consequence. We will discuss the possibilities of reversing maladaptive responses leading to the successful treatment of focal hand dystonia, which relies on basic research about cortical reorganization. This example elucidates how neuroscientific progress can guide the development of practice guidelines and therapeutic measures for the benefit of professional musicians.

  11. Reversible Deactivation of Motor Cortex Reveals Functional Connectivity with Posterior Parietal Cortex in the Prosimian Galago (Otolemur garnettii)

    PubMed Central

    Cooke, Dylan F.; Stepniewska, Iwona; Miller, Daniel J.; Kaas, Jon H.

    2015-01-01

    We examined the functional macrocircuitry of frontoparietal networks in the neocortex of prosimian primates (Otolemur garnettii) using a microfluidic thermal regulator to reversibly deactivate selected regions of motor cortex (M1). During deactivation of either forelimb or mouth/face movement domains within M1, we used long-train intracortical microstimulation techniques to evoke movements from the rostral division of posterior parietal cortex (PPCr). We found that deactivation of M1 movement domains in most instances abolished movements evoked in PPCr. The most common effect of deactivating M1 was to abolish evoked movements in a homotopic domain in PPCr. For example, deactivating M1 forelimb lift domains resulted in loss of evoked movement in forelimb domains in PPCr. However, at some sites, we also observed heterotopic effects; deactivating a specific domain in M1 (e.g., forelimb lift) resulted in loss of evoked movement in a different movement domain in PPCr (e.g., hand-to-mouth or eye-blink). At most sites examined in PPCr, rewarming M1 resulted in a reestablishment of the baseline movement at the same amplitude as that observed before cooling. However, at some sites, reactivation did not result in a return to baseline movement or to the full amplitude of the baseline movement. We discuss our findings in the context of frontoparietal circuits and how they may subserve a repertoire of ecologically relevant behaviors. SIGNIFICANCE STATEMENT The posterior parietal cortex (PPC) of primates integrates sensory information used to guide movements. Different modules within PPC and motor cortex (M1) appear to control various motor behaviors (e.g., reaching, defense, and feeding). How these modules work together may vary across species and may explain differences in dexterity and even the capacity for tool use. We investigated the functional connectivity of these modules in galagos, a prosimian primate with relatively simple frontoparietal circuitry. By deactivating a

  12. Running Induces Widespread Structural Alterations in the Hippocampus and Entorhinal Cortex

    PubMed Central

    Stranahan, Alexis M.; Khalil, David; Gould, Elizabeth

    2010-01-01

    Physical activity enhances hippocampal function but its effects on neuronal structure remain relatively unexplored outside of the dentate gyrus. Using Golgi impregnation and the lipophilic tracer DiI, we show that long-term voluntary running increases the density of dendritic spines in the entorhinal cortex and hippocampus of adult rats. Exercise was associated with increased dendritic spine density not only in granule neurons of the dentate gyrus, but also in CA1 pyramidal neurons, and in layer III pyramidal neurons of the entorhinal cortex. In the CA1 region, changes in dendritic spine density are accompanied by changes in dendritic arborization and alterations in the morphology of individual spines. These findings suggest that physical activity exerts pervasive effects on neuronal morphology in the hippocampus and one of its afferent populations. These structural changes may contribute to running-induced changes in cognitive function. PMID:17636549

  13. Altered neuronal architecture and plasticity in the visual cortex of adult MMP-3-deficient mice.

    PubMed

    Aerts, Jeroen; Nys, Julie; Moons, Lieve; Hu, Tjing-Tjing; Arckens, Lutgarde

    2015-09-01

    Matrix metalloproteinases (MMPs) are Zn(2+)-dependent endopeptidases considered to be essential for normal brain development and neuroplasticity by modulating extracellular matrix proteins, receptors, adhesion molecules, growth factors and cytoskeletal proteins. Specifically, MMP-3 has recently been implicated in synaptic plasticity, hippocampus-dependent learning and neuronal development and migration in the cerebellum. However, the function(s) of this enzyme in the neocortex is understudied. Therefore, we explored the phenotypical characteristics of the neuronal architecture and the capacity for experience-dependent cortical plasticity in the visual cortex of adult MMP-3-deficient (MMP-3(-/-)) mice. Golgi-Cox stainings revealed a significant reduction in apical dendritic length and an increased number of apical obliques for layer V pyramidal neurons in the visual cortex of adult MMP-3(-/-) mice compared to wild-type (WT) animals. In addition, a significant upregulation of both phosphorylated and non-phosphorylated neurofilament protein (NF)-high, phosphorylated NF-medium, NF-low and α-internexin was detected in the visual cortex of MMP-3(-/-) mice. To assess the effect of MMP-3 deficiency on cortical plasticity, we monocularly enucleated adult MMP-3(-/-) mice and analyzed the reactivation of the contralateral visual cortex 7 weeks post-enucleation. In contrast to previous results in C57Bl/6J adult mice, activity remained confined to the binocular zone and did not expand into the monocular regions indicative for an aberrant open-eye potentiation. Permanent hypoactivity in the monocular cortex lateral and medial to V1 also indicated a lack of cross-modal plasticity. These observations demonstrate that genetic inactivation of MMP-3 has profound effects on the structural integrity and plasticity response of the visual cortex of adult mice.

  14. Altered SPECT 123I-iomazenil Binding in the Cingulate Cortex of Children with Anorexia Nervosa

    PubMed Central

    Nagamitsu, Shinichiro; Sakurai, Rieko; Matsuoka, Michiko; Chiba, Hiromi; Ozono, Shuichi; Tanigawa, Hitoshi; Yamashita, Yushiro; Kaida, Hayato; Ishibashi, Masatoshi; Kakuma, Tatsuki; Croarkin, Paul E.; Matsuishi, Toyojiro

    2016-01-01

    Several lines of evidence suggest that anxiety plays a key role in the development and maintenance of anorexia nervosa (AN) in children. The purpose of this study was to examine cortical GABA(A)-benzodiazepine receptor binding before and after treatment in children beginning intensive AN treatment. Brain single-photon emission computed tomography (SPECT) measurements using 123I-iomazenil, which binds to GABA(A)-benzodiazepine receptors, was performed in 26 participants with AN who were enrolled in a multimodal treatment program. Sixteen of the 26 participants underwent a repeat SPECT scan immediately before discharge at conclusion of the intensive treatment program. Eating behavior and mood disturbances were assessed using Eating Attitudes Test with 26 items (EAT-26) and the short form of the Profile of Mood States (POMS). Clinical outcome scores were evaluated after a 1-year period. We examined association between relative iomazenil-binding activity in cortical regions of interest and psychometric profiles and determined which psychometric profiles show interaction effects with brain regions. Further, we determined if binding activity could predict clinical outcome and treatment changes. Higher EAT-26 scores were significantly associated with lower iomazenil-binding activity in the anterior and posterior cingulate cortex. Higher POMS subscale scores were significantly associated with lower iomazenil-binding activity in the left frontal, parietal cortex, and posterior cingulate cortex (PCC). “Depression–Dejection” and “Confusion” POMS subscale scores, and total POMS score showed interaction effects with brain regions in iomazenil-binding activity. Decreased binding in the anterior cingulate cortex and left parietal cortex was associated with poor clinical outcomes. Relative binding increases throughout the PCC and occipital gyrus were observed after weight gain in children with AN. These findings suggest that cortical GABAergic receptor binding is altered

  15. Correlates of perceptual awareness in human primary auditory cortex revealed by an informational masking experiment.

    PubMed

    Wiegand, Katrin; Gutschalk, Alexander

    2012-05-15

    The presence of an auditory event may remain undetected in crowded environments, even when it is well above the sensory threshold. This effect, commonly known as informational masking, allows for isolating neural activity related to perceptual awareness, by comparing repetitions of the same physical stimulus where the target is either detected or not. Evidence from magnetoencephalography (MEG) suggests that auditory-cortex activity in the latency range 50-250 ms is closely coupled with perceptual awareness. Here, BOLD fMRI and MEG were combined to investigate at which stage in the auditory cortex neural correlates of conscious auditory perception can be observed. Participants were asked to indicate the perception of a regularly repeating target tone, embedded within a random multi-tone masking background. Results revealed widespread activation within the auditory cortex for detected target tones, which was delayed but otherwise similar to the activation of an unmasked control stimulus. The contrast of detected versus undetected targets revealed activity confined to medial Heschl's gyrus, where the primary auditory cortex is located. These results suggest that activity related to conscious perception involves the primary auditory cortex and is not restricted to activity in secondary areas.

  16. Prenatal alcohol exposure alters the cerebral cortex proteome in weanling rats.

    PubMed

    Canales, Lorena; Gambrell, Caitlin; Chen, Jing; Neal, Rachel E

    2013-08-01

    Maternal consumption of alcohol during pregnancy impairs neurodevelopment in offspring. Utilizing a rodent model of continuous moderate dose alcohol exposure throughout gestation [gestation day 1 (GD1)-GD22; BAC ~70 mg/dL], the impact of developmental alcohol exposure on juvenile cerebral cortex protein abundances was determined. At weaning, cerebral cortex tissue was collected from pups for 2D SDS-PAGE based proteome analysis with statistical analysis by Partial Least Squares-Discriminant Analysis (PLS-DA). Gestational alcohol exposure increased the abundance of post-translationally modified forms of cytoskeletal proteins and the abundance of proteins within the small molecule biochemistry (includes glucose metabolism) pathway and proteosome processing pathways though ubiquitin conjugating enzymes and chaperones were decreased in abundance. In weanling offspring exposed prenatally to alcohol, alterations in cytoskeletal protein post-translational modifications were noted. Increased abundance of proteins from the small molecule biochemistry pathway, which includes glucose metabolism, and proteosome processing pathways were also noted. Decreased abundances of ubiquitin conjugating enzyme and chaperone protein were noted in the cerebral cortex of these offspring.

  17. Altered gene expression in the dorsolateral prefrontal cortex of individuals with schizophrenia

    PubMed Central

    Guillozet-Bongaarts, A L; Hyde, T M; Dalley, R A; Hawrylycz, M J; Henry, A; Hof, P R; Hohmann, J; Jones, A R; Kuan, C L; Royall, J; Shen, E; Swanson, B; Zeng, H; Kleinman, J E

    2014-01-01

    The underlying pathology of schizophrenia (SZ) is likely as heterogeneous as its symptomatology. A variety of cortical and subcortical regions, including the prefrontal cortex, have been implicated in its pathology, and a number of genes have been identified as risk factors for disease development. We used in situ hybridization (ISH) to examine the expression of 58 genes in the dorsolateral prefrontal cortex (DLPFC, comprised of Brodmann areas 9 and 46) from 19 individuals with a premorbid diagnosis of SZ and 33 control individuals. Genes were selected based on: (1) previous identification as risk factors for SZ; (2) cell type markers or (3) laminar markers. Cell density and staining intensity were compared in the DLPFC, as well as separately in Brodmann areas 9 and 46. The expression patterns of a variety of genes, many of which are associated with the GABAergic system, were altered in SZ when compared with controls. Additional genes, including C8orf79 and NR4A2, showed alterations in cell density or staining intensity between the groups, highlighting the need for additional studies. Alterations were, with only a few exceptions, limited to Brodmann area 9, suggesting regional specificity of pathology in the DLPFC. Our results agree with previous studies on the GABAergic involvement in SZ, and suggest that areas 9 and 46 may be differentially affected in the disease. This study also highlights additional genes that may be altered in SZ, and indicates that these potentially interesting genes can be identified by ISH and high-throughput image analysis techniques. PMID:23528911

  18. Interactions between behaviorally relevant rhythms and synaptic plasticity alter coding in the piriform cortex.

    PubMed

    Oswald, Anne-Marie M; Urban, Nathaniel N

    2012-05-01

    Understanding how neural and behavioral timescales interact to influence cortical activity and stimulus coding is an important issue in sensory neuroscience. In air-breathing animals, voluntary changes in respiratory frequency alter the temporal patterning olfactory input. In the olfactory bulb, these behavioral timescales are reflected in the temporal properties of mitral/tufted (M/T) cell spike trains. As the odor information contained in these spike trains is relayed from the bulb to the cortex, interactions between presynaptic spike timing and short-term synaptic plasticity dictate how stimulus features are represented in cortical spike trains. Here, we demonstrate how the timescales associated with respiratory frequency, spike timing, and short-term synaptic plasticity interact to shape cortical responses. Specifically, we quantified the timescales of short-term synaptic facilitation and depression at excitatory synapses between bulbar M/T cells and cortical neurons in slices of mouse olfactory cortex. We then used these results to generate simulated M/T population synaptic currents that were injected into real cortical neurons. M/T population inputs were modulated at frequencies consistent with passive respiration or active sniffing. We show how the differential recruitment of short-term plasticity at breathing versus sniffing frequencies alters cortical spike responses. For inputs at sniffing frequencies, cortical neurons linearly encoded increases in presynaptic firing rates with increased phase-locked, firing rates. In contrast, at passive breathing frequencies, cortical responses saturated with changes in presynaptic rate. Our results suggest that changes in respiratory behavior can gate the transfer of stimulus information between the olfactory bulb and cortex.

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  1. Temporal Lobe Epilepsy Induces Intrinsic Alterations in Na Channel Gating in Layer II Medial Entorhinal Cortex Neurons

    PubMed Central

    Hargus, Nicholas J.; Merrick, Ellen C.; Nigam, Aradhya; Kalmar, Christopher L.; Baheti, Aparna R.; Bertram, Edward H.; Patel, Manoj K.

    2010-01-01

    Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy involving the limbic structures of the temporal lobe. Layer II neurons of the entorhinal cortex (EC) form the major excitatory input into the hippocampus via the perforant path and consist of non-stellate and stellate neurons. These neurons are spared and hyper-excitable in TLE. The basis for the hyper-excitability is likely multifactorial and may include alterations in intrinsic properties. In a rat model of TLE, medial EC (mEC) non-stellate and stellate neurons had significantly higher action potential (AP) firing frequencies than in control. The increase remained in the presence of synaptic blockers, suggesting intrinsic mechanisms. Since sodium (Na) channels play a critical role in AP generation and conduction we sought to determine if Na channel gating parameters and expression levels were altered in TLE. Na channel currents recorded from isolated mEC TLE neurons revealed increased Na channel conductances, depolarizing shifts in inactivation parameters and larger persistent (INaP) and resurgent (INaR) Na currents. Immunofluorescence experiments revealed increased staining of Nav1.6 within the axon initial segment and Nav1.2 within the cell bodies of mEC TLE neurons. These studies provide support for additional intrinsic alterations within mEC layer II neurons in TLE and implicate alterations in Na channel activity and expression, in part, for establishing the profound increase in intrinsic membrane excitability of mEC layer II neurons in TLE. These intrinsic changes, together with changes in the synaptic network, could support seizure activity in TLE. PMID:20946956

  2. Altered gene expression profiles in the hippocampus and prefrontal cortex of type 2 diabetic rats

    PubMed Central

    2012-01-01

    Background There has been an increasing body of epidemiologic and biochemical evidence implying the role of cerebral insulin resistance in Alzheimer-type dementia. For a better understanding of the insulin effect on the central nervous system, we performed microarray-based global gene expression profiling in the hippocampus, striatum and prefrontal cortex of streptozotocin-induced and spontaneously diabetic Goto-Kakizaki rats as model animals for type 1 and type 2 diabetes, respectively. Results Following pathway analysis and validation of gene lists by real-time polymerase chain reaction, 30 genes from the hippocampus, such as the inhibitory neuropeptide galanin, synuclein gamma and uncoupling protein 2, and 22 genes from the prefrontal cortex, e.g. galanin receptor 2, protein kinase C gamma and epsilon, ABCA1 (ATP-Binding Cassette A1), CD47 (Cluster of Differentiation 47) and the RET (Rearranged During Transfection) protooncogene, were found to exhibit altered expression levels in type 2 diabetic model animals in comparison to non-diabetic control animals. These gene lists proved to be partly overlapping and encompassed genes related to neurotransmission, lipid metabolism, neuronal development, insulin secretion, oxidative damage and DNA repair. On the other hand, no significant alterations were found in the transcriptomes of the corpus striatum in the same animals. Changes in the cerebral gene expression profiles seemed to be specific for the type 2 diabetic model, as no such alterations were found in streptozotocin-treated animals. Conclusions According to our knowledge this is the first characterization of the whole-genome expression changes of specific brain regions in a diabetic model. Our findings shed light on the complex role of insulin signaling in fine-tuning brain functions, and provide further experimental evidence in support of the recently elaborated theory of type 3 diabetes. PMID:22369239

  3. Structural and functional cellular alterations underlying the toxicity of methamphetamine in rat retina and prefrontal cortex.

    PubMed

    Prudêncio, Cristina; Abrantes, Bruno; Lopes, Isabel; Tavares, Maria Amélia

    2002-06-01

    The consumption of illicit drugs is an increasing problem in contemporary societies, and is one of the major causes of death and illness all over the world. Methamphetamine is among the drugs more widely used. Although evidence for a role of reactive species--especially reactive oxygen species (ROS) and apoptotic events--has been shown, the mechanism(s) underlying the cellular toxicity induced by this drug is not yet fully identified. In this context the elucidation of the cytotoxic effects induced by methamphetamine in rat frontal cortex and retina, which compromise cell viability and ultimately result in cell death, can further contribute to the understanding of its mechanism of action. This knowledge may provide new insights into the development of new therapeutic approaches to prevent or ameliorate deleterious alterations of the nervous system. The use of epifluorescence microscopy associated with different fluorescent probes, markers of structural and/or functional cell parameters, can be used as a powerful tool to carry out those studies, in particular, the viability probes propidium iodide (PI) to assess plasma membrane integrity and fluorescein diacetate (FDA), which can monitor intracellular esterase activity and/or pH. In a preliminary study, the kinetic assessment of cellular changes induced by different drug concentrations (0, 1.2, 3, and 6 mM) allowed detection of dose-dependent alterations that are observed earlier in the retina. In fact, in the retina it was possible to monitor alterations (at 4 h of incubation) both in plasma membrane integrity and in esterase activity and/or pH for the lowest drug concentration (1.2 mM). In the prefrontal cortex these changes were only visible for drug concentrations > or = 3 mM. This work is a novel approach to the mechanisms of action of illicit drugs in the central nervous system and will provide the foundations and guidelines for further investigations in the context of tolerance, dependence, and addiction.

  4. Neurochemical alterations in frontal cortex of the rat after one week of hypobaric hypoxia

    PubMed Central

    Bogdanova, Olena V.; Abdullah, Osama; Kanekar, Shami; Bogdanov, Volodymyr B.; Prescot, Andrew P.; Renshaw, Perry F.

    2015-01-01

    Residing at high altitude may lead to reduced blood oxygen saturation in the brain and altered metabolism in frontal cortical brain areas, probably due to chronic hypobaric hypoxia. These changes may underlie the increased rates of depression and suicidal behavior that have been associated with life at higher altitudes. To test the hypothesis that hypobaric hypoxia is responsible for development of mood disorders due to alterations in neurochemistry, we assessed depression-like behavior in parallel to levels of brain metabolites in rats housed at simulated altitude. 32 female Sprague Dawley rats were housed either in a hypobaric hypoxia chamber at 10,000 ft of simulated altitude for 1 week or at local conditions (4500 ft of elevation in Salt Lake City, Utah). Depression-like behavior was assessed using the forced swim test (FST) and levels of neurometabolites were estimated by in vivo proton magnetic resonance spectroscopy in the frontal cortex, the striatum and the hippocampus at baseline and after a week of exposure to hypobaric hypoxia. After hypoxia exposure the animals demonstrated increased immobility behavior and shortened latency to immobility in the FST. Elevated ratios of myo-inositol, glutamate, and the sum of myo-inositol and glycine to total creatine were observed in the frontal cortex of hypoxia treated rats. A decrease in the ratio of alanine to total creatine was also noted. This study shows that hypoxia induced alterations in frontal lobe brain metabolites, aggravated depression-like behavior and might be a factor in increased rates of psychiatric disorders observed in populations living at high altitudes. PMID:24486259

  5. Neurochemical alterations in frontal cortex of the rat after one week of hypobaric hypoxia.

    PubMed

    Bogdanova, Olena V; Abdullah, Osama; Kanekar, Shami; Bogdanov, Volodymyr B; Prescot, Andrew P; Renshaw, Perry F

    2014-04-15

    Residing at high altitude may lead to reduced blood oxygen saturation in the brain and altered metabolism in frontal cortical brain areas, probably due to chronic hypobaric hypoxia. These changes may underlie the increased rates of depression and suicidal behavior that have been associated with life at higher altitudes. To test the hypothesis that hypobaric hypoxia is responsible for development of mood disorders due to alterations in neurochemistry, we assessed depression-like behavior in parallel to levels of brain metabolites in rats housed at simulated altitude. 32 female Sprague Dawley rats were housed either in a hypobaric hypoxia chamber at 10,000 ft of simulated altitude for 1 week or at local conditions (4500 ft of elevation in Salt Lake City, Utah). Depression-like behavior was assessed using the forced swim test (FST) and levels of neurometabolites were estimated by in vivo proton magnetic resonance spectroscopy in the frontal cortex, the striatum and the hippocampus at baseline and after a week of exposure to hypobaric hypoxia. After hypoxia exposure the animals demonstrated increased immobility behavior and shortened latency to immobility in the FST. Elevated ratios of myo-inositol, glutamate, and the sum of myo-inositol and glycine to total creatine were observed in the frontal cortex of hypoxia treated rats. A decrease in the ratio of alanine to total creatine was also noted. This study shows that hypoxia induced alterations in frontal lobe brain metabolites, aggravated depression-like behavior and might be a factor in increased rates of psychiatric disorders observed in populations living at high altitudes.

  6. Alterations of the cerebral cortex in sporadic small vessel disease: A systematic review of in vivo MRI data.

    PubMed

    Peres, Roxane; De Guio, François; Chabriat, Hugues; Jouvent, Eric

    2016-04-01

    Cerebral small vessel diseases of the brain are a major determinant of cognitive impairment in the elderly. In small vessel diseases, the most easily identifiable lesions, both at post-mortem evaluation and magnetic resonance imaging, lie in subcortical areas. However, recent results obtained post-mortem, particularly in severe cases, have highlighted the burden of cortex lesions such as microinfarcts and diffuse neuronal loss. The recent development of image post-processing methods allows now assessing in vivo multiple aspects of the cerebral cortex. This systematic review aimed to analyze in vivo magnetic resonance imaging studies evaluating cortex alterations at different stages of small vessel diseases. Studies assessing the relationships between small vessel disease magnetic resonance imaging markers obtained at the subcortical level and cortex estimates were reviewed both in community-dwelling elderly and in patients with symptomatic small vessel diseases. Thereafter, studies analyzing cortex estimates in small vessel disease patients compared with healthy subjects were evaluated. The results support that important cortex alterations develop along the course of small vessel diseases independently of concomitant neurodegenerative processes. Easy detection and quantification of cortex changes in small vessel diseases as well as understanding their underlying mechanisms are challenging tasks for better understanding cognitive decline in small vessel diseases. PMID:26787108

  7. Tonotopic organization in human auditory cortex revealed by progressions of frequency sensitivity.

    PubMed

    Talavage, Thomas M; Sereno, Martin I; Melcher, Jennifer R; Ledden, Patrick J; Rosen, Bruce R; Dale, Anders M

    2004-03-01

    Functional neuroimaging experiments have revealed an organization of frequency-dependent responses in human auditory cortex suggestive of multiple tonotopically organized areas. Numerous studies have sampled cortical responses to isolated narrow-band stimuli, revealing multiple locations in auditory cortex at which the position of response varies systematically with frequency content. Because appropriate anatomical or functional grouping of these distinct frequency-dependent responses is uncertain, the number and location of tonotopic mappings within human auditory cortex remains unclear. Further, sampling does not address whether the observed mappings exhibit continuity as a function of position. This functional magnetic resonance imaging study used frequency-swept stimuli to identify progressions of frequency sensitivity across the cortical surface. The center-frequency of narrow-band, amplitude-modulated noise was slowly swept between 125 and 8,000 Hz. The latency of response relative to sweep onset was determined for each cortical surface location. Because frequency varied systematically with time, response latency indicated the frequency to which a location was maximally sensitive. Areas of cortex exhibiting a progressive change in response latency with position were considered tonotopically organized. There exist two main findings. First, six progressions of frequency sensitivity (i.e., tonotopic mappings) were repeatably observed in the superior temporal plane. Second, the locations of the higher- and lower-frequency endpoints of these progressions were approximately congruent with regions reported to be most responsive to discrete higher- and lower-frequency stimuli. Based on these findings and previous anatomical work, we propose a correspondence between these progressions and anatomically defined cortical areas, suggesting that five areas in human auditory cortex exhibit at least six tonotopic organizations.

  8. Memory impairment and alterations in prefrontal cortex gamma band activity following methamphetamine sensitization

    PubMed Central

    Linsenbardt, David N.; Lapish, Christopher C.

    2015-01-01

    Rationale Repeated methamphetamine (MA) use leads to increases in the incentive motivational properties of the drug as well as cognitive impairments. These behavioral alterations persist for some time following abstinence, and neuroadaptations in the structure and function of the prefrontal cortex (PFC) are particularly important for their expression. However, there is a weak understanding of the changes in neural firing and oscillatory activity in the PFC evoked by repeated drug use, thus complicating the development of novel treatment strategies for addiction. Objectives The purpose of the current study was to assess changes in cognitive and brain function following MA sensitization. Methods Sensitization was induced in rats, then temporal and recognition memory were assessed after 1 or 30 days of abstinence. Electrophysiological recordings from the medial PFC were also acquired from rats whereupon simultaneous measures of oscillatory and spiking activity were examined. Results Impaired temporal memory was observed after 1 and 30 days of abstinence. However, recognition memory was only impaired after 1 day of abstinence. An injection of MA profoundly decreased neuronal firing rate and the anesthesia-induced slow oscillation (SO) in both sensitized (SENS) and control (CTRL) rats. Strong correlations were observed between the SO and gamma band power, which was altered in SENS animals. A decrease in the number of neurons phase-locked to the gamma oscillation was also observed in SENS animals. Conclusions The changes observed in PFC function may play an integral role in the expression of the altered behavioral phenotype evoked by MA sensitization. PMID:25572530

  9. Calbindin Knockout Alters Sex-Specific Regulation of Behavior and Gene Expression in Amygdala and Prefrontal Cortex.

    PubMed

    Harris, Erin P; Abel, Jean M; Tejada, Lucia D; Rissman, Emilie F

    2016-05-01

    Calbindin-D(28K) (Calb1), a high-affinity calcium buffer/sensor, shows abundant expression in neurons and has been associated with a number of neurobehavioral diseases, many of which are sexually dimorphic in incidence. Behavioral and physiological end points are affected by experimental manipulations of calbindin levels, including disruption of spatial learning, hippocampal long-term potentiation, and circadian rhythms. In this study, we investigated novel aspects of calbindin function on social behavior, anxiety-like behavior, and fear conditioning in adult mice of both sexes by comparing wild-type to littermate Calb1 KO mice. Because Calb1 mRNA and protein are sexually dimorphic in some areas of the brain, we hypothesized that sex differences in behavioral responses of these behaviors would be eliminated or revealed in Calb1 KO mice. We also examined gene expression in the amygdala and prefrontal cortex, two areas of the brain intimately connected with limbic system control of the behaviors tested, in response to sex and genotype. Our results demonstrate that fear memory and social behavior are altered in male knockout mice, and Calb1 KO mice of both sexes show less anxiety. Moreover, gene expression studies of the amygdala and prefrontal cortex revealed several significant genotype and sex effects in genes related to brain-derived neurotrophic factor signaling, hormone receptors, histone deacetylases, and γ-aminobutyric acid signaling. Our findings are the first to directly link calbindin with affective and social behaviors in rodents; moreover, the results suggest that sex differences in calbindin protein influence behavior.

  10. TRPV1-Dependent and -Independent Alterations in the Limbic Cortex of Neuropathic Mice: Impact on Glial Caspases and Pain Perception

    PubMed Central

    Giordano, Catia; Cristino, Luigia; Luongo, Livio; Siniscalco, Dario; Petrosino, Stefania; Piscitelli, Fabiana; Marabese, Ida; Gatta, Luisa; Rossi, Francesca; Imperatore, Roberta; Palazzo, Enza; de Novellis, Vito; Di Marzo, Vincenzo

    2012-01-01

    During neuropathic pain, caspases are activated in the limbic cortex. We investigated the role of TRPV1 channels and glial caspases in the mouse prelimbic and infralimbic (PL-IL) cortex after spared nerve injury (SNI). Reverse transcriptase-polymerase chain reaction, western blots, and immunfluorescence showed overexpression of several caspases in the PL-IL cortex 7 days postinjury. Caspase-3 release and upregulation of AMPA receptors in microglia, caspase-1 and IL-1β release in astrocytes, and upregulation of Il-1 receptor-1, TRPV1, and VGluT1 in glutamatergic neurons, were also observed. Of these alterations, only those in astrocytes persisted in SNI Trpv1−/− mice. A pan-caspase inhibitor, injected into the PL-IL cortex, reduced mechanical allodynia, this effect being reduced but not abolished in Trpv1−/− mice. Single-unit extracellular recordings in vivo following electrical stimulation of basolateral amygdala or application of pressure on the hind paw, showed increased excitatory pyramidal neuron activity in the SNI PL-IL cortex, which also contained higher levels of the endocannabinoid 2-arachidonoylglycerol. Intra-PL-IL cortex injection of mGluR5 and NMDA receptor antagonists and AMPA exacerbated, whereas TRPV1 and AMPA receptor antagonists and a CB1 agonist inhibited, allodynia. We suggest that SNI triggers both TRPV1-dependent and independent glutamate- and caspase-mediated cross-talk among IL-PL cortex neurons and glia, which either participates or counteracts pain. PMID:22139792

  11. TRPV1-dependent and -independent alterations in the limbic cortex of neuropathic mice: impact on glial caspases and pain perception.

    PubMed

    Giordano, Catia; Cristino, Luigia; Luongo, Livio; Siniscalco, Dario; Petrosino, Stefania; Piscitelli, Fabiana; Marabese, Ida; Gatta, Luisa; Rossi, Francesca; Imperatore, Roberta; Palazzo, Enza; de Novellis, Vito; Di Marzo, Vincenzo; Maione, Sabatino

    2012-11-01

    During neuropathic pain, caspases are activated in the limbic cortex. We investigated the role of TRPV1 channels and glial caspases in the mouse prelimbic and infralimbic (PL-IL) cortex after spared nerve injury (SNI). Reverse transcriptase-polymerase chain reaction, western blots, and immunfluorescence showed overexpression of several caspases in the PL-IL cortex 7 days postinjury. Caspase-3 release and upregulation of AMPA receptors in microglia, caspase-1 and IL-1β release in astrocytes, and upregulation of Il-1 receptor-1, TRPV1, and VGluT1 in glutamatergic neurons, were also observed. Of these alterations, only those in astrocytes persisted in SNI Trpv1(-/-) mice. A pan-caspase inhibitor, injected into the PL-IL cortex, reduced mechanical allodynia, this effect being reduced but not abolished in Trpv1(-/-) mice. Single-unit extracellular recordings in vivo following electrical stimulation of basolateral amygdala or application of pressure on the hind paw, showed increased excitatory pyramidal neuron activity in the SNI PL-IL cortex, which also contained higher levels of the endocannabinoid 2-arachidonoylglycerol. Intra-PL-IL cortex injection of mGluR5 and NMDA receptor antagonists and AMPA exacerbated, whereas TRPV1 and AMPA receptor antagonists and a CB(1) agonist inhibited, allodynia. We suggest that SNI triggers both TRPV1-dependent and independent glutamate- and caspase-mediated cross-talk among IL-PL cortex neurons and glia, which either participates or counteracts pain.

  12. Functional magnetic resonance imaging adaptation reveals a noncategorical representation of hue in early visual cortex.

    PubMed

    Persichetti, Andrew S; Thompson-Schill, Sharon L; Butt, Omar H; Brainard, David H; Aguirre, Geoffrey K

    2015-01-01

    Color names divide the fine-grained gamut of color percepts into discrete categories. A categorical transition must occur somewhere between the initial encoding of the continuous spectrum of light by the cones and the verbal report of the name of a color stimulus. Here, we used a functional magnetic resonance imaging (fMRI) adaptation experiment to examine the representation of hue in the early visual cortex. Our stimuli varied in hue between blue and green. We found in the early visual areas (V1, V2/3, and hV4) a smoothly increasing recovery from adaptation with increasing hue distance between adjacent stimuli during both passive viewing (Experiment 1) and active categorization (Experiment 2). We examined the form of the adaptation effect and found no evidence that a categorical representation mediates the release from adaptation for stimuli that cross the blue-green color boundary. Examination of the direct effect of stimulus hue on the fMRI response did, however, reveal an enhanced response to stimuli near the blue-green category border. This was largest in hV4 and when subjects were engaged in active categorization of the stimulus hue. In contrast with a recent report from another laboratory (Bird, Berens, Horner, & Franklin, 2014), we found no evidence for a categorical representation of color in the middle frontal gyrus. A post hoc whole-brain analysis, however, revealed several regions in the frontal cortex with a categorical effect in the adaptation response. Overall, our results support the idea that the representation of color in the early visual cortex is primarily fine grained and does not reflect color categories. PMID:26024465

  13. Primary motor cortex of the parkinsonian monkey: altered neuronal responses to muscle stretch

    PubMed Central

    Pasquereau, Benjamin; Turner, Robert S.

    2013-01-01

    Exaggeration of the long-latency stretch reflex (LLSR) is a characteristic neurophysiologic feature of Parkinson's disease (PD) that contributes to parkinsonian rigidity. To explore one frequently-hypothesized mechanism, we studied the effects of fast muscle stretches on neuronal activity in the macaque primary motor cortex (M1) before and after the induction of parkinsonism by unilateral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We compared results from the general population of M1 neurons and two antidromically-identified subpopulations: distant-projecting pyramidal-tract type neurons (PTNs) and intra-telecenphalic-type corticostriatal neurons (CSNs). Rapid rotations of elbow or wrist joints evoked short-latency responses in 62% of arm-related M1 neurons. As in PD, the late electromyographic responses that constitute the LLSR were enhanced following MPTP. This was accompanied by a shortening of M1 neuronal response latencies and a degradation of directional selectivity, but surprisingly, no increase in single unit response magnitudes. The results suggest that parkinsonism alters the timing and specificity of M1 responses to muscle stretch. Observation of an exaggerated LLSR with no change in the magnitude of proprioceptive responses in M1 is consistent with the idea that the increase in LLSR gain that contributes to parkinsonian rigidity is localized to the spinal cord. PMID:24324412

  14. dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients.

    PubMed

    Manitt, C; Eng, C; Pokinko, M; Ryan, R T; Torres-Berrío, A; Lopez, J P; Yogendran, S V; Daubaras, M J J; Grant, A; Schmidt, E R E; Tronche, F; Krimpenfort, P; Cooper, H M; Pasterkamp, R J; Kolb, B; Turecki, G; Wong, T P; Nestler, E J; Giros, B; Flores, C

    2013-12-17

    Adolescence is a period of heightened susceptibility to psychiatric disorders of medial prefrontal cortex (mPFC) dysfunction and cognitive impairment. mPFC dopamine (DA) projections reach maturity only in early adulthood, when their control over cognition becomes fully functional. The mechanisms governing this protracted and unique development are unknown. Here we identify dcc as the first DA neuron gene to regulate mPFC connectivity during adolescence and dissect the mechanisms involved. Reduction or loss of dcc from DA neurons by Cre-lox recombination increased mPFC DA innervation. Underlying this was the presence of ectopic DA fibers that normally innervate non-cortical targets. Altered DA input changed the anatomy and electrophysiology of mPFC circuits, leading to enhanced cognitive flexibility. All phenotypes only emerged in adulthood. Using viral Cre, we demonstrated that dcc organizes mPFC wiring specifically during adolescence. Variations in DCC may determine differential predisposition to mPFC disorders in humans. Indeed, DCC expression is elevated in brains of antidepressant-free subjects who committed suicide.

  15. Asynchronous inputs alter excitability, spike timing, and topography in primary auditory cortex.

    PubMed

    Pandya, Pritesh K; Moucha, Raluca; Engineer, Navzer D; Rathbun, Daniel L; Vazquez, Jessica; Kilgard, Michael P

    2005-05-01

    Correlation-based synaptic plasticity provides a potential cellular mechanism for learning and memory. Studies in the visual and somatosensory systems have shown that behavioral and surgical manipulation of sensory inputs leads to changes in cortical organization that are consistent with the operation of these learning rules. In this study, we examine how the organization of primary auditory cortex (A1) is altered by tones designed to decrease the average input correlation across the frequency map. After one month of separately pairing nucleus basalis stimulation with 2 and 14 kHz tones, a greater proportion of A1 neurons responded to frequencies below 2 kHz and above 14 kHz. Despite the expanded representation of these tones, cortical excitability was specifically reduced in the high and low frequency regions of A1, as evidenced by increased neural thresholds and decreased response strength. In contrast, in the frequency region between the two paired tones, driven rates were unaffected and spontaneous firing rate was increased. Neural response latencies were increased across the frequency map when nucleus basalis stimulation was associated with asynchronous activation of the high and low frequency regions of A1. This set of changes did not occur when pulsed noise bursts were paired with nucleus basalis stimulation. These results are consistent with earlier observations that sensory input statistics can shape cortical map organization and spike timing.

  16. Asynchronous inputs alter excitability, spike timing, and topography in primary auditory cortex

    PubMed Central

    Pandya, Pritesh K.; Moucha, Raluca; Engineer, Navzer D.; Rathbun, Daniel L.; Vazquez, Jessica; Kilgard, Michael P.

    2010-01-01

    Correlation-based synaptic plasticity provides a potential cellular mechanism for learning and memory. Studies in the visual and somatosensory systems have shown that behavioral and surgical manipulation of sensory inputs leads to changes in cortical organization that are consistent with the operation of these learning rules. In this study, we examine how the organization of primary auditory cortex (A1) is altered by tones designed to decrease the average input correlation across the frequency map. After one month of separately pairing nucleus basalis stimulation with 2 and 14 kHz tones, a greater proportion of A1 neurons responded to frequencies below 2 kHz and above 14 kHz. Despite the expanded representation of these tones, cortical excitability was specifically reduced in the high and low frequency regions of A1, as evidenced by increased neural thresholds and decreased response strength. In contrast, in the frequency region between the two paired tones, driven rates were unaffected and spontaneous firing rate was increased. Neural response latencies were increased across the frequency map when nucleus basalis stimulation was associated with asynchronous activation of the high and low frequency regions of A1. This set of changes did not occur when pulsed noise bursts were paired with nucleus basalis stimulation. These results are consistent with earlier observations that sensory input statistics can shape cortical map organization and spike timing. PMID:15855025

  17. Vagus Nerve Stimulation Alters Phase Synchrony of the Anterior Cingulate Cortex and Facilitates Decision Making in Rats

    PubMed Central

    Cao, Bing; Wang, Jun; Shahed, Mahadi; Jelfs, Beth; Chan, Rosa H. M.; Li, Ying

    2016-01-01

    Vagus nerve stimulation (VNS) can enhance memory and cognitive functions in both rats and humans. Studies have shown that VNS influenced decision-making in epileptic patients. However, the sites of action involved in the cognitive-enhancement are poorly understood. By employing a conscious rat model equipped with vagus nerve cuff electrode, we assess the role of chronic VNS on decision-making in rat gambling task (RGT). Simultaneous multichannel-recordings offer an ideal setup to test the hypothesis that VNS may induce alterations of in both spike-field-coherence and synchronization of theta oscillations across brain areas in the anterior cingulate cortex (ACC) and basolateral amygdala (BLA). Daily VNS, administered immediately following training sessions of RGT, caused an increase in ‘good decision-maker’ rats. Neural spikes in the ACC became synchronized with the ongoing theta oscillations of local field potential (LFP) in BLA following VNS. Moreover, cross-correlation analysis revealed synchronization between the ACC and BLA. Our results provide specific evidence that VNS facilitates decision-making and unveils several important roles for VNS in regulating LFP and spike phases, as well as enhancing spike-phase coherence between key brain areas involved in cognitive performance. These data may serve to provide fundamental notions regarding neurophysiological biomarkers for therapeutic VNS in cognitive impairment. PMID:27731403

  18. Alterations in cortical thickness and neuronal density in the frontal cortex of Albert Einstein.

    PubMed

    Anderson, B; Harvey, T

    1996-06-01

    Neuronal density, neuron size, and the number of neurons under 1 mm2 of cerebral cortical surface area were measured in the right pre-frontal cortex of Albert Einstein and five elderly control subjects. Measurement of neuronal density used the optical dissector technique on celloidin-embedded cresyl violet-stained sections. The neurons counted provided a systematic random sample for the measurement of cell body cross-sectional area. Einstein's cortex did not differ from the control subjects in the number of neurons under 1 mm2 of cerebral cortex or in mean neuronal size. Because Einstein's cortex was thinner than the controls he had a greater neuronal density.

  19. Limited ethanol exposure selectively alters the proliferation of precursor cells in the cerebral cortex.

    PubMed

    Miller, M W

    1996-02-01

    The present in vivo study tests the hypothesis that limited (4-day) exposure to ethanol differentially affects the proliferation of cortical precursors in the two cortical germinal zones [the ventricular zone (VZ) and the subventricular zone (SZ)] and their descendants in the mature brain. The offspring of pregnant rats fed a liquid diet containing 6.7% (v/v) ethanol when prosencephalic stem cells [gestation day (G) 6-69], VZ cells (G12-G15), and SZ cells were proliferating (G18- G21) throughout much of gestation (G6-G21). In addition, the offspring of rats pair-fed a liquid control diet or fed chow were examined. The pregnant dams were administered with bromodeoxyuridine (BrdU) on either G15 or G21. The ratio of the number of cells that incorporated BrdU to the total number (the labeling index) was determined 1-hr postinjection (i.e., on G15 or G21) or on postnatal day 60, Ethanol treatment between G6 and G21 reduced the ratio of cells labeled by an injection of BrdU on G15 in the fetus and in the adult, and increased the ratio of cells labeled on G21. Regardless of when the injection was placed, ethanol treatment between G6 and G9 had no effect upon the ratio of BrdU-labeled cells in the fetus or mature cortex. Exposure from G12 to G15 decreased the number of VZ cells in the fetus and the number of immunolabeled cells in the adult cortex labeled by an injection on G15. This exposure had no effect on the incorporation by SZ cells. In contrast, ethanol exposure from G18 to G21 increased the labeling indices for fetal SZ cells and for cells in the adult, but it had no effect on the ratio of labeled VZ cells. Although ethanol had no apparent effect on the proliferation of stem cells, it did alter the proliferation of cells in the VZ and SZ. These effects are time-dependent and underlie the ethanol-induced changes in the number of cells in the adult.

  20. Developmental Exposure to the Organochlorine Insecticide Endosulfan Alters Expression of Proteins Associated with Neurotransmission in the Frontal Cortex

    PubMed Central

    Wilson, W. Wyatt; Onyenwe, Wellington; Bradner, Joshua M.; Nennig, Sadie E.; Caudle, W. Michael

    2014-01-01

    Exposure to environmental contaminants, such as organochlorine insecticides during critical periods of neurodevelopment has been shown to be a major contributor to several neuropsychological deficits seen in children, adolescence, and adults. Although the neurobehavioral outcomes resulting from exposure to these compounds are known the neurotransmitter circuitry and molecular targets that mediate these endpoints have not been identified. Given the importance of the frontal cortex in facilitating numerous neuropsychological processes, our current study sought to investigate the effects of developmental exposure to the organochlorine insecticide, endosulfan, on the expression of specific proteins associated with neurotransmission in the frontal cortex. Utilizing in vitro models we were able to show endosulfan reduces cell viability in IMR-32 neuroblastoma cells in addition to reducing synaptic puncta and neurite outgrowth in primary cultured neurons isolated from the frontal cortex of mice. Elaborating these findings to an in vivo model we found that developmental exposure of female mice to endosulfan during gestation and lactation elicited significant alterations to the GABAergic (GAT1, vGAT, GABAA receptor), glutamatergic (vGlut and GluN2B receptor), and dopaminergic (DAT, TH, VMAT2, and D2 receptor) neurotransmitter systems in the frontal cortex of male offspring. These findings identify damage to critical neurotransmitter circuits and proteins in the frontal cortex, which may underlie the neurobehavioral deficits observed following developmental exposure to endosulfan and other organochlorine insecticides. PMID:25042905

  1. Structural and Functional Alterations in Right Dorsomedial Prefrontal and Left Insular Cortex Co-Localize in Adolescents with Aggressive Behaviour: An ALE Meta-Analysis

    PubMed Central

    Raschle, Nora Maria; Menks, Willeke Martine; Fehlbaum, Lynn Valérie; Tshomba, Ebongo; Stadler, Christina

    2015-01-01

    Recent neuroimaging work has suggested that aggressive behaviour (AB) is associated with structural and functional brain abnormalities in processes subserving emotion processing and regulation. However, most neuroimaging studies on AB to date only contain relatively small sample sizes. To objectively investigate the consistency of previous structural and functional research in adolescent AB, we performed a systematic literature review and two coordinate-based activation likelihood estimation meta-analyses on eight VBM and nine functional neuroimaging studies in a total of 783 participants (408 [224AB/184 controls] and 375 [215 AB/160 controls] for structural and functional analysis respectively). We found 19 structural and eight functional foci of significant alterations in adolescents with AB, mainly located within the emotion processing and regulation network (including orbitofrontal, dorsomedial prefrontal and limbic cortex). A subsequent conjunction analysis revealed that functional and structural alterations co-localize in right dorsomedial prefrontal cortex and left insula. Our results are in line with meta-analytic work as well as structural, functional and connectivity findings to date, all of which make a strong point for the involvement of a network of brain areas responsible for emotion processing and regulation, which is disrupted in AB. Increased knowledge about the behavioural and neuronal underpinnings of AB is crucial for the development of novel and implementation of existing treatment strategies. Longitudinal research studies will have to show whether the observed alterations are a result or primary cause of the phenotypic characteristics in AB. PMID:26339798

  2. Perinatal asphyxia alters neuregulin-1 and COMT gene expression in the medial prefrontal cortex in rats.

    PubMed

    Wakuda, Tomoyasu; Iwata, Keiko; Iwata, Yasuhide; Anitha, Ayyappan; Takahashi, Taro; Yamada, Kohei; Vasu, Mahesh Mundalil; Matsuzaki, Hideo; Suzuki, Katsuaki; Mori, Norio

    2015-01-01

    Epidemiological studies suggest that perinatal complications, particularly hypoxia-related ones, increase the risk of schizophrenia. Recent genetic studies of the disorder have identified several putative susceptibility genes, some of which are known to be regulated by hypoxia. It can be postulated therefore that birth complications that cause hypoxia in the fetal brain may be associated with a dysregulation in the expression of some of the schizophrenia candidate genes. To test this, we used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Caesarean section birth, and examined the expression of mRNA of five of the putative susceptibility genes (NRG1, ErbB4, AKT1, COMT and BDNF) by real-time quantitative PCR in the medial prefrontal cortex (mPFC) and the hippocampus at 6 and 12 weeks after birth. The expression of NRG1 mRNA was significantly decreased in the mPFC, but not in the hippocampus, at 6 and 12 weeks after birth. In addition, a significant increase in COMT mRNA expression was observed in the mPFC at 12 weeks. The alteration in mRNA levels of NRG1 and COMT was not associated with a change in their protein levels. These results suggest that perinatal asphyxia may lead to disturbances in the PFC, which in turn may exert a long-lasting influence on the expression of specific genes, such as NRG1 and COMT. Our results also suggest that translational interruption may occur in this model of perinatal asphyxia. PMID:25194460

  3. Speech training alters tone frequency tuning in rat primary auditory cortex

    PubMed Central

    Engineer, Crystal T.; Perez, Claudia A.; Carraway, Ryan S.; Chang, Kevin Q.; Roland, Jarod L.; Kilgard, Michael P.

    2013-01-01

    Previous studies in both humans and animals have documented improved performance following discrimination training. This enhanced performance is often associated with cortical response changes. In this study, we tested the hypothesis that long-term speech training on multiple tasks can improve primary auditory cortex (A1) responses compared to rats trained on a single speech discrimination task or experimentally naïve rats. Specifically, we compared the percent of A1 responding to trained sounds, the responses to both trained and untrained sounds, receptive field properties of A1 neurons, and the neural discrimination of pairs of speech sounds in speech trained and naïve rats. Speech training led to accurate discrimination of consonant and vowel sounds, but did not enhance A1 response strength or the neural discrimination of these sounds. Speech training altered tone responses in rats trained on six speech discrimination tasks but not in rats trained on a single speech discrimination task. Extensive speech training resulted in broader frequency tuning, shorter onset latencies, a decreased driven response to tones, and caused a shift in the frequency map to favor tones in the range where speech sounds are the loudest. Both the number of trained tasks and the number of days of training strongly predict the percent of A1 responding to a low frequency tone. Rats trained on a single speech discrimination task performed less accurately than rats trained on multiple tasks and did not exhibit A1 response changes. Our results indicate that extensive speech training can reorganize the A1 frequency map, which may have downstream consequences on speech sound processing. PMID:24344364

  4. Altered structural and functional connectivity between the bilateral primary motor cortex in unilateral subcortical stroke

    PubMed Central

    Zhang, Yong; Li, Kuang-Shi; Ning, Yan-Zhe; Fu, Cai-Hong; Liu, Hong-Wei; Han, Xiao; Cui, Fang-Yuan; Ren, Yi; Zou, Yi-Huai

    2016-01-01

    Abstract A large number of functional imaging studies have focused on the understanding of motor-related neural activities after ischemic stroke. However, the knowledge is still limited in the structural and functional changes of the interhemispheric connections of the bilateral primary motor cortices (M1s) and their potential influence on motor function recovery following stroke. Twenty-four stroke patients with right hemispheric subcortical infarcts and 25 control subjects were recruited to undergo multimodal magnetic resonance imaging examinations. Structural impairments between the bilateral M1s were measured by fractional anisotropy. Functional changes of the bilateral M1s were assessed via M1-M1 resting-state functional connectivity. Task-evoked activation analysis was applied to identify the roles of the bilateral hemispheres in motor function recovery. Compared with control subjects, unilateral subcortical stroke patients revealed significantly decreased fractional anisotropy and functional connectivity between the bilateral M1s. Stroke patients also revealed higher activations in multiple brain regions in both hemispheres and that more regions were located in the contralesional hemisphere. This study increased our understanding of the structural and functional alterations between the bilateral M1s that occur in unilateral subcortical stroke and provided further evidence for the compensatory role played by the contralesional hemisphere for these alterations during motor function recovery. PMID:27495109

  5. Self responses along cingulate cortex reveal quantitative neural phenotype for high functioning autism

    PubMed Central

    Chiu, Pearl H.; Kayali, M. Amin; Kishida, Kenneth T.; Tomlin, Damon; Klinger, Laura G.; Klinger, Mark R.; Montague, P. Read

    2014-01-01

    Summary Attributing behavioral outcomes correctly to oneself or to other agents is essential for all productive social exchange. We approach this issue in high-functioning males with autism spectrum disorder (ASD) using two separate fMRI paradigms. First, using a visual imagery task, we extract a basis set for responses along the cingulate cortex of control subjects that reveals an agent-specific eigenvector (self eigenmode) associated with imagining oneself executing a specific motor act. Second, we show that the same self eigenmode arises during one's own decision (the self phase) in an interpersonal exchange game (iterated trust game). Third, using this exchange game, we show that ASD males exhibit a severely diminished self eigenmode when playing the game with a human partner. This diminished response covaries parametrically with their behaviorally assessed symptom severity suggesting its value as an objective endophenotype. These findings may provide a quantitative assessment tool for high functioning ASD. PMID:18255038

  6. Molecularly Defined Circuitry Reveals Input-Output Segregation in Deep Layers of the Medial Entorhinal Cortex.

    PubMed

    Sürmeli, Gülşen; Marcu, Daniel Cosmin; McClure, Christina; Garden, Derek L F; Pastoll, Hugh; Nolan, Matthew F

    2015-12-01

    Deep layers of the medial entorhinal cortex are considered to relay signals from the hippocampus to other brain structures, but pathways for routing of signals to and from the deep layers are not well established. Delineating these pathways is important for a circuit level understanding of spatial cognition and memory. We find that neurons in layers 5a and 5b have distinct molecular identities, defined by the transcription factors Etv1 and Ctip2, and divergent targets, with extensive intratelencephalic projections originating in layer 5a, but not 5b. This segregation of outputs is mirrored by the organization of glutamatergic input from stellate cells in layer 2 and from the hippocampus, with both preferentially targeting layer 5b over 5a. Our results suggest a molecular and anatomical organization of input-output computations in deep layers of the MEC, reveal precise translaminar microcircuitry, and identify molecularly defined pathways for spatial signals to influence computation in deep layers.

  7. Network Clustering Revealed the Systemic Alterations of Mitochondrial Protein Expression

    PubMed Central

    Koo, Hyun-Jung; Park, Wook-Ha; Yang, Jae-Seong; Yu, Myeong-Hee; Kim, Sanguk; Pak, Youngmi Kim

    2011-01-01

    The mitochondrial protein repertoire varies depending on the cellular state. Protein component modifications caused by mitochondrial DNA (mtDNA) depletion are related to a wide range of human diseases; however, little is known about how nuclear-encoded mitochondrial proteins (mt proteome) changes under such dysfunctional states. In this study, we investigated the systemic alterations of mtDNA-depleted (ρ0) mitochondria by using network analysis of gene expression data. By modularizing the quantified proteomics data into protein functional networks, systemic properties of mitochondrial dysfunction were analyzed. We discovered that up-regulated and down-regulated proteins were organized into two predominant subnetworks that exhibited distinct biological processes. The down-regulated network modules are involved in typical mitochondrial functions, while up-regulated proteins are responsible for mtDNA repair and regulation of mt protein expression and transport. Furthermore, comparisons of proteome and transcriptome data revealed that ρ0 cells attempted to compensate for mtDNA depletion by modulating the coordinated expression/transport of mt proteins. Our results demonstrate that mt protein composition changed to remodel the functional organization of mitochondrial protein networks in response to dysfunctional cellular states. Human mt protein functional networks provide a framework for understanding how cells respond to mitochondrial dysfunctions. PMID:21738461

  8. Plasticity and alterations of trunk motor cortex following spinal cord injury and non-stepping robot and treadmill training.

    PubMed

    Oza, Chintan S; Giszter, Simon F

    2014-06-01

    Spinal cord injury (SCI) induces significant reorganization in the sensorimotor cortex. Trunk motor control is crucial for postural stability and propulsion after low thoracic SCI and several rehabilitative strategies are aimed at trunk stability and control. However little is known about the effect of SCI and rehabilitation training on trunk motor representations and their plasticity in the cortex. Here, we used intracortical microstimulation to examine the motor cortex representations of the trunk in relation to other representations in three groups of chronic adult complete low thoracic SCI rats: chronic untrained, treadmill trained (but 'non-stepping') and robot assisted treadmill trained (but 'non-stepping') and compared with a group of normal rats. Our results demonstrate extensive and significant reorganization of the trunk motor cortex after chronic adult SCI which includes (1) expansion and rostral displacement of trunk motor representations in the cortex, with the greatest significant increase observed for rostral (to injury) trunk, and slight but significant increase of motor representation for caudal (to injury) trunk at low thoracic levels in all spinalized rats; (2) significant changes in coactivation and the synergy representation (or map overlap) between different trunk muscles and between trunk and forelimb. No significant differences were observed between the groups of transected rats for the majority of the comparisons. However, (3) the treadmill and robot-treadmill trained groups of rats showed a further small but significant rostral migration of the trunk representations, beyond the shift caused by transection alone. We conclude that SCI induces a significant reorganization of the trunk motor cortex, which is not qualitatively altered by non-stepping treadmill training or non-stepping robot assisted treadmill training, but is shifted further from normal topography by the training. This shift may potentially make subsequent rehabilitation with

  9. Alterations in neuronal morphology in infralimbic cortex predict resistance to fear extinction following acute stress

    PubMed Central

    Moench, Kelly M.; Maroun, Mouna; Kavushansky, Alexandra; Wellman, Cara

    2015-01-01

    Dysfunction in corticolimbic circuits that mediate the extinction of learned fear responses is thought to underlie the perseveration of fear in stress-related psychopathologies, including post-traumatic stress disorder. Chronic stress produces dendritic hypertrophy in basolateral amygdala (BLA) and dendritic hypotrophy in medial prefrontal cortex, whereas acute stress leads to hypotrophy in both BLA and prelimbic cortex. Additionally, both chronic and acute stress impair extinction retrieval. Here, we examined the effects of a single elevated platform stress on extinction learning and dendritic morphology in infralimbic cortex, a region considered to be critical for extinction. Acute stress produced resistance to extinction, as well as dendritic retraction in infralimbic cortex. Spine density on apical and basilar terminal branches was unaffected by stress. However, animals that underwent conditioning and extinction had decreased spine density on apical terminal branches. Thus, whereas dendritic morphology in infralimbic cortex appears to be particularly sensitive to stress, changes in spines may more sensitively reflect learning. Further, in stressed rats that underwent conditioning and extinction, the level of extinction learning was correlated with spine densities, in that rats with poorer extinction retrieval had more immature spines and fewer thin spines than rats with better extinction retrieval, suggesting that stress may have impaired learning-related spine plasticity. These results may have implications for understanding the role of medial prefrontal cortex in learning deficits associated with stress-related pathologies. PMID:26844245

  10. Cannabis use and brain structural alterations of the cingulate cortex in early psychosis.

    PubMed

    Rapp, Charlotte; Walter, Anna; Studerus, Erich; Bugra, Hilal; Tamagni, Corinne; Röthlisberger, Michel; Borgwardt, Stefan; Aston, Jacqueline; Riecher-Rössler, Anita

    2013-11-30

    As cannabis use is more frequent in patients with psychosis than in the general population and is known to be a risk factor for psychosis, the question arises whether cannabis contributes to recently detected brain volume reductions in schizophrenic psychoses. This study is the first to investigate how cannabis use is related to the cingulum volume, a brain region involved in the pathogenesis of schizophrenia, in a sample of both at-risk mental state (ARMS) and first episode psychosis (FEP) subjects. A cross-sectional magnetic resonance imaging (MRI) study of manually traced cingulum in 23 FEP and 37 ARMS subjects was performed. Cannabis use was assessed with the Basel Interview for Psychosis. By using repeated measures analyses of covariance, we investigated whether current cannabis use is associated with the cingulum volume, correcting for age, gender, alcohol consumption, whole brain volume and antipsychotic medication. There was a significant three-way interaction between region (anterior/posterior cingulum), hemisphere (left/right cingulum) and cannabis use (yes/no). Post-hoc analyses revealed that this was due to a significant negative effect of cannabis use on the volume of the posterior cingulum which was independent of the hemisphere and diagnostic group and all other covariates we controlled for. In the anterior cingulum, we found a significant negative effect only for the left hemisphere, which was again independent of the diagnostic group. Overall, we found negative associations of current cannabis use with grey matter volume of the cingulate cortex, a region rich in cannabinoid CB1 receptors. As this finding has not been consistently found in healthy controls, it might suggest that both ARMS and FEP subjects are particularly sensitive to exogenous activation of these receptors.

  11. Prenatal stress alters the behavior and dendritic morphology of the medial orbitofrontal cortex in mouse offspring during lactation.

    PubMed

    Gutiérrez-Rojas, Cristian; Pascual, Rodrigo; Bustamante, Carlos

    2013-11-01

    Several preclinical and clinical studies have shown that prenatal stress alters neuronal dendritic development in the prefrontal cortex, together with behavioral disturbances (anxiety). Nevertheless, neither whether these alterations are present during the lactation period, nor whether such findings may reflect the onset of anxiety disorders observed in childhood and adulthood has been studied. The central aim of the present study was to determine the effects of prenatal stress on the neuronal development and behavior of mice offspring during lactation (postnatal days 14 and 21). We studied 24 CF-1 male mice, grouped as follows: (i) control P14 (n=6), (ii) stressed P14 (n=6), (iii) control P21 (n=6) and (iv) stressed P21 (n=6). On the corresponding days, animals were evaluated with the open field test and sacrificed. Their brains were then stained in Golgi-Cox solution for 30 days. The morphological analysis dealt with the study of 96 pyramidal neurons. The results showed, first, that prenatal stress resulted in a significant (i) decrease in the apical dendritic length of pyramidal neurons in the orbitofrontal cortex at postnatal day 14, (ii) increase in the apical dendritic length of pyramidal neurons in the orbitofrontal cortex at postnatal day 21, and (iii) reduction in exploratory behavior at postnatal day 14 and 21.

  12. Voxel-based morphometry reveals reduced grey matter volume in the temporal cortex of developmental prosopagnosics

    PubMed Central

    Furl, Nicholas; Draganski, Bogdan; Weiskopf, Nikolaus; Stevens, John; Tan, Geoffrey Chern-Yee; Driver, Jon; Dolan, Ray J.; Duchaine, Bradley

    2009-01-01

    Individuals with developmental prosopagnosia exhibit severe and lasting difficulties in recognizing faces despite the absence of apparent brain abnormalities. We used voxel-based morphometry to investigate whether developmental prosopagnosics show subtle neuroanatomical differences from controls. An analysis based on segmentation of T1-weighted images from 17 developmental prosopagnosics and 18 matched controls revealed that they had reduced grey matter volume in the right anterior inferior temporal lobe and in the superior temporal sulcus/middle temporal gyrus bilaterally. In addition, a voxel-based morphometry analysis based on the segmentation of magnetization transfer parameter maps showed that developmental prosopagnosics also had reduced grey matter volume in the right middle fusiform gyrus and the inferior temporal gyrus. Multiple regression analyses relating three distinct behavioural component scores, derived from a principal component analysis, to grey matter volume revealed an association between a component related to facial identity and grey matter volume in the left superior temporal sulcus/middle temporal gyrus plus the right middle fusiform gyrus/inferior temporal gyrus. Grey matter volume in the lateral occipital cortex was associated with component scores related to object recognition tasks. Our results demonstrate that developmental prosopagnosics have reduced grey matter volume in several regions known to respond selectively to faces and provide new evidence that integrity of these areas relates to face recognition ability. PMID:19887506

  13. Altered expression of neuropeptides in the primary somatosensory cortex of the Down syndrome model Ts65Dn.

    PubMed

    Hernández, Samuel; Gilabert-Juan, Javier; Blasco-Ibáñez, José Miguel; Crespo, Carlos; Nácher, Juan; Varea, Emilio

    2012-02-01

    Down syndrome is the most common genetic disorder associated with mental retardation. Subjects and mice models for Down syndrome (such as Ts65Dn) show defects in the formation of neuronal networks in both the hippocampus and the cerebral cortex. The principal neurons display alterations in the morphology, density and distribution of dendritic spines in the cortex as well as in the hippocampus. Several evidences point to the possibility that the atrophy observed in principal neurons could be mediated by changes in their inhibitory inputs and, in fact, an imbalance between excitation and inhibition has been observed in Ts65Dn mice in these regions, which are crucial for learning and information processing. These animals have an increased density of interneurons in the primary somatosensory cortex, especially of those expressing calretinin and calbindin D-28k. Here, we have analysed the expression and distribution of several neuropeptides in the primary somatosensory cortex of Ts65Dn mice in order to investigate whether these subpopulations of interneurons are affected. We have observed an increase in the total density of somatostatin expressing interneurons and of those expressing VIP in layer IV in Ts65Dn mice. The typology of the somatostatin and VIP interneurons was unaltered as attested by the pattern of co-expression with other markers. Somatostatin immunoreactive neurons co-express mainly D-28k calbindin and VIP expressing interneurons maintain its pattern of co-expression with calcium binding proteins. These alterations, in case they were also present in subjects with Down syndrome, could be related to their impairment in cognitive profile and could be involved in the neurological defects observed in this disorder.

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

    PubMed

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

    2012-08-01

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

  15. Cortical connectivity maps reveal anatomically distinct areas in the parietal cortex of the rat

    PubMed Central

    Wilber, Aaron A.; Clark, Benjamin J.; Demecha, Alexis J.; Mesina, Lilia; Vos, Jessica M.; McNaughton, Bruce L.

    2015-01-01

    A central feature of theories of spatial navigation involves the representation of spatial relationships between objects in complex environments. The parietal cortex has long been linked to the processing of spatial visual information and recent evidence from single unit recording in rodents suggests a role for this region in encoding egocentric and world-centered frames. The rat parietal cortex can be subdivided into four distinct rostral-caudal and medial-lateral regions, which includes a zone previously characterized as secondary visual cortex. At present, very little is known regarding the relative connectivity of these parietal subdivisions. Thus, we set out to map the connectivity of the entire anterior-posterior and medial-lateral span of this region. To do this we used anterograde and retrograde tracers in conjunction with open source neuronal segmentation and tracer detection tools to generate whole brain connectivity maps of parietal inputs and outputs. Our present results show that inputs to the parietal cortex varied significantly along the medial-lateral, but not the rostral-caudal axis. Specifically, retrosplenial connectivity is greater medially, but connectivity with visual cortex, though generally sparse, is more significant laterally. Finally, based on connection density, the connectivity between parietal cortex and hippocampus is indirect and likely achieved largely via dysgranular retrosplenial cortex. Thus, similar to primates, the parietal cortex of rats exhibits a difference in connectivity along the medial-lateral axis, which may represent functionally distinct areas. PMID:25601828

  16. Prenatal stress alters dendritic morphology and synaptic connectivity in the prefrontal cortex and hippocampus of developing offspring.

    PubMed

    Mychasiuk, Richelle; Gibb, Robbin; Kolb, Bryan

    2012-04-01

    The current study used stereological techniques in combination with Golg-Cox methods to examine the neuroanatomical alterations in the prefrontal cortex and hippocampus of developing offspring exposed to gestational stress. Morphological changes in dendritic branching, length, and spine density, were examined at weaning along with changes in actual numbers of neurons. Using this information we generated a gross estimation of synaptic connectivity. The results showed region-specific and sex-dependent alterations to neuroanatomy in response to prenatal stress. The two regions of the prefrontal cortex, medial prefrontal, and orbital prefrontal cortices, exhibited sexually dimorphic, opposite changes, in synaptic connectivity in response to the same experience. Both male and female offspring demonstrated a loss of neuron number and estimated synapse number in the hippocampus despite exhibiting increased spine density. The results from this study suggest that prenatal stress alters normal development and the organization of neuronal circuits in both neocortex and hippocampus early in development and thus likely influences the course of later experience-dependent synaptic changes.

  17. Noradrenaline depletion blocks behavioral sparing and alters cortical morphogenesis after neonatal frontal cortex damage in rats.

    PubMed

    Kolb, B; Sutherland, R J

    1992-06-01

    The possibility that cortical noradrenaline (NA) is necessary for sparing of function that occurs after neonatal frontal cortex damage was examined. Spatial localization by rats with frontal cortex damage on postnatal day 7 (P7) was better than that by rats with similar damage sustained as adults. The sparing was abolished in rats depleted of cortical NA by means of neonatal 6-hydroxydopamine (6HDA) administration. The blockade of sparing in the P7 frontal operates was associated with a smaller brain, thinner cortex, and reduced cortical dendritic branching relative to saline-treated P7 frontal operates. NA depletion alone in unoperated rats did not affect spatial learning but did reduce brain size and dendritic branching. Rats with frontal lesions on P4 did not show sparing of spatial localization, and 6HDA administration had no additional behavioral effect. Overall, these data are consistent with the notion that NA has some general function in maintaining some forms of plasticity in posterior cortex. PMID:1607943

  18. Altered somatosensory barrel cortex refinement in the developing brain of Mecp2-null mice.

    PubMed

    Moroto, M; Nishimura, A; Morimoto, M; Isoda, K; Morita, T; Yoshida, M; Morioka, S; Tozawa, T; Hasegawa, T; Chiyonobu, T; Yoshimoto, K; Hosoi, H

    2013-11-01

    Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MeCP2) gene. In previous studies, monoaminergic dysfunctions have been detected in patients with RTT and in a murine model of RTT, the Mecp2-null mouse. Therefore, the pathogenesis of RTT is thought to involve impairments in the monoaminergic systems. However, there have been limited data showing that the impairment of monoamines leads to early symptoms during development. We used histochemistry to study the somatosensory barrel cortex in the B6.129P2(C)-Mecp2(tm1.1Bird) mouse model of RTT. The barrel cortex is widely used to investigate neuronal development and its regulation by various neurotransmitters including 5-HT. 5-HT levels were measured by high performance liquid chromatography with electrochemical detection (HPLC/EC), and serotonin transporter (SERT) and 5-HT1B receptor mRNAs were measured in the somatosensory cortex, thalamus and striatum on postnatal days (P) 10, P20 and P40. Mecp2-null mice (Mecp2-/y) had significantly smaller barrel fields than age-matched wild-type controls (Mecp2+/y) on P10 and P40, but the topographic map was accurately formed. Levels of 5-HT, and SERT and 5-HT1B receptor mRNA expression in the somatosensory cortex did not differ significantly between the Mecp2-null and wild-type mice on P10. However, thalamic 5-HT was reduced in Mecp2-null mice. Our data indicate that a lack of MeCP2 may disturb the refinement of the barrel cortex in the early postnatal period. Our findings suggest that a decrease in thalamic 5-HT might be involved in this phenomenon.

  19. Multivariate synaptic and behavioral profiling reveals new developmental endophenotypes in the prefrontal cortex

    PubMed Central

    Iafrati, Jillian; Malvache, Arnaud; Gonzalez Campo, Cecilia; Orejarena, M. Juliana; Lassalle, Olivier; Bouamrane, Lamine; Chavis, Pascale

    2016-01-01

    The postnatal maturation of the prefrontal cortex (PFC) represents a period of increased vulnerability to risk factors and emergence of neuropsychiatric disorders. To disambiguate the pathophysiological mechanisms contributing to these disorders, we revisited the endophenotype approach from a developmental viewpoint. The extracellular matrix protein reelin which contributes to cellular and network plasticity, is a risk factor for several psychiatric diseases. We mapped the aggregate effect of the RELN risk allele on postnatal development of PFC functions by cross-sectional synaptic and behavioral analysis of reelin-haploinsufficient mice. Multivariate analysis of bootstrapped datasets revealed subgroups of phenotypic traits specific to each maturational epoch. The preeminence of synaptic AMPA/NMDA receptor content to pre-weaning and juvenile endophenotypes shifts to long-term potentiation and memory renewal during adolescence followed by NMDA-GluN2B synaptic content in adulthood. Strikingly, multivariate analysis shows that pharmacological rehabilitation of reelin haploinsufficient dysfunctions is mediated through induction of new endophenotypes rather than reversion to wild-type traits. By delineating previously unknown developmental endophenotypic sequences, we conceived a promising general strategy to disambiguate the molecular underpinnings of complex psychiatric disorders and for the rational design of pharmacotherapies in these disorders. PMID:27765946

  20. Activity in human visual and parietal cortex reveals object-based attention in working memory.

    PubMed

    Peters, Benjamin; Kaiser, Jochen; Rahm, Benjamin; Bledowski, Christoph

    2015-02-25

    Visual attention enables observers to select behaviorally relevant information based on spatial locations, features, or objects. Attentional selection is not limited to physically present visual information, but can also operate on internal representations maintained in working memory (WM) in service of higher-order cognition. However, only little is known about whether attention to WM contents follows the same principles as attention to sensory stimuli. To address this question, we investigated in humans whether the typically observed effects of object-based attention in perception are also evident for object-based attentional selection of internal object representations in WM. In full accordance with effects in visual perception, the key behavioral and neuronal characteristics of object-based attention were observed in WM. Specifically, we found that reaction times were shorter when shifting attention to memory positions located on the currently attended object compared with equidistant positions on a different object. Furthermore, functional magnetic resonance imaging and multivariate pattern analysis of visuotopic activity in visual (areas V1-V4) and parietal cortex revealed that directing attention to one position of an object held in WM also enhanced brain activation for other positions on the same object, suggesting that attentional selection in WM activates the entire object. This study demonstrated that all characteristic features of object-based attention are present in WM and thus follows the same principles as in perception.

  1. Natural grouping of neural responses reveals spatially segregated clusters in prearcuate cortex

    PubMed Central

    Kiani, Roozbeh; Cueva, Christopher J.; Reppas, John B.; Peixoto, Diogo; Ryu, Stephen I.; Newsome, William T.

    2015-01-01

    Summary A fundamental challenge in studying the frontal lobe is to parcellate this cortex into ‘natural’ functional modules despite the absence of topographic maps, which are so helpful in primary sensory areas. Here we show that unsupervised clustering algorithms, applied to 96-channel array recordings from prearcuate gyrus, reveal spatially segregated sub-networks that remain stable across behavioral contexts. Looking for natural groupings of neurons based on response similarities, we discovered that the recorded area includes at least two spatially segregated sub-networks that differentially represent behavioral choice and reaction time. Importantly, these sub-networks are detectable during different behavioral states, and surprisingly, are defined better by ‘common noise’ than task-evoked responses. Our parcellation process works well on ‘spontaneous’ neural activity, and thus bears strong resemblance to the identification of ‘resting state’ networks in fMRI datasets. Our results demonstrate a powerful new tool for identifying cortical sub-networks by objective classification of simultaneously recorded electrophysiological activity. PMID:25728571

  2. Altered temporal dynamics of neural adaptation in the aging human auditory cortex.

    PubMed

    Herrmann, Björn; Henry, Molly J; Johnsrude, Ingrid S; Obleser, Jonas

    2016-09-01

    Neural response adaptation plays an important role in perception and cognition. Here, we used electroencephalography to investigate how aging affects the temporal dynamics of neural adaptation in human auditory cortex. Younger (18-31 years) and older (51-70 years) normal hearing adults listened to tone sequences with varying onset-to-onset intervals. Our results show long-lasting neural adaptation such that the response to a particular tone is a nonlinear function of the extended temporal history of sound events. Most important, aging is associated with multiple changes in auditory cortex; older adults exhibit larger and less variable response magnitudes, a larger dynamic response range, and a reduced sensitivity to temporal context. Computational modeling suggests that reduced adaptation recovery times underlie these changes in the aging auditory cortex and that the extended temporal stimulation has less influence on the neural response to the current sound in older compared with younger individuals. Our human electroencephalography results critically narrow the gap to animal electrophysiology work suggesting a compensatory release from cortical inhibition accompanying hearing loss and aging. PMID:27459921

  3. NMDA receptor blockade alters stress-induced dendritic remodeling in medial prefrontal cortex.

    PubMed

    Martin, Kathryn P; Wellman, Cara L

    2011-10-01

    The development and relapse of many psychopathologies can be linked to both stress and prefrontal cortex dysfunction. Glucocorticoid stress hormones target medial prefrontal cortex (mPFC) and either chronic stress or chronic administration of glucocorticoids produces dendritic remodeling in prefrontal pyramidal neurons. Exposure to stress also causes an increase in the release of the excitatory amino acid glutamate, which binds to N-methyl-D-aspartate (NMDA) receptors, which are plentiful in mPFC. NMDA receptor activation is crucial for producing hippocampal dendritic remodeling due to stress and for dendritic reorganization in frontal cortex after cholinergic deafferentation. Thus, NMDA receptors could mediate stress-induced dendritic retraction in mPFC. To test this hypothesis, dendritic morphology of pyramidal cells in mPFC was assessed after blocking NMDA receptors with the competitive NMDA antagonist ±3-(2-carboxypiperazin-4yl)propyl-1-phosphonic acid (CPP) during restraint stress. Administration of CPP prevented stress-induced dendritic atrophy. Instead, CPP-injected stressed rats showed hypertrophy of apical dendrites compared with controls. These results suggest that NMDA activation is crucial for stress-induced dendritic atrophy in mPFC. Furthermore, NMDA receptor blockade uncovers a new pattern of stress-induced dendritic changes, suggesting that other neurohormonal changes in concert with NMDA receptor activation underlie the net dendritic retraction seen after chronic stress.

  4. Computational Image Analysis Reveals Intrinsic Multigenerational Differences between Anterior and Posterior Cerebral Cortex Neural Progenitor Cells

    PubMed Central

    Winter, Mark R.; Liu, Mo; Monteleone, David; Melunis, Justin; Hershberg, Uri; Goderie, Susan K.; Temple, Sally; Cohen, Andrew R.

    2015-01-01

    Summary Time-lapse microscopy can capture patterns of development through multiple divisions for an entire clone of proliferating cells. Images are taken every few minutes over many days, generating data too vast to process completely by hand. Computational analysis of this data can benefit from occasional human guidance. Here we combine improved automated algorithms with minimized human validation to produce fully corrected segmentation, tracking, and lineaging results with dramatic reduction in effort. A web-based viewer provides access to data and results. The improved approach allows efficient analysis of large numbers of clones. Using this method, we studied populations of progenitor cells derived from the anterior and posterior embryonic mouse cerebral cortex, each growing in a standardized culture environment. Progenitors from the anterior cortex were smaller, less motile, and produced smaller clones compared to those from the posterior cortex, demonstrating cell-intrinsic differences that may contribute to the areal organization of the cerebral cortex. PMID:26344906

  5. Sleep Deprivation Reveals Altered Brain Perfusion Patterns in Somnambulism

    PubMed Central

    Dang-Vu, Thien Thanh; Zadra, Antonio; Labelle, Marc-Antoine; Petit, Dominique; Soucy, Jean-Paul; Montplaisir, Jacques

    2015-01-01

    Background Despite its high prevalence, relatively little is known about the pathophysiology of somnambulism. Increasing evidence indicates that somnambulism is associated with functional abnormalities during wakefulness and that sleep deprivation constitutes an important drive that facilitates sleepwalking in predisposed patients. Here, we studied the neural mechanisms associated with somnambulism using Single Photon Emission Computed Tomography (SPECT) with 99mTc-Ethylene Cysteinate Dimer (ECD), during wakefulness and after sleep deprivation. Methods Ten adult sleepwalkers and twelve controls with normal sleep were scanned using 99mTc-ECD SPECT in morning wakefulness after a full night of sleep. Eight of the sleepwalkers and nine of the controls were also scanned during wakefulness after a night of total sleep deprivation. Between-group comparisons of regional cerebral blood flow (rCBF) were performed to characterize brain activity patterns during wakefulness in sleepwalkers. Results During wakefulness following a night of total sleep deprivation, rCBF was decreased bilaterally in the inferior temporal gyrus in sleepwalkers compared to controls. Conclusions Functional neural abnormalities can be observed during wakefulness in somnambulism, particularly after sleep deprivation and in the inferior temporal cortex. Sleep deprivation thus not only facilitates the occurrence of sleepwalking episodes, but also uncovers patterns of neural dysfunction that characterize sleepwalkers during wakefulness. PMID:26241047

  6. Physical exercise improves brain cortex and cerebellum mitochondrial bioenergetics and alters apoptotic, dynamic and auto(mito)phagy markers.

    PubMed

    Marques-Aleixo, I; Santos-Alves, E; Balça, M M; Rizo-Roca, D; Moreira, P I; Oliveira, P J; Magalhães, J; Ascensão, A

    2015-08-20

    We here investigate the effects of two exercise modalities (endurance treadmill training-TM and voluntary free-wheel activity-FW) on the brain cortex and cerebellum mitochondrial bioenergetics, permeability transition pore (mPTP), oxidative stress, as well as on proteins involved in mitochondrial biogenesis, apoptosis, and quality control. Eighteen male rats were assigned to sedentary-SED, TM and FW groups. Behavioral alterations and ex vivo brain mitochondrial function endpoints were assessed. Proteins involved in oxidative phosphorylation (OXPHOS, including the adenine nucleotide translocator), oxidative stress markers and regulatory proteins (SIRT3, p66shc, UCP2, carbonyls, MDA, -SH, aconitase, Mn-SOD), as well as proteins involved in mitochondrial biogenesis (PGC1α, TFAM) were evaluated. Apoptotic signaling was measured through quantifying caspase 3, 8 and 9-like activities, Bax, Bcl2, CypD, and cofilin expression. Mitochondrial dynamics (Mfn1/2, OPA1 and DRP1) and auto(mito)phagy (LC3II, Beclin1, Pink1, Parkin, p62)-related proteins were also measured by Western blotting. Only the TM exercise group showed increased spontaneous alternation and exploratory activity. Both exercise regimens improved mitochondrial respiratory activity, increased OXPHOS complexes I, III and V subunits in both brain subareas and decreased oxidative stress markers. Increased resistance to mPTP and decreased apoptotic signaling were observed in the brain cortex from TM and in the cerebellum from TM and FW groups. Also, exercise increased the expression of proteins involved in mitochondrial biogenesis, autophagy and fusion, simultaneous with decreased expression of mitochondrial fission-related protein DRP1. In conclusion, physical exercise improves brain cortex and cerebellum mitochondrial function, decreasing oxidative stress and apoptotic related markers. It is also possible that favorable alterations in mitochondrial biogenesis, dynamics and autophagy signaling induced by exercise

  7. Intracranial recordings reveal transient response dynamics during information maintenance in human cerebral cortex.

    PubMed

    Noy, Niv; Bickel, Stephan; Zion-Golumbic, Elana; Harel, Michal; Golan, Tal; Davidesco, Ido; Schevon, Catherine A; McKhann, Guy M; Goodman, Robert R; Schroeder, Charles E; Mehta, Ashesh D; Malach, Rafael

    2015-10-01

    Despite an extensive body of work, it is still not clear how short term maintenance of information is implemented in the human brain. Most prior research has focused on "working memory"-typically involving the storage of a number of items, requiring the use of a phonological loop and focused attention during the delay period between encoding and retrieval. These studies largely support a model of enhanced activity in the delay interval as the central mechanism underlying working memory. However, multi-item working memory constitutes only a subset of storage phenomena that may occur during daily life. A common task in naturalistic situations is short term memory of a single item-for example, blindly reaching to a previously placed cup of coffee. Little is known about such single-item, effortless, storage in the human brain. Here, we examined the dynamics of brain responses during a single-item maintenance task, using intracranial recordings implanted for clinical purpose in patients (ECoG). Our results reveal that active electrodes were dominated by transient short latency visual and motor responses, reflected in broadband high frequency power increases in occipito-temporal, frontal, and parietal cortex. Only a very small set of electrodes showed activity during the early part of the delay period. Interestingly, no cortical site displayed a significant activation lasting to the response time. These results suggest that single item encoding is characterized by transient high frequency ECoG responses, while the maintenance of information during the delay period may be mediated by mechanisms necessitating only low-levels of neuronal activations.

  8. Intracranial recordings reveal transient response dynamics during information maintenance in human cerebral cortex.

    PubMed

    Noy, Niv; Bickel, Stephan; Zion-Golumbic, Elana; Harel, Michal; Golan, Tal; Davidesco, Ido; Schevon, Catherine A; McKhann, Guy M; Goodman, Robert R; Schroeder, Charles E; Mehta, Ashesh D; Malach, Rafael

    2015-10-01

    Despite an extensive body of work, it is still not clear how short term maintenance of information is implemented in the human brain. Most prior research has focused on "working memory"-typically involving the storage of a number of items, requiring the use of a phonological loop and focused attention during the delay period between encoding and retrieval. These studies largely support a model of enhanced activity in the delay interval as the central mechanism underlying working memory. However, multi-item working memory constitutes only a subset of storage phenomena that may occur during daily life. A common task in naturalistic situations is short term memory of a single item-for example, blindly reaching to a previously placed cup of coffee. Little is known about such single-item, effortless, storage in the human brain. Here, we examined the dynamics of brain responses during a single-item maintenance task, using intracranial recordings implanted for clinical purpose in patients (ECoG). Our results reveal that active electrodes were dominated by transient short latency visual and motor responses, reflected in broadband high frequency power increases in occipito-temporal, frontal, and parietal cortex. Only a very small set of electrodes showed activity during the early part of the delay period. Interestingly, no cortical site displayed a significant activation lasting to the response time. These results suggest that single item encoding is characterized by transient high frequency ECoG responses, while the maintenance of information during the delay period may be mediated by mechanisms necessitating only low-levels of neuronal activations. PMID:26147431

  9. Cell and Receptor Type-Specific Alterations in Markers of GABA Neurotransmission in the Prefrontal Cortex of Subjects with Schizophrenia

    PubMed Central

    Lewis, David A.; Hashimoto, Takanori; Morris, Harvey M.

    2010-01-01

    Impairments in cognitive control, such as those involved in working memory, are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC) in individuals with schizophrenia. This dysfunction appears to result, at least in part, from abnormalities in GABA-mediated neurotransmission. In this paper, we review recent findings indicating that the altered DLPFC circuitry in subjects with schizophrenia reflects changes in the expression of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission. Specifically, using a combination of methods, we found that subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding presynaptic regulators of GABA neurotransmission, neuropeptide markers of specific subpopulations of GABA neurons, and certain subunits of the GABAA receptor. In particular, alterations in the expression of the neuropeptide somatostatin suggested that GABA neurotransmission is impaired in the Martinotti subset of GABA neurons that target the dendrites of pyramidal cells. In contrast, none of the GABA-related transcripts assessed to date were altered in the DLPFC of monkeys chronically exposed to antipsychotic medications, suggesting that the effects observed in the human studies reflect the disease process and not its treatment. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia may be attributable to altered GABA neurotransmission in specific DLPFC microcircuits. PMID:19073429

  10. LSD alters eyes-closed functional connectivity within the early visual cortex in a retinotopic fashion.

    PubMed

    Roseman, Leor; Sereno, Martin I; Leech, Robert; Kaelen, Mendel; Orban, Csaba; McGonigle, John; Feilding, Amanda; Nutt, David J; Carhart-Harris, Robin L

    2016-08-01

    The question of how spatially organized activity in the visual cortex behaves during eyes-closed, lysergic acid diethylamide (LSD)-induced "psychedelic imagery" (e.g., visions of geometric patterns and more complex phenomena) has never been empirically addressed, although it has been proposed that under psychedelics, with eyes-closed, the brain may function "as if" there is visual input when there is none. In this work, resting-state functional connectivity (RSFC) data was analyzed from 10 healthy subjects under the influence of LSD and, separately, placebo. It was suspected that eyes-closed psychedelic imagery might involve transient local retinotopic activation, of the sort typically associated with visual stimulation. To test this, it was hypothesized that, under LSD, patches of the visual cortex with congruent retinotopic representations would show greater RSFC than incongruent patches. Using a retinotopic localizer performed during a nondrug baseline condition, nonadjacent patches of V1 and V3 that represent the vertical or the horizontal meridians of the visual field were identified. Subsequently, RSFC between V1 and V3 was measured with respect to these a priori identified patches. Consistent with our prior hypothesis, the difference between RSFC of patches with congruent retinotopic specificity (horizontal-horizontal and vertical-vertical) and those with incongruent specificity (horizontal-vertical and vertical-horizontal) increased significantly under LSD relative to placebo, suggesting that activity within the visual cortex becomes more dependent on its intrinsic retinotopic organization in the drug condition. This result may indicate that under LSD, with eyes-closed, the early visual system behaves as if it were seeing spatially localized visual inputs. Hum Brain Mapp 37:3031-3040, 2016. © 2016 Wiley Periodicals, Inc. PMID:27125770

  11. LSD alters eyes-closed functional connectivity within the early visual cortex in a retinotopic fashion.

    PubMed

    Roseman, Leor; Sereno, Martin I; Leech, Robert; Kaelen, Mendel; Orban, Csaba; McGonigle, John; Feilding, Amanda; Nutt, David J; Carhart-Harris, Robin L

    2016-08-01

    The question of how spatially organized activity in the visual cortex behaves during eyes-closed, lysergic acid diethylamide (LSD)-induced "psychedelic imagery" (e.g., visions of geometric patterns and more complex phenomena) has never been empirically addressed, although it has been proposed that under psychedelics, with eyes-closed, the brain may function "as if" there is visual input when there is none. In this work, resting-state functional connectivity (RSFC) data was analyzed from 10 healthy subjects under the influence of LSD and, separately, placebo. It was suspected that eyes-closed psychedelic imagery might involve transient local retinotopic activation, of the sort typically associated with visual stimulation. To test this, it was hypothesized that, under LSD, patches of the visual cortex with congruent retinotopic representations would show greater RSFC than incongruent patches. Using a retinotopic localizer performed during a nondrug baseline condition, nonadjacent patches of V1 and V3 that represent the vertical or the horizontal meridians of the visual field were identified. Subsequently, RSFC between V1 and V3 was measured with respect to these a priori identified patches. Consistent with our prior hypothesis, the difference between RSFC of patches with congruent retinotopic specificity (horizontal-horizontal and vertical-vertical) and those with incongruent specificity (horizontal-vertical and vertical-horizontal) increased significantly under LSD relative to placebo, suggesting that activity within the visual cortex becomes more dependent on its intrinsic retinotopic organization in the drug condition. This result may indicate that under LSD, with eyes-closed, the early visual system behaves as if it were seeing spatially localized visual inputs. Hum Brain Mapp 37:3031-3040, 2016. © 2016 Wiley Periodicals, Inc.

  12. Sleep loss alters synaptic and intrinsic neuronal properties in mouse prefrontal cortex

    PubMed Central

    Winters, Bradley D.; Huang, Yanhua H.; Dong, Yan; Krueger, James M.

    2011-01-01

    Despite sleep-loss-induced cognitive deficits, little is known about the cellular adaptations that occur with sleep loss. We used brain slices obtained from mice that were sleep deprived for 8 h to examine the electrophysiological effects of sleep deprivation (SD). We employed a modified pedestal (flowerpot) over water method for SD that eliminated rapid eye movement sleep and greatly reduced non-rapid eye movement sleep. In layer V/VI pyramidal cells of the medial prefrontal cortex, miniature excitatory post synaptic current amplitude was slightly reduced, miniature inhibitory post synaptic currents were unaffected, and intrinsic membrane excitability was increased after SD. PMID:21962531

  13. Sensory deprivation alters aggrecan and perineuronal net expression in the mouse barrel cortex.

    PubMed

    McRae, Paulette A; Rocco, Mary M; Kelly, Gail; Brumberg, Joshua C; Matthews, Russell T

    2007-05-16

    An important role for the neural extracellular matrix in modulating cortical activity-dependent synaptic plasticity has been established by a number of recent studies. However, identification of the critical molecular components of the neural matrix that mediate these processes is far from complete. Of particular interest is the perineuronal net (PN), an extracellular matrix component found surrounding the cell body and proximal neurites of a subset of neurons. Because of the apposition of the PN to synapses and expression of this structure coincident with the close of the critical period, it has been hypothesized that nets could play uniquely important roles in synapse stabilization and maturation. Interestingly, previous work has also shown that expression of PNs is dependent on appropriate sensory stimulation in the visual system. Here, we investigated whether PNs in the mouse barrel cortex are expressed in an activity-dependent manner by manipulating sensory input through whisker trimming. Importantly, this manipulation did not lead to a global loss of PNs but instead led to a specific decrease in PNs, detected with the antibody Cat-315, in layer IV of the barrel cortex. In addition, we identified a key activity-regulated component of PNs is the proteoglycan aggrecan. We also demonstrate that these Cat-315-positive neurons virtually all also express parvalbumin. Together, these data are in support of an important role for aggrecan in the activity-dependent formation of PNs on parvalbumin-expressing cells and suggest a role for expression of these nets in regulating the close of the critical period.

  14. Short-Term Monocular Deprivation Alters GABA in the Adult Human Visual Cortex

    PubMed Central

    Lunghi, Claudia; Emir, Uzay E.; Morrone, Maria Concetta; Bridge, Holly

    2016-01-01

    Summary Neuroplasticity is a fundamental property of the nervous system that is maximal early in life, within the critical period [1–3]. Resting GABAergic inhibition is necessary to trigger ocular dominance plasticity and to modulate the onset and offset of the critical period [4, 5]. GABAergic inhibition also plays a crucial role in neuroplasticity of adult animals: the balance between excitation and inhibition in the primary visual cortex (V1), measured at rest, modulates the susceptibility of ocular dominance to deprivation [6–10]. In adult humans, short-term monocular deprivation strongly modifies ocular balance, unexpectedly boosting the deprived eye, reflecting homeostatic plasticity [11, 12]. There is no direct evidence, however, to support resting GABAergic inhibition in homeostatic plasticity induced by visual deprivation. Here, we tested the hypothesis that GABAergic inhibition, measured at rest, is reduced by deprivation, as demonstrated by animal studies. GABA concentration in V1 of adult humans was measured using ultra-high-field 7T magnetic resonance spectroscopy before and after short-term monocular deprivation. After monocular deprivation, resting GABA concentration decreased in V1 but was unaltered in a control parietal area. Importantly, across participants, the decrease in GABA strongly correlated with the deprived eye perceptual boost measured by binocular rivalry. Furthermore, after deprivation, GABA concentration measured during monocular stimulation correlated with the deprived eye dominance. We suggest that reduction in resting GABAergic inhibition triggers homeostatic plasticity in adult human V1 after a brief period of abnormal visual experience. These results are potentially useful for developing new therapeutic strategies that could exploit the intrinsic residual plasticity of the adult human visual cortex. PMID:26004760

  15. Functional imaging with cellular resolution reveals precise micro-architecture in visual cortex

    NASA Astrophysics Data System (ADS)

    Ohki, Kenichi; Chung, Sooyoung; Ch'ng, Yeang H.; Kara, Prakash; Reid, R. Clay

    2005-02-01

    Neurons in the cerebral cortex are organized into anatomical columns, with ensembles of cells arranged from the surface to the white matter. Within a column, neurons often share functional properties, such as selectivity for stimulus orientation; columns with distinct properties, such as different preferred orientations, tile the cortical surface in orderly patterns. This functional architecture was discovered with the relatively sparse sampling of microelectrode recordings. Optical imaging of membrane voltage or metabolic activity elucidated the overall geometry of functional maps, but is averaged over many cells (resolution >100µm). Consequently, the purity of functional domains and the precision of the borders between them could not be resolved. Here, we labelled thousands of neurons of the visual cortex with a calcium-sensitive indicator in vivo. We then imaged the activity of neuronal populations at single-cell resolution with two-photon microscopy up to a depth of 400µm. In rat primary visual cortex, neurons had robust orientation selectivity but there was no discernible local structure; neighbouring neurons often responded to different orientations. In area 18 of cat visual cortex, functional maps were organized at a fine scale. Neurons with opposite preferences for stimulus direction were segregated with extraordinary spatial precision in three dimensions, with columnar borders one to two cells wide. These results indicate that cortical maps can be built with single-cell precision.

  16. Mechanisms of migraine aura revealed by functional MRI in human visual cortex

    PubMed Central

    Hadjikhani, Nouchine; Sanchez del Rio, Margarita; Wu, Ona; Schwartz, Denis; Bakker, Dick; Fischl, Bruce; Kwong, Kenneth K.; Cutrer, F. Michael; Rosen, Bruce R.; Tootell, Roger B. H.; Sorensen, A. Gregory; Moskowitz, Michael A.

    2001-01-01

    Cortical spreading depression (CSD) has been suggested to underlie migraine visual aura. However, it has been challenging to test this hypothesis in human cerebral cortex. Using high-field functional MRI with near-continuous recording during visual aura in three subjects, we observed blood oxygenation level-dependent (BOLD) signal changes that demonstrated at least eight characteristics of CSD, time-locked to percept/onset of the aura. Initially, a focal increase in BOLD signal (possibly reflecting vasodilation), developed within extrastriate cortex (area V3A). This BOLD change progressed contiguously and slowly (3.5 ± 1.1 mm/min) over occipital cortex, congruent with the retinotopy of the visual percept. Following the same retinotopic progression, the BOLD signal then diminished (possibly reflecting vasoconstriction after the initial vasodilation), as did the BOLD response to visual activation. During periods with no visual stimulation, but while the subject was experiencing scintillations, BOLD signal followed the retinotopic progression of the visual percept. These data strongly suggest that an electrophysiological event such as CSD generates the aura in human visual cortex. PMID:11287655

  17. Microstimulation Reveals Opposing Influences of Prelimbic and Infralimbic Cortex on the Expression of Conditioned Fear

    ERIC Educational Resources Information Center

    Vidal-Gonzalez, Ivan; Rauch, Scott L.; Quirk, Gregory J.; Vidal-Gonzalez, Benjamin

    2006-01-01

    Recent studies using lesion, infusion, and unit-recording techniques suggest that the infralimbic (IL) subregion of medial prefrontal cortex (mPFC) is necessary for the inhibition of conditioned fear following extinction. Brief microstimulation of IL paired with conditioned tones, designed to mimic neuronal tone responses, reduces the expression…

  18. Gray matter alterations in visual cortex of patients with loss of central vision due to hereditary retinal dystrophies.

    PubMed

    Plank, Tina; Frolo, Jozef; Brandl-Rühle, Sabine; Renner, Agnes B; Hufendiek, Karsten; Helbig, Horst; Greenlee, Mark W

    2011-06-01

    In patients with central visual field scotomata a large part of visual cortex is not adequately stimulated. Over time this lack of input could lead to a reduction of gray matter in the affected cortical areas. We used Voxel Based Morphometry to investigate structural brain changes in patients with central scotomata due to hereditary retinal dystrophies and compared their results to those of normal sighted subjects. Additionally we correlated clinical and demographic characteristics like duration of disease, scotoma size, visual acuity, fixation stability and reading speed to the amount of gray matter in whole brain analyses within the patient group. We found a decrease in gray matter around the lesion projection zone in visual cortex of patients in comparison to controls. Gray matter loss along the posterior and middle portions of the calcarine sulcus is also correlated with scotoma size, indicating that indeed the lack of functional input provokes the gray matter alterations. In whole brain regression analyses within the patient group we found an additional cluster in the right superior and middle frontal gyri, slightly anterior to the frontal eye fields, where gray matter correlated positively with fixation stability. This could be regarded as a consequence of oculomotor learning.

  19. Genomic Interaction Profiles in Breast Cancer Reveal Altered Chromatin Architecture

    PubMed Central

    Zeitz, Michael J.; Ay, Ferhat; Heidmann, Julia D.; Lerner, Paula L.

    2013-01-01

    Gene transcription can be regulated by remote enhancer regions through chromosome looping either in cis or in trans. Cancer cells are characterized by wholesale changes in long-range gene interactions, but the role that these long-range interactions play in cancer progression and metastasis is not well understood. In this study, we used IGFBP3, a gene involved in breast cancer pathogenesis, as bait in a 4C-seq experiment comparing normal breast cells (HMEC) with two breast cancer cell lines (MCF7, an ER positive cell line, and MDA-MB-231, a triple negative cell line). The IGFBP3 long-range interaction profile was substantially altered in breast cancer. Many interactions seen in normal breast cells are lost and novel interactions appear in cancer lines. We found that in HMEC, the breast carcinoma amplified sequence gene family (BCAS) 1–4 were among the top 10 most significantly enriched regions of interaction with IGFBP3. 3D-FISH analysis indicated that the translocation-prone BCAS genes, which are located on chromosomes 1, 17, and 20, are in close physical proximity with IGFBP3 and each other in normal breast cells. We also found that epidermal growth factor receptor (EGFR), a gene implicated in tumorigenesis, interacts significantly with IGFBP3 and that this interaction may play a role in their regulation. Breakpoint analysis suggests that when an IGFBP3 interacting region undergoes a translocation an additional interaction detectable by 4C is gained. Overall, our data from multiple lines of evidence suggest an important role for long-range chromosomal interactions in the pathogenesis of cancer. PMID:24019942

  20. Ventromedial prefrontal cortex damage alters relative risk tolerance for prospective gains and losses.

    PubMed

    Pujara, Maia S; Wolf, Richard C; Baskaya, Mustafa K; Koenigs, Michael

    2015-12-01

    One paradigmatic example of "irrational" bias in human economic decision-making-known as the "reflection effect"-is a tendency to prefer sure amounts over risky gambles in situations involving potential gain, but to prefer risky gambles over sure amounts in situations involving potential loss. To date, there is no causal evidence regarding the neural basis of the reflection effect. The ventromedial prefrontal cortex (vmPFC) is believed to play a critical role in mediating value-based decision-making. In this study, we administered a behavioral test of the reflection effect to three groups of subjects: neurosurgical patients with focal bilateral vmPFC lesions, neurosurgical patients with lesions outside vmPFC, and neurologically healthy adults. Subjects made a series of choices between a sure amount (e.g., gain of $50) and a gamble (e.g., 50% chance of gaining $100, 50% chance of gaining $0). Half the trials featured potential gains while the other half featured potential losses. The sure amounts varied across trials. Relative to the two comparison groups, the vmPFC lesion patients exhibited a significantly greater reflection effect; more gambles selected in the loss condition and fewer gambles selected in the gain condition. This finding demonstrates a critical role for vmPFC in governing susceptibility to bias in decision-making. PMID:26597003

  1. Mild systemic inflammation and moderate hypoxia transiently alter neuronal excitability in mouse somatosensory cortex.

    PubMed

    Mordel, Jérôme; Sheikh, Aminah; Tsohataridis, Simeon; Kanold, Patrick O; Zehendner, Christoph M; Luhmann, Heiko J

    2016-04-01

    During the perinatal period, the brain is highly vulnerable to hypoxia and inflammation, which often cause white matter injury and long-term neuronal dysfunction such as motor and cognitive deficits or epileptic seizures. We studied the effects of moderate hypoxia (HYPO), mild systemic inflammation (INFL), or the combination of both (HYPO+INFL) in mouse somatosensory cortex induced during the first postnatal week on network activity and compared it to activity in SHAM control animals. By performing in vitro electrophysiological recordings with multi-electrode arrays from slices prepared directly after injury (P8-10), one week after injury (P13-16), or in young adults (P28-30), we investigated how the neocortical network developed following these insults. No significant difference was observed between the four groups in an extracellular solution close to physiological conditions. In extracellular 8mM potassium solution, slices from the HYPO, INFL, and HYPO+INFL group were more excitable than SHAM at P8-10 and P13-16. In these two age groups, the number and frequency of spontaneous epileptiform events were significantly increased compared to SHAM. The frequency of epileptiform events was significantly reduced by the NMDA antagonist D-APV in HYPO, INFL, and HYPO+INFL, but not in SHAM, indicating a contribution of NMDA receptors to this pathophysiological activity. In addition, the AMPA/kainate receptor antagonist CNQX suppressed the remaining epileptiform activity. Electrical stimulation evoked prominent epileptiform activity in slices from HYPO, INFL and HYPO+INFL animals. Stimulation threshold to elicit epileptiform events was lower in these groups than in SHAM. Evoked events spread over larger areas and lasted longer in treated animals than in SHAM. In addition, the evoked epileptiform activity was reduced in the older (P28-30) group indicating that cortical dysfunction induced by hypoxia and inflammation was transient and compensated during early development.

  2. Exposure to a novel stimulus environment alters patterns of lateralization in avian auditory cortex.

    PubMed

    Yang, L M; Vicario, D S

    2015-01-29

    Perceptual filters formed early in development provide an initial means of parsing the incoming auditory stream. However, these filters may not remain fixed, and may be updated by subsequent auditory input, such that, even in an adult organism, the auditory system undergoes plastic changes to achieve a more efficient representation of the recent auditory environment. Songbirds are an excellent model system for experimental studies of auditory phenomena due to many parallels between song learning in birds and language acquisition in humans. In the present study, we explored the effects of passive immersion in a novel heterospecific auditory environment on neural responses in caudo-medial neostriatum (NCM), a songbird auditory area similar to the secondary auditory cortex in mammals. In zebra finches, a well-studied species of songbirds, NCM responds selectively to conspecific songs and contains a neuronal memory for tutor and other familiar conspecific songs. Adult male zebra finches were randomly assigned to either a conspecific or heterospecific auditory environment. After 2, 4 or 9 days of exposure, subjects were presented with heterospecific and conspecific songs during awake electrophysiological recording. The neural response strength and rate of adaptation to the testing stimuli were recorded bilaterally. Controls exposed to conspecific environment sounds exhibited the normal pattern of hemispheric lateralization with higher absolute response strength and faster adaptation in the right hemisphere. The pattern of lateralization was fully reversed in birds exposed to heterospecific environment for 4 or 9 days and partially reversed in birds exposed to heterospecific environment for 2 days. Our results show that brief passive exposure to a novel category of sounds was sufficient to induce a gradual reorganization of the left and right secondary auditory cortices. These changes may reflect modification of perceptual filters to form a more efficient representation

  3. Depressive-like history alters persistent pain behavior in rats: Opposite contribution of frontal cortex and amygdala implied

    PubMed Central

    Qi, Wei-Jing; Wang, Wei; Wang, Ning; Wang, Jin-Yan; Luo, Fei

    2015-01-01

    Numerous studies have shown that pain perception is strongly influenced by depression. However, very few studies have examined whether pain perception is altered in the remission period of depression, and what role the fronto-limbic circuits may play in the behavioral changes associated with remission. Using an unpredictable chronic mild stress (UCMS) animal model of depression, the present study investigated pain-related behaviors in rats with prior exposure to a UCMS stimulus. The γ-aminobutyric acid (GABA)A receptor agonist muscimol was microinjected bilaterally into the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) to examine the modulation of pain by these brain regions in the recovery state. Rats with a depression-like history displayed increased ongoing pain behavior in the formalin test, although their thermal pain thresholds were unchanged. Intra-BLA muscimol during the recovery phase dramatically decreased formalin-induced pain behavior and also significantly increased rats’ sucrose preference. By contrast, in the mPFC, muscimol produced the opposite effect, suggesting different, perhaps opposing, roles of the BLA and mPFC in mediating the influence of prior UCMS exposure on pain perception. Taken together, these results demonstrated that a depressive experience may cause long-term alterations in limbic circuit excitability and thus lead to long-lasting changes in pain perception. PMID:26229589

  4. Alterations in Somatostatin mRNA Expression in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia or Schizoaffective Disorder

    PubMed Central

    Morris, Harvey M.; Hashimoto, Takanori; Lewis, David A.

    2010-01-01

    Alterations in the inhibitory circuitry of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia include reduced expression of the messenger RNA (mRNA) for somatostatin (SST), a neuropeptide present in a subpopulation of γ-aminobutyric acid (GABA) neurons. However, neither the cellular substrate nor the causal mechanisms for decreased SST mRNA levels in schizophrenia are known. We used in situ hybridization to quantify the compartmental, laminar, and cellular levels of SST mRNA expression in the DLPFC of 23 pairs of schizophrenia or schizoaffective disorder and control subjects. We also explored potential causal mechanisms by utilizing similar methods to analyze SST mRNA expression in 2 animal models. The expression of SST mRNA was significantly decreased in layers 2–superficial 6 of subjects with schizophrenia, but not in layer 1, deep 6 or the white matter. At the cellular level, both the density of cortical SST mRNA-positive neurons and the expression of SST mRNA per neuron were reduced in the subjects with schizophrenia. These alterations were not due to potential confounds and appeared to be a downstream consequence of impaired neurotrophin signaling through the trkB receptor. These findings support the hypothesis that a marked reduction in SST mRNA expression in a subset of GABA neurons contributes to DLPFC dysfunction in schizophrenia. PMID:18203698

  5. Genetic elimination of GABAergic neurotransmission reveals two distinct pacemakers for spontaneous waves of activity in the developing mouse cortex.

    PubMed

    Easton, Curtis R; Weir, Keiko; Scott, Adina; Moen, Samantha P; Barger, Zeke; Folch, Albert; Hevner, Robert F; Moody, William J

    2014-03-12

    Many structures of the mammalian CNS generate propagating waves of electrical activity early in development. These waves are essential to CNS development, mediating a variety of developmental processes, such as axonal outgrowth and pathfinding, synaptogenesis, and the maturation of ion channel and receptor properties. In the mouse cerebral cortex, waves of activity occur between embryonic day 18 and postnatal day 8 and originate in pacemaker circuits in the septal nucleus and the piriform cortex. Here we show that genetic knock-out of the major synthetic enzyme for GABA, GAD67, selectively eliminates the picrotoxin-sensitive fraction of these waves. The waves that remain in the GAD67 knock-out have a much higher probability of propagating into the dorsal neocortex, as do the picrotoxin-resistant fraction of waves in controls. Field potential recordings at the point of wave initiation reveal different electrical signatures for GABAergic and glutamatergic waves. These data indicate that: (1) there are separate GABAergic and glutamatergic pacemaker circuits within the piriform cortex, each of which can initiate waves of activity; (2) the glutamatergic pacemaker initiates waves that preferentially propagate into the neocortex; and (3) the initial appearance of the glutamatergic pacemaker does not require preceding GABAergic waves. In the absence of GAD67, the electrical activity underlying glutamatergic waves shows greatly increased tendency to burst, indicating that GABAergic inputs inhibit the glutamatergic pacemaker, even at stages when GABAergic pacemaker circuitry can itself initiate waves.

  6. Neural oscillation, network, eloquent cortex and epileptogenic zone revealed by magnetoencephalography and awake craniotomy

    PubMed Central

    Idris, Zamzuri; Kandasamy, Regunath; Reza, Faruque; Abdullah, Jafri M.

    2014-01-01

    Background: Magnetoencephalography (MEG) is a method of functional neuroimaging. The concomitant use of MEG and electrocorticography has been found to be useful in elucidating neural oscillation and network, and to localize epileptogenic zone and functional cortex. We describe our early experience using MEG in neurosurgical patients, emphasizing on its impact on patient management as well as the enrichment of our knowledge in neurosciences. Materials and Methods: A total of 10 subjects were included; five patients had intraaxial tumors, one with an extraaxial tumor and brain compression, two with arteriovenous malformations, one with cerebral peduncle hemorrhage and one with sensorimotor cortical dysplasia. All patients underwent evoked and spontaneous MEG recordings. MEG data was processed at band-pass filtering frequency of between 0.1 and 300 Hz with a sampling rate of 1 kHz. MEG source localization was performed using either overdetermined equivalent current dipoles or underdetermined inversed solution. Neuromag collection of events software was used to study brain network and epileptogenic zone. The studied data were analyzed for neural oscillation in three patients; brain network and clinical manifestation in five patients; and for the location of epileptogenic zone and eloquent cortex in two patients. Results: We elucidated neural oscillation in three patients. One demonstrated oscillatory phenomenon on stimulation of the motor-cortex during awake surgery, and two had improvement in neural oscillatory parameters after surgery. Brain networks corresponding to clinico-anatomical relationships were depicted in five patients, and two networks were illustrated here. Finally, we demonstrated epilepsy cases in which MEG data was found to be useful in localizing the epileptogenic zones and functional cortices. Conclusion: The application of MEG while enhancing our knowledge in neurosciences also has a useful role in epilepsy and awake surgery. PMID:25685205

  7. Diffusion tensor imaging reveals thalamus and posterior cingulate cortex abnormalities in internet gaming addicts.

    PubMed

    Dong, Guangheng; DeVito, Elise; Huang, Jie; Du, Xiaoxia

    2012-09-01

    Internet gaming addiction (IGA) is increasingly recognized as a widespread disorder with serious psychological and health consequences. Diminished white matter integrity has been demonstrated in a wide range of other addictive disorders which share clinical characteristics with IGA. Abnormal white matter integrity in addictive populations has been associated with addiction severity, treatment response and cognitive impairments. This study assessed white matter integrity in individuals with internet gaming addiction (IGA) using diffusion tensor imaging (DTI). IGA subjects (N = 16) showed higher fractional anisotropy (FA), indicating greater white matter integrity, in the thalamus and left posterior cingulate cortex (PCC) relative to healthy controls (N = 15). Higher FA in the thalamus was associated with greater severity of internet addiction. Increased regional FA in individuals with internet gaming addiction may be a pre-existing vulnerability factor for IGA, or may arise secondary to IGA, perhaps as a direct result of excessive internet game playing.

  8. Auditory sequence processing reveals evolutionarily conserved regions of frontal cortex in macaques and humans

    PubMed Central

    Wilson, Benjamin; Kikuchi, Yukiko; Sun, Li; Hunter, David; Dick, Frederic; Smith, Kenny; Thiele, Alexander; Griffiths, Timothy D.; Marslen-Wilson, William D.; Petkov, Christopher I.

    2015-01-01

    An evolutionary account of human language as a neurobiological system must distinguish between human-unique neurocognitive processes supporting language and evolutionarily conserved, domain-general processes that can be traced back to our primate ancestors. Neuroimaging studies across species may determine whether candidate neural processes are supported by homologous, functionally conserved brain areas or by different neurobiological substrates. Here we use functional magnetic resonance imaging in Rhesus macaques and humans to examine the brain regions involved in processing the ordering relationships between auditory nonsense words in rule-based sequences. We find that key regions in the human ventral frontal and opercular cortex have functional counterparts in the monkey brain. These regions are also known to be associated with initial stages of human syntactic processing. This study raises the possibility that certain ventral frontal neural systems, which play a significant role in language function in modern humans, originally evolved to support domain-general abilities involved in sequence processing. PMID:26573340

  9. Diffusion tensor imaging reveals thalamus and posterior cingulate cortex abnormalities in internet gaming addicts

    PubMed Central

    Dong, Guangheng; DeVito, Elise; Huang, Jie; Du, Xiaoxia

    2013-01-01

    Internet gaming addiction (IGA) is increasingly recognized as a widespread disorder with serious psychological and health consequences. Diminished white matter integrity has been demonstrated in a wide range of other addictive disorders which share clinical characteristics with IGA. Abnormal white matter integrity in addictive populations has been associated with addiction severity, treatment response and cognitive impairments. This study assessed white matter integrity in individuals with internet gaming addiction (IGA) using diffusion tensor imaging (DTI). IGA subjects (N=16) showed higher fractional anisotropy (FA), indicating greater white matter integrity, in the thalamus and left posterior cingulate cortex (PCC) relative to healthy controls (N=15). Higher FA in the thalamus was associated with greater severity of internet addiction. Increased regional FA in individuals with internet gaming addiction may be a pre-existing vulnerability factor for IGA, or may arise secondary to IGA, perhaps as a direct result of excessive internet game playing. PMID:22727905

  10. Turning visual shapes into sounds: early stages of reading acquisition revealed in the ventral occipitotemporal cortex.

    PubMed

    Perrone-Bertolotti, M; Vidal, J R; de Palma, L; Hamamé, C M; Ossandon, T; Kahane, P; Minotti, L; Bertrand, O; Lachaux, J-P

    2014-04-15

    The exact role of the left ventral occipitotemporal cortex (VOTC) during the initial stages of reading acquisition is a hotly debated issue, especially regarding the comparative effect of learning on early stimulus-dependent vs. later task-dependent processes. We show that this controversy can be solved with high-temporal resolution intracerebral EEG recordings of the VOTC. We measured High-Frequency Activity (50-150 Hz) as a proxy of population-level spiking activity while participants learned Japanese Katakana symbols, and found that learning primarily affects top-down/task-dependent neural processing, after a few minutes only. In contrast, adaptation of early bottom-up/stimulus-dependent processing takes several days to adapt and provides the basis for fluent reading. Such evidence that two consecutive stages of neural processing, stimulus- and task-dependent are differentially affected by learning, can reconcile seemingly opposite hypotheses on the role of the VOTC during reading acquisition.

  11. Imaging studies in congenital anophthalmia reveal preservation of brain architecture in 'visual' cortex.

    PubMed

    Bridge, Holly; Cowey, Alan; Ragge, Nicola; Watkins, Kate

    2009-12-01

    The functional specialization of the human brain means that many regions are dedicated to processing a single sensory modality. When a modality is absent, as in congenital total blindness, 'visual' regions can be reliably activated by non-visual stimuli. The connections underlying this functional adaptation, however, remain elusive. In this study, using structural and diffusion-weighted magnetic resonance imaging, we investigated the structural differences in the brains of six bilaterally anophthalmic subjects compared with sighted subjects. Surprisingly, the gross structural differences in the brains were small, even in the occipital lobe where only a small region of the primary visual cortex showed a bilateral reduction in grey matter volume in the anophthalmic subjects compared with controls. Regions of increased cortical thickness were apparent on the banks of the Calcarine sulcus, but not in the fundus. Subcortically, the white matter volume around the optic tract and internal capsule in anophthalmic subjects showed a large decrease, yet the optic radiation volume did not differ significantly. However, the white matter integrity, as measured with fractional anisotropy showed an extensive reduction throughout the brain in the anophthalmic subjects, with the greatest difference in the optic radiations. In apparent contradiction to the latter finding, the connectivity between the lateral geniculate nucleus and primary visual cortex measured with diffusion tractography did not differ between the two populations. However, these findings can be reconciled by a demonstration that at least some of the reduction in fractional anisotropy in the optic radiation is due to an increase in the strength of fibres crossing the radiations. In summary, the major changes in the 'visual' brain in anophthalmic subjects may be subcortical, although the evidence of decreased fractional anisotropy and increased crossing fibres could indicate considerable re-organization.

  12. Suppressive responses by visual food cues in postprandial activities of insular cortex as revealed by magnetoencephalography.

    PubMed

    Yoshikawa, Takahiro; Tanaka, Masaaki; Ishii, Akira; Watanabe, Yasuyoshi

    2014-06-01

    'Hara-Hachibu' in Japanese means a subjective sense by which we stop eating just before the motivation to eat is completely lost, a similar concept to caloric restriction (CR). Insular cortex is a critical platform which integrates sensory information into decision-making processes in eating behavior. We compared the responses of insular cortex, as assessed by magnetoencephalography (MEG), immediately after presentation of food images in the Fasting condition with those in the 'Hara-Hachibu' condition. Eleven healthy, right-handed males [age, 27.2±9.6 years; body mass index, 22.6±2.1kg/m(2) (mean±SD)] were enrolled in a randomized, two-crossover experiment (Fasting and 'Hara-Hachibu' conditions). Before the MEG recordings in the 'Hara-Hachibu' condition, the participants consumed rice balls as much as they judged themselves to have consumed shortly before reaching satiety. During the MEG recordings, they viewed food pictures projected on a screen. The intensities of MEG responses to viewing food pictures were significantly lower in the 'Hara-Hachibu' condition than those in the Fasting condition (P<0.05). The intensities of the MEG responses to the visual food stimuli in the 'Hara-Hachibu' condition was positively associated with the factor-3 (food tasted) (r=0.693, P=0.018) and aggregated scores (r=0.659, P=0.027) of the Power of Food Scale, a self-report measure of hedonic hunger. These findings may help to elucidate the neural basis of variability of appetite phenotypes under the condition of CR among individuals, and to develop possible strategies for the maintenance of adequate CR in daily life.

  13. tDCS-induced alterations in GABA concentration within primary motor cortex predict motor learning and motor memory: a 7 T magnetic resonance spectroscopy study.

    PubMed

    Kim, Soyoung; Stephenson, Mary C; Morris, Peter G; Jackson, Stephen R

    2014-10-01

    Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that alters cortical excitability in a polarity specific manner and has been shown to influence learning and memory. tDCS may have both on-line and after-effects on learning and memory, and the latter are thought to be based upon tDCS-induced alterations in neurochemistry and synaptic function. We used ultra-high-field (7 T) magnetic resonance spectroscopy (MRS), together with a robotic force adaptation and de-adaptation task, to investigate whether tDCS-induced alterations in GABA and Glutamate within motor cortex predict motor learning and memory. Note that adaptation to a robot-induced force field has long been considered to be a form of model-based learning that is closely associated with the computation and 'supervised' learning of internal 'forward' models within the cerebellum. Importantly, previous studies have shown that on-line tDCS to the cerebellum, but not to motor cortex, enhances model-based motor learning. Here we demonstrate that anodal tDCS delivered to the hand area of the left primary motor cortex induces a significant reduction in GABA concentration. This effect was specific to GABA, localised to the left motor cortex, and was polarity specific insofar as it was not observed following either cathodal or sham stimulation. Importantly, we show that the magnitude of tDCS-induced alterations in GABA concentration within motor cortex predicts individual differences in both motor learning and motor memory on the robotic force adaptation and de-adaptation task.

  14. Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia.

    PubMed

    Lindenbach, D; Conti, M M; Ostock, C Y; Dupre, K B; Bishop, C

    2015-12-01

    Treatment of Parkinson's disease (PD) with dopamine replacement relieves symptoms of poverty of movement, but often causes drug-induced dyskinesias. Accumulating clinical and pre-clinical evidence suggests that the primary motor cortex (M1) is involved in the pathophysiology of PD and that modulating cortical activity may be a therapeutic target in PD and dyskinesia. However, surprisingly little is known about how M1 neurotransmitter tone or gene expression is altered in PD, dyskinesia or associated animal models. The present study utilized the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD/dyskinesia to characterize structural and functional changes taking place in M1 monoamine innervation and gene expression. 6-OHDA caused dopamine pathology in M1, although the lesion was less severe than in the striatum. Rats with 6-OHDA lesions showed a PD motor impairment and developed dyskinesia when given L-DOPA or the D1 receptor agonist, SKF81297. M1 expression of two immediate-early genes (c-Fos and ARC) was strongly enhanced by either L-DOPA or SKF81297. At the same time, expression of genes specifically involved in glutamate and GABA signaling were either modestly affected or unchanged by lesion and/or treatment. We conclude that M1 neurotransmission and signal transduction in the rat 6-OHDA model of PD/dyskinesia mirror features of human PD, supporting the utility of the model to study M1 dysfunction in PD and the elucidation of novel pathophysiological mechanisms and therapeutic targets. PMID:26363150

  15. Altered CB receptor-signaling in prefrontal cortex from an animal model of depression is reversed by chronic fluoxetine.

    PubMed

    Rodríguez-Gaztelumendi, Antonio; Rojo, M Luisa; Pazos, Angel; Díaz, Alvaro

    2009-03-01

    Bilateral olfactory bulbectomy in the rat (OBX) induces behavioral, neurochemical, and structural abnormalities similar to those observed in human depression that are normalized after chronic, but not acute, treatment with antidepressants. In our study, OBX animals exhibited significant increases in both CB(1) receptor density ([(3)H]CP55490 binding) and functionality (stimulation of [(35)S]GTPgammaS binding by the cannabinoid (CB) agonist WIN 55212-2) at the prefrontal cortex (PFC). After chronic treatment with fluoxetine (10 mg/kg/day, 14 days, s.c.), OBX-induced hyperactivity in the open-field test was fully abolished. Interestingly, chronic fluoxetine fully reversed the enhanced CB(1)-receptor signaling in PFC observed following OBX. The CB agonist Delta(9)-tetrahydrocannabinol (5 mg/kg, i.p., 1 day) did not produce any behavioral effect in sham-operated animals but returned locomotor activity to control values in OBX rats. As both acute administration of Delta(9)-tetrahydrocannabinol and chronic fluoxetine elicited a similar behavioral effect in the OBX rat, it is not unlikely that the regionally selective enhancement of CB(1) receptor-signaling in the PFC could be related with the altered OBX behavior. Our findings reinforce the utility of this animal model to further investigating the implication of the endocannabinoid system in the modulation of emotional processes and its potential role in the adaptive responses to chronic antidepressants.

  16. Alterations of the synaptosomal membrane 'microviscosity' in the brain cortex of rats during aging and centrophenoxine treatment.

    PubMed

    Nagy, K; Nagy, V; Bertoni-Freddari, C; Nagy, I

    1983-07-01

    Synaptosomal and myelin fractions were isolated from the brain cortex of young, adult and old male CFY rats (2, 12 and 24 mth, respectively). The purity of the fractions was tested by transmission electron microscopy and marker enzyme assays. The cholesterol content of the fractions was also determined. Samples of the fractions were labelled with diphenylhexatriene (DPH) and the fluorescence anisotropy (r) of the label was measured at various optical densities. The values of r extrapolated to zero optical density were compared in the age groups and used for calculating the 'microviscosity' of the membranes. The 'microviscosity' of synaptosomal membranes displayed a significant age-dependent increase: from 2.3 +/- 0.02 (SD) in the young group it increased to 2.6 +/- 0.03 poise by the age of 24 mth at 37 degrees C. Most of this increase occurred between the adult and old age. The cholesterol content of the synaptosomes also increased significantly during aging. Centrophenoxine (CPH)-treatment with 100 mg/kg body weight daily dose for 2 mth was able to reverse the age-dependent alterations of both the membrane 'microviscosity' and the cholesterol content in the synaptosomes: the values returned nearly to the adult level. The results obtained are interpreted in terms of the membrane hypothesis of aging attributing to primary role to the free-radical induced membrane damage in cellular aging.

  17. Semaphorin and plexin gene expression is altered in the prefrontal cortex of schizophrenia patients with and without auditory hallucinations.

    PubMed

    Gilabert-Juan, Javier; Sáez, Ana Rosa; Lopez-Campos, Guillermo; Sebastiá-Ortega, Noelia; González-Martínez, Rocio; Costa, Juan; Haro, Josep María; Callado, Luis F; Meana, J Javier; Nacher, Juán; Sanjuán, Julio; Moltó, María Dolores

    2015-10-30

    Auditory hallucinations (AH) are clinical hallmarks of schizophrenia, however little is known about molecular genetics of these symptoms. In this study, gene expression profiling of postmortem brain samples from prefrontal cortex of schizophrenic patients without AH (SNA), patients with AH (SA) and control subjects were compared. Genome-wide expression analysis was conducted using samples of three individuals of each group and the Affymetrix GeneChip Human-Gene 1.0 ST-Array. This analysis identified the Axon Guidance pathway as one of the most differentially expressed network among SNA, SA and CNT. To confirm the transcriptome results, mRNA level quantification of seventeen genes involved in this pathway was performed in a larger sample. PLXNB1, SEMA3A, SEMA4D and SEM6C were upregulated in SNA or SA patients compared to controls. PLXNA1 and SEMA3D showed down-regulation in their expression in the patient's samples, but differences remained statistically significant between the SNA patients and controls. Differences between SNA and SA were found in PLXNB1 expression which is decreased in SA patients. This study strengthens the contribution of brain plasticity in pathophysiology of schizophrenia and shows that non-hallucinatory patients present more alterations in frontal regions than patients with hallucinations concerning neural plasticity.

  18. Altered functional connectivity between the insula and the cingulate cortex in patients with TMD – a pilot study

    PubMed Central

    Ichesco, Eric; Quintero, Andres; Clauw, Daniel J.; Peltier, Scott; Sundgren, Pia M.; Gerstner, Geoffrey E.; Schmidt-Wilcke, Tobias

    2011-01-01

    Background Amongst the most common chronic pain conditions, yet poorly understood, are temporomandibular disorders (TMDs), with a prevalence estimate of 3 – 15% for Western populations. Although it is increasingly acknowledged that central nervous system mechanisms contribute to pain amplification and chronicity in TMDs, further research is needed to unravel neural correlates that might abet the development of chronic pain. Objective The insular cortex (IC) and cingulate cortex (CC) are both critically involved in the experience of pain. The current study sought specifically to investigate IC-CC functional connectivity in TMD patients and healthy controls (HCs), both during resting state and during the application of a painful stimulus. Method Eight patients with TMD, and 8 age and sex matched healthy controls (HCs) were enrolled in the present study. FMRI data during resting state and during the performance of a pressure pain stimulus to the temple were acquired. Predefined seed regions were placed in the IC (anterior and posterior insular cortices) and the extracted signal was correlated with brain activity throughout the whole brain. Specifically we were interested whether TMD patients and HCs would show differences in IC – CC connectivity, both during resting state and during the application of a painful stimulus to the face. Results As a main finding functional connectivity analyses revealed an increased functional connectivity between the left anterior IC and pregenual ACC in TMD patients, during both resting state and applied pressure pain. Within the patient group there was a negative correlation between the anterior IC - ACC connectivity and clinical pain intensity as measured by a VAS. Conclusions Since the pregenual region of the ACC is critically involved in antinociception, we hypothesize that an increase in anterior IC – ACC connectivity is indicative of an adaptation of the pain modulatory system early in the chronification process. PMID

  19. Post-Stroke Longitudinal Alterations of Inter-Hemispheric Correlation and Hemispheric Dominance in Mouse Pre-Motor Cortex

    PubMed Central

    Panarese, Alessandro; Alia, Claudia; Micera, Silvestro; Caleo, Matteo; Di Garbo, Angelo

    2016-01-01

    Purpose Limited restoration of function is known to occur spontaneously after an ischemic injury to the primary motor cortex. Evidence suggests that Pre-Motor Areas (PMAs) may “take over” control of the disrupted functions. However, little is known about functional reorganizations in PMAs. Forelimb movements in mice can be driven by two cortical regions, Caudal and Rostral Forelimb Areas (CFA and RFA), generally accepted as primary motor and pre-motor cortex, respectively. Here, we examined longitudinal changes in functional coupling between the two RFAs following unilateral photothrombotic stroke in CFA (mm from Bregma: +0.5 anterior, +1.25 lateral). Methods Local field potentials (LFPs) were recorded from the RFAs of both hemispheres in freely moving injured and naïve mice. Neural signals were acquired at 9, 16 and 23 days after surgery (sub-acute period in stroke animals) through one bipolar electrode per hemisphere placed in the center of RFA, with a ground screw over the occipital bone. LFPs were pre-processed through an efficient method of artifact removal and analysed through: spectral,cross-correlation, mutual information and Granger causality analysis. Results Spectral analysis demonstrated an early decrease (day 9) in the alpha band power in both the RFAs. In the late sub-acute period (days 16 and 23), inter-hemispheric functional coupling was reduced in ischemic animals, as shown by a decrease in the cross-correlation and mutual information measures. Within the gamma and delta bands, correlation measures were already reduced at day 9. Granger analysis, used as a measure of the symmetry of the inter-hemispheric causal connectivity, showed a less balanced activity in the two RFAs after stroke, with more frequent oscillations of hemispheric dominance. Conclusions These results indicate robust electrophysiological changes in PMAs after stroke. Specifically, we found alterations in transcallosal connectivity, with reduced inter-hemispheric functional

  20. Velocity Selective Networks in Human Cortex Reveal Two Functionally Distinct Auditory Motion Systems

    PubMed Central

    Meng, Jhao-An; Saberi, Kourosh; Hsieh, I-Hui

    2016-01-01

    The auditory system encounters motion cues through an acoustic object’s movement or rotation of the listener’s head in a stationary sound field, generating a wide range of naturally occurring velocities from a few to several hundred degrees per second. The angular velocity of moving acoustic objects relative to a listener is typically slow and does not exceed tens of degrees per second, whereas head rotations in a stationary acoustic field may generate fast-changing spatial cues in the order of several hundred degrees per second. We hypothesized that these two types of systems (i.e., encoding slow movements of an object or fast head rotations) may engage functionally distinct substrates in processing spatially dynamic auditory cues, with the latter potentially involved in maintaining perceptual constancy in a stationary field during head rotations and therefore possibly involving corollary-discharge mechanisms in premotor cortex. Using fMRI, we examined cortical response patterns to sound sources moving at a wide range of velocities in 3D virtual auditory space. We found a significant categorical difference between fast and slow moving sounds, with stronger activations in response to higher velocities in the posterior superior temporal regions, the planum temporale, and notably the premotor ventral-rostral (PMVr) area implicated in planning neck and head motor functions. PMID:27294673

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

    PubMed

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

    2015-01-01

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

  2. Nonlinear properties of medial entorhinal cortex neurons reveal frequency selectivity during multi-sinusoidal stimulation.

    PubMed

    Magnani, Christophe; Economo, Michael N; White, John A; Moore, Lee E

    2014-01-01

    The neurons in layer II of the medial entorhinal cortex are part of the grid cell network involved in the representation of space. Many of these neurons are likely to be stellate cells with specific oscillatory and firing properties important for their function. A fundamental understanding of the nonlinear basis of these oscillatory properties is critical for the development of theories of grid cell firing. In order to evaluate the behavior of stellate neurons, measurements of their quadratic responses were used to estimate a second order Volterra kernel. This paper uses an operator theory, termed quadratic sinusoidal analysis (QSA), which quantitatively determines that the quadratic response accounts for a major part of the nonlinearity observed at membrane potential levels characteristic of normal synaptic events. Practically, neurons were probed with multi-sinusoidal stimulations to determine a Hermitian operator that captures the quadratic function in the frequency domain. We have shown that the frequency content of the stimulation plays an important role in the characteristics of the nonlinear response, which can distort the linear response as well. Stimulations with enhanced low frequency amplitudes evoked a different nonlinear response than broadband profiles. The nonlinear analysis was also applied to spike frequencies and it was shown that the nonlinear response of subthreshold membrane potential at resonance frequencies near the threshold is similar to the nonlinear response of spike trains. PMID:25191226

  3. Chronic stress alters the dendritic morphology of callosal neurons and the acute glutamate stress response in the rat medial prefrontal cortex.

    PubMed

    Luczynski, Pauline; Moquin, Luc; Gratton, Alain

    2015-01-01

    We have previously reported that interhemispheric regulation of medial prefrontal cortex (PFC)-mediated stress responses is subserved by glutamate (GLU)- containing callosal neurons. Evidence of chronic stress-induced dendritic and spine atrophy among PFC pyramidal neurons led us to examine how chronic restraint stress (CRS) might alter the apical dendritic morphology of callosal neurons and the acute GLU stress responses in the left versus right PFC. Morphometric analyses of retrogradely labeled, dye-filled PFC callosal neurons revealed hemisphere-specific CRS-induced dendritic retraction; whereas significant dendritic atrophy occurred primarily within the distal arbor of left PFC neurons, it was observed within both the proximal and distal arbor of right PFC neurons. Overall, CRS also significantly reduced spine densities in both hemispheres with the greatest loss occurring among left PFC neurons, mostly at the distal extent of the arbor. While much of the overall decrease in dendritic spine density was accounted by the loss of thin spines, the density of mushroom-shaped spines, despite being fewer in number, was halved. Using microdialysis we found that, compared to controls, basal PFC GLU levels were significantly reduced in both hemispheres of CRS animals and that their GLU response to 30 min of tail-pinch stress was significantly prolonged in the left, but not the right PFC. Together, these findings show that a history of chronic stress alters the dendritic morphology and spine density of PFC callosal neurons and suggest a mechanism by which this might disrupt the interhemispheric regulation of PFC-mediated responses to subsequent stressors.

  4. Region-specific alterations of A-to-I RNA editing of serotonin 2c receptor in the cortex of suicides with major depression.

    PubMed

    Weissmann, D; van der Laan, S; Underwood, M D; Salvetat, N; Cavarec, L; Vincent, L; Molina, F; Mann, J J; Arango, V; Pujol, J F

    2016-01-01

    Brain region-specific abnormalities in serotonergic transmission appear to underlie suicidal behavior. Alterations of RNA editing on the serotonin receptor 2C (HTR2C) pre-mRNA in the brain of suicides produce transcripts that attenuate 5-HT2CR signaling by impairing intracellular G-protein coupling and subsequent intracellular signal transduction. In brain, the distribution of RNA-editing enzymes catalyzing deamination (A-to-I modification) shows regional variation, including within the cerebral cortex. We tested the hypothesis that altered pre-mRNA 5-HT2CR receptor editing in suicide is region-specific. To this end, we investigated the complete 5-HT2CR mRNA-editing profile in two architectonically distinct cortical areas involved in mood regulation and decision-making in a clinically well-characterized cohort of age- and sex-matched non-psychiatric drug-free controls and depressed suicides. By using an original biochemical detection method, that is, capillary electrophoresis single-stranded conformational polymorphism (CE-SSCP), we corroborated the 5-HT2CR mRNA-editing profile previously described in the dorsolateral prefrontal cortex (Brodmann area 9 (BA9)). Editing of 5-HT2CR mRNA displayed clear regional difference when comparing dorsolateral prefrontal cortex (BA9) and anterior cingulate cortex (BA24). Compared with non-psychiatric control individuals, alterations of editing levels of 5-HT2CR mRNA were detected in both cortical areas of depressed suicides. A marked increase in editing on 5-HT2CR was especially observed in the anterior cingulate cortex in suicides, implicating this cortical area in suicide risk. The results suggest that region-specific changes in RNA editing of 5-HT2CR mRNA and deficient receptor function likely contribute to the etiology of major depressive disorder or suicide. PMID:27576167

  5. Region-specific alterations of A-to-I RNA editing of serotonin 2c receptor in the cortex of suicides with major depression

    PubMed Central

    Weissmann, D; van der Laan, S; Underwood, M D; Salvetat, N; Cavarec, L; Vincent, L; Molina, F; Mann, J J; Arango, V; Pujol, J F

    2016-01-01

    Brain region-specific abnormalities in serotonergic transmission appear to underlie suicidal behavior. Alterations of RNA editing on the serotonin receptor 2C (HTR2C) pre-mRNA in the brain of suicides produce transcripts that attenuate 5-HT2CR signaling by impairing intracellular G-protein coupling and subsequent intracellular signal transduction. In brain, the distribution of RNA-editing enzymes catalyzing deamination (A-to-I modification) shows regional variation, including within the cerebral cortex. We tested the hypothesis that altered pre-mRNA 5-HT2CR receptor editing in suicide is region-specific. To this end, we investigated the complete 5-HT2CR mRNA-editing profile in two architectonically distinct cortical areas involved in mood regulation and decision-making in a clinically well-characterized cohort of age- and sex-matched non-psychiatric drug-free controls and depressed suicides. By using an original biochemical detection method, that is, capillary electrophoresis single-stranded conformational polymorphism (CE-SSCP), we corroborated the 5-HT2CR mRNA-editing profile previously described in the dorsolateral prefrontal cortex (Brodmann area 9 (BA9)). Editing of 5-HT2CR mRNA displayed clear regional difference when comparing dorsolateral prefrontal cortex (BA9) and anterior cingulate cortex (BA24). Compared with non-psychiatric control individuals, alterations of editing levels of 5-HT2CR mRNA were detected in both cortical areas of depressed suicides. A marked increase in editing on 5-HT2CR was especially observed in the anterior cingulate cortex in suicides, implicating this cortical area in suicide risk. The results suggest that region-specific changes in RNA editing of 5-HT2CR mRNA and deficient receptor function likely contribute to the etiology of major depressive disorder or suicide. PMID:27576167

  6. Ectopic Aire Expression in the Thymic Cortex Reveals Inherent Properties of Aire as a Tolerogenic Factor within the Medulla.

    PubMed

    Nishijima, Hitoshi; Kitano, Satsuki; Miyachi, Hitoshi; Morimoto, Junko; Kawano, Hiroshi; Hirota, Fumiko; Morita, Ryoko; Mouri, Yasuhiro; Masuda, Kiyoshi; Imoto, Issei; Ikuta, Koichi; Matsumoto, Mitsuru

    2015-11-15

    Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs) play essential roles in the positive and negative selection of developing thymocytes, respectively. Aire in mTECs plays an essential role in the latter process through expression of broad arrays of tissue-restricted Ags. To determine whether the location of Aire within the medulla is absolutely essential or whether Aire could also function within the cortex for establishment of self-tolerance, we used bacterial artificial chromosome technology to establish a semiknockin strain of NOD-background (β5t/Aire-transgenic) mice expressing Aire under control of the promoter of β5t, a thymoproteasome expressed exclusively in the cortex. Although Aire was expressed in cTECs as typical nuclear dot protein in β5t/Aire-Tg mice, cTECs expressing Aire ectopically did not confer transcriptional expression of either Aire-dependent or Aire-independent tissue-restricted Ag genes. We then crossed β5t/Aire-Tg mice with Aire-deficient NOD mice, generating a strain in which Aire expression was confined to cTECs. Despite the presence of Aire(+) cTECs, these mice succumbed to autoimmunity, as did Aire-deficient NOD mice. The thymic microenvironment harboring Aire(+) cTECs, within which many Aire-activated genes were present, also showed no obvious alteration of positive selection, suggesting that Aire's unique property of generating a self-tolerant T cell repertoire is functional only in mTECs.

  7. Cell-Targeted Optogenetics and Electrical Microstimulation Reveal the Primate Koniocellular Projection to Supra-granular Visual Cortex.

    PubMed

    Klein, Carsten; Evrard, Henry C; Shapcott, Katharine A; Haverkamp, Silke; Logothetis, Nikos K; Schmid, Michael C

    2016-04-01

    Electrical microstimulation and more recently optogenetics are widely used to map large-scale brain circuits. However, the neuronal specificity achieved with both methods is not well understood. Here we compare cell-targeted optogenetics and electrical microstimulation in the macaque monkey brain to functionally map the koniocellular lateral geniculate nucleus (LGN) projection to primary visual cortex (V1). Selective activation of the LGN konio neurons with CamK-specific optogenetics caused selective electrical current inflow in the supra-granular layers of V1. Electrical microstimulation targeted at LGN konio layers revealed the same supra-granular V1 activation pattern as the one elicited by optogenetics. Taken together, these findings establish a selective koniocellular LGN influence on V1 supra-granular layers, and they indicate comparable capacities of both stimulation methods to isolate thalamo-cortical circuits in the primate brain.

  8. Alteration in IGF-I binding in the cerebral cortex and cerebellum of neonatal rats during protein-calorie malnutrition.

    PubMed

    Maheshwari, H G; Mermelstein, S; vonSchlegell, A S; Shambaugh, G E

    1997-03-01

    Neonatal brain development in the rat is adversely affected by malnutrition. Alterations in tissue binding of IGF-I in the malnourished brain were tested in rat pups from mothers who were fed a 20% protein diet (C) or a 4% protein diet (M) starting from day 21 of gestation and continued throughout suckling. IGF-I binding in both cortex and cerebellum decreased progressively in C and M groups from day 6 to day 13. At day 9, 11, and 13, the binding was significantly greater (p < 0.02) in M compared to C groups. To investigate whether these changes might be related to the alteration in receptor activity, membranes were incubated with 125I-IGF in the presence of excess insulin with or without unlabeled IGF-I. In the absence of insulin, specific IGF-I binding in the M group was increased by 41.8 +/- 13.8% (mean +/- SEM p < 0.05) relative to C group. Insulin produced a consistent but incomplete inhibition of binding in both C and M, of 75% and 67% respectively. In addition, the specific IGF-I binding in the presence of insulin was increased in M group by 70.2 +/- 9.4% relative to C, p < 0.05. To characterize the nature of this binding, cerebral cortical membranes, from both groups, incubated with 125I-IGF-I were cross-linked, and electrophoresed on 6% and 10% SDS-PAGE gels under reducing conditions. Autoradiography of the 6% gel showed two specific bands at 115 kD and 240 kD, consistent with monomeric and dimeric forms of the IGF-I receptor, which were inhibited by excess insulin. In contrast, a 10% gel showed an additional band at 35 kD (IGF-binding protein) that was not inhibited by insulin. In both gels, membrane preparations from the M group showed a heightened intensity of the bands relative to C. The increase in binding protein relative to the receptor suggests a disequilibrium that may limit the availability of exogenous IGF-I to the tissues.

  9. Creatine and pyruvate prevent the alterations caused by tyrosine on parameters of oxidative stress and enzyme activities of phosphoryltransfer network in cerebral cortex of Wistar rats.

    PubMed

    de Andrade, Rodrigo Binkowski; Gemelli, Tanise; Rojas, Denise Bertin; Bonorino, Narielle Ferner; Costa, Bruna May Lopes; Funchal, Cláudia; Dutra-Filho, Carlos Severo; Wannmacher, Clovis Milton Duval

    2015-01-01

    Tyrosine accumulates in inborn errors of tyrosine catabolism, especially in tyrosinemia type II. In this disease caused by tyrosine aminotransferase deficiency, eyes, skin, and central nervous system disturbances are found. In the present study, we investigated the chronic effect of tyrosine methyl ester (TME) and/or creatine plus pyruvate on some parameters of oxidative stress and enzyme activities of phosphoryltransfer network in cerebral cortex homogenates of 21-day-old Wistar. Chronic administration of TME induced oxidative stress and altered the activities of adenylate kinase and mitochondrial and cytosolic creatine kinase. Total sulfhydryls content, GSH content, and GPx activity were significantly diminished, while DCFH oxidation, TBARS content, and SOD activity were significantly enhanced by TME. On the other hand, TME administration decreased the activity of CK from cytosolic and mitochondrial fractions but enhanced AK activity. In contrast, TME did not affect the carbonyl content and PK activity in cerebral cortex of rats. Co-administration of creatine plus pyruvate was effective in the prevention of alterations provoked by TME administration on the oxidative stress and the enzymes of phosphoryltransfer network, except in mitochondrial CK, AK, and SOD activities. These results indicate that chronic administration of TME may stimulate oxidative stress and alter the enzymes of phosphoryltransfer network in cerebral cortex of rats. In case this also occurs in the patients affected by these disorders, it may contribute, along with other mechanisms, to the neurological dysfunction of hypertyrosinemias, and creatine and pyruvate supplementation could be beneficial to the patients.

  10. Experimentally-induced maternal hypothyroidism alters crucial enzyme activities in the frontal cortex and hippocampus of the offspring rat.

    PubMed

    Koromilas, Christos; Tsakiris, Stylianos; Kalafatakis, Konstantinos; Zarros, Apostolos; Stolakis, Vasileios; Kimpizi, Despoina; Bimpis, Alexios; Tsagianni, Anastasia; Liapi, Charis

    2015-02-01

    Thyroid hormone insufficiency during neurodevelopment can result into significant structural and functional changes within the developing central nervous system (CNS), and is associated with the establishment of serious cognitive impairment and neuropsychiatric symptomatology. The aim of the present study was to shed more light on the effects of gestational and/or lactational maternal exposure to propylthiouracil (PTU)-induced hypothyroidism as a multilevel experimental approach to the study of hypothyroidism-induced changes on crucial brain enzyme activities of 21-day-old Wistar rat offspring in a brain region-specific manner. This experimental approach has been recently developed and characterized by the authors based on neurochemical analyses performed on newborn and 21-day-old rat offspring whole brain homogenates; as a continuum to this effort, the current study focused on two CNS regions of major significance for cognitive development: the frontal cortex and the hippocampus. Maternal exposure to PTU in the drinking water during gestation and/or lactation resulted into changes in the activities of acetylcholinesterase and two important adenosinetriphosphatases (Na(+),K(+)- and Mg(2+)-ATPase), that seemed to take place in a CNS-region-specific manner and that were dependent upon the PTU-exposure timeframe followed. As these findings are analyzed and compared to the available literature, they: (i) highlight the variability involved in the changes of the aforementioned enzymatic parameters in the studied CNS regions (attributed to both the different neuroanatomical composition and the thyroid-hormone-dependent neurodevelopmental growth/differentiation patterns of the latter), (ii) reveal important information with regards to the neurochemical mechanisms that could be involved in the way clinical hypothyroidism could affect optimal neurodevelopment and, ultimately, cognitive function, as well as (iii) underline the need for the adoption of more consistent

  11. A ‘complex’ of brain metabolites distinguish altered chemistry in the cingulate cortex of episodic migraine patients

    PubMed Central

    Becerra, L.; Veggeberg, R.; Prescot, A.; Jensen, J.E.; Renshaw, P.; Scrivani, S.; Spierings, E.L.H.; Burstein, R.; Borsook, D.

    2016-01-01

    Despite the prevalence of migraine, the pathophysiology of the disease remains unclear. Current understanding of migraine has alluded to the possibility of a hyperexcitable brain. The aim of the current study is to investigate human brain metabolite differences in the anterior cingulate cortex (ACC) during the interictal phase in migraine patients. We hypothesized that there may be differences in levels of excitatory neurotransmitters and/or their derivatives in the migraine cohort in support of the theory of hyperexcitability in migraine. 2D J-resolved proton magnetic resonance spectroscopy (1H-MRS) data were acquired on a 3 Tesla (3 T) MRI from a voxel placed over the ACC of 32 migraine patients (MP; 23 females, 9 males, age 33 ± 9.6 years) and 33 healthy controls (HC; 25 females, 8 males, age 32 ± 9.6 years). Amplitude correlation matrices were constructed for each subject to evaluate metabolite discriminability. ProFit-estimated metabolite peak areas were normalized to a water reference signal to assess subject differences. The initial analysis of variance (ANOVA) was performed to test for group differences for all metabolites/creatine (Cre) ratios between healthy controls and migraineurs but showed no statistically significant differences. In addition, we used a multivariate approach to distinguish migraineurs from healthy subjects based on the metabolite/Cre ratio. A quadratic discriminant analysis (QDA) model was used to identify 3 metabolite ratios sufficient to minimize minimum classification error (MCE). The 3 selected metabolite ratios were aspartate (Asp)/Cre, N-acetyl aspartate (NAA)/Cre, and glutamine (Gln)/Cre. These findings are in support of a ‘complex’ of metabolite alterations, which may underlie changes in neuronal chemistry in the migraine brain. Furthermore, the parallel changes in the three-metabolite ‘complex’ may confer more subtle but biological processes that are ongoing. The data also support the current theory that the

  12. Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory.

    PubMed

    Camer, Danielle; Yu, Yinghua; Szabo, Alexander; Fernandez, Francesca; Dinh, Chi H L; Huang, Xu-Feng

    2015-06-01

    High fat (HF) diets are known to induce changes in synaptic plasticity in the forebrain leading to learning and memory impairments. Previous studies of oleanolic acid derivatives have found that these compounds can cross the blood-brain barrier to prevent neuronal cell death. We examined the hypothesis that the oleanolic acid derivative, bardoxolone methyl (BM) would prevent diet-induced cognitive deficits in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC) (5% of energy as fat), a HF (40% of energy as fat), or a HF diet supplemented with 10mg/kg/day BM orally for 21weeks. Recognition memory was assessed by performing a novel object recognition test on the treated mice. Downstream brain-derived neurotrophic factor (BDNF) signalling molecules were examined in the prefrontal cortex (PFC) and hippocampus of mice via Western blotting and N-methyl-d-aspartate (NMDA) receptor binding. BM treatment prevented HF diet-induced impairment in recognition memory (p<0.001). In HF diet fed mice, BM administration attenuated alterations in the NMDA receptor binding density in the PFC (p<0.05), however, no changes were seen in the hippocampus (p>0.05). In the PFC and hippocampus of the HF diet fed mice, BM administration improved downstream BDNF signalling as indicated by increased protein levels of BDNF, phosphorylated tropomyosin related kinase B (pTrkB) and phosphorylated protein kinase B (pAkt), and increased phosphorylated AMP-activated protein kinase (pAMPK) (p<0.05). BM administration also prevented the HF diet-induced increase in the protein levels of inflammatory molecules, phosphorylated c-Jun N-terminal kinase (pJNK) in the PFC, and protein tyrosine phosphatase 1B (PTP1B) in both the PFC and hippocampus. In summary, these findings suggest that BM prevents HF diet-induced impairments in recognition memory by improving downstream BDNF signal transduction, increasing pAMPK, and reducing inflammation in the PFC and hippocampus.

  13. Voltage-Sensitive Dyes And Imaging Techniques Reveal New Patterns Of Electrical Activity In Heart Cortex

    NASA Astrophysics Data System (ADS)

    Salama, Guy

    1988-04-01

    Voltage-sensitive dyes bind to the plasms membrane of excitable cells (ie., muscle or nerve cells) and exhibit fluorescence and/or absorption changes that vary linearly with changes in transmembrane electrical potential. These potentiometric optical probes can be used to measure local changes in transmembrane potential by monitoring optical signals from dye molecules bound to the surface membrane. Consequently, when excitable cells are stained with such a dye and are stimulated to fire an electrical impulse (ie., an action potential (AP)), the changes in dye fluorescence have the characteristic shape and time course of APs recorded with an intracellular micro-electrode. Potentiometric dyes in conjuction with imaging techniques can now be used to visualize complex patterns and propagation of electrical activity. With photodiode arrays on video imaging techniques, patterns of biological electrical activity can be obtained with high temporal and spatial resolution which could not be obtained by conventional micro-electrodes. These methods reveal new details and offer powerful approaches to study fundamental problem in cardiac electrophysiology, communication in nerve networks, and the organization of cortical neurons.

  14. Transcranial magnetic stimulation reveals the content of visual short-term memory in the visual cortex.

    PubMed

    Silvanto, Juha; Cattaneo, Zaira

    2010-05-01

    Cortical areas involved in sensory analysis are also believed to be involved in short-term storage of that sensory information. Here we investigated whether transcranial magnetic stimulation (TMS) can reveal the content of visual short-term memory (VSTM) by bringing this information to visual awareness. Subjects were presented with two random-dot displays (moving either to the left or to the right) and they were required to maintain one of these in VSTM. In Experiment 1, TMS was applied over the motion-selective area V5/MT+ above phosphene threshold during the maintenance phase. The reported phosphene contained motion features of the memory item, when the phosphene spatially overlapped with memory item. Specifically, phosphene motion was enhanced when the memory item moved in the same direction as the subjects' V5/MT+ baseline phosphene, whereas it was reduced when the motion direction of the memory item was incongruent with that of the baseline V5/MT+ phosphene. There was no effect on phosphene reports when there was no spatial overlap between the phosphene and the memory item. In Experiment 2, VSTM maintenance did not influence the appearance of phosphenes induced from the lateral occipital region. These interactions between VSTM maintenance and phosphene appearance demonstrate that activity in V5/MT+ reflects the motion qualities of items maintained in VSTM. Furthermore, these results also demonstrate that information in VSTM can modulate the pattern of visual activation reaching awareness, providing evidence for the view that overlapping neuronal populations are involved in conscious visual perception and VSTM.

  15. Stress and combined exposure to low doses of pyridostigmine bromide, DEET, and permethrin produce neurochemical and neuropathological alterations in cerebral cortex, hippocampus, and cerebellum.

    PubMed

    Abdel-Rahman, A; Abou-Donia, Suzanne; El-Masry, Eman; Shetty, Ashok; Abou-Donia, Mohamed

    2004-01-23

    Exposure to a combination of stress and low doses of the chemicals pyridostigmine bromide (PB), DEET, and permethrin in adult rats, a model of Gulf War exposure, produces blood-brain barrier (BBB) disruption and neuronal cell death in the cingulate cortex, dentate gyrus, thalamus, and hypothalamus. In this study, neuropathological alterations in other areas of the brain where no apparent BBB disruption was observed was studied following such exposure. Animals exposed to both stress and chemical exhibited decreased brain acetylcholinesterase (AChE) activity in the midbrain, brainstem, and cerebellum and decreased m2 muscarinic acetylcholine (ACh) receptor ligand binding in the midbrain and cerebellum. These alterations were associated with significant neuronal cell death, reduced microtubule-associated protein (MAP-2) expression, and increased glial fibrillary acidic protein (GFAP) expression in the cerebral cortex and the hippocampal subfields CA1 and CA3. In the cerebellum, the neurochemical alterations were associated with Purkinje cell loss and increased GFAP immunoreactivity in the white matter. However, animals subjected to either stress or chemicals alone did not show any of these changes in comparison to vehicle-treated controls. Collectively, these results suggest that prolonged exposure to a combination of stress and the chemicals PB, DEET, and permethrin can produce significant damage to the cerebral cortex, hippocampus, and cerebellum, even in the absence of apparent BBB damage. As these areas of the brain are respectively important for the maintenance of motor and sensory functions, learning and memory, and gait and coordination of movements, such alterations could lead to many physiological, pharmacological, and behavioral abnormalities, particularly motor deficits and learning and memory dysfunction. PMID:14675905

  16. An integrated multi-omics study revealed metabolic alterations underlying the effects of coffee consumption.

    PubMed

    Takahashi, Shoko; Saito, Kenji; Jia, Huijuan; Kato, Hisanori

    2014-01-01

    Many epidemiological studies have indicated that coffee consumption may reduce the risks of developing obesity and diabetes, but the underlying mechanisms of these effects are poorly understood. Our previous study revealed the changes on gene expression profiles in the livers of C57BL/6J mice fed a high-fat diet containing three types of coffee (caffeinated, decaffeinated and green unroasted coffee), using DNA microarrays. The results revealed remarkable alterations in lipid metabolism-related molecules which may be involved in the anti-obesity effects of coffee. We conducted the present study to further elucidate the metabolic alterations underlying the effects of coffee consumption through comprehensive proteomic and metabolomic analyses. Proteomics revealed an up-regulation of isocitrate dehydrogenase (a key enzyme in the TCA cycle) and its related proteins, suggesting increased energy generation. The metabolomics showed an up-regulation of metabolites involved in the urea cycle, with which the transcriptome data were highly consistent, indicating accelerated energy expenditure. The TCA cycle and the urea cycle are likely be accelerated in a concerted manner, since they are directly connected by mutually providing each other's intermediates. The up-regulation of these pathways might result in a metabolic shift causing increased ATP turnover, which is related to the alterations of lipid metabolism. This mechanism may play an important part in the suppressive effects of coffee consumption on obesity, inflammation, and hepatosteatosis. This study newly revealed global metabolic alterations induced by coffee intake, providing significant insights into the association between coffee intake and the prevention of type 2 diabetes, utilizing the benefits of multi-omics analyses. PMID:24618914

  17. An Integrated Multi-Omics Study Revealed Metabolic Alterations Underlying the Effects of Coffee Consumption

    PubMed Central

    Takahashi, Shoko; Saito, Kenji; Jia, Huijuan; Kato, Hisanori

    2014-01-01

    Many epidemiological studies have indicated that coffee consumption may reduce the risks of developing obesity and diabetes, but the underlying mechanisms of these effects are poorly understood. Our previous study revealed the changes on gene expression profiles in the livers of C57BL/6J mice fed a high-fat diet containing three types of coffee (caffeinated, decaffeinated and green unroasted coffee), using DNA microarrays. The results revealed remarkable alterations in lipid metabolism-related molecules which may be involved in the anti-obesity effects of coffee. We conducted the present study to further elucidate the metabolic alterations underlying the effects of coffee consumption through comprehensive proteomic and metabolomic analyses. Proteomics revealed an up-regulation of isocitrate dehydrogenase (a key enzyme in the TCA cycle) and its related proteins, suggesting increased energy generation. The metabolomics showed an up-regulation of metabolites involved in the urea cycle, with which the transcriptome data were highly consistent, indicating accelerated energy expenditure. The TCA cycle and the urea cycle are likely be accelerated in a concerted manner, since they are directly connected by mutually providing each other's intermediates. The up-regulation of these pathways might result in a metabolic shift causing increased ATP turnover, which is related to the alterations of lipid metabolism. This mechanism may play an important part in the suppressive effects of coffee consumption on obesity, inflammation, and hepatosteatosis. This study newly revealed global metabolic alterations induced by coffee intake, providing significant insights into the association between coffee intake and the prevention of type 2 diabetes, utilizing the benefits of multi-omics analyses. PMID:24618914

  18. Nonlinear optical microscopy reveals invading endothelial cells anisotropically alter three-dimensional collagen matrices

    SciTech Connect

    Lee, P.-F.; Yeh, Alvin T.; Bayless, Kayla J.

    2009-02-01

    The interactions between endothelial cells (ECs) and the extracellular matrix (ECM) are fundamental in mediating various steps of angiogenesis, including cell adhesion, migration and sprout formation. Here, we used a noninvasive and non-destructive nonlinear optical microscopy (NLOM) technique to optically image endothelial sprouting morphogenesis in three-dimensional (3D) collagen matrices. We simultaneously captured signals from collagen fibers and endothelial cells using second harmonic generation (SHG) and two-photon excited fluorescence (TPF), respectively. Dynamic 3D imaging revealed EC interactions with collagen fibers along with quantifiable alterations in collagen matrix density elicited by EC movement through and morphogenesis within the matrix. Specifically, we observed increased collagen density in the area between bifurcation points of sprouting structures and anisotropic increases in collagen density around the perimeter of lumenal structures, but not advancing sprout tips. Proteinase inhibition studies revealed membrane-associated matrix metalloproteinase were utilized for sprout advancement and lumen expansion. Rho-associated kinase (p160ROCK) inhibition demonstrated that the generation of cell tension increased collagen matrix alterations. This study followed sprouting ECs within a 3D matrix and revealed that the advancing structures recognize and significantly alter their extracellular environment at the periphery of lumens as they progress.

  19. Simultaneous fNIRS and thermal infrared imaging during cognitive task reveal autonomic correlates of prefrontal cortex activity

    NASA Astrophysics Data System (ADS)

    Pinti, Paola; Cardone, Daniela; Merla, Arcangelo

    2015-12-01

    Functional Near Infrared-Spectroscopy (fNIRS) represents a powerful tool to non-invasively study task-evoked brain activity. fNIRS assessment of cortical activity may suffer for contamination by physiological noises of different origin (e.g. heart beat, respiration, blood pressure, skin blood flow), both task-evoked and spontaneous. Spontaneous changes occur at different time scales and, even if they are not directly elicited by tasks, their amplitude may result task-modulated. In this study, concentration changes of hemoglobin were recorded over the prefrontal cortex while simultaneously recording the facial temperature variations of the participants through functional infrared thermal (fIR) imaging. fIR imaging provides touch-less estimation of the thermal expression of peripheral autonomic. Wavelet analysis revealed task-modulation of the very low frequency (VLF) components of both fNIRS and fIR signals and strong coherence between them. Our results indicate that subjective cognitive and autonomic activities are intimately linked and that the VLF component of the fNIRS signal is affected by the autonomic activity elicited by the cognitive task. Moreover, we showed that task-modulated changes in vascular tone occur both at a superficial and at larger depth in the brain. Combined use of fNIRS and fIR imaging can effectively quantify the impact of VLF autonomic activity on the fNIRS signals.

  20. Tactile Object Familiarity in the Blind Brain Reveals the Supramodal Perceptual-Mnemonic Nature of the Perirhinal Cortex

    PubMed Central

    Cacciamani, Laura; Likova, Lora T.

    2016-01-01

    This study is the first to investigate the neural underpinnings of tactile object familiarity in the blind during both perception and memory. In the sighted, the perirhinal cortex (PRC) has been implicated in the assessment of visual object familiarity—a crucial everyday task—as evidenced by reduced activation when an object becomes familiar. Here, to examine the PRC’s role in tactile object familiarity in the absence of vision, we trained blind participants on a unique memory-guided drawing technique and measured brain activity while they perceptually explored raised-line drawings, drew them from tactile memory, and scribbled (control). Functional magnetic resonance imaging (fMRI) before and after a week of training revealed a significant decrease in PRC activation from pre- to post-training (i.e., from unfamiliar to familiar) during perceptual exploration as well as memory-guided drawing, but not scribbling. This familiarity-based reduction is the first evidence that the PRC represents tactile object familiarity in the blind. Furthermore, the finding of this effect during both tactile perception and tactile memory provides the critical link in establishing the PRC as a structure whose representations are supramodal for both perception and memory. PMID:27148002

  1. Simultaneous fNIRS and thermal infrared imaging during cognitive task reveal autonomic correlates of prefrontal cortex activity

    PubMed Central

    Pinti, Paola; Cardone, Daniela; Merla, Arcangelo

    2015-01-01

    Functional Near Infrared-Spectroscopy (fNIRS) represents a powerful tool to non-invasively study task-evoked brain activity. fNIRS assessment of cortical activity may suffer for contamination by physiological noises of different origin (e.g. heart beat, respiration, blood pressure, skin blood flow), both task-evoked and spontaneous. Spontaneous changes occur at different time scales and, even if they are not directly elicited by tasks, their amplitude may result task-modulated. In this study, concentration changes of hemoglobin were recorded over the prefrontal cortex while simultaneously recording the facial temperature variations of the participants through functional infrared thermal (fIR) imaging. fIR imaging provides touch-less estimation of the thermal expression of peripheral autonomic. Wavelet analysis revealed task-modulation of the very low frequency (VLF) components of both fNIRS and fIR signals and strong coherence between them. Our results indicate that subjective cognitive and autonomic activities are intimately linked and that the VLF component of the fNIRS signal is affected by the autonomic activity elicited by the cognitive task. Moreover, we showed that task-modulated changes in vascular tone occur both at a superficial and at larger depth in the brain. Combined use of fNIRS and fIR imaging can effectively quantify the impact of VLF autonomic activity on the fNIRS signals. PMID:26632763

  2. Voltage-sensitive dye imaging reveals improved topographic activation of cortex in response to manipulation of thalamic microstimulation parameters

    NASA Astrophysics Data System (ADS)

    Wang, Qi; Millard, Daniel C.; Zheng, He J. V.; Stanley, Garrett B.

    2012-04-01

    Voltage-sensitive dye imaging was used to quantify in vivo, network level spatiotemporal cortical activation in response to electrical microstimulation of the thalamus in the rat vibrissa pathway. Thalamic microstimulation evoked a distinctly different cortical response than natural sensory stimulation, with response to microstimulation spreading over a larger area of cortex and being topographically misaligned with the cortical column to which the stimulated thalamic region projects. Electrical stimulation with cathode-leading asymmetric waveforms reduced this topographic misalignment while simultaneously increasing the spatial specificity of the cortical activation. Systematically increasing the asymmetry of the microstimulation pulses revealed a continuum between symmetric and asymmetric stimulation that gradually reduced the topographic bias. These data strongly support the hypothesis that manipulation of the electrical stimulation waveform can be used to selectively activate specific neural elements. Specifically, our results are consistent with the prediction that cathode-leading asymmetric waveforms preferentially stimulate cell bodies over axons, while symmetric waveforms preferentially activate axons over cell bodies. The findings here provide some initial steps toward the design and optimization of microstimulation of neural circuitry, and open the door to more sophisticated engineering tools, such as nonlinear system identification techniques, to develop technologies for more effective control of activity in the nervous system.

  3. Brain networks of affective mentalizing revealed by the tear effect: The integrative role of the medial prefrontal cortex and precuneus.

    PubMed

    Takahashi, Haruka K; Kitada, Ryo; Sasaki, Akihiro T; Kawamichi, Hiroaki; Okazaki, Shuntaro; Kochiyama, Takanori; Sadato, Norihiro

    2015-12-01

    Affective mentalizing involves the integration of various social signals in order to infer the affective states of others. Previous neuroimaging studies have shown that the medial prefrontal cortex, the precuneus/posterior cingulate cortex, and the temporo-parietal junction constitute the core affective mentalizing network. However, the relative contributions of these regions to affective mentalizing remain unclear. We used functional magnetic resonance imaging to investigate which of these nodes are involved in the integration of two social signals: emotional tears and facial expressions. We assumed that this integration would produce a supra-additive effect, indicated by greater activity than the sum of the effects of the individual social signals. Female subjects rated the sadness of faces with either tears or tear-like circles, and either sad or neutral expressions. We observed the supra-additive effect in the medial prefrontal cortex and precuneus/posterior cingulate cortex but not in the temporo-parietal junction. These results indicate that the medial prefrontal cortex and precuneus/posterior cingulate cortex play an important role in integrating tears and facial expressions during affective mentalizing.

  4. Protracted abstinence from chronic ethanol exposure alters the structure of neurons and expression of oligodendrocytes and myelin in the medial prefrontal cortex

    PubMed Central

    Navarro, Alvaro I.; Mandyam, Chitra D.

    2015-01-01

    In rodents, chronic intermittent ethanol vapor exposure (CIE) produces alcohol dependence, alters the structure and activity of pyramidal neurons and decreases the number of oligodendroglial progenitors in the medial prefrontal cortex (mPFC). In this study, adult Wistar rats were exposed to seven weeks of CIE and were withdrawn from CIE for 21 days (protracted abstinence; PA) and tissue enriched in the mPFC was processed for Western blot analysis and Golgi-Cox staining to investigate the long-lasting effects of CIE on structure of mPFC neurons and levels of myelin associated proteins. PA increased dendritic arborization within apical dendrites of pyramidal neurons and these changes occurred concurrently with hypophosphorylation of the NMDA receptor 2B (NR2B) at Tyr-1472. PA increased myelin basic protein (MBP) levels that occurred concurrently with hypophosphorylation of the premyelinating oligodendrocyte bHLH transcription factor Olig2 in the mPFC. Given that PA is associated with increased sensitivity to stress and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and stress alters oligodendrocyte expression as a function of glucocorticoid receptor (GR) activation, the levels of total GR and phosphorylated GR were also evaluated. PA produces hypophosphorylation of the GR at Ser-232 without affecting expression of total protein. These findings demonstrate persistent and compensatory effects of ethanol in the mPFC long after cessation of CIE, including enhanced myelin production and impaired GR function. Collectively, these results suggest a novel relationship between oligodendrocytes and GR in the mPFC, in which stress may alter frontal cortex function in alcohol dependent subjects by promoting hypermyelination, thereby altering the cellular composition and white matter structure in the mPFC. PMID:25732140

  5. Protracted abstinence from chronic ethanol exposure alters the structure of neurons and expression of oligodendrocytes and myelin in the medial prefrontal cortex.

    PubMed

    Navarro, A I; Mandyam, C D

    2015-05-01

    In rodents, chronic intermittent ethanol vapor exposure (CIE) produces alcohol dependence, alters the structure and activity of pyramidal neurons and decreases the number of oligodendroglial progenitors in the medial prefrontal cortex (mPFC). In this study, adult Wistar rats were exposed to seven weeks of CIE and were withdrawn from CIE for 21 days (protracted abstinence; PA). Tissue enriched in the mPFC was processed for Western blot analysis and Golgi-Cox staining to investigate the long-lasting effects of CIE on the structure of mPFC neurons and the levels of myelin-associated proteins. PA increased dendritic arborization within apical dendrites of pyramidal neurons. These changes occurred concurrently with hypophosphorylation of the N-methyl-d-aspartate (NMDA) receptor 2B (NR2B) at Tyr-1472. PA increased myelin basic protein (MBP) levels which occurred concurrently with hypophosphorylation of the premyelinating oligodendrocyte bHLH transcription factor Olig2 in the mPFC. Given that PA is associated with increased sensitivity to stress and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and stress alters oligodendrocyte expression as a function of glucocorticoid receptor (GR) activation, the levels of total GR and phosphorylated GR were also evaluated. PA produced hypophosphorylation of the GR at Ser-232 without affecting expression of total protein. These findings demonstrate persistent and compensatory effects of ethanol in the mPFC long after cessation of CIE, including enhanced myelin production and impaired GR function. Collectively, these results suggest a novel relationship between oligodendrocytes and GR in the mPFC, in which stress may alter frontal cortex function in alcohol dependent subjects by promoting hypermyelination, thereby altering the cellular composition and white matter structure in the mPFC.

  6. Correlations of neuronal and microvascular densities in murine cortex revealed by direct counting and colocalization of nuclei and vessels

    PubMed Central

    Tsai, Philbert S.; Kaufhold, John P.; Blinder, Pablo; Friedman, Beth; Drew, Patrick J.; Karten, Harvey J.; Lyden, Patrick D.; Kleinfeld, David

    2016-01-01

    It is well known that the density of neurons varies within the adult brain. In neocortex, this includes variations in neuronal density between different lamina as well as between different regions. Yet the concomitant variation of the microvessels is largely uncharted. Here we present automated histological, imaging, and analysis tools to simultaneously map the locations of all neuronal and non-neuronal nuclei and the centerlines and diameters of all blood vessels within thick slabs of neocortex from mice. Based on total inventory measurements of different cortical regions (~ 107 cells vectorized across brains), these methods revealed: (1) In three dimensions, the mean distance of the center of neuronal somata to the closest microvessel was 14 μm. (2) Volume samples within lamina of a given region show that the density of microvessels does not match the strong laminar variation in neuronal density. This holds for both agranular and granular cortex. (3) Volume samples in successive radii from the midline to the ventral-lateral edge, where each volume summed the number of cells and microvessels from the pia to the white matter, show a significant correlation between neuronal and microvessel densities. These data show that while neuronal and vascular densities do not track each other on the 100 μm scale of cortical lamina, they do track each other on the 1 – 10 mm scale of the cortical mantle. The absence of a disproportionate density of blood vessels in granular lamina is argued to be consistent with the initial locus of functional brain imaging signals. PMID:19923289

  7. Alteration in 5-HT₂C, NMDA receptor and IP3 in cerebral cortex of epileptic rats: restorative role of Bacopa monnieri.

    PubMed

    Krishnakumar, Amee; Anju, T R; Abraham, Pretty Mary; Paulose, C S

    2015-01-01

    Bacopa monnieri is effective in stress management, brain function and a balanced mood. 5-HT2C receptors have been implicated in stress whereas NMDA receptors and mGlu5 play crucial role in memory and cognition. In the present study, we investigated the role of B. monnieri extract in ameliorating pilocarpine induced temporal lobe epilepsy through regulation of 5-HT2C and NMDA receptors in cerebral cortex. Our studies confirmed an increased 5-HT2C receptor function during epilepsy thereby facilitating IP3 release. We also observed an decreased NMDA receptor function with an elevated mGlu5 and GLAST gene expression in epileptic condition indicating the possibility for glutamate mediated excitotoxicity. These alterations lead to impaired behavioural functions as indicated by the Elevated Plus maze test. Carbamazepine and B. monnieri treatments to epileptic rats reversed the alterations in 5-HT2C, NMDA receptor functions and IP3 content thereby effectively managing the neurotransmitter balance in the cerebral cortex.

  8. Muscle biopsies from human muscle diseases with myopathic pathology reveal common alterations in mitochondrial function.

    PubMed

    Sunitha, Balaraju; Gayathri, Narayanappa; Kumar, Manish; Keshava Prasad, Thottethodi Subrahmanya; Nalini, Atchayaram; Padmanabhan, Balasundaram; Srinivas Bharath, Muchukunte Mukunda

    2016-07-01

    Muscle diseases are clinically and genetically heterogeneous and manifest as dystrophic, inflammatory and myopathic pathologies, among others. Our previous study on the cardiotoxin mouse model of myodegeneration and inflammation linked muscle pathology with mitochondrial damage and oxidative stress. In this study, we investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from muscle disease patients, represented by dysferlinopathy (dysfy) (dystrophic pathology; n = 43), polymyositis (PM) (inflammatory pathology; n = 24), and distal myopathy with rimmed vacuoles (DMRV) (distal myopathy; n = 31) were analyzed. Mitochondrial damage (ragged blue and COX-deficient fibers) was revealed in dysfy, PM, and DMRV cases by enzyme histochemistry (SDH and COX-SDH), electron microscopy (vacuolation and altered cristae) and biochemical assays (significantly increased ADP/ATP ratio). Proteomic analysis of muscle mitochondria from all three muscle diseases by isobaric tag for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis demonstrated down-regulation of electron transport chain (ETC) complex subunits, assembly factors and Krebs cycle enzymes. Interestingly, 80 of the under-expressed proteins were common among the three pathologies. Assay of ETC and Krebs cycle enzyme activities validated the MS data. Mitochondrial proteins from muscle pathologies also displayed higher tryptophan (Trp) oxidation and the same was corroborated in the cardiotoxin model. Molecular modeling predicted Trp oxidation to alter the local structure of mitochondrial proteins. Our data highlight mitochondrial alterations in muscle pathologies, represented by morphological changes, altered mitochondrial proteome and protein oxidation, thereby establishing the role of mitochondrial damage in human muscle diseases. We investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies

  9. Muscle biopsies from human muscle diseases with myopathic pathology reveal common alterations in mitochondrial function.

    PubMed

    Sunitha, Balaraju; Gayathri, Narayanappa; Kumar, Manish; Keshava Prasad, Thottethodi Subrahmanya; Nalini, Atchayaram; Padmanabhan, Balasundaram; Srinivas Bharath, Muchukunte Mukunda

    2016-07-01

    Muscle diseases are clinically and genetically heterogeneous and manifest as dystrophic, inflammatory and myopathic pathologies, among others. Our previous study on the cardiotoxin mouse model of myodegeneration and inflammation linked muscle pathology with mitochondrial damage and oxidative stress. In this study, we investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from muscle disease patients, represented by dysferlinopathy (dysfy) (dystrophic pathology; n = 43), polymyositis (PM) (inflammatory pathology; n = 24), and distal myopathy with rimmed vacuoles (DMRV) (distal myopathy; n = 31) were analyzed. Mitochondrial damage (ragged blue and COX-deficient fibers) was revealed in dysfy, PM, and DMRV cases by enzyme histochemistry (SDH and COX-SDH), electron microscopy (vacuolation and altered cristae) and biochemical assays (significantly increased ADP/ATP ratio). Proteomic analysis of muscle mitochondria from all three muscle diseases by isobaric tag for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis demonstrated down-regulation of electron transport chain (ETC) complex subunits, assembly factors and Krebs cycle enzymes. Interestingly, 80 of the under-expressed proteins were common among the three pathologies. Assay of ETC and Krebs cycle enzyme activities validated the MS data. Mitochondrial proteins from muscle pathologies also displayed higher tryptophan (Trp) oxidation and the same was corroborated in the cardiotoxin model. Molecular modeling predicted Trp oxidation to alter the local structure of mitochondrial proteins. Our data highlight mitochondrial alterations in muscle pathologies, represented by morphological changes, altered mitochondrial proteome and protein oxidation, thereby establishing the role of mitochondrial damage in human muscle diseases. We investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies

  10. Altered Spontaneous Brain Activity in Patients with Acute Spinal Cord Injury Revealed by Resting-State Functional MRI

    PubMed Central

    Zhu, Ling; Wu, Guangyao; Zhou, Xin; Li, Jielan; Wen, Zhi; Lin, Fuchun

    2015-01-01

    Background Previous neuroimaging studies have provided evidence of structural and functional reorganization of brain in patients with chronic spinal cord injury (SCI). However, it remains unknown whether the spontaneous brain activity changes in acute SCI. In this study, we investigated intrinsic brain activity in acute SCI patients using a regional homogeneity (ReHo) analysis based on resting-state functional magnetic resonance imaging. Methods A total of 15 patients with acute SCI and 16 healthy controls participated in the study. The ReHo value was used to evaluate spontaneous brain activity, and voxel-wise comparisons of ReHo were performed to identify brain regions with altered spontaneous brain activity between groups. We also assessed the associations between ReHo and the clinical scores in brain regions showing changed spontaneous brain activity. Results Compared with the controls, the acute SCI patients showed decreased ReHo in the bilateral primary motor cortex/primary somatosensory cortex, bilateral supplementary motor area/dorsal lateral prefrontal cortex, right inferior frontal gyrus, bilateral dorsal anterior cingulate cortex and bilateral caudate; and increased ReHo in bilateral precuneus, the left inferior parietal lobe, the left brainstem/hippocampus, the left cingulate motor area, bilateral insula, bilateral thalamus and bilateral cerebellum. The average ReHo values of the left thalamus and right insula were negatively correlated with the international standards for the neurological classification of spinal cord injury motor scores. Conclusion Our findings indicate that acute distant neuronal damage has an immediate impact on spontaneous brain activity. In acute SCI patients, the ReHo was prominently altered in brain regions involved in motor execution and cognitive control, default mode network, and which are associated with sensorimotor compensatory reorganization. Abnormal ReHo values in the left thalamus and right insula could serve as

  11. Regional Coherence Alterations Revealed by Resting-State fMRI in Post-Stroke Patients with Cognitive Dysfunction

    PubMed Central

    Peng, Cheng-Yu; Chen, Yu-Chen; Cui, Ying; Zhao, Deng-Ling; Jiao, Yun; Tang, Tian-Yu; Ju, Shenghong; Teng, Gao-Jun

    2016-01-01

    Objectives Post-stroke cognitive dysfunction greatly influences patients’ quality of life after stroke. However, its neurophysiological basis remains unknown. This study utilized resting-state functional magnetic resonance imaging (fMRI) to investigate the alterations in regional coherence in patients after subcortical stroke. Methods Resting-state fMRI measurements were acquired from 16 post-stroke patients with poor cognitive function (PSPC), 16 post-stroke patients with good cognitive function (PSGC) and 30 well-matched healthy controls (HC). Regional homogeneity (ReHo) was used to detect alterations in regional coherence. Abnormalities in regional coherence correlated with scores on neuropsychological scales. Results Compared to the HC and the PSGC, the PSPC showed remarkably decreased ReHo in the bilateral anterior cingulate cortex and the left posterior cingulate cortex/precuneus. ReHo in the bilateral anterior cingulate cortex positively correlated with the scores on the Symbol Digit Modalities Test (r = 0.399, P = 0.036) and the Complex Figure Test-delayed recall subtest (r = 0.397, P = 0.036) in all post-stroke patients. Moreover, ReHo in the left posterior cingulate cortex/precuneus positively correlated with the scores on the Forward Digit Span Test (r = 0.485, P = 0.009) in all post-stroke patients. Conclusions Aberrant regional coherence was observed in the anterior and posterior cingulate cortices in post-stroke patients with cognitive dysfunction. ReHo could represent a promising indicator of neurobiological deficiencies in post-stroke patients. PMID:27454170

  12. Transcriptional profiling reveals that C5a alters microRNA in brain endothelial cells

    PubMed Central

    Eadon, Michael T; Jacob, Alexander; Cunningham, Patrick N; Quigg, Richard J; Garcia, Joe G N; Alexander, Jessy J

    2014-01-01

    Blood–brain barrier (BBB) disturbance is a crucial occurrence in many neurological diseases, including systemic lupus erythematosus (SLE). Our previous studies showed that experimental lupus serum altered the integrity of the mouse brain endothelial layer, an important constituent of the BBB. Complement activation occurs in lupus with increased circulating complement components. Using a genomics approach, we identified the microRNA (miRNA) altered in mouse brain endothelial cells (bEnd3) by lupus serum and the complement protein, C5a. Of the 318 miRNA evaluated, 23 miRNAs were altered by lupus serum and 32 were altered by C5a alone compared with controls. Seven miRNAs (P < 0·05) were differentially expressed by both treatments: mmu-miR-133a*, mmu-miR-193*, mmu-miR-26b, mmu-miR-28*, mmu-miR-320a, mmu-miR-423-3p and mmu-miR-509-5p. The microarray results were validated by quantitative RT-PCR. In line with the in vitro results, expression of miR-26b and miR-28* were also significantly up-regulated in lupus mouse brain which was reduced by C5a receptor inhibition. Target prediction analysis revealed miR gene targets encoding components involved in inflammation, matrix arrangement, and apoptosis, pathways known to play important roles in central nervous system lupus. Our findings suggest that the miRNAs reported in this study may represent novel therapeutic targets in central nervous system lupus and other similar neuroinflammatory settings. PMID:24801999

  13. Transcriptional profiling reveals that C5a alters microRNA in brain endothelial cells.

    PubMed

    Eadon, Michael T; Jacob, Alexander; Cunningham, Patrick N; Quigg, Richard J; Garcia, Joe G N; Alexander, Jessy J

    2014-11-01

    Blood-brain barrier (BBB) disturbance is a crucial occurrence in many neurological diseases, including systemic lupus erythematosus (SLE). Our previous studies showed that experimental lupus serum altered the integrity of the mouse brain endothelial layer, an important constituent of the BBB. Complement activation occurs in lupus with increased circulating complement components. Using a genomics approach, we identified the microRNA (miRNA) altered in mouse brain endothelial cells (bEnd3) by lupus serum and the complement protein, C5a. Of the 318 miRNA evaluated, 23 miRNAs were altered by lupus serum and 32 were altered by C5a alone compared with controls. Seven miRNAs (P < 0 · 05) were differentially expressed by both treatments: mmu-miR-133a*, mmu-miR-193*, mmu-miR-26b, mmu-miR-28*, mmu-miR-320a, mmu-miR-423-3p and mmu-miR-509-5p. The microarray results were validated by quantitative RT-PCR. In line with the in vitro results, expression of miR-26b and miR-28* were also significantly up-regulated in lupus mouse brain which was reduced by C5a receptor inhibition. Target prediction analysis revealed miR gene targets encoding components involved in inflammation, matrix arrangement, and apoptosis, pathways known to play important roles in central nervous system lupus. Our findings suggest that the miRNAs reported in this study may represent novel therapeutic targets in central nervous system lupus and other similar neuroinflammatory settings.

  14. Transcriptional profiling reveals that C5a alters microRNA in brain endothelial cells.

    PubMed

    Eadon, Michael T; Jacob, Alexander; Cunningham, Patrick N; Quigg, Richard J; Garcia, Joe G N; Alexander, Jessy J

    2014-11-01

    Blood-brain barrier (BBB) disturbance is a crucial occurrence in many neurological diseases, including systemic lupus erythematosus (SLE). Our previous studies showed that experimental lupus serum altered the integrity of the mouse brain endothelial layer, an important constituent of the BBB. Complement activation occurs in lupus with increased circulating complement components. Using a genomics approach, we identified the microRNA (miRNA) altered in mouse brain endothelial cells (bEnd3) by lupus serum and the complement protein, C5a. Of the 318 miRNA evaluated, 23 miRNAs were altered by lupus serum and 32 were altered by C5a alone compared with controls. Seven miRNAs (P < 0 · 05) were differentially expressed by both treatments: mmu-miR-133a*, mmu-miR-193*, mmu-miR-26b, mmu-miR-28*, mmu-miR-320a, mmu-miR-423-3p and mmu-miR-509-5p. The microarray results were validated by quantitative RT-PCR. In line with the in vitro results, expression of miR-26b and miR-28* were also significantly up-regulated in lupus mouse brain which was reduced by C5a receptor inhibition. Target prediction analysis revealed miR gene targets encoding components involved in inflammation, matrix arrangement, and apoptosis, pathways known to play important roles in central nervous system lupus. Our findings suggest that the miRNAs reported in this study may represent novel therapeutic targets in central nervous system lupus and other similar neuroinflammatory settings. PMID:24801999

  15. Altered Modulation of Silent Period in Tongue Motor Cortex of Persistent Developmental Stuttering in Relation to Stuttering Severity

    PubMed Central

    Busan, Pierpaolo; Del Ben, Giovanni; Bernardini, Simona; Natarelli, Giulia; Bencich, Marco; Monti, Fabrizio; Manganotti, Paolo; Battaglini, Piero Paolo

    2016-01-01

    Motor balance in developmental stuttering (DS) was investigated with Transcranial Magnetic Stimulation (TMS), with the aim to define novel neural markers of persistent DS in adulthood. Eleven DS adult males were evaluated with TMS on tongue primary motor cortex, compared to 15 matched fluent speakers, in a “state” condition (i.e. stutterers vs. fluent speakers, no overt stuttering). Motor and silent period thresholds (SPT), recruitment curves, and silent period durations were acquired by recording tongue motor evoked potentials. Tongue silent period duration was increased in DS, especially in the left hemisphere (P<0.05; Hedge’s g or Cohen’s dunbiased = 1.054, i.e. large effect size), suggesting a “state” condition of higher intracortical inhibition in left motor cortex networks. Differences in motor thresholds (different excitatory/inhibitory ratios in DS) were evident, as well as significant differences in SPT. In fluent speakers, the left hemisphere may be marginally more excitable than the right one in motor thresholds at lower muscular activation, while active motor thresholds and SPT were higher in the left hemisphere of DS with respect to the right one, resulting also in a positive correlation with stuttering severity. Pre-TMS electromyography data gave overlapping evidence. Findings suggest the existence of a complex intracortical balance in DS tongue primary motor cortex, with a particular interplay between excitatory and inhibitory mechanisms, also in neural substrates related to silent periods. Findings are discussed with respect to functional and structural impairments in stuttering, and are also proposed as novel neural markers of a stuttering “state” in persistent DS, helping to define more focused treatments (e.g. neuro-modulation). PMID:27711148

  16. Competitive (AP7) and non-competitive (MK-801) NMDA receptor antagonists differentially alter glucose utilization in rat cortex

    SciTech Connect

    Clow, D.W.; Lee, S.J.; Hammer, R.P. Jr. )

    1991-04-01

    The effects of D,L-2-amino-7-phosphonoheptanoic acid (AP7), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and MK-801, a non-competitive NMDA receptor antagonist, on regional brain metabolism were studied in unanesthetized, freely moving rats by using the quantitative {sup 14}C2-deoxyglucose autoradiographic procedure. AP7 (338 or 901 mg/kg) produced a dose-dependent decrease of metabolic activity throughout most of the regions studied including sensory, motor, and limbic cortices. In contrast, MK-801 (0.1 or 1.0 mg/kg) resulted in a dose-dependent decrease of metabolic activity in sensory cortices, and an increase in limbic regions such as the hippocampal stratum lacunosum moleculare and entorhinal cortex. MK-801 also produced a biphasic response in agranular motor cortex, whereby the low dose increased while the high dose decreased labeling. In addition, MK-801 produced heterogeneous effects on regional cerebral metabolism in sensory cortices. Metabolic activity decreased in layer IV relative to layer Va following MK-801 treatment in primary somatosensory (SI) and visual (VI) cortices, suggesting a shift in activity from afferent fibers innervating layer IV to those innervating layer Va. MK-801 administration also decreased metabolic activity in granular SI relative to dysgranular SI, and in VI relative to secondary visual cortex (VII), thus providing a relative sparing of activity in dysgranular SI and VII. Thus, the non-competitive NMDA receptor antagonist suppressed activity from extrinsic neocortical sources, enhancing relative intracortical activity and stimulating limbic regions, while the competitive NMDA antagonist depressed metabolic activity in all cortical regions.

  17. Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq.

    PubMed

    Zeisel, Amit; Muñoz-Manchado, Ana B; Codeluppi, Simone; Lönnerberg, Peter; La Manno, Gioele; Juréus, Anna; Marques, Sueli; Munguba, Hermany; He, Liqun; Betsholtz, Christer; Rolny, Charlotte; Castelo-Branco, Gonçalo; Hjerling-Leffler, Jens; Linnarsson, Sten

    2015-03-01

    The mammalian cerebral cortex supports cognitive functions such as sensorimotor integration, memory, and social behaviors. Normal brain function relies on a diverse set of differentiated cell types, including neurons, glia, and vasculature. Here, we have used large-scale single-cell RNA sequencing (RNA-seq) to classify cells in the mouse somatosensory cortex and hippocampal CA1 region. We found 47 molecularly distinct subclasses, comprising all known major cell types in the cortex. We identified numerous marker genes, which allowed alignment with known cell types, morphology, and location. We found a layer I interneuron expressing Pax6 and a distinct postmitotic oligodendrocyte subclass marked by Itpr2. Across the diversity of cortical cell types, transcription factors formed a complex, layered regulatory code, suggesting a mechanism for the maintenance of adult cell type identity.

  18. Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex.

    PubMed

    García-Díaz, Beatriz; Riquelme, Raquel; Varela-Nieto, Isabel; Jiménez, Antonio Jesús; de Diego, Isabel; Gómez-Conde, Ana Isabel; Matas-Rico, Elisa; Aguirre, José Ángel; Chun, Jerold; Pedraza, Carmen; Santín, Luis Javier; Fernández, Oscar; Rodríguez de Fonseca, Fernando; Estivill-Torrús, Guillermo

    2015-11-01

    Lysophosphatidic acid (LPA) is an intercellular signaling lipid that regulates multiple cellular functions, acting through specific G-protein coupled receptors (LPA(1-6)). Our previous studies using viable Malaga variant maLPA1-null mice demonstrated the requirement of the LPA1 receptor for normal proliferation, differentiation, and survival of the neuronal precursors. In the cerebral cortex LPA1 is expressed extensively in differentiating oligodendrocytes, in parallel with myelination. Although exogenous LPA-induced effects have been investigated in myelinating cells, the in vivo contribution of LPA1 to normal myelination remains to be demonstrated. This study identified a relevant in vivo role for LPA1 as a regulator of cortical myelination. Immunochemical analysis in adult maLPA1-null mice demonstrated a reduction in the steady-state levels of the myelin proteins MBP, PLP/DM20, and CNPase in the cerebral cortex. The myelin defects were confirmed using magnetic resonance spectroscopy and electron microscopy. Stereological analysis limited the defects to adult differentiating oligodendrocytes, without variation in the NG2+ precursor cells. Finally, a possible mechanism involving oligodendrocyte survival was demonstrated by the impaired intracellular transport of the PLP/DM20 myelin protein which was accompanied by cellular loss, suggesting stress-induced apoptosis. These findings describe a previously uncharacterized in vivo functional role for LPA1 in the regulation of oligodendrocyte differentiation and myelination in the CNS, underlining the importance of the maLPA1-null mouse as a model for the study of demyelinating diseases.

  19. Mice lacking the transcriptional coactivator PGC-1α exhibit alterations in inhibitory synaptic transmission in the motor cortex.

    PubMed

    Dougherty, S E; Bartley, A F; Lucas, E K; Hablitz, J J; Dobrunz, L E; Cowell, R M

    2014-06-20

    Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator known to regulate gene programs in a cell-specific manner in energy-demanding tissues, and its dysfunction has been implicated in numerous neurological and psychiatric disorders. Previous work from the Cowell laboratory indicates that PGC-1α is concentrated in inhibitory interneurons and is required for the expression of the calcium buffer parvalbumin (PV) in the cortex; however, the impact of PGC-1α deficiency on inhibitory neurotransmission in the motor cortex is not known. Here, we show that mice lacking PGC-1α exhibit increased amplitudes and decreased frequency of spontaneous inhibitory postsynaptic currents in layer V pyramidal neurons. Upon repetitive train stimulation at the gamma frequency, decreased GABA release is observed. Furthermore, PV-positive interneurons in PGC-1α -/- mice display reductions in intrinsic excitability and excitatory input without changes in gross interneuron morphology. Taken together, these data show that PGC-1α is required for normal inhibitory neurotransmission and cortical PV-positive interneuron function. Given the pronounced motor dysfunction in PGC-1α -/- mice and the essential role of PV-positive interneurons in maintenance of cortical excitatory:inhibitory balance, it is possible that deficiencies in PGC-1α expression could contribute to cortical hyperexcitability and motor abnormalities in multiple neurological disorders.

  20. Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson's disease and incidental Parkinson's disease.

    PubMed

    Fabelo, Noemí; Martín, Virginia; Santpere, Gabriel; Marín, Raquel; Torrent, Laia; Ferrer, Isidre; Díaz, Mario

    2011-01-01

    Lipid rafts are cholesterol- and sphingomyelin-enriched microdomains that provide a highly saturated and viscous physicochemical microenvironment to promote protein-lipid and protein-protein interactions. We purified lipid rafts from human frontal cortex from normal, early motor stages of Parkinson's disease (PD) and incidental Parkinson's disease (iPD) subjects and analyzed their lipid composition. We observed that lipid rafts from PD and iPD cortices exhibit dramatic reductions in their contents of n-3 and n-6 long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (22:6-n3) and arachidonic acid (20:4n-6). Also, saturated fatty acids (16:0 and 18:0) were significantly higher than in control brains. Paralleling these findings, unsaturation and peroxidability indices were considerably reduced in PD and iPD lipid rafts. Lipid classes were also affected in PD and iPD lipid rafts. Thus, phosphatidylserine and phosphatidylinositol were increased in PD and iPD, whereas cerebrosides and sulfatides and plasmalogen levels were considerably diminished. Our data pinpoint a dramatic increase in lipid raft order due to the aberrant biochemical structure in PD and iPD and indicate that these abnormalities of lipid rafts in the frontal cortex occur at early stages of PD pathology. The findings correlate with abnormal lipid raft signaling and cognitive decline observed during the development of these neurodegenerative disorders. PMID:21717034

  1. Continuous theta-burst stimulation (cTBS) over the lateral prefrontal cortex alters reinforcement learning bias.

    PubMed

    Ott, Derek V M; Ullsperger, Markus; Jocham, Gerhard; Neumann, Jane; Klein, Tilmann A

    2011-07-15

    The prefrontal cortex is known to play a key role in higher-order cognitive functions. Recently, we showed that this brain region is active in reinforcement learning, during which subjects constantly have to integrate trial outcomes in order to optimize performance. To further elucidate the role of the dorsolateral prefrontal cortex (DLPFC) in reinforcement learning, we applied continuous theta-burst stimulation (cTBS) either to the left or right DLPFC, or to the vertex as a control region, respectively, prior to the performance of a probabilistic learning task in an fMRI environment. While there was no influence of cTBS on learning performance per se, we observed a stimulation-dependent modulation of reward vs. punishment sensitivity: Left-hemispherical DLPFC stimulation led to a more reward-guided performance, while right-hemispherical cTBS induced a more avoidance-guided behavior. FMRI results showed enhanced prediction error coding in the ventral striatum in subjects stimulated over the left as compared to the right DLPFC. Both behavioral and imaging results are in line with recent findings that left, but not right-hemispherical stimulation can trigger a release of dopamine in the ventral striatum, which has been suggested to increase the relative impact of rewards rather than punishment on behavior. PMID:21554966

  2. Intracranial electroencephalography reveals different temporal profiles for dorsal- and ventro-lateral prefrontal cortex in preparing to stop action.

    PubMed

    Swann, Nicole C; Tandon, Nitin; Pieters, Thomas A; Aron, Adam R

    2013-10-01

    Preparing to stop an inappropriate action requires keeping in mind the task goal and using this to influence the action control system. We tested the hypothesis that different subregions of prefrontal cortex show different temporal profiles consistent with dissociable contributions to preparing-to-stop, with dorsolateral prefrontal cortex (DLPFC) representing the task goal and ventrolateral prefrontal cortex (VLPFC) implementing action control. Five human subjects were studied using electrocorticography recorded from subdural grids over right lateral frontal cortex. On each trial, a task cue instructed the subject whether stopping might be needed or not (Maybe Stop [MS] or No Stop [NS]), followed by a go cue, and on some MS trials, a subsequent stop signal. We focused on go trials, comparing MS with NS. In the DLPFC, most subjects had an increase in high gamma activity following the task cue and the go cue. In contrast, in the VLPFC, all subjects had activity after the go cue near the time of the motor response on MS trials, related to behavioral slowing, and significantly later than the DLPFC activity. These different temporal profiles suggest that DLPFC and VLPFC could have dissociable roles, with DLPFC representing task goals and VLPFC implementing action control.

  3. Association between As and Cu renal cortex accumulation and physiological and histological alterations after chronic arsenic intake

    SciTech Connect

    Rubatto Birri, Paolo N.; Perez, Roberto D.; Cremonezzi, David; Perez, Carlos A.; Rubio, Marcelo; Bongiovanni, Guillermina A.

    2010-07-15

    Arsenic (As) is one of the most abundant hazards in the environment and it is a human carcinogen. Related to excretory functions, the kidneys in humans, animal models or naturally exposed fauna, are target organs for As accumulation and deleterious effects. Previous studies carried out using X-ray fluorescence spectrometry by synchrotron radiation (SR-{mu}XRF) showed a high concentration of As in the renal cortex of chronically exposed rats, suggesting that this is a suitable model for studies on renal As accumulation. This accumulation was accompanied by a significant increase in copper (Cu) concentration. The present study focused on the localization of these elements in the renal cortex and their correlation with physiological and histological As-related renal effects. Experiments were performed on nine male Wistar rats, divided into three experimental groups. Two groups received 100 {mu}g/ml sodium arsenite in drinking water for 60 and 120 consecutive days, respectively. The control group received water without sodium arsenite (<50 ppb As). For histological analysis, 5-{mu}m-thick sections of kidneys were stained with hematoxylin and eosin. Biochemical analyses were used to determine concentrations of plasma urea and creatinine. The As and Cu mapping were carried out by SR-{mu}XRF using a collimated white synchrotron spectrum (300 {mu}mx300 {mu}m) on kidney slices (2 mm thick) showing As and Cu co-distribution in the renal cortex. Then, renal cortical slices (100 {mu}m thick) were scanned with a focused white synchrotron spectrum (30 {mu}mx30 {mu}m). Peri-glomerular accumulation of As and Cu at 60 and 120 days was found. The effects of 60 days of arsenic consumption were seen in a decreased Bowman's space as well as a decreased plasma blood urea nitrogen (BUN)/creatinine ratio. Major deleterious effects; however, were seen on tubules at 120 days of exposition. This study supports the hypothesis that tubular accumulation of As-Cu may have some bearing on the

  4. The BTBR mouse model of autism spectrum disorders has learning and attentional impairments and alterations in acetylcholine and kynurenic acid in prefrontal cortex.

    PubMed

    McTighe, Stephanie M; Neal, Sarah J; Lin, Qian; Hughes, Zoë A; Smith, Daniel G

    2013-01-01

    Autism is a complex spectrum of disorders characterized by core behavioral deficits in social interaction, communication, repetitive stereotyped behaviors and restricted interests. Autism frequently presents with additional cognitive symptoms, including attentional deficits and intellectual disability. Preclinical models are important tools for studying the behavioral domains and biological underpinnings of autism, and potential treatment targets. The inbred BTBR T+tf/J (BTBR) mouse strain has been used as an animal model of core behavioral deficits in autism. BTBR mice exhibit repetitive behaviors and deficits in sociability and communication, but other aspects of their cognitive phenotype, including attentional performance, are not well characterized. We examined the attentional abilities of BTBR mice in the 5-choice serial reaction time task (5-CSRTT) using an automated touchscreen testing apparatus. The 5-CSRTT is an analogue of the human continuous performance task of attention, and so both the task and apparatus have translational relevance to human touchscreen cognitive testing. We also measured basal extracellular levels of a panel of neurotransmitters within the medial prefrontal cortex, a brain region critically important for performing the 5-CSRTT. We found that BTBR mice have increased impulsivity, defined as an inability to withhold responding, and decreased motivation, as compared to C57Bl/6J mice. Both of these features characterize attentional deficit disorders in humans. BTBR mice also display decreased accuracy in detecting short stimuli, lower basal levels of extracellular acetylcholine and higher levels of kynurenic acid within the prefrontal cortex. Intact cholinergic transmission in prefrontal cortex is required for accurate performance of the 5-CSRTT, consequently this cholinergic deficit may underlie less accurate performance in BTBR mice. Based on our findings that BTBR mice have attentional impairments and alterations in a key neural

  5. Social play in juvenile hamsters alters dendritic morphology in the medial prefrontal cortex and attenuates effects of social stress in adulthood.

    PubMed

    Burleson, Cody A; Pedersen, Robert W; Seddighi, Sahba; DeBusk, Lauren E; Burghardt, Gordon M; Cooper, Matthew A

    2016-08-01

    Social play is a fundamental aspect of behavioral development in many species. Social play deprivation in rats alters dendritic morphology in the ventromedial prefrontal cortex (vmPFC) and we have shown that this brain region regulates responses to social defeat stress in Syrian hamsters. In this study, we tested whether play deprivation during the juvenile period disrupts dendritic morphology in the prefrontal cortex and potentiates the effects of social defeat stress. At weaning, male hamsters were either group-housed with peers or pair-housed with their mother, with whom they do not play. In adulthood, animals received acute social defeat stress or no-defeat control treatment. The hamsters were then tested for a conditioned defeat response in a social interaction test with a novel intruder, and were also tested for social avoidance of a familiar opponent. Brains were collected for Golgi-Cox staining and analysis of dendritic morphology in the infralimbic (IL), prelimbic (PL), and orbitofrontal cortex (OFC). Play-deprived animals showed an increased conditioned defeat response and elevated avoidance of a familiar opponent compared with play-exposed animals. Furthermore, play-deprived animals showed increased total length and branch points in apical dendrites of pyramidal neurons in the IL and PL cortices, but not in the OFC. These findings suggest that social play deprivation in juvenile hamsters disrupts neuronal development in the vmPFC and increases vulnerability to the effects of social stress in adulthood. Overall, these results suggest that social play is necessary for the natural dendritic pruning process during adolescence and promotes coping with stress in adulthood. (PsycINFO Database Record PMID:27176563

  6. Social play in juvenile hamsters alters dendritic morphology in the medial prefrontal cortex and attenuates effects of social stress in adulthood.

    PubMed

    Burleson, Cody A; Pedersen, Robert W; Seddighi, Sahba; DeBusk, Lauren E; Burghardt, Gordon M; Cooper, Matthew A

    2016-08-01

    Social play is a fundamental aspect of behavioral development in many species. Social play deprivation in rats alters dendritic morphology in the ventromedial prefrontal cortex (vmPFC) and we have shown that this brain region regulates responses to social defeat stress in Syrian hamsters. In this study, we tested whether play deprivation during the juvenile period disrupts dendritic morphology in the prefrontal cortex and potentiates the effects of social defeat stress. At weaning, male hamsters were either group-housed with peers or pair-housed with their mother, with whom they do not play. In adulthood, animals received acute social defeat stress or no-defeat control treatment. The hamsters were then tested for a conditioned defeat response in a social interaction test with a novel intruder, and were also tested for social avoidance of a familiar opponent. Brains were collected for Golgi-Cox staining and analysis of dendritic morphology in the infralimbic (IL), prelimbic (PL), and orbitofrontal cortex (OFC). Play-deprived animals showed an increased conditioned defeat response and elevated avoidance of a familiar opponent compared with play-exposed animals. Furthermore, play-deprived animals showed increased total length and branch points in apical dendrites of pyramidal neurons in the IL and PL cortices, but not in the OFC. These findings suggest that social play deprivation in juvenile hamsters disrupts neuronal development in the vmPFC and increases vulnerability to the effects of social stress in adulthood. Overall, these results suggest that social play is necessary for the natural dendritic pruning process during adolescence and promotes coping with stress in adulthood. (PsycINFO Database Record

  7. Analysis of microdissected neurons by 18O mass spectrometry reveals altered protein expression in Alzheimer's disease

    PubMed Central

    Hashimoto, Masakazu; Bogdanovic, Nenad; Nakagawa, Hiroyuki; Volkmann, Inga; Aoki, Mikio; Winblad, Bengt; Sakai, Jun; Tjernberg, Lars O

    2012-01-01

    Abstract It is evident that the symptoms of Alzheimer's disease (AD) are derived from severe neuronal damage, and especially pyramidal neurons in the hippocampus are affected pathologically. Here, we analysed the proteome of hippocampal neurons, isolated from post-mortem brains by laser capture microdissection. By using 18O labelling and mass spectrometry, the relative expression levels of 150 proteins in AD and controls were estimated. Many of the identified proteins are involved in transcription and nucleotide binding, glycolysis, heat-shock response, microtubule stabilization, axonal transport or inflammation. The proteins showing the most altered expression in AD were selected for immunohistochemical analysis. These analyses confirmed the altered expression levels, and showed in many AD cases a pathological pattern. For comparison, we also analysed hippocampal sections by Western blot. The expression levels found by this method showed poor correlation with the neuron-specific analysis. Hence, we conclude that cell-specific proteome analysis reveals differences in the proteome that cannot be detected by bulk analysis. PMID:21883897

  8. Transcriptomic profiling of urine extracellular vesicles reveals alterations of CDH3 in prostate cancer

    PubMed Central

    Sanchez-Mosquera, Pilar; Ugalde-Olano, Aitziber; González, Esperanza; Cortazar, Ana R.; Palomo, Laura; Fernández-Ruiz, Sonia; Lacasa-Viscasillas, Isabel; Berdasco, Maria; Sutherland, James D.; Barrio, Rosa; Zabala-Letona, Amaia; Martín-Martín, Natalia; Arruabarrena-Aristorena, Amaia; Valcarcel-Jimenez, Lorea; Caro-Maldonado, Alfredo; Gonzalez-Tampan, Jorge; Cachi-Fuentes, Guido; Esteller, Manel; Aransay, Ana M.; Unda, Miguel

    2016-01-01

    Extracellular vesicles (EV) are emerging structures with promising properties for intercellular communication. In addition, the characterization of EV in biofluids is an attractive source of non-invasive diagnostic, prognostic and predictive biomarkers. Here we show that urinary EV (uEV) from prostate cancer (PCa) patients exhibit genuine and differential physical and biological properties compared to benign prostate hyperplasia (BPH). Importantly, transcriptomics characterization of uEVs led us to define the decreased abundance of Cadherin 3, type 1 (CDH3) transcript in uEV from PCa patients. Tissue and cell line analysis strongly suggested that the status of CDH3 in uEVs is a distal reflection of changes in the expression of this cadherin in the prostate tumor. CDH3 was negatively regulated at the genomic, transcriptional, and epigenetic level in PCa. Our results reveal that uEVs could represent a non-invasive tool to inform about the molecular alterations in PCa. PMID:26771841

  9. Historical comparisons reveal altered competitive interactions in a guild of crustose coralline algae.

    PubMed

    McCoy, S J; Pfister, C A

    2014-04-01

    As the ocean environment changes over time, a paucity of long-term data sets and historical comparisons limits the exploration of community dynamics over time in natural systems. Here, we used a long-term experimental data set to present evidence for a reversal of competitive dominance within a group of crustose coralline algae (CCA) from the 1980s to present time in the northeast Pacific Ocean. CCA are cosmopolitan species distributed globally, and dominant space holders in intertidal and subtidal systems. Competition experiments showed a markedly lower competitive ability of the previous competitively dominant species and a decreased response of competitive dynamics to grazer presence. Competitive networks obtained from survey data showed concordance between the 1980s and 2013, yet also revealed reductions in interaction strengths across the assemblage. We discuss the potential role of environmental change, including ocean acidification, in altered ecological dynamics in this system.

  10. Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex.

    PubMed

    García-Díaz, Beatriz; Riquelme, Raquel; Varela-Nieto, Isabel; Jiménez, Antonio Jesús; de Diego, Isabel; Gómez-Conde, Ana Isabel; Matas-Rico, Elisa; Aguirre, José Ángel; Chun, Jerold; Pedraza, Carmen; Santín, Luis Javier; Fernández, Oscar; Rodríguez de Fonseca, Fernando; Estivill-Torrús, Guillermo

    2015-11-01

    Lysophosphatidic acid (LPA) is an intercellular signaling lipid that regulates multiple cellular functions, acting through specific G-protein coupled receptors (LPA(1-6)). Our previous studies using viable Malaga variant maLPA1-null mice demonstrated the requirement of the LPA1 receptor for normal proliferation, differentiation, and survival of the neuronal precursors. In the cerebral cortex LPA1 is expressed extensively in differentiating oligodendrocytes, in parallel with myelination. Although exogenous LPA-induced effects have been investigated in myelinating cells, the in vivo contribution of LPA1 to normal myelination remains to be demonstrated. This study identified a relevant in vivo role for LPA1 as a regulator of cortical myelination. Immunochemical analysis in adult maLPA1-null mice demonstrated a reduction in the steady-state levels of the myelin proteins MBP, PLP/DM20, and CNPase in the cerebral cortex. The myelin defects were confirmed using magnetic resonance spectroscopy and electron microscopy. Stereological analysis limited the defects to adult differentiating oligodendrocytes, without variation in the NG2+ precursor cells. Finally, a possible mechanism involving oligodendrocyte survival was demonstrated by the impaired intracellular transport of the PLP/DM20 myelin protein which was accompanied by cellular loss, suggesting stress-induced apoptosis. These findings describe a previously uncharacterized in vivo functional role for LPA1 in the regulation of oligodendrocyte differentiation and myelination in the CNS, underlining the importance of the maLPA1-null mouse as a model for the study of demyelinating diseases. PMID:25226845

  11. Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia.

    PubMed

    Cannon, Tyrone D; Thompson, Paul M; van Erp, Theo G M; Toga, Arthur W; Poutanen, Veli-Pekka; Huttunen, Matti; Lonnqvist, Jouko; Standerskjold-Nordenstam, Carl-Gustav; Narr, Katherine L; Khaledy, Mohammad; Zoumalan, Chris I; Dail, Rajneesh; Kaprio, Jaakko

    2002-03-01

    The symptoms of schizophrenia imply disruption to brain systems supporting higher-order cognitive activity, but whether these systems are impacted differentially against a background of diffuse cortical gray-matter deficit remains ambiguous. Some unaffected first-degree relatives of schizophrenics also manifest cortical gray-matter deficits, but it is unclear whether these changes are isomorphic with those in patients, and the answer is critical to understanding the neurobiological conditions necessary for disease expression given a predisposing genotype. Here we report three-dimensional cortical surface maps (probabilistic atlases matching subjects' anatomy point by point throughout cortex) in monozygotic (MZ) and dizygotic (DZ) twins discordant for chronic schizophrenia along with demographically matched control twins. A map encoding the average differences between schizophrenia patients and their unaffected MZ co-twins revealed deficits primarily in dorsolateral prefrontal cortex, superior temporal gyrus, and superior parietal lobule. A map encoding variation associated with genetic proximity to a patient (MZ co-twins > DZ co-twins > control twins) isolated deficits primarily in polar and dorsolateral prefrontal cortex. In each case, the statistical significance was confirmed through analysis of 10,000 Monte Carlo permutations, and the remaining cortex was shown to be significantly less affected by contrast analysis. The disease-related deficits in gray matter were correlated with measures of symptom severity and cognitive dysfunction but not with duration of illness or antipsychotic drug treatment. Genetic and disease-specific influences thus affect gray matter in partially nonoverlapping areas of predominantly heteromodal association cortex, changes that may act synergistically in producing overt behavioral features of the disorder. PMID:11867725

  12. Streptozotocin diabetic mice display depressive-like behavior and alterations in the structure, neurotransmission and plasticity of medial prefrontal cortex interneurons.

    PubMed

    Castillo-Gómez, Esther; Coviello, Simona; Perez-Rando, Marta; Curto, Yasmina; Carceller, Héctor; Salvador, Alicia; Nacher, Juan

    2015-07-01

    Diabetes mellitus patients are at increased risk of developing depression, although the neurobiological bases of this comorbidity are not yet fully understood. These patients show CNS alterations, similar to those found in major depression, including changes in the structure and neurotransmission of excitatory neurons. However, although depressive patients and animal models also display alterations in inhibitory networks, little is known about the effects of diabetes on interneurons. Our main objective was to study the impact of diabetes on interneurons of the medial prefrontal cortex (mPFC), one of the regions most affected by major depression. For this purpose we have induced diabetes with high-dose streptozotozin in transgenic mice displaying fluorescent interneurons. These animals showed a depressive-like behavior (increased immobility time in tail suspension test) in parallel with reductions in interneuronal dendritic arborization and in the expression of GAD67, the enzyme that synthetizes the inhibitory neurotransmitter GABA. However, the levels of PSA-NCAM, a plasticity-related molecule exclusively expressed by interneurons in the mPFC, were unaltered in the different regions and layers of this cortical area. Interestingly, diabetic mice also showed increased levels of synaptophysin, a synaptic vesicle protein. These results indicate that the structure and neurotransmission of interneurons is altered in the mPFC of diabetic mice and suggest that these changes may play a key role in the depressive symptoms associated to diabetes. PMID:26112471

  13. Alterations of the Ceramide Metabolism in the Peri-Infarct Cortex Are Independent of the Sphingomyelinase Pathway and Not Influenced by the Acid Sphingomyelinase Inhibitor Fluoxetine

    PubMed Central

    Brunkhorst, R.; Friedlaender, F.; Ferreirós, N.; Schwalm, S.; Koch, A.; Grammatikos, G.; Toennes, S.; Foerch, C.; Pfeilschifter, J.; Pfeilschifter, W.

    2015-01-01

    Ceramides induce important intracellular signaling pathways, modulating proliferation, migration, apoptosis, and inflammation. However, the relevance of the ceramide metabolism in the reconvalescence phase after stroke is unclear. Besides its well-known property as a selective serotonin reuptake inhibitor, fluoxetine has been reported to inhibit the acid sphingomyelinase (ASM), a key regulator of ceramide levels which derives ceramide from sphingomyelin. Furthermore, fluoxetine has shown therapeutic potential in a randomized controlled rehabilitation trial in stroke patients. Our aim was to investigate and modulate ceramide concentrations in the peri-infarct cortex, whose morphological and functional properties correlate with long-term functional outcome in stroke. We show that certain ceramide species are modulated after experimental stroke and that these changes do not result from alterations of ASM activity, but rather from nontranscriptional induction of the ceramide de novo pathway. Unexpectedly, although reducing lesion size, fluoxetine did not improve functional outcome in our model and had no significant influence on ASM activity or the concentration of ceramides. The ceramide metabolism could emerge as a potential therapeutic target in the reconvalescence phase after stroke, as its accumulation in the peri-infarct cortex potentially influences membrane functions as well as signaling events in the tissue essential for neurological recovery. PMID:26605090

  14. Prenatal exposure to ethanol alters the postnatal development and transformation of radial glia to astrocytes in the cortex.

    PubMed

    Miller, M W; Robertson, S

    1993-11-01

    Postmitotic neurons migrate from a zone(s) near the ventricles to the neocortex. During this migration, neurons associate with radial glia. After serving their role as guides for neuronal migration, the radial glia transform into astrocytes. Prenatal exposure to ethanol causes abnormal neuronal migration. We examined the effects of gestational exposure to ethanol on radial glia and astrocytes. Radial glia were stained immunohistochemically with the antibody RAT-401, and astrocytes were labeled with an antibody directed against glial fibrillary acidic protein (GFAP). The subjects were the offspring of rats fed an ethanol-containing liquid diet (Et), pair-fed a liquid control diet (Ct), or fed chow and water (Ch). During the first postnatal week, radial glial fibers (in Et-treated rats and controls) stretched from the ventricular surface through the developing cerebral wall to the pial surface. In the Et-treated rats, the radial processes were less dense and more poorly fasciculated than they were in the Ch- and Ct-treated rats. Moreover, by postnatal day (P) 5, there was a significant reduction in RAT-401 immunostaining in the Et-treated rats, particularly in the superficial cortex. A similar reduction in control rats did not begin until P10. In all three treatment groups, GFAP-immunoreactive astrocytes were in the cortex throughout the period from P1 to P45. In neonates, GFAP-positive cells were distributed in the marginal zone (layer I) and the intermediate zone (the white matter). The number of GFAP-positive cells in the cortical plate increased steadily with time so that, by P26, GFAP-immunoreactive astrocytes were distributed evenly through all cortical laminae. Interestingly, between P5 and P12, the number of astrocytes was significantly greater in Et-treated rats than in controls. Thus prenatal exposure to ethanol induces the premature loss of RAT-401-positive processes and the precocious increase in GFAP immunostaining. These ethanol-induced changes in glial

  15. Our Faces in the Dog's Brain: Functional Imaging Reveals Temporal Cortex Activation during Perception of Human Faces.

    PubMed

    Cuaya, Laura V; Hernández-Pérez, Raúl; Concha, Luis

    2016-01-01

    Dogs have a rich social relationship with humans. One fundamental aspect of it is how dogs pay close attention to human faces in order to guide their behavior, for example, by recognizing their owner and his/her emotional state using visual cues. It is well known that humans have specific brain regions for the processing of other human faces, yet it is unclear how dogs' brains process human faces. For this reason, our study focuses on describing the brain correlates of perception of human faces in dogs using functional magnetic resonance imaging (fMRI). We trained seven domestic dogs to remain awake, still and unrestrained inside an MRI scanner. We used a visual stimulation paradigm with block design to compare activity elicited by human faces against everyday objects. Brain activity related to the perception of faces changed significantly in several brain regions, but mainly in the bilateral temporal cortex. The opposite contrast (i.e., everyday objects against human faces) showed no significant brain activity change. The temporal cortex is part of the ventral visual pathway, and our results are consistent with reports in other species like primates and sheep, that suggest a high degree of evolutionary conservation of this pathway for face processing. This study introduces the temporal cortex as candidate to process human faces, a pillar of social cognition in dogs.

  16. Our Faces in the Dog's Brain: Functional Imaging Reveals Temporal Cortex Activation during Perception of Human Faces.

    PubMed

    Cuaya, Laura V; Hernández-Pérez, Raúl; Concha, Luis

    2016-01-01

    Dogs have a rich social relationship with humans. One fundamental aspect of it is how dogs pay close attention to human faces in order to guide their behavior, for example, by recognizing their owner and his/her emotional state using visual cues. It is well known that humans have specific brain regions for the processing of other human faces, yet it is unclear how dogs' brains process human faces. For this reason, our study focuses on describing the brain correlates of perception of human faces in dogs using functional magnetic resonance imaging (fMRI). We trained seven domestic dogs to remain awake, still and unrestrained inside an MRI scanner. We used a visual stimulation paradigm with block design to compare activity elicited by human faces against everyday objects. Brain activity related to the perception of faces changed significantly in several brain regions, but mainly in the bilateral temporal cortex. The opposite contrast (i.e., everyday objects against human faces) showed no significant brain activity change. The temporal cortex is part of the ventral visual pathway, and our results are consistent with reports in other species like primates and sheep, that suggest a high degree of evolutionary conservation of this pathway for face processing. This study introduces the temporal cortex as candidate to process human faces, a pillar of social cognition in dogs. PMID:26934715

  17. Nocifensive behavior-related laser heat-evoked component in the rostral agranular insular cortex revealed using morphine analgesia.

    PubMed

    Wu, Wen-Yi; Liu, Chan-Ying; Tsai, Meng-Li; Yen, Chen-Tung

    2016-02-01

    The rostral agranular insular cortex (RAIC), an opioid-responsive site, is essential for modulating nociception in rats. Our previous studies have shown that morphine suppressed long latency laser heat-evoked nociceptive responses in the primary somatosensory cortex (SmI). By contrast, morphine significantly attenuated both short and long latency responses in the anterior cingulate cortex (ACC). The present study assessed the effect of morphine on laser heat-evoked responses in the RAIC. Laser heat irradiation applied to the rat forepaws at graded levels was used as a specific noxious stimulus. In the RAIC, the first part of the long latency component (140-250ms) of the laser heat-evoked response was enhanced by intraperitoneal morphine (5mg/kg). When the laser heat-evoked cortical responses were examined for trials showing strong nocifensive movement (paw licking), moderate nocifensive movement (paw lifting), and no nocifensive movement, a 140-250ms period enhancement was observed in the RAIC only for the paw lifting movement. This enhancement was absent in the SmI. Thus, our data suggest that the RAIC has a pain-related behavior-dependent neuronal component. Furthermore, the RAIC, ACC, and SmI are differentially modulated by morphine analgesia.

  18. Our Faces in the Dog's Brain: Functional Imaging Reveals Temporal Cortex Activation during Perception of Human Faces

    PubMed Central

    Cuaya, Laura V.; Hernández-Pérez, Raúl; Concha, Luis

    2016-01-01

    Dogs have a rich social relationship with humans. One fundamental aspect of it is how dogs pay close attention to human faces in order to guide their behavior, for example, by recognizing their owner and his/her emotional state using visual cues. It is well known that humans have specific brain regions for the processing of other human faces, yet it is unclear how dogs’ brains process human faces. For this reason, our study focuses on describing the brain correlates of perception of human faces in dogs using functional magnetic resonance imaging (fMRI). We trained seven domestic dogs to remain awake, still and unrestrained inside an MRI scanner. We used a visual stimulation paradigm with block design to compare activity elicited by human faces against everyday objects. Brain activity related to the perception of faces changed significantly in several brain regions, but mainly in the bilateral temporal cortex. The opposite contrast (i.e., everyday objects against human faces) showed no significant brain activity change. The temporal cortex is part of the ventral visual pathway, and our results are consistent with reports in other species like primates and sheep, that suggest a high degree of evolutionary conservation of this pathway for face processing. This study introduces the temporal cortex as candidate to process human faces, a pillar of social cognition in dogs. PMID:26934715

  19. In vitro binding assays using (3)H nisoxetine and (3)H WIN 35,428 reveal selective effects of gonadectomy and hormone replacement in adult male rats on norepinephrine but not dopamine transporter sites in the cerebral cortex.

    PubMed

    Meyers, B; Kritzer, M F

    2009-03-01

    The prefrontal cortices mediate cognitive functions that critically depend on local dopamine levels. In male rats, many prefrontal tasks where performance is disrupted by changes in dopamine signaling are also impaired by gonadectomy, a manipulation that increases cortical dopamine concentration, prefrontal dopamine axon density and possibly extracellular prefrontal dopamine levels as well. Because these actions could be responsible for the impairing effects of gonadectomy on prefrontal function, the question of how they might arise comes to the fore. Accordingly, the present studies asked whether dopamine levels might be increased via a hormone sensitivity of transporter-mediated dopamine uptake. Specifically, (3)H WIN 35,428 and (3)H nisoxetine, ligands selective for the dopamine (DAT)- and norepinephrine transporter (NET) respectively, were used in in vitro binding assays to ask whether gonadectomy altered transporter affinity (Kd) and/or binding site number (Bmax) in prefrontal cortex, sensorimotor cortex and/or caudate. Assays performed on tissues dissected from sham-operated, gonadectomized and gonadectomized rats supplemented with testosterone propionate or estradiol for 4 or 28 days revealed no significant group differences or obvious trends in Kd or Bmax for DAT binding or in measures of Bmax for NET binding. However, affinity constants for (3)H nisoxetine were found to be significantly higher in sensorimotor and/or prefrontal cortex of rats gonadectomized and gonadectomized and supplemented with estradiol for 4 or 28 days but similar to control in gonadectomized rats given testosterone. Because the NET contributes substantially to extracellular prefrontal dopamine clearance, these androgen-mediated effects could influence prefrontal dopamine levels and might thus be relevant for observed effects of gonadectomy on dopamine-dependent prefrontal behaviors. A hormone sensitivity of the NET could also have bearing on the prefrontal dopamine dysfunction seen in

  20. Electrophysiology Alterations in Primary Visual Cortex Neurons of Retinal Degeneration (S334ter-line-3) Rats

    PubMed Central

    Chen, Ke; Wang, Yi; Liang, Xiaohua; Zhang, Yihuai; Ng, Tsz Kin; Chan, Leanne Lai Hang

    2016-01-01

    The dynamic nature of the brain is critical for the success of treatments aimed at restoring vision at the retinal level. The success of these treatments relies highly on the functionality of the surviving neurons along the entire visual pathway. Electrophysiological properties at the retina level have been investigated during the progression of retinal degeneration; however, little is known about the changes in electrophysiological properties that occur in the primary visual cortex (V1) during the course of retinal degeneration. By conducting extracellular recording, we examined the electrophysiological properties of V1 in S334ter-line-3 rats (a transgenic model of retinal degeneration developed to express a rhodopsin mutation similar to that found in human retinitis pigmentosa patients). We measured the orientation tuning, spatial and temporal frequency tunings and the receptive field (RF) size for 127 V1 neurons from 11 S334ter-3 rats and 10 Long-Evans (LE) rats. V1 neurons in the S334ter-3 rats showed weaker orientation selectivity, lower optimal spatial and temporal frequency values and a smaller receptive field size compared to the LE rats. These results suggest that the visual cognitive ability significantly changes during retinal degeneration. PMID:27225415

  1. Adolescent Risperidone treatment alters protein expression associated with protein trafficking and cellular metabolism in the adult rat prefrontal cortex.

    PubMed

    Farrelly, Lorna A; Dicker, Patrick; Wynne, Kieran; English, Jane; Cagney, Gerard; Föcking, Melanie; Cotter, David R

    2014-06-01

    The prefrontal cortex (PFC) is associated with mental health illnesses including schizophrenia, depression, bipolar disorder, and autism spectrum disorders. It richly expresses neuroreceptors which are the target for antipsychotics. However, as the precise mechanism of action of antipsychotic medications is not known, proteomic studies of the effects of antipsychotic drugs on the brain are warranted. In the current study, we aimed to characterize protein expression in the adult rodent PFC (n = 5 per group) following low-dose treatment with Risperidone or saline in adolescence (postnatal days 34-47). The PFC was examined by triplicate 1 h runs of label-free LC-MS/MS. The raw mass spectral data were analyzed with the MaxQuant(TM) software. Statistical analysis was carried out using SAS® Version 9.1. Pathway and functional analysis was performed with IngenuityPathway Analysis and in the Database for Annotation, Visualization and Integrated Discovery (DAVID), respectively, the most implicated pathways were found to be related to mitochondrial function, protein trafficking, and the cytoskeleton. This report adds to the current repertoire of data available concerning the effects of antipsychotic drugs on the brain and sheds light on their biological mechanisms. The MS data have been deposited with the ProteomeXchange Consortium with dataset identifier PXD000480. PMID:24733778

  2. Metabolomic Profiling Reveals Potential Markers and Bioprocesses Altered in Bladder Cancer Progression

    PubMed Central

    Putluri, Nagireddy; Shojaie, Ali; Vasu, Vihas T; Vareed, Shaiju K.; Nalluri, Srilatha; Putluri, Vasanta; Thangjam, Gagan Singh; Panzitt, Katrin; Tallman, Christopher T.; Butler, Charles; Sana, Theodore R.; Fischer, Steven M.; Sica, Gabriel; Brat, Daniel J.; Shi, Huidong; Palapattu, Ganesh S; Lotan, Yair; Weizer, Alon Z.; Terris, Martha K.; Shariat, Shahrokh F.; Michailidis, George; Sreekumar, Arun

    2011-01-01

    While alterations in xenobiotic metabolism are considered causal in the development of bladder cancer (BCa), the precise mechanisms involved are poorly understood. In this study, we used high-throughput mass spectrometry to measure over 2,000 compounds in 58 clinical specimens, identifying 35 metabolites which exhibited significant changes in BCa. This metabolic signature distinguished both normal and benign bladder from BCa. Exploratory analyses of this metabolomic signature in urine showed promise in distinguishing BCa from controls, and also non-muscle from muscle-invasive BCa. Subsequent enrichment-based bioprocess mapping revealed alterations in phase I/II metabolism and suggested a possible role for DNA methylation in perturbing xenobiotic metabolism in BCa. In particular, we validated tumor-associated hypermethylation in the CYP1A1 and CYP1B1 promoters of BCa tissues by bisulfite sequence analysis and methylation-specific PCR, and also by in vitro treatment of T-24 BCa cell line with the DNA demethylating agent 5-aza-2′-deoxycytidine. Further, we showed that expression of CYP1A1 and CYP1B1 was reduced significantly in an independent cohort of BCa specimens compared to matched benign adjacent tissues. In summary, our findings identified candidate diagnostic and prognostic markers and highlighted mechanisms associated with the silencing of xenobiotic metabolism. The metabolomic signature we describe offers potential as a urinary biomarker for early detection and staging of BCa, highlighting the utility of evaluating metabolomic profiles of cancer to gain insights into bioprocesses perturbed during tumor development and progression. PMID:21990318

  3. Metabolomic profiling reveals potential markers and bioprocesses altered in bladder cancer progression.

    PubMed

    Putluri, Nagireddy; Shojaie, Ali; Vasu, Vihas T; Vareed, Shaiju K; Nalluri, Srilatha; Putluri, Vasanta; Thangjam, Gagan Singh; Panzitt, Katrin; Tallman, Christopher T; Butler, Charles; Sana, Theodore R; Fischer, Steven M; Sica, Gabriel; Brat, Daniel J; Shi, Huidong; Palapattu, Ganesh S; Lotan, Yair; Weizer, Alon Z; Terris, Martha K; Shariat, Shahrokh F; Michailidis, George; Sreekumar, Arun

    2011-12-15

    Although alterations in xenobiotic metabolism are considered causal in the development of bladder cancer, the precise mechanisms involved are poorly understood. In this study, we used high-throughput mass spectrometry to measure over 2,000 compounds in 58 clinical specimens, identifying 35 metabolites which exhibited significant changes in bladder cancer. This metabolic signature distinguished both normal and benign bladder from bladder cancer. Exploratory analyses of this metabolomic signature in urine showed promise in distinguishing bladder cancer from controls and also nonmuscle from muscle-invasive bladder cancer. Subsequent enrichment-based bioprocess mapping revealed alterations in phase I/II metabolism and suggested a possible role for DNA methylation in perturbing xenobiotic metabolism in bladder cancer. In particular, we validated tumor-associated hypermethylation in the cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) promoters of bladder cancer tissues by bisulfite sequence analysis and methylation-specific PCR and also by in vitro treatment of T-24 bladder cancer cell line with the DNA demethylating agent 5-aza-2'-deoxycytidine. Furthermore, we showed that expression of CYP1A1 and CYP1B1 was reduced significantly in an independent cohort of bladder cancer specimens compared with matched benign adjacent tissues. In summary, our findings identified candidate diagnostic and prognostic markers and highlighted mechanisms associated with the silencing of xenobiotic metabolism. The metabolomic signature we describe offers potential as a urinary biomarker for early detection and staging of bladder cancer, highlighting the utility of evaluating metabolomic profiles of cancer to gain insights into bioprocesses perturbed during tumor development and progression. PMID:21990318

  4. Area-Specific Alterations of Synaptic Plasticity in the 5XFAD Mouse Model of Alzheimer’s Disease: Dissociation between Somatosensory Cortex and Hippocampus

    PubMed Central

    Crouzin, Nadine; Baranger, Kevin; Cavalier, Mélanie; Marchalant, Yannick; Cohen-Solal, Catherine; Roman, François S.; Khrestchatisky, Michel; Rivera, Santiago; Féron, François; Vignes, Michel

    2013-01-01

    Transgenic mouse models of Alzheimer’s disease (AD) that overproduce the amyloid beta peptide (Aβ) have highlighted impairments of hippocampal long-term synaptic plasticity associated with the progression of the disease. Here we examined whether the characteristics of one of the hallmarks of AD, i.e. Aβ deposition, in both the somatosensory cortex and the hippocampus, correlated with specific losses of synaptic plasticity in these areas. For this, we evaluated the occurrence of long-term potentiation (LTP) in the cortex and the hippocampus of 6-month old 5xFAD transgenic mice that exhibited massive Aβ deposition in both regions but with different features: in cortical areas a majority of Aβ deposits comprised a dense core surrounded by a diffuse corona while such kind of Aβ deposition was less frequently observed in the hippocampus. In order to simultaneously monitor synaptic changes in both areas, we developed a method based on the use of Multi-Electrode Arrays (MEA). When compared with wild-type (WT) mice, basal transmission was significantly reduced in both areas in 5xFAD mice, while short-term synaptic plasticity was unaffected. The induction of long-term changes of synaptic transmission by different protocols revealed that in 5xFAD mice, LTP in the layer 5 of the somatosensory cortex was more severely impaired than LTP triggered in the CA1 area of the hippocampus. We conclude that cortical plasticity is deficient in the 5xFAD model and that this deficit could be correlated with the proportion of diffuse plaques in 5xFAD mice. PMID:24069328

  5. Extensive and Diverse Alteration Revealed in Noctis Labyrinthus Using CRISM Data

    NASA Astrophysics Data System (ADS)

    Thollot, P.; Mangold, N.; Le Mouélic, S.

    2014-07-01

    We analyzed 113 CRISM cubes in Noctis Labyrinthus. We found 10 classes of alteration minerals including clays and sulfates, sometimes associated in the same setting. Fe and Al sulfates argue for acidic hydrothermal alteration.

  6. Alterations in functional connectivity between the hippocampus and prefrontal cortex as a correlate of depressive symptoms in temporal lobe epilepsy.

    PubMed

    Kemmotsu, Nobuko; Kucukboyaci, N Erkut; Cheng, Christopher E; Girard, Holly M; Tecoma, Evelyn S; Iragui, Vicente J; McDonald, Carrie R

    2013-12-01

    Depression is a common comorbidity in temporal lobe epilepsy (TLE) that is thought to have a neurobiological basis. This study investigated the functional connectivity (FC) of medial temporal networks in depression symptomatology of TLE and the relative contribution of structural versus FC measures. Volumetric MRI and functional connectivity MRI (fcMRI) were performed on nineteen patients with TLE and 20 controls. The hippocampi and amygdalae were selected as seeds, and five prefrontal and five cingulate regions of interest (ROIs) were selected as targets. Low-frequency blood-oxygen-level-dependent signals were isolated from fcMRI data, and ROIs with synchronous signal fluctuations with the seeds were identified. Depressive symptoms were measured by the Beck Depression Inventory-II. The patients with TLE showed greater ipsilateral hippocampal atrophy (HA) and reduced FC between the ipsilateral hippocampus and the ventral posterior cingulate cortex (vPCC). Neither HA nor hippocampal-vPCC FC asymmetry was a robust contributor to depressive symptoms. Rather, hippocampal-anterior prefrontal FC was a stronger contributor to depressive symptoms in left TLE (LTLE). Conversely, right amygdala FC was correlated with depressive symptoms in both patient groups, with a positive and negative correlation in LTLE and right TLE (RTLE), respectively. Frontolimbic network dysfunction is a strong contributor to levels of depressive symptoms in TLE and a better contributor than HA in LTLE. In addition, the right amygdala may play a role in depression symptomatology regardless of the side of the epileptogenic focus. These findings may inform the treatment of depressive symptoms in TLE and inspire future research to help guide surgical planning.

  7. Environmental Enrichment Alters Nicotine-Mediated Locomotor Sensitization and Phosphorylation of DARPP-32 and CREB in Rat Prefrontal Cortex

    PubMed Central

    Gomez, Adrian M.; Midde, Narasimha M.; Mactutus, Charles F.; Booze, Rosemarie M.; Zhu, Jun

    2012-01-01

    Exposure within an environmental enrichment paradigm results in neurobiological adaptations and decreases the baseline of locomotor activity. The current study determined activation of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein-32) and CREB (cAMP response element binding protein), and locomotor activity in rats raised in enriched (EC), impoverished (IC), and standard (SC) conditions following repeated administration of nicotine or saline. In the saline-control group, the basal phosphorylation state of DARPP-32 at Threonine-34 site (pDARPP-32 Thr34) in the prefrontal cortex (PFC) was lower in EC compared to IC and SC rats, which was positively correlated with their respective baseline activities. While nicotine (0.35 mg/kg, freebase) produced locomotor sensitization across all housing conditions when the nicotine-mediated locomotor activity was expressed as a percent change from their respective saline control, EC rats displayed greater sensitization to nicotine than IC and SC rats. Consistent with the behavioral findings, repeated nicotine injection increased pDARPP-32 Thr34 in PFC of EC and IC rats and in nucleus accumbens of EC rats; however, the magnitude of change from saline control in nicotine-induced enhancement of pDARPP-32 Thr34 in PFC was strikingly increased in EC rats relative to IC rats. Moreover, EC rats had lower basal phosphorylation levels of CREB at serine 133 in PFC and nucleus accumbens compared to IC and SC rats, whereas the nicotine-induced increase in phosphorylated CREB-Ser133 was more pronounced in PFC of EC rats relative to IC and SC rats. Collectively, these findings suggest innovative insights into advancing our understanding of the molecular mechanisms of enrichment-induced changes in the motivational effects of nicotine, and aiding in the identification of new therapeutic strategies for tobacco smokers. PMID:22952905

  8. Bimodal stimulus timing-dependent plasticity in primary auditory cortex is altered after noise exposure with and without tinnitus.

    PubMed

    Basura, Gregory J; Koehler, Seth D; Shore, Susan E

    2015-12-01

    Central auditory circuits are influenced by the somatosensory system, a relationship that may underlie tinnitus generation. In the guinea pig dorsal cochlear nucleus (DCN), pairing spinal trigeminal nucleus (Sp5) stimulation with tones at specific intervals and orders facilitated or suppressed subsequent tone-evoked neural responses, reflecting spike timing-dependent plasticity (STDP). Furthermore, after noise-induced tinnitus, bimodal responses in DCN were shifted from Hebbian to anti-Hebbian timing rules with less discrete temporal windows, suggesting a role for bimodal plasticity in tinnitus. Here, we aimed to determine if multisensory STDP principles like those in DCN also exist in primary auditory cortex (A1), and whether they change following noise-induced tinnitus. Tone-evoked and spontaneous neural responses were recorded before and 15 min after bimodal stimulation in which the intervals and orders of auditory-somatosensory stimuli were randomized. Tone-evoked and spontaneous firing rates were influenced by the interval and order of the bimodal stimuli, and in sham-controls Hebbian-like timing rules predominated as was seen in DCN. In noise-exposed animals with and without tinnitus, timing rules shifted away from those found in sham-controls to more anti-Hebbian rules. Only those animals with evidence of tinnitus showed increased spontaneous firing rates, a purported neurophysiological correlate of tinnitus in A1. Together, these findings suggest that bimodal plasticity is also evident in A1 following noise damage and may have implications for tinnitus generation and therapeutic intervention across the central auditory circuit.

  9. Liquid-diet with alcohol alters maternal, fetal and placental weights and the expression of molecules involved in integrin signaling in the fetal cerebral cortex.

    PubMed

    Rout, Ujjwal K; Dhossche, Julie M

    2010-11-01

    Maternal alcohol consumption during pregnancy causes wide range of behavioral and structural deficits in children, commonly known as Fetal Alcohol Syndrome (FAS). Children with FAS may suffer behavioral deficits in the absence of obvious malformations. In rodents, the exposure to alcohol during gestation changes brain structures and weights of offspring. The mechanism of FAS is not completely understood. In the present study, an established rat (Long-Evans) model of FAS was used. The litter size and the weights of mothers, fetuses and placentas were examined on gestation days 18 or 20. On gestation day 18, the effects of chronic alcohol on the expression levels of integrin receptor subunits, phospholipase-Cγ and N-cadherin were examined in the fetal cerebral cortices. Presence of alcohol in the liquid-diet reduced the consumption and decreased weights of mothers and fetuses but increased the placental weights. Expression levels of β(1) and α(3) integrin subunits and phospholipase-Cγ(2) were significantly altered in the fetal cerebral cortices of mothers on alcohol containing diet. Results show that alcohol consumption during pregnancy even with protein, mineral and vitamin enriched diet may affect maternal and fetal health, and alter integrin receptor signaling pathways in the fetal cerebral cortex disturbing the development of fetal brains.

  10. Alterations in brain connectivity in three sub-regions of the anterior cingulate cortex in heroin-dependent individuals: Evidence from resting state fMRI.

    PubMed

    Zhang, Y; Gong, J; Xie, C; Ye, E M; Jin, X; Song, H; Yang, Z; Shao, Y

    2015-01-22

    Previous studies that utilized task-based approaches have demonstrated that the chronic use of heroin is associated with altered activity of the anterior cingulate cortex (ACC). However, few studies have focused on examining the variation in resting-state functional connectivity in heroin-dependent individuals, which might help further understanding the mechanisms underlying heroin addiction. Due to the structural and functional heterogeneity of the ACC, we systematically mapped the resting-state functional connectivity patterns of three sub-regions of the ACC in heroin-dependent individuals, wondered whether the partition of three sub-regions of the ACC is feasible in heroin-dependent individuals, and identified how heroin affected the correlated activities among three sub-regions of the ACC using resting-state functional magnetic resonance imaging (fMRI). In the present study, fMRI data were acquired from 21 heroin-dependent individuals (Her group) and 15 non-addicted controls (CN group). Compared to controls, there were reduced functional connectivities in the dorsal ACC (dACC) and rostral ACC (rACC) networks with different areas of the dorsal striatum (the caudate and the putamen) in the Her group. Meanwhile, there exhibited an inverted alteration of pattern for orbital frontal cortex (OFC) and superior frontal gyrus (SFG) in the functional connectivity network with the dACC and subcallosal ACC (sACC), and a different alteration of the cerebellum and the amygdala in the functional connectivity network with the rACC and the sACC. In addition, we also found reduced connectivities between dACC and rACC, as well as reduced connectivities between sACC and dACC. Our findings of variations of functional connectivities in three sub-regions of ACC in Her group implied that these sub-regions of the ACC together with other key brain areas (such as dorsal striatum, OFC, SFG, cerebellum, amygdale, etc.) might potentially play independent and/or overlapping roles in heroin

  11. (1)H NMR based metabolomic profiling revealed doxorubicin-induced systematic alterations in a rat model.

    PubMed

    Niu, Qian-Yun; Li, Zhen-Yu; Du, Guan-Hua; Qin, Xue-Mei

    2016-01-25

    Doxorubicin (DOX) is used as a chemotherapy drug with severe carditoxicity. In this study, an integrated echocardiography along with pathological examination and (1)H NMR analysis of multiple biological matrices (urine, serum, heart, and kidney) was employed to systemically assess the toxicity of DOX. Echocardiographic results showed that impaired left ventricular contractility and degenerative pathology lesions in DOX group, which were in consistent with pathology. The endogenous metabolites in the urine, serum, heart and kidney was identified by comparison with the data from the literature and databases. Multivariate analysis, including PCA and OPLS, revealed 8 metabolites in urine, including succinate, 2-ketoglutarate, citrate, hippurate, methylamine, benzoate, allantion, and acetate were the potential changed biomarkers. In serum, perturbed metabolites include elevation of leucine, β-glucose, O-acetyl-glycoprotein, creatine, lysine, glycerin, dimethylglycine, trimethylamine-N-oxide, myo-inositol, and N-acetyl-glycoprotein, together with level decreases of acetone, lipid, lactate, glutamate, phosphocholine, acetoacetate and pyruvate. For heart, DOX exposure caused decline of lipid, lactate, leucine, alanine, glutamate, choline, xanthine, glycerin, carnitine, and fumarate, together with elevation of glutamine, creatine, inosine, taurine and malate. Metabolic changes of kidney were mainly involved in the accumulation of α-glucose, lactate, phosphocholine, betaine, threonine, choline, taurine, glycine, urea, hypoxanthine, glutamate, and nicotinamide, coupled with reduction of asparagine, valine, methionine, tyrosine, lysine, alanine, leucine, ornithine, creatine, lipid, and acetate. In addition, alterations of urinary metabolites exhibited a time-dependent manner. Complementary evidences by multiple matrices revealed disturbed pathways concerning energy metabolism, fatty acids oxidation, amino acids and purine metabolism, choline metabolism, and gut microbiota

  12. Correlative nonlinear optical microscopy and infrared nanoscopy reveals collagen degradation in altered parchments.

    PubMed

    Latour, Gaël; Robinet, Laurianne; Dazzi, Alexandre; Portier, François; Deniset-Besseau, Ariane; Schanne-Klein, Marie-Claire

    2016-05-19

    This paper presents the correlative imaging of collagen denaturation by nonlinear optical microscopy (NLO) and nanoscale infrared (IR) spectroscopy to obtain morphological and chemical information at different length scales. Such multiscale correlated measurements are applied to the investigation of ancient parchments, which are mainly composed of dermal fibrillar collagen. The main issue is to characterize gelatinization, the ultimate and irreversible alteration corresponding to collagen denaturation to gelatin, which may also occur in biological tissues. Key information about collagen and gelatin signatures is obtained in parchments and assessed by characterizing the denaturation of pure collagen reference samples. A new absorbing band is observed near the amide I band in the IR spectra, correlated to the onset of fluorescence signals in NLO images. Meanwhile, a strong decrease is observed in Second Harmonic signals, which are a structural probe of the fibrillar organization of the collagen at the micrometer scale. NLO microscopy therefore appears as a powerful tool to reveal collagen degradation in a non-invasive way. It should provide a relevant method to assess or monitor the condition of collagen-based materials in museum and archival collections and opens avenues for a broad range of applications regarding this widespread biological material.

  13. Microarray analysis reveals altered circulating microRNA expression in mice infected with Coxsackievirus B3

    PubMed Central

    Sun, Chaoyu; Tong, Lei; Zhao, Wenran; Wang, Yan; Meng, Yuan; Lin, Lexun; Liu, Bingchen; Zhai, Yujia; Zhong, Zhaohua; Li, Xueqi

    2016-01-01

    Coxsackievirus B3 (CVB3) is a common causative agent in the development of inflammatory cardiomyopathy. However, whether the expression of peripheral blood microRNAs (miRNAs) is altered in this process is unknown. The present study investigated changes to miRNA expression in the peripheral blood of CVB3-infected mice. Utilizing miRNA microarray technology, differential miRNA expression was examined between normal and CVB3-infected mice. The present results suggest that specific miRNAs were differentially expressed in the peripheral blood of mice infected with CVB3, varying with infection duration. Using miRNA microarray analysis, a total of 96 and 89 differentially expressed miRNAs were identified in the peripheral blood of mice infected with CVB3 for 3 and 6 days, respectively. Quantitative polymerase chain reaction was used to validate differentially expressed miRNAs, revealing a consistency of these results with the miRNA microarray analysis results. The biological functions of the differentially expressed miRNAs were then predicted by bioinformatics analysis. The potential biological roles of differentially expressed miRNAs included hypertrophic cardiomyopathy, dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. These results may provide important insights into the mechanisms responsible for the progression of CVB3 infection. PMID:27698715

  14. Flicker-assisted localization microscopy reveals altered mitochondrial architecture in hypertension

    PubMed Central

    Chalmers, Susan; Saunter, Christopher D.; Girkin, John M.; McCarron, John G.

    2015-01-01

    Mitochondrial morphology is central to normal physiology and disease development. However, in many live cells and tissues, complex mitochondrial structures exist and morphology has been difficult to quantify. We have measured the shape of electrically-discrete mitochondria, imaging them individually to restore detail hidden in clusters and demarcate functional boundaries. Stochastic “flickers” of mitochondrial membrane potential were visualized with a rapidly-partitioning fluorophore and the pixel-by-pixel covariance of spatio-temporal fluorescence changes analyzed. This Flicker-assisted Localization Microscopy (FaLM) requires only an epifluorescence microscope and sensitive camera. In vascular myocytes, the apparent variation in mitochondrial size was partly explained by densely-packed small mitochondria. In normotensive animals, mitochondria were small spheres or rods. In hypertension, mitochondria were larger, occupied more of the cell volume and were more densely clustered. FaLM provides a convenient tool for increased discrimination of mitochondrial architecture and has revealed mitochondrial alterations that may contribute to hypertension. PMID:26593883

  15. Microarray analysis reveals altered circulating microRNA expression in mice infected with Coxsackievirus B3

    PubMed Central

    Sun, Chaoyu; Tong, Lei; Zhao, Wenran; Wang, Yan; Meng, Yuan; Lin, Lexun; Liu, Bingchen; Zhai, Yujia; Zhong, Zhaohua; Li, Xueqi

    2016-01-01

    Coxsackievirus B3 (CVB3) is a common causative agent in the development of inflammatory cardiomyopathy. However, whether the expression of peripheral blood microRNAs (miRNAs) is altered in this process is unknown. The present study investigated changes to miRNA expression in the peripheral blood of CVB3-infected mice. Utilizing miRNA microarray technology, differential miRNA expression was examined between normal and CVB3-infected mice. The present results suggest that specific miRNAs were differentially expressed in the peripheral blood of mice infected with CVB3, varying with infection duration. Using miRNA microarray analysis, a total of 96 and 89 differentially expressed miRNAs were identified in the peripheral blood of mice infected with CVB3 for 3 and 6 days, respectively. Quantitative polymerase chain reaction was used to validate differentially expressed miRNAs, revealing a consistency of these results with the miRNA microarray analysis results. The biological functions of the differentially expressed miRNAs were then predicted by bioinformatics analysis. The potential biological roles of differentially expressed miRNAs included hypertrophic cardiomyopathy, dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. These results may provide important insights into the mechanisms responsible for the progression of CVB3 infection.

  16. Super-resolution microscopy reveals altered desmosomal protein organization in pemphigus vulgaris patient tissue

    PubMed Central

    Stahley, Sara N.; Warren, Maxine F.; Feldman, Ron J.; Swerlick, Robert A.; Mattheyses, Alexa L.; Kowalczyk, Andrew P.

    2015-01-01

    Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease in which autoantibodies (IgG) are directed against the desmosomal cadherin desmoglein 3 (Dsg3). In order to better understand how PV IgG alters desmosome morphology and function in vivo, PV patient biopsies were analyzed by structured illumination microscopy (SIM), a form of super-resolution fluorescence microscopy. In patient tissue, desmosomal proteins were aberrantly clustered and localized to PV IgG-containing endocytic linear arrays. Patient IgG also colocalized with markers for lipid rafts and endosomes. Additionally, steady-state levels of Dsg3 were decreased and desmosomes were reduced in size in patient tissue. Desmosomes at blister sites were occasionally split, with PV IgG decorating the extracellular faces of split desmosomes. Desmosome splitting was recapitulated in vitro by exposing cultured keratinocytes both to PV IgG and to mechanical stress, demonstrating that splitting at the blister interface in patient tissue is due to compromised desmosomal adhesive function. These findings indicate that Dsg3 clustering and endocytosis are associated with reduced desmosome size and adhesion defects in PV patient tissue. Further, this study reveals that super-resolution optical imaging is powerful approach for studying epidermal adhesion structures in normal and diseased skin. PMID:26763424

  17. Correlative nonlinear optical microscopy and infrared nanoscopy reveals collagen degradation in altered parchments

    NASA Astrophysics Data System (ADS)

    Latour, Gaël; Robinet, Laurianne; Dazzi, Alexandre; Portier, François; Deniset-Besseau, Ariane; Schanne-Klein, Marie-Claire

    2016-05-01

    This paper presents the correlative imaging of collagen denaturation by nonlinear optical microscopy (NLO) and nanoscale infrared (IR) spectroscopy to obtain morphological and chemical information at different length scales. Such multiscale correlated measurements are applied to the investigation of ancient parchments, which are mainly composed of dermal fibrillar collagen. The main issue is to characterize gelatinization, the ultimate and irreversible alteration corresponding to collagen denaturation to gelatin, which may also occur in biological tissues. Key information about collagen and gelatin signatures is obtained in parchments and assessed by characterizing the denaturation of pure collagen reference samples. A new absorbing band is observed near the amide I band in the IR spectra, correlated to the onset of fluorescence signals in NLO images. Meanwhile, a strong decrease is observed in Second Harmonic signals, which are a structural probe of the fibrillar organization of the collagen at the micrometer scale. NLO microscopy therefore appears as a powerful tool to reveal collagen degradation in a non-invasive way. It should provide a relevant method to assess or monitor the condition of collagen-based materials in museum and archival collections and opens avenues for a broad range of applications regarding this widespread biological material.

  18. Inflammation-related alterations of lipids after spinal cord injury revealed by Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Tamosaityte, Sandra; Galli, Roberta; Uckermann, Ortrud; Sitoci-Ficici, Kerim H.; Koch, Maria; Later, Robert; Schackert, Gabriele; Koch, Edmund; Steiner, Gerald; Kirsch, Matthias

    2016-06-01

    Spinal cord injury (SCI) triggers several lipid alterations in nervous tissue. It is characterized by extensive demyelination and the inflammatory response leads to accumulation of activated microglia/macrophages, which often transform into foam cells by accumulation of lipid droplets after engulfment of the damaged myelin sheaths. Using an experimental rat model, Raman microspectroscopy was applied to retrieve the modifications of the lipid distribution following SCI. Coherent anti-Stokes Raman scattering (CARS) and endogenous two-photon fluorescence (TPEF) microscopies were used for the detection of lipid-laden inflammatory cells. The Raman mapping of CH2 deformation mode intensity at 1440 cm-1 retrieved the lipid-depleted injury core. Preserved white matter and inflammatory regions with myelin fragmentation and foam cells were localized by specifically addressing the distribution of esterified lipids, i.e., by mapping the intensity of the carbonyl Raman band at 1743 cm-1, and were in agreement with CARS/TPEF microscopy. Principal component analysis revealed that the inflammatory regions are notably rich in saturated fatty acids. Therefore, Raman spectroscopy enabled to specifically detect inflammation after SCI and myelin degradation products.

  19. Glycoproteomic Study Reveals Altered Plasma Proteins Associated with HIV Elite Suppressors

    PubMed Central

    Yang, Weiming; Laeyendecker, Oliver; Wendel, Sarah K.; Zhang, Bai; Sun, Shisheng; Zhou, Jian-Ying; Ao, Minghui; Moore, Richard D.; Jackson, J. Brooks; Zhang, Hui

    2014-01-01

    HIV elite suppressors (ES) or controllers are individuals achieving control of viremia by their natural immunological mechanisms without highly active antiretroviral therapy (HAART). Study of the mechanisms responsible for the immunological suppression of viremia in ES may lead to the detection of individuals with ES and the effective control of HIV infection. We hypothesize that plasma glycoproteins play essential roles in the immune system of ES since plasma proteins are critical and highly relevant in anti-viral immunity and most plasma proteins are glycoproteins. To examine glycoproteins associated with ES, plasma samples from ES individuals (n=20), and from individuals on HAART (n=20), with AIDS (n=20), and no HIV infection (n=10) were analyzed by quantitative glycoproteomics. We found that a number of glycoproteins changed between ES versus HAART, AIDS and HIV- individuals. In sharp contrast, the level of plasma glycoproteins in the HAART cohort showed fewer changes compared with AIDS and HIV- individuals. These results showed that although both ES and HAART effectively suppress viremia, ES appeared to profoundly affect immunologically relevant glycoproteins in plasma as consequence of or support for anti-viral immunity. Bioinformatic analysis revealed that altered proteins in ES plasma were mainly associated with inflammation. This analysis suggests that overlapping, while distinguishable, glycoprotein profiles for inflammation and immune activation appeared to be present between ES and non-ES (HAART+AIDS) cohorts, indicating different triggers for inflammation and immune activation between natural and treatment-related viral suppression. PMID:25285165

  20. Correlative nonlinear optical microscopy and infrared nanoscopy reveals collagen degradation in altered parchments

    PubMed Central

    Latour, Gaël; Robinet, Laurianne; Dazzi, Alexandre; Portier, François; Deniset-Besseau, Ariane; Schanne-Klein, Marie-Claire

    2016-01-01

    This paper presents the correlative imaging of collagen denaturation by nonlinear optical microscopy (NLO) and nanoscale infrared (IR) spectroscopy to obtain morphological and chemical information at different length scales. Such multiscale correlated measurements are applied to the investigation of ancient parchments, which are mainly composed of dermal fibrillar collagen. The main issue is to characterize gelatinization, the ultimate and irreversible alteration corresponding to collagen denaturation to gelatin, which may also occur in biological tissues. Key information about collagen and gelatin signatures is obtained in parchments and assessed by characterizing the denaturation of pure collagen reference samples. A new absorbing band is observed near the amide I band in the IR spectra, correlated to the onset of fluorescence signals in NLO images. Meanwhile, a strong decrease is observed in Second Harmonic signals, which are a structural probe of the fibrillar organization of the collagen at the micrometer scale. NLO microscopy therefore appears as a powerful tool to reveal collagen degradation in a non-invasive way. It should provide a relevant method to assess or monitor the condition of collagen-based materials in museum and archival collections and opens avenues for a broad range of applications regarding this widespread biological material. PMID:27194180

  1. Correlative nonlinear optical microscopy and infrared nanoscopy reveals collagen degradation in altered parchments.

    PubMed

    Latour, Gaël; Robinet, Laurianne; Dazzi, Alexandre; Portier, François; Deniset-Besseau, Ariane; Schanne-Klein, Marie-Claire

    2016-01-01

    This paper presents the correlative imaging of collagen denaturation by nonlinear optical microscopy (NLO) and nanoscale infrared (IR) spectroscopy to obtain morphological and chemical information at different length scales. Such multiscale correlated measurements are applied to the investigation of ancient parchments, which are mainly composed of dermal fibrillar collagen. The main issue is to characterize gelatinization, the ultimate and irreversible alteration corresponding to collagen denaturation to gelatin, which may also occur in biological tissues. Key information about collagen and gelatin signatures is obtained in parchments and assessed by characterizing the denaturation of pure collagen reference samples. A new absorbing band is observed near the amide I band in the IR spectra, correlated to the onset of fluorescence signals in NLO images. Meanwhile, a strong decrease is observed in Second Harmonic signals, which are a structural probe of the fibrillar organization of the collagen at the micrometer scale. NLO microscopy therefore appears as a powerful tool to reveal collagen degradation in a non-invasive way. It should provide a relevant method to assess or monitor the condition of collagen-based materials in museum and archival collections and opens avenues for a broad range of applications regarding this widespread biological material. PMID:27194180

  2. The microRNA network is altered in anterior cingulate cortex of patients with unipolar and bipolar depression.

    PubMed

    Azevedo, Joshua A; Carter, Bradley S; Meng, Fan; Turner, David L; Dai, Manhong; Schatzberg, Alan F; Barchas, Jack D; Jones, Edward G; Bunney, William E; Myers, Richard M; Akil, Huda; Watson, Stanley J; Thompson, Robert C

    2016-11-01

    MicroRNAs (miRNAs) are small, non-coding RNAs acting as post-transcriptional regulators of gene expression. Though implicated in multiple CNS disorders, miRNAs have not been examined in any psychiatric disease state in anterior cingulate cortex (AnCg), a brain region centrally involved in regulating mood. We performed qPCR analyses of 29 miRNAs previously implicated in psychiatric illness (major depressive disorder (MDD), bipolar disorder (BP) and/or schizophrenia (SZ)) in AnCg of patients with MDD and BP versus controls. miR-132, miR-133a and miR-212 were initially identified as differentially expressed in BP, miR-184 in MDD and miR-34a in both MDD and BP (although none survived multiple correction testing and must be considered preliminary). In silico target prediction algorithms identified putative targets of differentially expressed miRNAs. Nuclear Co-Activator 1 (NCOA1), Nuclear Co-Repressor 2 (NCOR2) and Phosphodiesterase 4B (PDE4B) were selected based upon predicted targeting by miR-34a (with NCOR2 and PDE4B both targeted by miR-184) and published relevance to psychiatric illness. Luciferase assays identified PDE4B as a target of miR-34a and miR-184, while NCOA1 and NCOR2 were targeted by miR-34a and 184, respectively. qPCR analyses were performed to determine whether changes in miRNA levels correlated with mRNA levels of validated targets. NCOA1 showed an inverse correlation with miR-34a in BP, while NCOR2 demonstrated a positive correlation. In sum, this is the first study to demonstrate miRNA changes in AnCg in psychiatric illness and validate miR-34a as differentially expressed in CNS in MDD. These findings support a mechanistic role for miRNAs in the regulation of stress-responsive genes disrupted in psychiatric illness. PMID:27468165

  3. Functionally Brain Network Connected to the Retrosplenial Cortex of Rats Revealed by 7T fMRI.

    PubMed

    Wang, Jingjuan; Nie, Binbin; Duan, Shaofeng; Zhu, Haitao; Liu, Hua; Shan, Baoci

    2016-01-01

    Functional networks are regarded as important mechanisms for increasing our understanding of brain function in healthy and diseased states, and increased interest has been focused on extending the study of functional networks to animal models because such models provide a functional understanding of disease progression, therapy and repair. In rodents, the retrosplenial cortex (RSC) is an important cortical region because it has a large size and presents transitional patterns of lamination between the neocortex and archicortex. In addition, a number of invasive studies have highlighted the importance of the RSC for many functions. However, the network based on the RSC in rodents remains unclear. Based on the critical importance of the RSC, we defined the bilateral RSCs as two regions of interest and estimated the network based on the RSC. The results showed that the related regions include the parietal association cortex, hippocampus, thalamus nucleus, midbrain structures, and hypothalamic mammillary bodies. Our findings indicate two possible major networks: a sensory-cognitive network that has a hub in the RSCs and processes sensory information, spatial learning, and episodic memory; and a second network that is involved in the regulation of visceral functions and arousal. In addition, functional asymmetry between the bilateral RSCs was observed.

  4. Connectivity profiles reveal the relationship between brain areas for social cognition in human and monkey temporoparietal cortex.

    PubMed

    Mars, Rogier B; Sallet, Jérôme; Neubert, Franz-Xaver; Rushworth, Matthew F S

    2013-06-25

    The human ability to infer the thoughts and beliefs of others, often referred to as "theory of mind," as well as the predisposition to even consider others, are associated with activity in the temporoparietal junction (TPJ) area. Unlike the case of most human brain areas, we have little sense of whether or how TPJ is related to brain areas in other nonhuman primates. It is not possible to address this question by looking for similar task-related activations in nonhuman primates because there is no evidence that nonhuman primates engage in theory-of-mind tasks in the same manner as humans. Here, instead, we explore the relationship by searching for areas in the macaque brain that interact with other macaque brain regions in the same manner as human TPJ interacts with other human brain regions. In other words, we look for brain regions with similar positions within a distributed neural circuit in the two species. We exploited the fact that human TPJ has a unique functional connectivity profile with cortical areas with known homologs in the macaque. For each voxel in the macaque temporal and parietal cortex we evaluated the similarity of its functional connectivity profile to that of human TPJ. We found that areas in the middle part of the superior temporal cortex, often associated with the processing of faces and other social stimuli, have the most similar connectivity profile. These results suggest that macaque face processing areas and human mentalizing areas might have a similar precursor.

  5. Regional inactivations of primate ventral prefrontal cortex reveal two distinct mechanisms underlying negative bias in decision making

    PubMed Central

    Clarke, Hannah F.; Horst, Nicole K.; Roberts, Angela C.

    2015-01-01

    Dysregulation of the orbitofrontal and ventrolateral prefrontal cortices is implicated in anxiety and mood disorders, but the specific contributions of each region are unknown, including how they gate the impact of threat on decision making. To address this, the effects of GABAergic inactivation of these regions were studied in marmoset monkeys performing an instrumental approach–avoidance decision-making task that is sensitive to changes in anxiety. Inactivation of either region induced a negative bias away from punishment that could be ameliorated with anxiolytic treatment. However, whereas the effects of ventrolateral prefrontal cortex inactivation on punishment avoidance were seen immediately, those of orbitofrontal cortex inactivation were delayed and their expression was dependent upon an amygdala–anterior hippocampal circuit. We propose that these negative biases result from deficits in attentional control and punishment prediction, respectively, and that they provide the basis for understanding how distinct regional prefrontal dysregulation contributes to the heterogeneity of anxiety disorders with implications for cognitive-behavioral treatment strategies. PMID:25775597

  6. Functionally Brain Network Connected to the Retrosplenial Cortex of Rats Revealed by 7T fMRI

    PubMed Central

    Wang, Jingjuan; Nie, Binbin; Duan, Shaofeng; Zhu, Haitao; Liu, Hua; Shan, Baoci

    2016-01-01

    Functional networks are regarded as important mechanisms for increasing our understanding of brain function in healthy and diseased states, and increased interest has been focused on extending the study of functional networks to animal models because such models provide a functional understanding of disease progression, therapy and repair. In rodents, the retrosplenial cortex (RSC) is an important cortical region because it has a large size and presents transitional patterns of lamination between the neocortex and archicortex. In addition, a number of invasive studies have highlighted the importance of the RSC for many functions. However, the network based on the RSC in rodents remains unclear. Based on the critical importance of the RSC, we defined the bilateral RSCs as two regions of interest and estimated the network based on the RSC. The results showed that the related regions include the parietal association cortex, hippocampus, thalamus nucleus, midbrain structures, and hypothalamic mammillary bodies. Our findings indicate two possible major networks: a sensory-cognitive network that has a hub in the RSCs and processes sensory information, spatial learning, and episodic memory; and a second network that is involved in the regulation of visceral functions and arousal. In addition, functional asymmetry between the bilateral RSCs was observed. PMID:26745803

  7. Functionally Brain Network Connected to the Retrosplenial Cortex of Rats Revealed by 7T fMRI.

    PubMed

    Wang, Jingjuan; Nie, Binbin; Duan, Shaofeng; Zhu, Haitao; Liu, Hua; Shan, Baoci

    2016-01-01

    Functional networks are regarded as important mechanisms for increasing our understanding of brain function in healthy and diseased states, and increased interest has been focused on extending the study of functional networks to animal models because such models provide a functional understanding of disease progression, therapy and repair. In rodents, the retrosplenial cortex (RSC) is an important cortical region because it has a large size and presents transitional patterns of lamination between the neocortex and archicortex. In addition, a number of invasive studies have highlighted the importance of the RSC for many functions. However, the network based on the RSC in rodents remains unclear. Based on the critical importance of the RSC, we defined the bilateral RSCs as two regions of interest and estimated the network based on the RSC. The results showed that the related regions include the parietal association cortex, hippocampus, thalamus nucleus, midbrain structures, and hypothalamic mammillary bodies. Our findings indicate two possible major networks: a sensory-cognitive network that has a hub in the RSCs and processes sensory information, spatial learning, and episodic memory; and a second network that is involved in the regulation of visceral functions and arousal. In addition, functional asymmetry between the bilateral RSCs was observed. PMID:26745803

  8. Low level postnatal methylmercury exposure in vivo alters developmental forms of short-term synaptic plasticity in the visual cortex of rat

    SciTech Connect

    Dasari, Sameera; Yuan, Yukun

    2009-11-01

    Methylmercury (MeHg) has been previously shown to affect neurotransmitter release. Short-term synaptic plasticity (STP) is primarily related to changes in the probability of neurotransmitter release. To determine if MeHg affects STP development, we examined STP forms in the visual cortex of rat following in vivo MeHg exposure. Neonatal rats received 0 (0.9% NaCl), 0.75 or 1.5 mg/kg/day MeHg subcutaneously for 15 or 30 days beginning on postnatal day 5, after which visual cortical slices were prepared for field potential recordings. In slices prepared from rats treated with vehicle, field excitatory postsynaptic potentials (fEPSPs) evoked by paired-pulse stimulation at 20-200 ms inter-stimulus intervals showed a depression (PPD) of the second fEPSP (fEPSP2). PPD was also seen in slices prepared from rats after 15 day treatment with 0.75 or 1.5 mg/kg/day MeHg. However, longer duration treatment (30 days) with either dose of MeHg resulted in paired-pulse facilitation (PPF) of fEPSP2 in the majority of slices examined. PPF remained observable in slices prepared from animals in which MeHg exposure had been terminated for 30 days after completion of the initial 30 day MeHg treatment, whereas slices from control animals still showed PPD. MeHg did not cause any frequency- or region-preferential effect on STP. Manipulations of [Ca{sup 2+}]{sub e} or application of the GABA{sub A} receptor antagonist bicuculline could alter the strength and polarity of MeHg-induced changes in STP. Thus, these data suggest that low level postnatal MeHg exposure interferes with the developmental transformation of STP in the visual cortex, which is a long-lasting effect.

  9. Characterization of 4-HNE modified L-FABP reveals alterations in structural and functional dynamics.

    PubMed

    Smathers, Rebecca L; Fritz, Kristofer S; Galligan, James J; Shearn, Colin T; Reigan, Philip; Marks, Michael J; Petersen, Dennis R

    2012-01-01

    4-Hydroxynonenal (4-HNE) is a reactive α,β-unsaturated aldehyde produced during oxidative stress and subsequent lipid peroxidation of polyunsaturated fatty acids. The reactivity of 4-HNE towards DNA and nucleophilic amino acids has been well established. In this report, using proteomic approaches, liver fatty acid-binding protein (L-FABP) is identified as a target for modification by 4-HNE. This lipid binding protein mediates the uptake and trafficking of hydrophobic ligands throughout cellular compartments. Ethanol caused a significant decrease in L-FABP protein (P<0.001) and mRNA (P<0.05), as well as increased poly-ubiquitinated L-FABP (P<0.001). Sites of 4-HNE adduction on mouse recombinant L-FABP were mapped using MALDI-TOF/TOF mass spectrometry on apo (Lys57 and Cys69) and holo (Lys6, Lys31, His43, Lys46, Lys57 and Cys69) L-FABP. The impact of 4-HNE adduction was found to occur in a concentration-dependent manner; affinity for the fluorescent ligand, anilinonaphthalene-8-sulfonic acid, was reduced from 0.347 µM to Kd(1) = 0.395 µM and Kd(2) = 34.20 µM. Saturation analyses revealed that capacity for ligand is reduced by approximately 50% when adducted by 4-HNE. Thermal stability curves of apo L-FABP was also found to be significantly affected by 4-HNE adduction (ΔTm = 5.44°C, P<0.01). Computational-based molecular modeling simulations of adducted protein revealed minor conformational changes in global protein structure of apo and holo L-FABP while more apparent differences were observed within the internal binding pocket, revealing reduced area and structural integrity. New solvent accessible portals on the periphery of the protein were observed following 4-HNE modification in both the apo and holo state, suggesting an adaptive response to carbonylation. The results from this study detail the dynamic process associated with L-FABP modification by 4-HNE and provide insight as to how alterations in structural integrity and ligand binding may a

  10. Learning-related representational changes reveal dissociable integration and separation signatures in the hippocampus and prefrontal cortex

    PubMed Central

    Schlichting, Margaret L.; Mumford, Jeanette A.; Preston, Alison R.

    2015-01-01

    The episodic memory system enables accurate retrieval while maintaining flexibility by representing both specific episodes and generalizations across events. Although theories suggest that the hippocampus (HPC) is dedicated to represent specific episodes while the medial prefrontal cortex (MPFC) generalizes, other accounts posit that HPC can also integrate related memories. Here we use high-resolution functional magnetic resonance imaging in humans to examine how representations of memory elements change to either differentiate or generalize across related events. We show that while posterior HPC and anterior MPFC maintain distinct memories for individual events, anterior HPC and posterior MPFC integrate across memories. Integration is particularly likely for established memories versus those encoded simultaneously, highlighting the greater impact of prior knowledge on new encoding. We also show dissociable coding signatures in ventrolateral PFC, a region previously implicated in interference resolution. These data highlight how memory elements are represented to simultaneously promote generalization across memories and protect from interference. PMID:26303198

  11. Learning-related representational changes reveal dissociable integration and separation signatures in the hippocampus and prefrontal cortex.

    PubMed

    Schlichting, Margaret L; Mumford, Jeanette A; Preston, Alison R

    2015-08-25

    The episodic memory system enables accurate retrieval while maintaining flexibility by representing both specific episodes and generalizations across events. Although theories suggest that the hippocampus (HPC) is dedicated to represent specific episodes while the medial prefrontal cortex (MPFC) generalizes, other accounts posit that HPC can also integrate related memories. Here we use high-resolution functional magnetic resonance imaging in humans to examine how representations of memory elements change to either differentiate or generalize across related events. We show that while posterior HPC and anterior MPFC maintain distinct memories for individual events, anterior HPC and posterior MPFC integrate across memories. Integration is particularly likely for established memories versus those encoded simultaneously, highlighting the greater impact of prior knowledge on new encoding. We also show dissociable coding signatures in ventrolateral PFC, a region previously implicated in interference resolution. These data highlight how memory elements are represented to simultaneously promote generalization across memories and protect from interference.

  12. Genomic Convergence Analysis of Schizophrenia: mRNA Sequencing Reveals Altered Synaptic Vesicular Transport in Post-Mortem Cerebellum

    PubMed Central

    Mudge, Joann; Miller, Neil A.; Khrebtukova, Irina; Lindquist, Ingrid E.; May, Gregory D.; Huntley, Jim J.; Luo, Shujun; Zhang, Lu; van Velkinburgh, Jennifer C.; Farmer, Andrew D.; Lewis, Sharon; Beavis, William D.; Schilkey, Faye D.; Virk, Selene M.; Black, C. Forrest; Myers, M. Kathy; Mader, Lar C.; Langley, Ray J.; Utsey, John P.; Kim, Ryan W.; Roberts, Rosalinda C.; Khalsa, Sat Kirpal; Garcia, Meredith; Ambriz-Griffith, Victoria; Harlan, Richard; Czika, Wendy; Martin, Stanton; Wolfinger, Russell D.; Perrone-Bizzozero, Nora I.; Schroth, Gary P.; Kingsmore, Stephen F.

    2008-01-01

    Schizophrenia (SCZ) is a common, disabling mental illness with high heritability but complex, poorly understood genetic etiology. As the first phase of a genomic convergence analysis of SCZ, we generated 16.7 billion nucleotides of short read, shotgun sequences of cDNA from post-mortem cerebellar cortices of 14 patients and six, matched controls. A rigorous analysis pipeline was developed for analysis of digital gene expression studies. Sequences aligned to approximately 33,200 transcripts in each sample, with average coverage of 450 reads per gene. Following adjustments for confounding clinical, sample and experimental sources of variation, 215 genes differed significantly in expression between cases and controls. Golgi apparatus, vesicular transport, membrane association, Zinc binding and regulation of transcription were over-represented among differentially expressed genes. Twenty three genes with altered expression and involvement in presynaptic vesicular transport, Golgi function and GABAergic neurotransmission define a unifying molecular hypothesis for dysfunction in cerebellar cortex in SCZ. PMID:18985160

  13. Brain-derived neurotrophic factor increases inhibitory synapses, revealed in solitary neurons cultured from rat visual cortex.

    PubMed

    Palizvan, M R; Sohya, K; Kohara, K; Maruyama, A; Yasuda, H; Kimura, F; Tsumoto, T

    2004-01-01

    To elucidate chronic actions of brain-derived neurotrophic factor (BDNF) on GABAergic synapses, we examined effects of a long-term application of BDNF for 10-15 days on autapses (synapses) of solitary GABAergic neurons cultured from rat visual cortex. Solitary neuron preparations were used to exclude a possible contamination of BDNF actions on excitatory neurons in dissociated neuron culture or slice preparations. Neurons were confirmed to be GABAergic pharmacologically with bicuculline, a selective antagonist for GABAA receptors and immunocytochemically with antibody against glutamic acid decarboxylase 65, a GABA synthesizing enzyme. To evaluate GABAergic synaptic function, evoked and/or miniature inhibitory postsynaptic currents (IPSCs) were recorded in the whole-cell voltage-clamp mode. The treatment with BDNF at a concentration of 100 ng/ml enhanced the amplitude of evoked IPSCs and the frequency of miniature IPSCs. In contrast, BDNF did not have a detectable effect on the amplitude of miniature IPSCs and the paired pulse ratio of IPSCs evoked by two, successive activations. To evaluate morphological changes, neurons were immunocytochemically stained with antibodies against microtubule-associated protein 2, to visualize somatodendritic region and synapsin I, to visualize presynaptic sites. The quantitative analysis indicated that BDNF increased the area of soma, the numbers of primary dendrites and dendritic branching points, the total length of dendrites and the number of synaptic sites. Such an action of BDNF was seen in both subgroups of GABAergic neurons, parvalbumin-positive and -negative neurons. To visualize functionally active presynaptic sites, neurons were stained with a styryl dye, FM1-43. BDNF increased the number of stained sites that was correlated with the frequency of miniature IPSCs. These results suggest that the chronic treatment with BDNF promotes dendritic and synaptic development of GABAergic neurons in visual cortex.

  14. Structure of Spike Count Correlations Reveals Functional Interactions between Neurons in Dorsolateral Prefrontal Cortex Area 8a of Behaving Primates

    PubMed Central

    Leavitt, Matthew L.; Pieper, Florian; Sachs, Adam; Joober, Ridha; Martinez-Trujillo, Julio C.

    2013-01-01

    Neurons within the primate dorsolateral prefrontal cortex (dlPFC) are clustered in microcolumns according to their visuospatial tuning. One issue that remains poorly investigated is how this anatomical arrangement influences functional interactions between neurons during behavior. To investigate this question we implanted 4 mm×4 mm multielectrode arrays in two macaques' dlPFC area 8a and measured spike count correlations (rsc) between responses of simultaneously recorded neurons when animals maintained stationary gaze. Positive and negative rsc were significantly higher than predicted by chance across a wide range of inter-neuron distances (from 0.4 to 4 mm). Positive rsc were stronger between neurons with receptive fields (RFs) separated by ≤90° of angular distance and progressively decreased as a function of inter-neuron physical distance. Negative rsc were stronger between neurons with RFs separated by >90° and increased as a function of inter-neuron distance. Our results show that short- and long-range functional interactions between dlPFC neurons depend on the physical distance between them and the relationship between their visuospatial tuning preferences. Neurons with similar visuospatial tuning show positive rsc that decay with inter-neuron distance, suggestive of excitatory interactions within and between adjacent microcolumns. Neurons with dissimilar tuning from spatially segregated microcolumns show negative rsc that increase with inter-neuron distance, suggestive of inhibitory interactions. This pattern of results shows that functional interactions between prefrontal neurons closely follow the pattern of connectivity reported in anatomical studies. Such interactions may be important for the role of the prefrontal cortex in the allocation of attention to targets in the presence of competing distracters. PMID:23630595

  15. Temporal precision in population—but not individual neuron—dynamics reveals rapid experience-dependent plasticity in the rat barrel cortex

    PubMed Central

    Eldawlatly, Seif; Oweiss, Karim G.

    2014-01-01

    Cortical reorganization following sensory deprivation is characterized by alterations in the connectivity between neurons encoding spared and deprived cortical inputs. The extent to which this alteration depends on Spike Timing Dependent Plasticity (STDP), however, is largely unknown. We quantified changes in the functional connectivity between layer V neurons in the vibrissal primary somatosensory cortex (vSI) (barrel cortex) of rats following sensory deprivation. One week after chronic implantation of a microelectrode array in vSI, sensory-evoked activity resulting from mechanical deflections of individual whiskers was recorded (control data) after which two whiskers on the contralateral side were paired by sparing them while trimming all other whiskers on the rat's mystacial pad. The rats' environment was then enriched by placing novel objects in the cages to encourage exploratory behavior with the spared whiskers. Sensory-evoked activity in response to individual stimulation of spared whiskers and adjacent re-grown whiskers was then recorded under anesthesia 1–2 days and 6–7 days post-trimming (plasticity data). We analyzed spike trains within 100 ms of stimulus onset and confirmed previously published reports documenting changes in receptive field sizes in the spared whisker barrels. We analyzed the same data using Dynamic Bayesian Networks (DBNs) to infer the functional connectivity between the recorded neurons. We found that DBNs inferred from population responses to stimulation of each of the spared whiskers exhibited graded increase in similarity that was proportional to the pairing duration. A significant early increase in network similarity in the spared-whisker barrels was detected 1–2 days post pairing, but not when single neuron responses were examined during the same period. These results suggest that rapid reorganization of cortical neurons following sensory deprivation may be mediated by an STDP mechanism. PMID:25505407

  16. A patient with altered mental status and possible seizure reveals an atypical aortic dissection upon workup.

    PubMed

    Lawal, Olufolahan J; Dhindsa, Harinder S; Loyd, Joshua W

    2014-05-01

    Aortic dissection occurs when a tear occurs in the inner muscle wall lining of the aorta, allowing blood to split the muscle layers of the aortic wall apart. It is classically characterized by pain that starts in the upper chest, which then radiates to the upper back and is tearing or ripping in quality. Our objective is to present a case followed by a brief literature review of aortic dissection and uncommon but important features that may be demonstrated. In this report, we present the case of a 57-year-old woman who was transported to the emergency department with an acute episode of altered mental status, presenting as a possible stroke with possible seizures. The patient's only complaint was mild low back pain. Physical examination revealed disorientation to time with no other neurologic deficits or abnormal findings. Results from initial noncontrast head computed tomography, chest radiograph, and laboratory studies were all normal, except for an elevated D-dimer and serum creatinine. Chest computed tomography with contrast demonstrated a type A aortic dissection. The patient was taken emergently to the operating room where the aortic valve and a portion of the ascending aorta were replaced. The patient did well and was discharged from the hospital 5 days later without any permanent sequalae. Aortic dissection is both rare and life threatening and may present with atypical signs. It is important to note that patients may show no signs of typical features or may even display other symptoms based on other branches from the aorta that have been occluded. PMID:24360026

  17. Untargeted Metabolomics Reveals Predominant Alterations in Lipid Metabolism Following Light Exposure in Broccoli Sprouts.

    PubMed

    Maldini, Mariateresa; Natella, Fausta; Baima, Simona; Morelli, Giorgio; Scaccini, Cristina; Langridge, James; Astarita, Giuseppe

    2015-01-01

    The consumption of vegetables belonging to the family Brassicaceae (e.g., broccoli and cauliflower) is linked to a reduced incidence of cancer and cardiovascular diseases. The molecular composition of such plants is strongly affected by growing conditions. Here we developed an unbiased metabolomics approach to investigate the effect of light and dark exposure on the metabolome of broccoli sprouts and we applied such an approach to provide a bird's-eye view of the overall metabolic response after light exposure. Broccoli seeds were germinated and grown hydroponically for five days in total darkness or with a light/dark photoperiod (16 h light/8 h dark cycle). We used an ultra-performance liquid-chromatography system coupled to an ion-mobility, time-of-flight mass spectrometer to profile the large array of metabolites present in the sprouts. Differences at the metabolite level between groups were analyzed using multivariate statistical analyses, including principal component analysis and correlation analysis. Altered metabolites were identified by searching publicly available and in-house databases. Metabolite pathway analyses were used to support the identification of subtle but significant changes among groups of related metabolites that may have gone unnoticed with conventional approaches. Besides the chlorophyll pathway, light exposure activated the biosynthesis and metabolism of sterol lipids, prenol lipids, and polyunsaturated lipids, which are essential for the photosynthetic machinery. Our results also revealed that light exposure increased the levels of polyketides, including flavonoids, and oxylipins, which play essential roles in the plant's developmental processes and defense mechanism against herbivores. This study highlights the significant contribution of light exposure to the ultimate metabolic phenotype, which might affect the cellular physiology and nutritional value of broccoli sprouts. Furthermore, this study highlights the potential of an

  18. Mars 520-d mission simulation reveals protracted crew hypokinesis and alterations of sleep duration and timing.

    PubMed

    Basner, Mathias; Dinges, David F; Mollicone, Daniel; Ecker, Adrian; Jones, Christopher W; Hyder, Eric C; Di Antonio, Adrian; Savelev, Igor; Kan, Kevin; Goel, Namni; Morukov, Boris V; Sutton, Jeffrey P

    2013-02-12

    The success of interplanetary human spaceflight will depend on many factors, including the behavioral activity levels, sleep, and circadian timing of crews exposed to prolonged microgravity and confinement. To address the effects of the latter, we used a high-fidelity ground simulation of a Mars mission to objectively track sleep-wake dynamics in a multinational crew of six during 520 d of confined isolation. Measurements included continuous recordings of wrist actigraphy and light exposure (4.396 million min) and weekly computer-based neurobehavioral assessments (n = 888) to identify changes in the crew's activity levels, sleep quantity and quality, sleep-wake periodicity, vigilance performance, and workload throughout the record-long 17 mo of mission confinement. Actigraphy revealed that crew sedentariness increased across the mission as evident in decreased waking movement (i.e., hypokinesis) and increased sleep and rest times. Light exposure decreased during the mission. The majority of crewmembers also experienced one or more disturbances of sleep quality, vigilance deficits, or altered sleep-wake periodicity and timing, suggesting inadequate circadian entrainment. The results point to the need to identify markers of differential vulnerability to hypokinesis and sleep-wake changes during the prolonged isolation of exploration spaceflight and the need to ensure maintenance of circadian entrainment, sleep quantity and quality, and optimal activity levels during exploration missions. Therefore, successful adaptation to such missions will require crew to transit in spacecraft and live in surface habitats that instantiate aspects of Earth's geophysical signals (appropriately timed light exposure, food intake, exercise) required for temporal organization and maintenance of human behavior.

  19. Untargeted Metabolomics Reveals Predominant Alterations in Lipid Metabolism Following Light Exposure in Broccoli Sprouts.

    PubMed

    Maldini, Mariateresa; Natella, Fausta; Baima, Simona; Morelli, Giorgio; Scaccini, Cristina; Langridge, James; Astarita, Giuseppe

    2015-06-15

    The consumption of vegetables belonging to the family Brassicaceae (e.g., broccoli and cauliflower) is linked to a reduced incidence of cancer and cardiovascular diseases. The molecular composition of such plants is strongly affected by growing conditions. Here we developed an unbiased metabolomics approach to investigate the effect of light and dark exposure on the metabolome of broccoli sprouts and we applied such an approach to provide a bird's-eye view of the overall metabolic response after light exposure. Broccoli seeds were germinated and grown hydroponically for five days in total darkness or with a light/dark photoperiod (16 h light/8 h dark cycle). We used an ultra-performance liquid-chromatography system coupled to an ion-mobility, time-of-flight mass spectrometer to profile the large array of metabolites present in the sprouts. Differences at the metabolite level between groups were analyzed using multivariate statistical analyses, including principal component analysis and correlation analysis. Altered metabolites were identified by searching publicly available and in-house databases. Metabolite pathway analyses were used to support the identification of subtle but significant changes among groups of related metabolites that may have gone unnoticed with conventional approaches. Besides the chlorophyll pathway, light exposure activated the biosynthesis and metabolism of sterol lipids, prenol lipids, and polyunsaturated lipids, which are essential for the photosynthetic machinery. Our results also revealed that light exposure increased the levels of polyketides, including flavonoids, and oxylipins, which play essential roles in the plant's developmental processes and defense mechanism against herbivores. This study highlights the significant contribution of light exposure to the ultimate metabolic phenotype, which might affect the cellular physiology and nutritional value of broccoli sprouts. Furthermore, this study highlights the potential of an

  20. Untargeted Metabolomics Reveals Predominant Alterations in Lipid Metabolism Following Light Exposure in Broccoli Sprouts

    PubMed Central

    Maldini, Mariateresa; Natella, Fausta; Baima, Simona; Morelli, Giorgio; Scaccini, Cristina; Langridge, James; Astarita, Giuseppe

    2015-01-01

    The consumption of vegetables belonging to the family Brassicaceae (e.g., broccoli and cauliflower) is linked to a reduced incidence of cancer and cardiovascular diseases. The molecular composition of such plants is strongly affected by growing conditions. Here we developed an unbiased metabolomics approach to investigate the effect of light and dark exposure on the metabolome of broccoli sprouts and we applied such an approach to provide a bird’s-eye view of the overall metabolic response after light exposure. Broccoli seeds were germinated and grown hydroponically for five days in total darkness or with a light/dark photoperiod (16 h light/8 h dark cycle). We used an ultra-performance liquid-chromatography system coupled to an ion-mobility, time-of-flight mass spectrometer to profile the large array of metabolites present in the sprouts. Differences at the metabolite level between groups were analyzed using multivariate statistical analyses, including principal component analysis and correlation analysis. Altered metabolites were identified by searching publicly available and in-house databases. Metabolite pathway analyses were used to support the identification of subtle but significant changes among groups of related metabolites that may have gone unnoticed with conventional approaches. Besides the chlorophyll pathway, light exposure activated the biosynthesis and metabolism of sterol lipids, prenol lipids, and polyunsaturated lipids, which are essential for the photosynthetic machinery. Our results also revealed that light exposure increased the levels of polyketides, including flavonoids, and oxylipins, which play essential roles in the plant’s developmental processes and defense mechanism against herbivores. This study highlights the significant contribution of light exposure to the ultimate metabolic phenotype, which might affect the cellular physiology and nutritional value of broccoli sprouts. Furthermore, this study highlights the potential of an

  1. Mars 520-d mission simulation reveals protracted crew hypokinesis and alterations of sleep duration and timing

    PubMed Central

    Basner, Mathias; Dinges, David F.; Mollicone, Daniel; Ecker, Adrian; Jones, Christopher W.; Hyder, Eric C.; Di Antonio, Adrian; Savelev, Igor; Kan, Kevin; Goel, Namni; Morukov, Boris V.; Sutton, Jeffrey P.

    2013-01-01

    The success of interplanetary human spaceflight will depend on many factors, including the behavioral activity levels, sleep, and circadian timing of crews exposed to prolonged microgravity and confinement. To address the effects of the latter, we used a high-fidelity ground simulation of a Mars mission to objectively track sleep–wake dynamics in a multinational crew of six during 520 d of confined isolation. Measurements included continuous recordings of wrist actigraphy and light exposure (4.396 million min) and weekly computer-based neurobehavioral assessments (n = 888) to identify changes in the crew's activity levels, sleep quantity and quality, sleep–wake periodicity, vigilance performance, and workload throughout the record-long 17 mo of mission confinement. Actigraphy revealed that crew sedentariness increased across the mission as evident in decreased waking movement (i.e., hypokinesis) and increased sleep and rest times. Light exposure decreased during the mission. The majority of crewmembers also experienced one or more disturbances of sleep quality, vigilance deficits, or altered sleep–wake periodicity and timing, suggesting inadequate circadian entrainment. The results point to the need to identify markers of differential vulnerability to hypokinesis and sleep–wake changes during the prolonged isolation of exploration spaceflight and the need to ensure maintenance of circadian entrainment, sleep quantity and quality, and optimal activity levels during exploration missions. Therefore, successful adaptation to such missions will require crew to transit in spacecraft and live in surface habitats that instantiate aspects of Earth's geophysical signals (appropriately timed light exposure, food intake, exercise) required for temporal organization and maintenance of human behavior. PMID:23297197

  2. Mars 520-d mission simulation reveals protracted crew hypokinesis and alterations of sleep duration and timing.

    PubMed

    Basner, Mathias; Dinges, David F; Mollicone, Daniel; Ecker, Adrian; Jones, Christopher W; Hyder, Eric C; Di Antonio, Adrian; Savelev, Igor; Kan, Kevin; Goel, Namni; Morukov, Boris V; Sutton, Jeffrey P

    2013-02-12

    The success of interplanetary human spaceflight will depend on many factors, including the behavioral activity levels, sleep, and circadian timing of crews exposed to prolonged microgravity and confinement. To address the effects of the latter, we used a high-fidelity ground simulation of a Mars mission to objectively track sleep-wake dynamics in a multinational crew of six during 520 d of confined isolation. Measurements included continuous recordings of wrist actigraphy and light exposure (4.396 million min) and weekly computer-based neurobehavioral assessments (n = 888) to identify changes in the crew's activity levels, sleep quantity and quality, sleep-wake periodicity, vigilance performance, and workload throughout the record-long 17 mo of mission confinement. Actigraphy revealed that crew sedentariness increased across the mission as evident in decreased waking movement (i.e., hypokinesis) and increased sleep and rest times. Light exposure decreased during the mission. The majority of crewmembers also experienced one or more disturbances of sleep quality, vigilance deficits, or altered sleep-wake periodicity and timing, suggesting inadequate circadian entrainment. The results point to the need to identify markers of differential vulnerability to hypokinesis and sleep-wake changes during the prolonged isolation of exploration spaceflight and the need to ensure maintenance of circadian entrainment, sleep quantity and quality, and optimal activity levels during exploration missions. Therefore, successful adaptation to such missions will require crew to transit in spacecraft and live in surface habitats that instantiate aspects of Earth's geophysical signals (appropriately timed light exposure, food intake, exercise) required for temporal organization and maintenance of human behavior. PMID:23297197

  3. Ethanol consumption during early pregnancy alters the disposition of tangentially migrating GABAergic interneurons in the fetal cortex.

    PubMed

    Cuzon, Verginia C; Yeh, Pamela W L; Yanagawa, Yuchio; Obata, Kunihiko; Yeh, Hermes H

    2008-02-20

    Consumption of alcohol (ethanol) during pregnancy can lead to developmental defects in the offspring, the most devastating being the constellation of symptoms collectively referred to as fetal alcohol syndrome (FAS). In the brain, a hallmark of FAS is abnormal cerebral cortical morphology consistent with insult during corticogenesis. Here, we report that exposure to a relatively low level of ethanol in utero (average maternal and fetal blood alcohol level of 25 mg/dl) promotes premature tangential migration into the cortical anlage of primordial GABAergic interneurons, including those originating in the medial ganglionic eminence (MGE). This ethanol-induced effect was evident in vivo at embryonic day 14.5 (E14.5) in GAD67 knock-in and BAC-Lhx6 embryos, as well as in vitro in isotypic telencephalic slice cocultures obtained from E14.5 embryos exposed to ethanol in utero. Analysis of heterotypic cocultures indicated that both cell-intrinsic and -extrinsic factors contribute to the aberrant migratory profile of MGE-derived cells. In this light, we provide evidence for an interaction between ethanol exposure in utero and the embryonic GABAergic system. Exposure to ethanol in utero elevated the ambient level of GABA and increased the sensitivity to GABA of MGE-derived cells. Our results uncovered for the first time an effect of ethanol consumption during pregnancy on the embryonic development of GABAergic cortical interneurons. We propose that ethanol exerts its effect on the tangential migration of GABAergic interneurons extrinsically by modulating extracellular levels of GABA and intrinsically by altering GABA(A) receptor function.

  4. Altered posterior cingulate cortical cyctoarchitecture, but normal density of neurons and interneurons in the posterior cingulate cortex and fusiform gyrus in autism

    PubMed Central

    Rosene, Douglas L.; Kemper, Thomas L.; Bauman, Margaret L.; Blatt, Gene J.

    2011-01-01

    (PCC), a component of the limbic system. Abnormal activation has also been noted in the fusiform gyrus (FFG), a region important for facial recognition and a key element in social interaction. A potential imbalance between excitatory and inhibitory interneurons in the cortex may contribute to altered information processing in autism. Furthermore, reduced numbers of GABA receptors have previously been reported in the autistic brain. Thionin stained sections were used to qualitatively assess cytoarchitectonic patterning and quantitatively determine the density of neurons and immunohistochemistry was used to determine the densities of a subset of GABAergic interneurons utilizing parvalbumin- and calbindin- immunoreactivity. In autism, the PCC displayed altered cytoarchitecture with irregularly distributed neurons, poorly demarcated layers IV and V, and increased presence of white matter neurons. In contrast, no neuropathology was observed in the FFG. There was no significant difference in the density of thionin, parvalbumin, or calbindin interneurons in either region and there was a trend towards a reduced density of calbindin neurons in the PCC. This study highlights the presence of abnormal findings in the PCC, which appear to be developmental in nature and could affect the local processing of social-emotional behaviors as well as functioning of interrelated areas. PMID:21360830

  5. Striatal patch compartment lesions alter methamphetamine-induced behavior and immediate early gene expression in the striatum, substantia nigra and frontal cortex.

    PubMed

    Murray, Ryan C; Gilbert, Yamiece E; Logan, Anna S; Hebbard, John C; Horner, Kristen A

    2014-07-01

    Methamphetamine (METH) induces stereotypy, which is characterized as inflexible, repetitive behavior. Enhanced activation of the patch compartment of the striatum has been correlated with stereotypy, suggesting that stereotypy may be related to preferential activation of this region. However, the specific contribution of the patch compartment to METH-induced stereotypy is not clear. To elucidate the involvement of the patch compartment to the development of METH-induced stereotypy, we determined if destruction of this sub-region altered METH-induced behaviors. Animals were bilaterally infused in the striatum with the neurotoxin dermorphin-saporin (DERM-SAP; 17 ng/μl) to specifically ablate the neurons of the patch compartment. Eight days later, animals were treated with METH (7.5 mg/kg), placed in activity chambers, observed for 2 h and killed. DERM-SAP pretreatment significantly reduced the number and total area of mu-labeled patches in the striatum. DERM-SAP pretreatment significantly reduced the intensity of METH-induced stereotypy and the spatial immobility typically observed with METH-induced stereotypy. In support of this observation, DERM-SAP pretreatment also significantly increased locomotor activity in METH-treated animals. In the striatum, DERM-SAP pretreatment attenuated METH-induced c-Fos expression in the patch compartment, while enhancing METH-induced c-Fos expression in the matrix compartment. DERM-SAP pretreatment followed by METH administration augmented c-Fos expression in the SNpc and reduced METH-induced c-Fos expression in the SNpr. In the medial prefrontal, but not sensorimotor cortex, c-Fos and zif/268 expression was increased following METH treatment in animals pre-treated with DERM-SAP. These data indicate that the patch compartment is necessary for the expression of repetitive behaviors and suggests that alterations in activity in the basal ganglia may contribute to this phenomenon.

  6. Early exposure to bisphenol A alters neuron and glia number in the rat prefrontal cortex of adult males, but not females

    PubMed Central

    Sadowski, Renee N.; Wise, Leslie M.; Park, Pul Y.; Schantz, Susan L.; Juraska, Janice M.

    2014-01-01

    Previous work has shown that exposure to bisphenol A (BPA) during early development can alter sexual differentiation of the brain in rodents, although few studies have examined effects on areas of the brain associated with cognition. The current study examined if developmental BPA exposure alters the total number of neurons and glia in the medial prefrontal cortex (mPFC) in adulthood. Pregnant Long-Evans rats were orally exposed to 0, 4, 40, or 400 μg/kg BPA in corn oil throughout pregnancy. From postnatal days 1-9, pups were given daily oral doses of oil or BPA, at doses corresponding to those given during gestation. Brains were examined in adulthood, and the volume of layers 2/3 and layers 5/6 of the mPFC were parcellated. The density of neurons and glia in these layers was quantified stereologically with the optical disector, and density was multiplied by volume for each animal. Males exposed to 400 μg/kg BPA were found to have increased numbers of neurons and glia in layers 5/6. Although there were no significant effects of BPA in layers 2/3, the pattern of increased neuron number in males exposed to 400 μg/kg BPA was similar to that seen in layers 5/6. No effects of BPA were seen in females or in males exposed to the other doses of BPA. This study indicates that males are more susceptible to the long-lasting effects of BPA on anatomy of the mPFC, an area implicated in neurological disorders. PMID:25193849

  7. Dopamine and corticotropin-releasing factor synergistically alter basolateral amygdala-to-medial prefrontal cortex synaptic transmission: functional switch after chronic cocaine administration.

    PubMed

    Orozco-Cabal, Luis; Liu, Jie; Pollandt, Sebastian; Schmidt, Kady; Shinnick-Gallagher, Patricia; Gallagher, Joel P

    2008-01-01

    Basolateral amygdala (BLA) neurons provide a major excitatory input to medial prefrontal cortex (mPFC)-layer V pyramidal neurons. Under stressful conditions, commonly associated with chronic cocaine abuse, altered BLA-to-mPFC synaptic transmission could lead to defective emotional information processing and decision making within the mPFC and result in misguided and inappropriate behaviors. We examined the effects of cocaine administered chronically in vivo on EPSCs recorded from a putative BLA-mPFC pathway in vitro and their modulation by dopamine (DA), corticotropin-releasing factor (CRF), and their combination (DA plus CRF). In saline-treated animals, activation of D(1/5) receptors depressed BLA-mPFC EPSCs, whereas CRF1 receptor activation alone had no effect on EPSCs. Activating D(1/5) and CRF1 receptors in combination, however, worked synergistically through presynaptic and postsynaptic mechanisms to depress EPSCs to levels greater than D(1/5) receptor activation alone. After chronic cocaine administration, the function of DA(1/5) and CRF receptors switched from inhibitory to excitatory. In slices from cocaine-treated animals, putative BLA-mPFC EPSCs were depressed through a presynaptic mechanism. Now, activation of either D(1/5) or CRF2 receptors increased the cocaine-induced, depressed EPSCs. Additionally, simultaneous activation of presynaptic D(1/5) and CRF2 receptors led to further enhancement of EPSCs. These data indicate that CRF acting synergistically with DA normally potentiates D(1/5)-induced synaptic depression. However, after chronic cocaine, the combined synergistic actions of DA and CRF switched polarity to enhance facilitation of BLA-mPFC glutamatergic transmission. Also unmasked after acute withdrawal from chronic cocaine are endogenous, tonic-inhibitory D2-like and tonic-facilitatory CRF2 receptor actions. These multiple functional and receptor changes may underlie the altered, possibly aberrant, decision-making process after chronic cocaine.

  8. Maternal separation and early stress cause long-lasting effects on dopaminergic and endocannabinergic systems and alters dendritic morphology in the nucleus accumbens and frontal cortex in rats.

    PubMed

    Romano-López, Antonio; Méndez-Díaz, Mónica; García, Fabio García; Regalado-Santiago, Citlalli; Ruiz-Contreras, Alejandra E; Prospéro-García, Oscar

    2016-08-01

    A considerable amount experimental studies have shown that maternal separation (MS) is associated with adult offspring abnormal behavior and cognition disorder. Accordingly, this experimental procedure has been proposed as a predictor for alcohol and drug dependence based on the neurodevelopmental soon after birth. Endocannabinoid system (eCBs) has been implicated in reward processes, including drug abuse and dependence. MS and associated stress causes changes in the eCBs that seem to facilitate alcohol consumption. In this study, we seek to evaluate potential morphological changes in neurons of the frontal cortex (FCx) and nucleus accumbens (NAcc), in the expression of receptors and enzymes of the endocannabinoid and dopamine systems and in second messengers, such as Akt, in adult rats subjected to MS and early stress (MS + ES; 2 × 180 min daily) vs. nonseparated rats (NMS). Results showed that MS + ES induces higher D2R expression and lower D3R, FAAH, and MAGL expression compared with NMS rats. Alterations in total dendritic length were also detected and were characterized by increases in the NAcc while there were decreases in the FCx. We believe MS + ES-induced changes in the dopaminergic and endocannabinergic systems and in the neuronal microstructure might be contributing to alcohol seeking behavior and, potential vulnerability to other drugs in rats. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 819-831, 2016.

  9. Location, Location, Location: Alterations in the Functional Topography of Face- but not Object- or Place-Related Cortex in Adolescents with Autism

    PubMed Central

    Scherf, K. Suzanne; Luna, Beatriz; Minshew, Nancy; Behrmann, Marlene

    2009-01-01

    In autism, impairments in face processing are a relatively recent discovery, but have quickly become a widely accepted aspect of the behavioral profile. Only a handful of studies have investigated potential atypicalities in autism in the development of the neural substrates mediating face processing. High-functioning individuals with autism (HFA) and matched typically developing (TD) controls watched dynamic movie vignettes of faces, common objects, buildings, and scenes of navigation while undergoing an fMRI scan. With these data, we mapped the functional topography of category-selective activation for faces bilaterally in the fusiform gyrus, occipital face area, and posterior superior temporal sulcus. Additionally, we mapped category-selective activation for objects in the lateral occipital area and for places in the parahippocampal place area in the two groups. Our findings do not indicate a generalized disruption in the development of the entire ventral visual pathway in autism. Instead, our results suggest that the functional topography of face-related cortex is selectively disrupted in autism and that this alteration is present in early adolescence. Furthermore, for those HFA adolescents who do exhibit face-selective activation, this activation tends to be located in traditionally object-related regions, which supports the hypothesis that perceptual processing of faces in autism may be more akin to the perceptual processing of common objects in TD individuals. PMID:20631857

  10. Cholinergic Neurotransmission in the Posterior Insular Cortex Is Altered in Preclinical Models of Neuropathic Pain: Key Role of Muscarinic M2 Receptors in Donepezil-Induced Antinociception

    PubMed Central

    Ferrier, Jérémy; Bayet-Robert, Mathilde; Dalmann, Romain; El Guerrab, Abderrahim; Aissouni, Youssef; Graveron-Demilly, Danielle; Chalus, Maryse; Pinguet, Jérémy; Eschalier, Alain; Richard, Damien; Daulhac, Laurence; Balayssac, David

    2015-01-01

    Neuropathic pain is one of the most debilitating pain conditions, yet no therapeutic strategy has been really effective for its treatment. Hence, a better understanding of its pathophysiological mechanisms is necessary to identify new pharmacological targets. Here, we report important metabolic variations in brain areas involved in pain processing in a rat model of oxaliplatin-induced neuropathy using HRMAS 1H-NMR spectroscopy. An increased concentration of choline has been evidenced in the posterior insular cortex (pIC) of neuropathic animal, which was significantly correlated with animals' pain thresholds. The screening of 34 genes mRNA involved in the pIC cholinergic system showed an increased expression of the high-affinity choline transporter and especially the muscarinic M2 receptors, which was confirmed by Western blot analysis in oxaliplatin-treated rats and the spared nerve injury model (SNI). Furthermore, pharmacological activation of M2 receptors in the pIC using oxotremorine completely reversed oxaliplatin-induced mechanical allodynia. Consistently, systemic treatment with donepezil, a centrally active acetylcholinesterase inhibitor, prevented and reversed oxaliplatin-induced cold and mechanical allodynia as well as social interaction impairment. Intracerebral microdialysis revealed a lower level of acetylcholine in the pIC of oxaliplatin-treated rats, which was significantly increased by donepezil. Finally, the analgesic effect of donepezil was markedly reduced by a microinjection of the M2 antagonist, methoctramine, within the pIC, in both oxaliplatin-treated rats and spared nerve injury rats. These findings highlight the crucial role of cortical cholinergic neurotransmission as a critical mechanism of neuropathic pain, and suggest that targeting insular M2 receptors using central cholinomimetics could be used for neuropathic pain treatment. SIGNIFICANCE STATEMENT Our study describes a decrease in cholinergic neurotransmission in the posterior insular

  11. Activity in ventromedial prefrontal cortex co-varies with revealed social preferences: evidence for person-invariant value

    PubMed Central

    López, Gilberto; Mitchell, Jason P.

    2014-01-01

    Although altruistic and selfish behaviors seem fundamentally incommensurable humans regularly choose between them. One model of such choices suggests that individuals ascribe a common form of subjective value to their own outcomes and those of others. To test this ‘person invariance’ hypothesis, we asked individuals to choose between allocating varying amounts of money to themselves or to a partner. Participants’ choice patterns provided an estimate of the relative value they placed on their own and others’ gains. These estimates were used to isolate neural activity correlating with the subjective value of gains irrespective of the recipient (self or other) during a separate set of trials in which rewards were offered only to the self or partner. Activity in ventromedial prefrontal cortex scaled with this person-invariant value parameter, consistent with earlier demonstrations that this region supports common value computation. These data suggest that individuals reduce the value associated with their own and others’ experiences to a common subjective scale, which is used to guide social decision-making. PMID:23314009

  12. Age-related decline of presumptive inhibitory synapses in the sensorimotor cortex as revealed by the physical disector.

    PubMed

    Poe, B H; Linville, C; Brunso-Bechtold, J

    2001-10-01

    The synapse, as the site of functional neural interaction, has been suggested as a possible substrate for age-related impairment of cognitive ability. Using the physical disector probe with tissue prepared for ultrastructural analysis, we find an age-related decline in the numerical density of presumptive inhibitory synapses in layer 2 of the sensorimotor cortex of the Brown Norway x Fisher 344 rat. This age-related decline in presumptive inhibitory synapses is maintained when the density of synapses is combined with the numerical density of neurons quantified from the same anatomical space to arrive at a ratio of synapses per neuron. The numerical density of these synapses declines between middle-aged (18 months) and old (29 months) animals by 36% whereas numerical density of neurons does not change between these ages, resulting in a decline in the ratio of presumptive inhibitory synapses per neuron in this cortical area. This study demonstrates a deficit in the intrinsic inhibitory circuitry of the aging neocortex, which suggests an anatomical substrate for age-related cognitive impairment.

  13. Two distinct auditory-motor circuits for monitoring speech production as revealed by content-specific suppression of auditory cortex.

    PubMed

    Ylinen, Sari; Nora, Anni; Leminen, Alina; Hakala, Tero; Huotilainen, Minna; Shtyrov, Yury; Mäkelä, Jyrki P; Service, Elisabet

    2015-06-01

    Speech production, both overt and covert, down-regulates the activation of auditory cortex. This is thought to be due to forward prediction of the sensory consequences of speech, contributing to a feedback control mechanism for speech production. Critically, however, these regulatory effects should be specific to speech content to enable accurate speech monitoring. To determine the extent to which such forward prediction is content-specific, we recorded the brain's neuromagnetic responses to heard multisyllabic pseudowords during covert rehearsal in working memory, contrasted with a control task. The cortical auditory processing of target syllables was significantly suppressed during rehearsal compared with control, but only when they matched the rehearsed items. This critical specificity to speech content enables accurate speech monitoring by forward prediction, as proposed by current models of speech production. The one-to-one phonological motor-to-auditory mappings also appear to serve the maintenance of information in phonological working memory. Further findings of right-hemispheric suppression in the case of whole-item matches and left-hemispheric enhancement for last-syllable mismatches suggest that speech production is monitored by 2 auditory-motor circuits operating on different timescales: Finer grain in the left versus coarser grain in the right hemisphere. Taken together, our findings provide hemisphere-specific evidence of the interface between inner and heard speech.

  14. Cross-adaptation combined with TMS reveals a functional overlap between vision and imagery in the early visual cortex.

    PubMed

    Cattaneo, Zaira; Bona, Silvia; Silvanto, Juha

    2012-02-01

    The extent to which the generation of mental images draws on the neuronal representations involved in visual perception has been the subject of much debate. To investigate this overlap, we assessed whether adaptation to visual stimuli affects the ability to generate visual mental images; such cross-adaptation would indicate shared neural representations between visual perception and imagery. Mental imagery was tested using a modified version of the clock task, in which subjects are presented with a digital time (e.g. "2.15") and are asked to generate a mental image of the clock hands displaying this time on an empty clock face. Participants were adapted to oriented lines either on the upper or lower side of the clock face prior to the mental image generation. The results showed that mental imagery was impaired when the mental image had to be generated in the adapted region of visual space (Experiment 1). In Experiment 2, we used TMS to determine whether this adaptation effect occurs in the early visual cortex (EVC; V1/V2). Relative to control conditions (No TMS and Vertex TMS), EVC TMS facilitated mental imagery generation when the mental image spatially overlapped with the adapter. Our results thus show that neuronal representations in the EVC which encode (and are suppressed by) visual input play a causal role in visual mental imagery.

  15. Functional organization of visual cortex in the prosimian bush baby revealed by optical imaging of intrinsic signals.

    PubMed

    Xu, Xiangmin; Bosking, William H; White, Leonard E; Fitzpatrick, David; Casagrande, Vivien A

    2005-10-01

    Cells in primary visual cortex (V1) of primates and carnivores respond most strongly to a visual stimulus presented to one eye, in a particular visual field location, and at a particular orientation. Each of these stimulus attributes is mapped across the cortical surface, and, in macaque monkeys and cats, strong geometrical relationships exist between these feature maps. In macaque V1 and V2, correlations between feature maps and cytochrome oxidase (CO)-rich modules have also been observed. To see if such relationships reflect a conserved principle of V1 functional architecture among primate species, we examined these maps in the prosimian bush baby, a species that has been proposed to represent the ancestral primate organization. We found that the layout of individual feature maps in bush baby V1 is similar to that of other primates, but we found an entirely different organization of orientation preference in bush baby V2 compared with that reported in simian primates. Another striking distinction between bush baby and simian species is that we observed no strong relationships among maps of orientation, ocular dominance, and CO blobs in V1. Thus our findings suggest that precise relationships between feature maps are not a common element of the functional organization in all primates and that such relationships are not necessary for achieving basic coverage of stimulus feature combinations. In addition, our results suggest that specific relationships between feature maps in V1, and the subdivision of V2 into functional compartments, may have arisen comparatively late in the evolution of primates. PMID:16000523

  16. Systems reconsolidation reveals a selective role for the anterior cingulate cortex in generalized contextual fear memory expression.

    PubMed

    Einarsson, Einar Ö; Pors, Jennifer; Nader, Karim

    2015-01-01

    After acquisition, hippocampus-dependent memories undergo a systems consolidation process, during which they become independent of the hippocampus and dependent on the anterior cingulate cortex (ACC) for memory expression. However, consolidated remote memories can become transiently hippocampus-dependent again following memory reactivation. How this systems reconsolidation affects the role of the ACC in remote memory expression is not known. Using contextual fear conditioning, we show that the expression of 30-day-old remote memory can transiently be supported by either the ACC or the dorsal hippocampus following memory reactivation, and that the ACC specifically mediates expression of remote generalized contextual fear memory. We found that suppression of neural activity in the ACC with the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) impaired the expression of remote, but not recent, contextual fear memory. Fear expression was not affected by this treatment if preceded by memory reactivation 6 h earlier, nor was it affected by suppression of neural activity in the dorsal hippocampus with the GABA-receptor agonist muscimol. However, simultaneous targeting of both the ACC and the dorsal hippocampus 6 h after memory reactivation disrupted contextual fear memory expression. Second, we observed that expression of a 30-day-old generalized contextual fear memory in a novel context was not affected by memory reactivation 6 h earlier. However, intra-ACC CNQX infusion before testing impaired contextual fear expression in the novel context, but not the original training context. Together, these data suggest that although the dorsal hippocampus may be recruited during systems reconsolidation, the ACC remains necessary for the expression of generalized contextual fear memory. PMID:25091528

  17. Altered spontaneous brain activity in patients with Parkinson's disease accompanied by depressive symptoms, as revealed by regional homogeneity and functional connectivity in the prefrontal-limbic system.

    PubMed

    Sheng, Ke; Fang, Weidong; Su, Meilan; Li, Rong; Zou, Dezhi; Han, Yu; Wang, Xuefeng; Cheng, Oumei

    2014-01-01

    As patients with Parkinson's disease (PD) are at high risk for comorbid depression, it is hypothesized that these two diseases are sharing common pathogenic pathways. Using regional homogeneity (ReHo) and functional connectivity approaches, we characterized human regional brain activity at resting state to examine specific brain networks in patients with PD and those with PD and depression (PDD). This study comprised 41 PD human patients and 25 normal human subjects. The patients completed the Hamilton Depression Rating Scale and were further divided into two groups: patients with depressive symptoms and non-depressed PD patients (nD-PD). Compared with the non-depressed patients, those with depressive symptoms exhibited significantly increased regional activity in the left middle frontal gyrus and right inferior frontal gyrus, and decreased ReHo in the left amygdala and bilateral lingual gyrus. Brain network connectivity analysis revealed decreased functional connectivity within the prefrontal-limbic system and increased functional connectivity in the prefrontal cortex and lingual gyrus in PDD compared with the nD-PD group. In summary, the findings showed regional brain activity alterations and disruption of the mood regulation network in PDD patients. The pathogenesis of PDD may be attributed to abnormal neural activity in multiple brain regions.

  18. Altered Spontaneous Activity in Patients with Persistent Somatoform Pain Disorder Revealed by Regional Homogeneity.

    PubMed

    Huang, Tianming; Zhao, Zhiyong; Yan, Chao; Lu, Jing; Li, Xuzhou; Tang, Chaozheng; Fan, Mingxia; Luo, Yanli

    2016-01-01

    Persistent somatoform pain disorder (PSPD) is a mental disorder un-associated with any somatic injury and can cause severe somatosensory and emotional impairments in patients. However, so far, the neuro-pathophysiological mechanism of the functional impairments in PSPD is still unclear. The present study assesses the difference in regional spontaneous activity between PSPD and healthy controls (HC) during a resting state, in order to elucidate the neural mechanisms underlying PSPD. Resting-state functional Magnetic Resonance Imaging data were obtained from 13 PSPD patients and 23 age- and gender-matched HC subjects in this study. Kendall's coefficient of concordance was used to measure regional homogeneity (ReHo), and a two-sample t-test was subsequently performed to investigate the ReHo difference between PSPD and HC. Additionally, the correlations between the mean ReHo of each survived area and the clinical assessments were further analyzed. Compared with the HC group, patients with PSPD exhibited decreased ReHo in the bilateral primary somatosensory cortex, posterior cerebellum, and occipital lobe, while increased ReHo in the prefrontal cortex (PFC) and default mode network (including the medial PFC, right inferior parietal lobe (IPL), and left supramarginal gyrus). In addition, significant positive correlations were found between the mean ReHo of both right IPL and left supramarginal gyrus and participants' Self-Rating Anxiety Scale (SAS) scores, and between the mean ReHo of the left middle frontal gyrus and Visual Analogue Scale (VAS) scores. Our results suggest that abnormal spontaneous brain activity in specific brain regions during a resting state may be associated with the dysfunctions in pain, memory and emotional processing commonly observed in patients with PSPD. These findings help us to understand the neural mechanisms underlying PSPD and suggest that the ReHo metric could be used as a clinical marker for PSPD. PMID:26977802

  19. Altered Spontaneous Activity in Patients with Persistent Somatoform Pain Disorder Revealed by Regional Homogeneity

    PubMed Central

    Yan, Chao; Lu, Jing; Li, Xuzhou; Tang, Chaozheng; Fan, Mingxia; Luo, Yanli

    2016-01-01

    Persistent somatoform pain disorder (PSPD) is a mental disorder un-associated with any somatic injury and can cause severe somatosensory and emotional impairments in patients. However, so far, the neuro-pathophysiological mechanism of the functional impairments in PSPD is still unclear. The present study assesses the difference in regional spontaneous activity between PSPD and healthy controls (HC) during a resting state, in order to elucidate the neural mechanisms underlying PSPD. Resting-state functional Magnetic Resonance Imaging data were obtained from 13 PSPD patients and 23 age- and gender-matched HC subjects in this study. Kendall’s coefficient of concordance was used to measure regional homogeneity (ReHo), and a two-sample t-test was subsequently performed to investigate the ReHo difference between PSPD and HC. Additionally, the correlations between the mean ReHo of each survived area and the clinical assessments were further analyzed. Compared with the HC group, patients with PSPD exhibited decreased ReHo in the bilateral primary somatosensory cortex, posterior cerebellum, and occipital lobe, while increased ReHo in the prefrontal cortex (PFC) and default mode network (including the medial PFC, right inferior parietal lobe (IPL), and left supramarginal gyrus). In addition, significant positive correlations were found between the mean ReHo of both right IPL and left supramarginal gyrus and participants’ Self-Rating Anxiety Scale (SAS) scores, and between the mean ReHo of the left middle frontal gyrus and Visual Analogue Scale (VAS) scores. Our results suggest that abnormal spontaneous brain activity in specific brain regions during a resting state may be associated with the dysfunctions in pain, memory and emotional processing commonly observed in patients with PSPD. These findings help us to understand the neural mechanisms underlying PSPD and suggest that the ReHo metric could be used as a clinical marker for PSPD. PMID:26977802

  20. Metabolomic Analyses of Brain Tissue in Sepsis Induced by Cecal Ligation Reveal Specific Redox Alterations--Protective Effects of the Oxygen Radical Scavenger Edaravone.

    PubMed

    Hara, Naomi; Chijiiwa, Miyuki; Yara, Miki; Ishida, Yusuke; Ogiwara, Yukihiko; Inazu, Masato; Kuroda, Masahiko; Karlsson, Michael; Sjovall, Fredrik; Elmér, Eskil; Uchino, Hiroyuki

    2015-12-01

    The pathophysiology of sepsis-associated encephalopathy (SAE) is complex and remains incompletely elucidated. Dysregulated reactive oxygen species (ROS) production and mitochondrial-mediated necrotic-apoptotic pathway have been proposed as part of the pathogenesis. The present study aimed at analyzing the preventive effect of the free radical scavenger edaravone on sepsis-induced brain alterations. Sepsis was induced by cecal ligation and puncture (CLP) and the mice were divided into three groups-CLP vehicle (CLPV), CLP and edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one) (CLPE), and sham-operated (Sham). Mice in CLPV and CLPE were injected with saline or edaravone intraperitoneally at a dose of 10 mg/kg twice daily. The treatments were initiated 4 days prior to the surgical procedure. Mortality, histological changes, electron microscopy (EM), and expression of Bcl-2 family genes (Bcl-2 and Bax) were analyzed in selected brain regions. CLPE showed significant improvement in survival compared with CLPV 18 h postinduction of sepsis (P < 0.05). At the same time point, pathohistological analysis also showed marked reduction of neuronal cell death in both parietal cortex and hippocampus in the CLPE (P < 0.05). RT-PCR and immunoblotting directed at the Bcl-2 family revealed increased Bax mRNA levels in hippocampus at 12 h in CLPV as well as an increased Bax/Bcl-2 protein ratio, changes that were significantly suppressed in CLPE. In conclusion, our study suggests that sepsis induced by cecal ligation alters cerebral redox status and supports a proapoptotic phenotype. The free radical scavenger edavarone reduces mortality of septic mice and protects against sepsis-induced neuronal cell death.

  1. Effects of enriched environment on alterations in the prefrontal cortex GFAP- and S100B-immunopositive astrocytes and behavioral deficits in MK-801-treated rats.

    PubMed

    Rahati, M; Nozari, M; Eslami, H; Shabani, M; Basiri, M

    2016-06-21

    A plethora of studies have indicated that enriched environment (EE) paradigm provokes plastic and morphological changes in astrocytes with accompanying increments of their density and positively affects the behavior of rodents. We also previously documented that EE could be employed to preclude several behavioral abnormalities, mainly cognitive deficits, attributed to postnatal N-methyl-d-aspartate (NMDA) receptor antagonist (MK-801) treatment, as a rodent model of schizophrenia (SCH) aspects. Given this, the current study quantitatively investigated the number of cells, presumed to be astrocytes, expressing two astroglia-associated proteins (S100B and glial fibrillary acidic protein (GFAP)) by immunohistochemistry in the prefrontal cortex (PFC), along with anxiety and passive avoidance (PA) learning behaviors by utilizing elevated plus maze (EPM) and shuttle-box tests, in MK-801-treated male wistar rats submitted to EE and non-EE rats. Following a treatment regime of sub-chronic MK-801 (1.0mg/kg i.p. daily for five consecutive days from postnatal day (P) 6), S-100B-positive cells and anxiety level were markedly increased, while the GFAP-positive cells and PA learning were notably attenuated. The trend of diminished GFAP-immunopositive cells and elevated S100B-immunostained cells in the PFC was reversed in the SCH-like rats by exposure of animals to EE, commencing from birth up to the time of experiments on P28-85. Additionally, EE exhibited an ameliorating effect on the behavioral abnormalities evoked by MK-801. Overall, present findings support that improper astrocyte functioning and behavioral changes, reminiscent of the many facets of SCH, occur consequential to repetitive administration of MK-801 and that raising rat pups in an EE mitigates these alterations.

  2. Repeated exposure to amphetamine during adolescence alters inhibitory tone in the medial prefrontal cortex following drug re-exposure in adulthood.

    PubMed

    Paul, Kush; Kang, Shuo; Cox, Charles L; Gulley, Joshua M

    2016-08-01

    Behavioral sensitization following repeated amphetamine (AMPH) exposure is associated with changes in GABA function in the medial prefrontal cortex (mPFC). In rats exposed to AMPH during adolescence compared to adulthood, there are unique patterns of sensitization that may reflect age-dependent differences in drug effects on prefrontal GABAergic function. In the current study, we used a sensitizing regimen of repeated AMPH exposure in adolescent and adult rats to determine if a post-withdrawal AMPH challenge would alter inhibitory transmission in the mPFC in a manner that depends on age of exposure. Male Sprague-Dawley rats were treated with saline or 3mg/kg AMPH (i.p.) during adolescence [postnatal day (P) 27-P45] or adulthood (P85- P103) and were sacrificed either at similar ages in adulthood (∼P133; experiment 1) or after similar withdrawal times (3-4 weeks; experiment 2). Spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded in vitro from deep layer pyramidal cells in the mPFC using the whole-cell configuration. We found no effect of AMPH pre-exposure on baseline sIPSC frequency. Subsequent application of AMPH (25μM) produced a stable increase in sIPSC frequency in controls, suggesting that AMPH increases inhibitory tone in the mPFC. However, AMPH failed to increase sIPSCs in adolescent- or adult-exposed rats. In experiment 2, where withdrawal period was kept similar for both exposure groups, AMPH induced a suppression of sIPSC activity in adolescent-exposed rats. These results suggest that sensitizing treatment with AMPH during adolescence or adulthood dampens inhibitory influences on mPFC pyramidal cells, but potentially through different mechanisms.

  3. Prenatal exposure to moderate levels of ethanol alters social behavior in adult rats: Relationship to structural plasticity and immediate early gene expression in frontal cortex

    PubMed Central

    Hamilton, Derek A.; Akers, Katherine G.; Rice, James P.; Johnson, Travis E.; Candelaria-Cook, Felicha T.; Maes, Levi I.; Rosenberg, Martina; Valenzuela, C. Fernando; Savage, Daniel D.

    2009-01-01

    The goals of the present study were to characterize the effects of prenatal exposure to moderate levels of ethanol on adult social behavior, and to evaluate fetal-ethanol-related effects on dendritic morphology, structural plasticity and activity-related immediate early gene (IEG) expression in the agranular insular (AID) and prelimbic (Cg3) regions of frontal cortex. Baseline fetal-ethanol-related alterations in social behavior were limited to reductions in social investigation in males. Repeated experience with novel cage-mates resulted in comparable increases in wrestling and social investigation among saccharin- and ethanol-exposed females, whereas social behavioral effects among males were more evident in ethanol-exposed animals. Male ethanol-exposed rats also displayed profound increases in wrestling when social interaction was motivated by 24 hours of isolation. Baseline decreases in dendritic length and spine density in AID were observed in ethanol-exposed rats that were always housed with the same cage-mate. Modest experience-related decreases in dendritic length and spine density in AID were observed in saccharin-exposed rats housed with various cage-mates. In contrast, fetal-ethanol-exposed rats displayed experience-related increases in dendritic length in AID, and no experience-related changes in spine density. The only effect observed in Cg3 was a baseline increase in basilar dendritic length among male ethanol-exposed rats. Robust increases in activity-related IEG expression in AID (c-fos and Arc) and Cg3 (c-fos) were observed following social interaction in saccharin-exposed rats, however, activity-related increases in IEG expression were not observed in fetal-ethanol-exposed rats in either region. The results indicate that deficits in social behavior are among the long-lasting behavioral consequences of moderate ethanol exposure during brain development, and implicate AID, and to a lesser degree Cg3, in fetal-ethanol-related social behavior

  4. Treatment with a clinically-relevant dose of methylphenidate alters NMDA receptor composition and synaptic plasticity in the juvenile rat prefrontal cortex.

    PubMed

    Urban, Kimberly R; Li, Yan-Chun; Gao, Wen-Jun

    2013-03-01

    Methylphenidate (Ritalin, MPH) is the most commonly prescribed psychoactive drug for children. Used to treat attention-deficit/hyperactivity disorder (ADHD) and for cognitive enhancement in healthy individuals, its cellular mechanisms of action and potential long-term effects are poorly understood. We recently reported that a clinically relevant (1 mg/kg i.p., single injection) dose of MPH significantly decreased neuronal excitability in the juvenile rat prefrontal cortical neurons. Here we further explore the actions of acute treatment with MPH on the level of NMDA receptor subunits and NMDA receptor-mediated short- and long-term synaptic plasticity in the juvenile rat prefrontal cortical neurons. We found that a single dose of MPH treatment (1 mg/kg, intraperitoneal) significantly decreased the surface and total protein levels of NMDA receptor subunits NR1 and NR2B, but not NR2A, in the juvenile prefrontal cortex. In addition, the amplitude, decay time and charge transfer of NMDA receptor-mediated EPSCs were significantly decreased whereas the amplitude and short-term depression of AMPA receptor-mediated EPSCs were significantly increased in the prefrontal neurons. Furthermore, MPH treatment also significantly increased the probability and magnitude of LTP induction, but had only a small effect on LTD induction in juvenile rat prefrontal cortical neurons. Our data thus present a novel mechanism of action of MPH, i.e., changes in glutamatergic receptor-mediated synaptic plasticity following early-life treatment. Furthermore, since a single dosage resulted in significant changes in NMDA receptors, off-label usage by healthy individuals, especially children and adolescents, may result in altered potential for plastic learning.

  5. Transcriptomes reveal alterations in gravity impact circadian clocks and activate mechanotransduction pathways with adaptation through epigenetic change.

    PubMed

    Casey, Theresa; Patel, Osman V; Plaut, Karen

    2015-04-01

    Few studies have investigated the impact of alterations in gravity on mammalian transcriptomes. Here, we describe the impact of spaceflight on mammary transcriptome of late pregnant rats and the effect of hypergravity exposure on mammary, liver, and adipose transcriptomes in late pregnancy and at the onset of lactation. RNA was isolated from mammary collected on pregnancy day 20 from rats exposed to spaceflight from days 11 to 20 of gestation. To measure the impact of hypergravity on mammary, liver, and adipose transcriptomes we isolated RNA from tissues collected on P20 and lactation day 1 from rats exposed to hypergravity beginning on pregnancy day 9. Gene expression was measured with Affymetrix GeneChips. Microarray analysis of variance revealed alterations in gravity affected the expression of genes that regulate circadian clocks and activate mechanotransduction pathways. Changes in these systems may explain global gene expression changes in immune response, metabolism, and cell proliferation. Expression of genes that modify chromatin structure and methylation was affected, suggesting adaptation to gravity alterations may proceed through epigenetic change. Altered gravity experiments offer insights into the role of forces omnipresent on Earth that shape genomes in heritable ways. Our study is the first to analyze the impact of alterations in gravity on transcriptomes of pregnant and lactating mammals. Findings provide insight into systems that sense gravity and the way in which they affect phenotype, as well as the possibility of sustaining life beyond Earth's orbit. PMID:25649141

  6. Unambiguous observation of blocked states reveals altered, blocker-induced, cardiac ryanodine receptor gating

    PubMed Central

    Mukherjee, Saptarshi; Thomas, N. Lowri; Williams, Alan J.

    2016-01-01

    The flow of ions through membrane channels is precisely regulated by gates. The architecture and function of these elements have been studied extensively, shedding light on the mechanisms underlying gating. Recent investigations have focused on ion occupancy of the channel’s selectivity filter and its ability to alter gating, with most studies involving prokaryotic K+ channels. Some studies used large quaternary ammonium blocker molecules to examine the effects of altered ionic flux on gating. However, the absence of blocking events that are visibly distinct from closing events in K+ channels makes unambiguous interpretation of data from single channel recordings difficult. In this study, the large K+ conductance of the RyR2 channel permits direct observation of blocking events as distinct subconductance states and for the first time demonstrates the differential effects of blocker molecules on channel gating. This experimental platform provides valuable insights into mechanisms of blocker-induced modulation of ion channel gating. PMID:27703263

  7. Perceptual suppression revealed by adaptive multi-scale entropy analysis of local field potential in monkey visual cortex.

    PubMed

    Hu, Meng; Liang, Hualou

    2013-04-01

    Generalized flash suppression (GFS), in which a salient visual stimulus can be rendered invisible despite continuous retinal input, provides a rare opportunity to directly study the neural mechanism of visual perception. Previous work based on linear methods, such as spectral analysis, on local field potential (LFP) during GFS has shown that the LFP power at distinctive frequency bands are differentially modulated by perceptual suppression. Yet, the linear method alone may be insufficient for the full assessment of neural dynamic due to the fundamentally nonlinear nature of neural signals. In this study, we set forth to analyze the LFP data collected from multiple visual areas in V1, V2 and V4 of macaque monkeys while performing the GFS task using a nonlinear method - adaptive multi-scale entropy (AME) - to reveal the neural dynamic of perceptual suppression. In addition, we propose a new cross-entropy measure at multiple scales, namely adaptive multi-scale cross-entropy (AMCE), to assess the nonlinear functional connectivity between two cortical areas. We show that: (1) multi-scale entropy exhibits percept-related changes in all three areas, with higher entropy observed during perceptual suppression; (2) the magnitude of the perception-related entropy changes increases systematically over successive hierarchical stages (i.e. from lower areas V1 to V2, up to higher area V4); and (3) cross-entropy between any two cortical areas reveals higher degree of asynchrony or dissimilarity during perceptual suppression, indicating a decreased functional connectivity between cortical areas. These results, taken together, suggest that perceptual suppression is related to a reduced functional connectivity and increased uncertainty of neural responses, and the modulation of perceptual suppression is more effective at higher visual cortical areas. AME is demonstrated to be a useful technique in revealing the underlying dynamic of nonlinear/nonstationary neural signal.

  8. High-Resolution Mapping of Anatomical Connections in Marmoset Extrastriate Cortex Reveals a Complete Representation of the Visual Field Bordering Dorsal V2

    PubMed Central

    Jeffs, Janelle; Federer, Frederick; Ichida, Jennifer M.

    2013-01-01

    The primate visual cortex consists of many areas. The posterior areas (V1, V2, V3, and middle temporal) are thought to be common to all primate species. However, the organization of cortex immediately anterior to area V2 (the “third tier” cortex) remains controversial, particularly in New World primates. The main point of contention has been whether the third tier cortex consists of a single area V3, representing lower and upper visual quadrants in dorsal and ventral cortex, respectively, or of 2 distinct areas (the dorsomedial [DM] area and a V3-like area). Resolving this controversy is crucial to understand the function and evolution of the third tier cortex. We have addressed this issue in marmosets, by performing high-precision mapping of corticocortical connections in cortex bordering dorsal V2. Multiple closely spaced neuroanatomical tracer injections were placed across the full width of dorsal V2 or adjacent anterior cortex, and the location of resulting labeled cells mapped throughout whole flattened visual cortex. The resulting topographic patterns of labeled connections allowed us to define areas and their boundaries. We found that a complete representation of the visual field borders dorsal V2 and that the third tier cortex consists of 2 distinct areas. These results unequivocally support the DM model. PMID:22523183

  9. Altered spontaneous activity in antisocial personality disorder revealed by regional homogeneity.

    PubMed

    Tang, Yan; Liu, Wangyong; Chen, Jingang; Liao, Jian; Hu, Dewen; Wang, Wei

    2013-08-01

    There is increasing evidence that antisocial personality disorder (ASPD) stems from brain abnormalities. However, there are only a few studies investigating brain structure in ASPD. The aim of this study was to find regional coherence abnormalities in resting-state functional MRI of ASPD. Thirty-two ASPD individuals and 34 controls underwent a resting-state functional MRI scan. The regional homogeneity (ReHo) approach was used to examine whether ASPD was related to alterations in resting-state neural activity. Support vector machine discriminant analysis was used to evaluate the sensitivity/specificity characteristics of the ReHo index in discriminating between the ASPD individuals and controls. The results showed that, compared with controls, ASPD individuals show lower ReHo in the right cerebellum posterior lobe (Crus1) and the right middle frontal gyrus, as well as higher ReHo in the right middle occipital gyrus (BA 19), left inferior temporal gyrus (BA 37), and right inferior occipital gyrus (cuneus, BA 18). All alternation regions reported a predictive accuracy above 70%. To our knowledge, this study was the first to study the change in regional activity coherence in the resting brain of ASPD individuals. These results not only elucidated the pathological mechanism of ASPD from a resting-state functional viewpoint but also showed that these alterations in ReHo may serve as potential markers for the detection of ASPD.

  10. Binding of the Galanthus nivalis agglutinin to thymocytes reveals alterations in surface glycosylation during T-cell development.

    PubMed

    Sinkora, J; Kolínská, J; Reháková, Z; Cerný, J; Doubravská, L

    2002-02-01

    Surface binding of the Galanthus nivalis agglutinin (GNA) to thymocyte subsets has been studied in pigs and rodents by multicolour flow cytometry. In all the species examined, analogous staining profiles have been recorded. Counter-staining with anti-CD3epsilon, anti-CD4 and anti-CD8 monoclonal antibodies (MoAb) revealed that a significant increase of the GNA targets on the cell surface occurred during early thymocyte differentiation and reached its maximum at the level of the CD3loCD4+CD8+ small cortical thymocyte. This was followed by a decrease in the GNA binding capacity upon terminal maturation to the single positive thymocytes. PAGE analysis has revealed a dominant GNA-binding glycoprotein (molar mass approx. 90 kDa) present on thymocyte plasma membranes and absent on the surface of splenic lymphocytes, although both the whole cell lysates from both organs contained GNA ligands of the same size. Our findings are in agreement with previous data showing that immature thymocytes differ from their mature counterparts and peripheral T lymphocytes in the surface glycosylation pattern, and support the hypothesis that lectin-glycoprotein interaction plays a significant role in the cell-to-cell crosstalk in the thymic cortex.

  11. Active Collisions in Altered Gravity Reveal Eye-Hand Coordination Strategies

    PubMed Central

    White, Olivier; Lefèvre, Philippe; Wing, Alan M.; Bracewell, R. Martyn; Thonnard, Jean-Louis

    2012-01-01

    Most object manipulation tasks involve a series of actions demarcated by mechanical contact events, and gaze is usually directed to the locations of these events as the task unfolds. Typically, gaze foveates the target 200 ms in advance of the contact. This strategy improves manual accuracy through visual feedback and the use of gaze-related signals to guide the hand/object. Many studies have investigated eye-hand coordination in experimental and natural tasks; most of them highlighted a strong link between eye movements and hand or object kinematics. In this experiment, we analyzed gaze strategies in a collision task but in a very challenging dynamical context. Participants performed collisions while they were exposed to alternating episodes of microgravity, hypergravity and normal gravity. First, by isolating the effects of inertia in microgravity, we found that peak hand acceleration marked the transition between two modes of grip force control. Participants exerted grip forces that paralleled load force profiles, and then increased grip up to a maximum shifted after the collision. Second, we found that the oculomotor strategy adapted visual feedback of the controlled object around the collision, as demonstrated by longer durations of fixation after collision in new gravitational environments. Finally, despite large variability of arm dynamics in altered gravity, we found that saccades were remarkably time-locked to the peak hand acceleration in all conditions. In conclusion, altered gravity allowed light to be shed on predictive mechanisms used by the central nervous system to coordinate gaze, hand and grip motor actions during a mixed task that involved transport of an object and high impact loads. PMID:22984488

  12. Active collisions in altered gravity reveal eye-hand coordination strategies.

    PubMed

    White, Olivier; Lefèvre, Philippe; Wing, Alan M; Bracewell, R Martyn; Thonnard, Jean-Louis

    2012-01-01

    Most object manipulation tasks involve a series of actions demarcated by mechanical contact events, and gaze is usually directed to the locations of these events as the task unfolds. Typically, gaze foveates the target 200 ms in advance of the contact. This strategy improves manual accuracy through visual feedback and the use of gaze-related signals to guide the hand/object. Many studies have investigated eye-hand coordination in experimental and natural tasks; most of them highlighted a strong link between eye movements and hand or object kinematics. In this experiment, we analyzed gaze strategies in a collision task but in a very challenging dynamical context. Participants performed collisions while they were exposed to alternating episodes of microgravity, hypergravity and normal gravity. First, by isolating the effects of inertia in microgravity, we found that peak hand acceleration marked the transition between two modes of grip force control. Participants exerted grip forces that paralleled load force profiles, and then increased grip up to a maximum shifted after the collision. Second, we found that the oculomotor strategy adapted visual feedback of the controlled object around the collision, as demonstrated by longer durations of fixation after collision in new gravitational environments. Finally, despite large variability of arm dynamics in altered gravity, we found that saccades were remarkably time-locked to the peak hand acceleration in all conditions. In conclusion, altered gravity allowed light to be shed on predictive mechanisms used by the central nervous system to coordinate gaze, hand and grip motor actions during a mixed task that involved transport of an object and high impact loads.

  13. Long-term abstinence from developmental cocaine exposure alters Arc/Arg3.1 modulation in the rat medial prefrontal cortex.

    PubMed

    Caffino, Lucia; Giannotti, Giuseppe; Malpighi, Chiara; Racagni, Giorgio; Filip, Malgorzata; Fumagalli, Fabio

    2014-10-01

    Cocaine is a psychostimulant whose abuse causes a social and economic burden for our society. Most of the published literature deals with acute effects of cocaine or short-term abstinence in adult animals but much less information exists on neuroplastic changes following long-term abstinence. We have recently shown that the long-term abstinence following developmental exposure to cocaine results in increased Activity-Regulated Cytoskeletal-associated protein (Arc/Arg3.1) expression in the crude synaptosomal fraction (Giannotti et al. Int J Neuropsychopharmacology 7(4):625-634, 2014). Given that Arc/Arg3.1 localizes not only at active synapse but also in the nucleus (Okuno et al. Cell 149:886-898, 2012; Korb et al. Nat Neurosci 16:874-883 2013; Bloomer et al. Brain Res 1153:20-33 2007), we investigated Arc/Arg3.1 protein levels in the whole homogenate and the nuclear fraction of animals exposed to cocaine during adolescence. We observed the increased expression of Arc/Arg3.1 in both the fractions, suggesting that up-regulation of Arc/Arg3.1 protein may be partly due to the increased nuclear expression of Arc/Arg3.1 in the medial prefrontal cortex (mPFC) of rats sacrificed at postnatal day 90, following 48 days of abstinence. This effect seems to cause reduced Gria1 transcription. We also found reduced expression of fragile X mental retardation gene (FMR1) which normally inhibits Arc/Arg3.1 translation together with reduced expression of Ubiquitin-protein ligase E3A (Ube3a) that normally causes Arc/Arg3.1 protein degradation via ubiquitination. Further, we found increased expression of metabotropic glutamate receptor 5 (GRM5) which is also involved in the regulation of Arc/Arg3.1 expression. Taken together, our findings show that abstinence from developmental exposure to cocaine is associated with alterations in the finely tuned mechanisms that regulate Arc/Arg3.1 expression. PMID:24810662

  14. Endosymbiosis of Chlorella species to the ciliate Paramecium bursaria alters the distribution of the host's trichocysts beneath the host cell cortex.

    PubMed

    Kodama, Yuuki; Fujishima, Masahiro

    2011-04-01

    Each symbiotic Chlorella of the ciliate Paramecium bursaria is enclosed in a perialgal vacuole membrane derived from the host digestive vacuole membrane. Alga-free paramecia and symbiotic algae can grow independently. Mixing them experimentally can cause reinfection. Earlier, we reported that the symbiotic algae appear to push the host trichocysts aside to become fixed beneath the host cell cortex during the algal reinfection process. Indirect immunofluorescence microscopy with a monoclonal antibody against the trichocysts demonstrates that the trichocysts change their locality to form algal attachment sites and decrease their density beneath the host cell cortex through algal reinfection. Transmission electron microscopy to detect acid phosphatase activity showed that some trichocysts near the host cell cortex are digested by the host lysosomal fusion during algal reinfection. Removal of algae from the host cell using cycloheximide recovers the trichocyst's arrangement and number near the host cell cortex. These results indicate that symbiotic algae compete for their attachment sites with preexisting trichocysts and that the algae have the ability to ensure algal attachment sites beneath the host cell cortex.

  15. Serum Metabolic Profiling Reveals Altered Metabolic Pathways in Patients with Post-traumatic Cognitive Impairments

    PubMed Central

    Yi, Lunzhao; Shi, Shuting; Wang, Yang; Huang, Wei; Xia, Zi-an; Xing, Zhihua; Peng, Weijun; Wang, Zhe

    2016-01-01

    Cognitive impairment, the leading cause of traumatic brain injury (TBI)-related disability, adversely affects the quality of life of TBI patients, and exacts a personal and economic cost that is difficult to quantify. The underlying pathophysiological mechanism is currently unknown, and an effective treatment of the disease has not yet been identified. This study aimed to advance our understanding of the mechanism of disease pathogenesis; thus, metabolomics based on gas chromatography/mass spectrometry (GC-MS), coupled with multivariate and univariate statistical methods were used to identify potential biomarkers and the associated metabolic pathways of post-TBI cognitive impairment. A biomarker panel consisting of nine serum metabolites (serine, pyroglutamic acid, phenylalanine, galactose, palmitic acid, arachidonic acid, linoleic acid, citric acid, and 2,3,4-trihydroxybutyrate) was identified to be able to discriminate between TBI patients with cognitive impairment, TBI patients without cognitive impairment and healthy controls. Furthermore, associations between these metabolite markers and the metabolism of amino acids, lipids and carbohydrates were identified. In conclusion, our study is the first to identify several serum metabolite markers and investigate the altered metabolic pathway that is associated with post-TBI cognitive impairment. These markers appear to be suitable for further investigation of the disease mechanisms of post-TBI cognitive impairment. PMID:26883691

  16. Magnetoencephalography reveals altered auditory information processing in youth with obsessive-compulsive disorder.

    PubMed

    Korostenskaja, Milena; Harris, Elana; Giovanetti, Cathy; Horn, Paul; Wang, Yingying; Rose, Douglas; Fujiwara, Hisako; Xiang, Jing

    2013-05-30

    Patients with obsessive-compulsive disorder (OCD) often report sensory intolerances which may lead to significant functional impairment. This study used auditory evoked fields (AEFs) to address the question of whether neural correlates of sensory auditory information processing differ in youth with OCD compared with healthy comparison subjects (HCS). AEFs, recorded with a whole head 275-channel magnetoencephalography system, were elicited in response to binaural auditory stimuli from 10 pediatric subjects with OCD (ages 8-13, mean 11 years, 6 males) and 10 age- and gender-matched HCS. Three major neuromagnetic responses were studied: M70 (60-80 ms), M100 (90-120 ms), and M150 (130-190 ms). When compared with HCS, subjects with OCD demonstrated delayed latency of the M100 response. In subjects with OCD the amplitude of the M100 and M150 responses was significantly greater in the right hemisphere compared with the left hemisphere. Current results suggest that when compared with HCS, subjects with OCD have altered auditory information processing, evident from the delayed latency of the M100 response, which is thought to be associated with the encoding of physical stimulus characteristics. Interhemispheric asymmetry with increased M100 and M150 amplitudes over the right hemisphere compared with the left hemisphere was found in young OCD subjects. These results should be interpreted with caution due to the high variability rate of responses in both HCS and OCD subjects, as well as the possible effect of medication in OCD subjects.

  17. Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations

    PubMed Central

    Apollo, Alessandro; Pescucci, Chiara; Licastro, Danilo; Urso, Carmelo; Gerlini, Gianni; Borgognoni, Lorenzo; Luzzatto, Lucio; Stecca, Barbara

    2016-01-01

    Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression. PMID:27095580

  18. Metabolic profiling reveals altered sugar and secondary metabolism in response to UGPase overexpression in Populus

    SciTech Connect

    Payyavula, Raja S.; Tschaplinski, Timothy J.; Jawdy, Sara; Sykes, Robert; Tuskan, Gerald A.; Kalluri, Udaya C.

    2014-10-07

    Background: UDP-glucose pyrophopharylase (UGPase) is a sugar metabolizing enzyme (E.C. 2.7.7.9) that catalyzes a reversible reaction of UDP-glucose and pyrophosphate from glucose-1-phosphate and uridine triphosphate glucose. UDP-glucose is a key intermediate sugar that is channeled to multiple metabolic pathways. The functional role of UGPase in woody plants such as Populus is poorly understood. Results: We characterized the functional role of UGPase in Populus deltoides by overexpressing a native gene. Overexpression of the native gene resulted in increased leaf area and leaf-to-shoot biomass ratio but decreased shoot and root growth. Metabolomic analyses showed that manipulation of UGPase results in perturbations in primary as well as secondary metabolism resulting in reduced sugar and starch levels and increased phenolics such as caffeoyl- and feruloyl conjugates. While cellulose and lignin levels in the cell walls were not significantly altered, the syringyl-to-guaiacyl ratio was significantly reduced. Conclusions: These results demonstrate that UGPase plays a key role in the tightly coupled primary and secondary metabolic pathways and perturbation in its function results in pronounced effects on growth and metabolism outside of cell wall biosynthesis of Populus.

  19. Metabolic profiling reveals altered sugar and secondary metabolism in response to UGPase overexpression in Populus

    DOE PAGES

    Payyavula, Raja S.; Tschaplinski, Timothy J.; Jawdy, Sara; Sykes, Robert; Tuskan, Gerald A.; Kalluri, Udaya C.

    2014-10-07

    Background: UDP-glucose pyrophopharylase (UGPase) is a sugar metabolizing enzyme (E.C. 2.7.7.9) that catalyzes a reversible reaction of UDP-glucose and pyrophosphate from glucose-1-phosphate and uridine triphosphate glucose. UDP-glucose is a key intermediate sugar that is channeled to multiple metabolic pathways. The functional role of UGPase in woody plants such as Populus is poorly understood. Results: We characterized the functional role of UGPase in Populus deltoides by overexpressing a native gene. Overexpression of the native gene resulted in increased leaf area and leaf-to-shoot biomass ratio but decreased shoot and root growth. Metabolomic analyses showed that manipulation of UGPase results in perturbations inmore » primary as well as secondary metabolism resulting in reduced sugar and starch levels and increased phenolics such as caffeoyl- and feruloyl conjugates. While cellulose and lignin levels in the cell walls were not significantly altered, the syringyl-to-guaiacyl ratio was significantly reduced. Conclusions: These results demonstrate that UGPase plays a key role in the tightly coupled primary and secondary metabolic pathways and perturbation in its function results in pronounced effects on growth and metabolism outside of cell wall biosynthesis of Populus.« less

  20. Tumor transcriptome sequencing reveals allelic expression imbalances associated with copy number alterations.

    PubMed

    Tuch, Brian B; Laborde, Rebecca R; Xu, Xing; Gu, Jian; Chung, Christina B; Monighetti, Cinna K; Stanley, Sarah J; Olsen, Kerry D; Kasperbauer, Jan L; Moore, Eric J; Broomer, Adam J; Tan, Ruoying; Brzoska, Pius M; Muller, Matthew W; Siddiqui, Asim S; Asmann, Yan W; Sun, Yongming; Kuersten, Scott; Barker, Melissa A; De La Vega, Francisco M; Smith, David I

    2010-02-19

    Due to growing throughput and shrinking cost, massively parallel sequencing is rapidly becoming an attractive alternative to microarrays for the genome-wide study of gene expression and copy number alterations in primary tumors. The sequencing of transcripts (RNA-Seq) should offer several advantages over microarray-based methods, including the ability to detect somatic mutations and accurately measure allele-specific expression. To investigate these advantages we have applied a novel, strand-specific RNA-Seq method to tumors and matched normal tissue from three patients with oral squamous cell carcinomas. Additionally, to better understand the genomic determinants of the gene expression changes observed, we have sequenced the tumor and normal genomes of one of these patients. We demonstrate here that our RNA-Seq method accurately measures allelic imbalance and that measurement on the genome-wide scale yields novel insights into cancer etiology. As expected, the set of genes differentially expressed in the tumors is enriched for cell adhesion and differentiation functions, but, unexpectedly, the set of allelically imbalanced genes is also enriched for these same cancer-related functions. By comparing the transcriptomic perturbations observed in one patient to his underlying normal and tumor genomes, we find that allelic imbalance in the tumor is associated with copy number mutations and that copy number mutations are, in turn, strongly associated with changes in transcript abundance. These results support a model in which allele-specific deletions and duplications drive allele-specific changes in gene expression in the developing tumor.

  1. Urinary proteome alterations in HER2 enriched breast cancer revealed by multipronged quantitative proteomics.

    PubMed

    Gajbhiye, Akshada; Dabhi, Raju; Taunk, Khushman; Vannuruswamy, Garikapati; RoyChoudhury, Sourav; Adhav, Ragini; Seal, Shubhendu; Mane, Anupama; Bayatigeri, Santhakumari; Santra, Manas K; Chaudhury, Koel; Rapole, Srikanth

    2016-09-01

    Globally, breast cancer is the second most common cancer among women. Although biomarker discoveries through various proteomic approaches of tissue and serum samples have been studied in breast cancer, urinary proteome alterations in breast cancer are least studied. Urine being a noninvasive biofluid and a significant source of proteins, it has the potential in early diagnosis of breast cancer. This study used complementary quantitative gel-based and gel-free proteomic approaches to find a panel of urinary protein markers that could discriminate HER2 enriched (HE) subtype breast cancer from the healthy controls. A total of 183 differentially expressed proteins were identified using three complementary approaches, namely 2D-DIGE, iTRAQ, and sequential window acquisition of all theoretical mass spectra. The differentially expressed proteins were subjected to various bioinformatics analyses for deciphering the biological context of these proteins using protein analysis through evolutionary relationships, database for annotation, visualization and integrated discovery, and STRING. Multivariate statistical analysis was undertaken to identify the set of most significant proteins, which could discriminate HE breast cancer from healthy controls. Immunoblotting and MRM-based validation in a separate cohort testified a panel of 21 proteins such as zinc-alpha2-glycoprotein, A2GL, retinol-binding protein 4, annexin A1, SAP3, SRC8, gelsolin, kininogen 1, CO9, clusterin, ceruloplasmin, and α1-antitrypsin could be a panel of candidate markers that could discriminate HE breast cancer from healthy controls. PMID:27324523

  2. Photosynthetic characterization of Rubisco transplantomic lines reveals alterations on photochemistry and mesophyll conductance.

    PubMed

    Galmés, Jeroni; Perdomo, Juan Alejandro; Flexas, Jaume; Whitney, Spencer M

    2013-07-01

    Improving Rubisco catalysis is considered a promising way to enhance C3-photosynthesis and photosynthetic water use efficiency (WUE) provided the introduced changes have little or no impact on other processes affecting photosynthesis such as leaf photochemistry or leaf CO2 diffusion conductances. However, the extent to which the factors affecting photosynthetic capacity are co-regulated is unclear. The aim of the present study was to characterize the photochemistry and CO2 transport processes in the leaves of three transplantomic tobacco genotypes expressing hybrid Rubisco isoforms comprising different Flaveria L-subunits that show variations in catalysis and differing trade-offs between the amount of Rubisco and its activation state. Stomatal conductance (g s) in each transplantomic tobacco line matched wild-type, while their photochemistry showed co-regulation with the variations in Rubisco catalysis. A tight co-regulation was observed between Rubisco activity and mesophyll conductance (g m) that was independent of g s thus producing plants with varying g m/g s ratios. Since the g m/g s ratio has been shown to positively correlate with intrinsic WUE, the present results suggest that altering photosynthesis by modifying Rubisco catalysis may also be useful for targeting WUE.

  3. Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations.

    PubMed

    Montagnani, Valentina; Benelli, Matteo; Apollo, Alessandro; Pescucci, Chiara; Licastro, Danilo; Urso, Carmelo; Gerlini, Gianni; Borgognoni, Lorenzo; Luzzatto, Lucio; Stecca, Barbara

    2016-05-24

    Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression.

  4. Magnetoencephalography reveals altered auditory information processing in youth with obsessive-compulsive disorder.

    PubMed

    Korostenskaja, Milena; Harris, Elana; Giovanetti, Cathy; Horn, Paul; Wang, Yingying; Rose, Douglas; Fujiwara, Hisako; Xiang, Jing

    2013-05-30

    Patients with obsessive-compulsive disorder (OCD) often report sensory intolerances which may lead to significant functional impairment. This study used auditory evoked fields (AEFs) to address the question of whether neural correlates of sensory auditory information processing differ in youth with OCD compared with healthy comparison subjects (HCS). AEFs, recorded with a whole head 275-channel magnetoencephalography system, were elicited in response to binaural auditory stimuli from 10 pediatric subjects with OCD (ages 8-13, mean 11 years, 6 males) and 10 age- and gender-matched HCS. Three major neuromagnetic responses were studied: M70 (60-80 ms), M100 (90-120 ms), and M150 (130-190 ms). When compared with HCS, subjects with OCD demonstrated delayed latency of the M100 response. In subjects with OCD the amplitude of the M100 and M150 responses was significantly greater in the right hemisphere compared with the left hemisphere. Current results suggest that when compared with HCS, subjects with OCD have altered auditory information processing, evident from the delayed latency of the M100 response, which is thought to be associated with the encoding of physical stimulus characteristics. Interhemispheric asymmetry with increased M100 and M150 amplitudes over the right hemisphere compared with the left hemisphere was found in young OCD subjects. These results should be interpreted with caution due to the high variability rate of responses in both HCS and OCD subjects, as well as the possible effect of medication in OCD subjects. PMID:23545237

  5. Exercise challenge in Gulf War Illness reveals two subgroups with altered brain structure and function.

    PubMed

    Rayhan, Rakib U; Stevens, Benson W; Raksit, Megna P; Ripple, Joshua A; Timbol, Christian R; Adewuyi, Oluwatoyin; VanMeter, John W; Baraniuk, James N

    2013-01-01

    Nearly 30% of the approximately 700,000 military personnel who served in Operation Desert Storm (1990-1991) have developed Gulf War Illness, a condition that presents with symptoms such as cognitive impairment, autonomic dysfunction, debilitating fatigue and chronic widespread pain that implicate the central nervous system. A hallmark complaint of subjects with Gulf War Illness is post-exertional malaise; defined as an exacerbation of symptoms following physical and/or mental effort. To study the causal relationship between exercise, the brain, and changes in symptoms, 28 Gulf War veterans and 10 controls completed an fMRI scan before and after two exercise stress tests to investigate serial changes in pain, autonomic function, and working memory. Exercise induced two clinical Gulf War Illness subgroups. One subgroup presented with orthostatic tachycardia (n = 10). This phenotype correlated with brainstem atrophy, baseline working memory compensation in the cerebellar vermis, and subsequent loss of compensation after exercise. The other subgroup developed exercise induced hyperalgesia (n = 18) that was associated with cortical atrophy and baseline working memory compensation in the basal ganglia. Alterations in cognition, brain structure, and symptoms were absent in controls. Our novel findings may provide an understanding of the relationship between the brain and post-exertional malaise in Gulf War Illness.

  6. Characterization of Gaucher disease bone marrow mesenchymal stromal cells reveals an altered inflammatory secretome

    PubMed Central

    Campeau, Philippe M.; Rafei, Moutih; Boivin, Marie-Noëlle; Sun, Ying; Grabowski, Gregory A.

    2009-01-01

    Gaucher disease causes pathologic skeletal changes that are not fully explained. Considering the important role of mesenchymal stromal cells (MSCs) in bone structural development and maintenance, we analyzed the cellular biochemistry of MSCs from an adult patient with Gaucher disease type 1 (N370S/L444P mutations). Gaucher MSCs possessed a low glucocerebrosidase activity and consequently had a 3-fold increase in cellular glucosylceramide. Gaucher MSCs have a typical MSC marker phenotype, normal osteocytic and adipocytic differentiation, growth, exogenous lactosylceramide trafficking, cholesterol content, lysosomal morphology, and total lysosomal content, and a marked increase in COX-2, prostaglandin E2, interleukin-8, and CCL2 production compared with normal controls. Transcriptome analysis on normal MSCs treated with the glucocerebrosidase inhibitor conduritol B epoxide showed an up-regulation of an array of inflammatory mediators, including CCL2, and other differentially regulated pathways. These cells also showed a decrease in sphingosine-1-phosphate. In conclusion, Gaucher disease MSCs display an altered secretome that could contribute to skeletal disease and immune disease manifestations in a manner distinct and additive to Gaucher macrophages themselves. PMID:19587377

  7. Proteomics study revealed altered proteome of Dichogaster curgensis upon exposure to fly ash.

    PubMed

    Markad, Vijaykumar L; Adav, Sunil S; Ghole, Vikram S; Sze, Siu Kwan; Kodam, Kisan M

    2016-10-01

    Fly ash is toxic and its escalating use as a soil amendment and disposal by dumping into environment is receiving alarming attention due to its impact on environment. Proteomics technology is being used for environmental studies since proteins respond rapidly when an organism is exposed to a toxicant, and hence soil engineers such as earthworms are used as model organisms to assess the toxic effects of soil toxicants. This study adopted proteomics technology and profiled proteome of earthworm Dichogaster curgensis that was exposed to fly ash, with main aim to elucidate fly ash effects on cellular and metabolic pathways. The functional classification of identified proteins revealed carbohydrate metabolism (14.36%), genetic information processing (15.02%), folding, sorting and degradation (10.83%), replication and repair (3.95%); environmental information processing (2.19%), signal transduction (9.61%), transport and catabolism (17.27%), energy metabolism (6.69%), etc. in the proteome. Proteomics data and functional assays revealed that the exposure of earthworm to fly ash induced protein synthesis, up-regulation of gluconeogenesis, disturbed energy metabolism, oxidative and cellular stress, and mis-folding of proteins. The regulation of ubiquitination, proteasome and modified alkaline comet assay in earthworm coelomocytes suggested DNA-protein cross link affecting chromatin remodeling and protein folding. PMID:27371791

  8. Dissociable effects of anodal and cathodal tDCS reveal distinct functional roles for right parietal cortex in the detection of single and competing stimuli.

    PubMed

    Filmer, Hannah L; Dux, Paul E; Mattingley, Jason B

    2015-07-01

    Spatial attention can be used to direct neural processing resources to a subset of task-relevant or otherwise salient items within the environment. Such selective processes are particularly important for resolving competition between multiple stimuli. Deficits in processing single stimuli can arise after damage to parietal, frontal and temporal brain regions, as is typical in patients with contralesional spatial neglect. By contrast, deficits in processing multiple competing stimuli may arise specifically following lesions of the posterior parietal cortex (PPC), as occurs in the disorder of spatial extinction. It remains unclear, however, whether mechanisms involved in selecting single and competing stimuli reflect the same or dissociable neural operations within the PPC. To address this issue, in separate sessions, we applied transcranial direct current stimulation (tDCS) to the left or right PPC and measured the effect on detecting and discriminating single and competing visual stimulus events. Our results revealed reliable tDCS modulations of stimulus processing, specific to the right PPC, as well as a dissociation in the detection of single and competing stimuli. For the right PPC only, single stimuli presented to the left (contralateral) visual field were affected selectively by anodal tDCS, whereas competing stimuli across the two visual fields were affected by both anodal and cathodal tDCS. These contrasting effects of anodal and cathodal tDCS on perception of single and competing stimuli suggest dissociable neural coding properties within the right PPC.

  9. Dissociable effects of anodal and cathodal tDCS reveal distinct functional roles for right parietal cortex in the detection of single and competing stimuli.

    PubMed

    Filmer, Hannah L; Dux, Paul E; Mattingley, Jason B

    2015-07-01

    Spatial attention can be used to direct neural processing resources to a subset of task-relevant or otherwise salient items within the environment. Such selective processes are particularly important for resolving competition between multiple stimuli. Deficits in processing single stimuli can arise after damage to parietal, frontal and temporal brain regions, as is typical in patients with contralesional spatial neglect. By contrast, deficits in processing multiple competing stimuli may arise specifically following lesions of the posterior parietal cortex (PPC), as occurs in the disorder of spatial extinction. It remains unclear, however, whether mechanisms involved in selecting single and competing stimuli reflect the same or dissociable neural operations within the PPC. To address this issue, in separate sessions, we applied transcranial direct current stimulation (tDCS) to the left or right PPC and measured the effect on detecting and discriminating single and competing visual stimulus events. Our results revealed reliable tDCS modulations of stimulus processing, specific to the right PPC, as well as a dissociation in the detection of single and competing stimuli. For the right PPC only, single stimuli presented to the left (contralateral) visual field were affected selectively by anodal tDCS, whereas competing stimuli across the two visual fields were affected by both anodal and cathodal tDCS. These contrasting effects of anodal and cathodal tDCS on perception of single and competing stimuli suggest dissociable neural coding properties within the right PPC. PMID:25637773

  10. Silicon isotopes reveal recycled altered oceanic crust in the mantle sources of Ocean Island Basalts

    NASA Astrophysics Data System (ADS)

    Pringle, Emily A.; Moynier, Frédéric; Savage, Paul S.; Jackson, Matthew G.; Moreira, Manuel; Day, James M. D.

    2016-09-01

    The study of silicon (Si) isotopes in Ocean Island Basalts (OIB) has the potential to discern between different models for the origins of geochemical heterogeneities in the mantle. Relatively large (∼several per mil per atomic mass unit) Si isotope fractionation occurs in low-temperature environments during biochemical and geochemical precipitation of dissolved Si, where the precipitate is preferentially enriched in the lighter isotopes relative to the dissolved Si. In contrast, only a limited range (∼tenths of a per mil) of Si isotope fractionation has been observed from high-temperature igneous processes. Therefore, Si isotopes may be useful as tracers for the presence of crustal material within OIB mantle source regions that experienced relatively low-temperature surface processes in a manner similar to other stable isotope systems, such as oxygen. Characterizing the isotopic composition of the mantle is also of central importance to the use of the Si isotope system as a basis for comparisons with other planetary bodies (e.g., Moon, Mars, asteroids). Here we present the first comprehensive suite of high-precision Si isotope data obtained by MC-ICP-MS for a diverse suite of OIB. Samples originate from ocean islands in the Pacific, Atlantic, and Indian Ocean basins and include representative end-members for the EM-1, EM-2, and HIMU mantle components. On average, δ30Si values for OIB (-0.32 ± 0.09‰, 2 sd) are in general agreement with previous estimates for the δ30Si value of Bulk Silicate Earth (-0.29 ± 0.07‰, 2 sd; Savage et al., 2014). Nonetheless, some small systematic variations are present; specifically, most HIMU-type (Mangaia; Cape Verde; La Palma, Canary Islands) and Iceland OIB are enriched in the lighter isotopes of Si (δ30Si values lower than MORB), consistent with recycled altered oceanic crust and lithospheric mantle in their mantle sources.

  11. Spaceflight Alters Bacterial Gene Expression and Virulence and Reveals Role for Global Regulator Hfq

    NASA Technical Reports Server (NTRS)

    Wilson, J. W.; Ott, C. M.; zuBentrup, K. Honer; Ramamurthy R.; Quick, L.; Porwollik, S.; Cheng, P.; McClellan, M.; Tsaprailis, G.; Radabaugh, T.; Hunt, A.; Fernandez, D.; Richter, E.; Shah, M.; Kilcoyne, M.; Joshi, L.; Nelman-Gonzalez, M.; Hing, S.; Parra, M.; Dumaras, P.; Norwood, K.; Nickerson, C. A.; Bober, R.; Devich, J.; Ruggles, A.

    2007-01-01

    A comprehensive analysis of both the molecular genetic and phenotypic responses of any organism to the spaceflight environment has never been accomplished due to significant technological and logistical hurdles. Moreover, the effects of spaceflight on microbial pathogenicity and associated infectious disease risks have not been studied. The bacterial pathogen Salmonella typhimurium was grown aboard Space Shuttle mission STS-115 and compared to identical ground control cultures. Global microarray and proteomic analyses revealed 167 transcripts and 73 proteins changed expression with the conserved RNA-binding protein Hfq identified as a likely global regulator involved in the response to this environment. Hfq involvement was confirmed with a ground based microgravity culture model. Spaceflight samples exhibited enhanced virulence in a murine infection model and extracellular matrix accumulation consistent with a biofilm. Strategies to target Hfq and related regulators could potentially decrease infectious disease risks during spaceflight missions and provide novel therapeutic options on Earth.

  12. Modulators of Stomatal Lineage Signal Transduction Alter Membrane Contact Sites and Reveal Specialization among ERECTA Kinases.

    PubMed

    Ho, Chin-Min Kimmy; Paciorek, Tomasz; Abrash, Emily; Bergmann, Dominique C

    2016-08-22

    Signal transduction from a cell's surface to its interior requires dedicated signaling elements and a cellular environment conducive to signal propagation. Plant development, defense, and homeostasis rely on plasma membrane receptor-like kinases to perceive endogenous and environmental signals, but little is known about their immediate downstream targets and signaling modifiers. Using genetics, biochemistry, and live-cell imaging, we show that the VAP-RELATED SUPPRESSOR OF TMM (VST) family is required for ERECTA-mediated signaling in growth and cell-fate determination and reveal a role for ERECTA-LIKE2 in modulating signaling by its sister kinases. We show that VSTs are peripheral plasma membrane proteins that can form complexes with integral ER-membrane proteins, thereby potentially influencing the organization of the membrane milieu to promote efficient and differential signaling from the ERECTA-family members to their downstream intracellular targets.

  13. Untargeted Metabolomics Analysis Reveals a Link between ETHE1-Mediated Disruptive Redox State and Altered Metabolic Regulation.

    PubMed

    Sahebekhtiari, Navid; Nielsen, Camilla Bak; Johannsen, Mogens; Palmfeldt, Johan

    2016-05-01

    Defects in the gene encoding the persulfide dioxygenase ETHE1 are known to cause the severe inherited metabolic disorder ethylmalonic encephalopathy (EE). In spite of known clinical characteristics, the molecular mechanisms underlying the ETHE1 deficiency are still obscure. Herein, to further analyze the molecular phenotype of the disease, we applied an untargeted metabolomics approach on cultivated fibroblasts of EE patients for pinpointing alterations in metabolite levels. Metabolites, as direct signatures of biochemical functions, can decipher biochemical pathways involved in the cellular phenotype of patient cells. Using liquid chromatography-mass spectrometry-based untargeted metabolomics, we identified 18 metabolites that have altered levels in fibroblasts from EE patients. Our data demonstrate disrupted redox state in EE patient cells, which is reflected by significantly decreased level of reduced glutathione. Furthermore, the down-regulation of several intermediate metabolites such as the redox cofactors NAD(+) and NADH as well as Krebs cycle intermediates revealed clear alteration in metabolic regulation. Pantothenic acid and several amino acids exhibited decreased levels, whereas the β-citrylglutamate with a putative role in brain development had an increased level in the EE patient cells. These observations indicate the severe impact of ETHE1 deficiency on cellular physiology and redox state, meanwhile suggesting targets for experimental studies on novel treatment options for the devastating metabolic disorder. PMID:27074420

  14. Multimodal Characterization of Proliferative Diabetic Retinopathy Reveals Alterations in Outer Retinal Function and Structure

    PubMed Central

    Boynton, Grace E.; Stem, Maxwell S.; Kwark, Leon; Jackson, Gregory R.; Farsiu, Sina; Gardner, Thomas W.

    2014-01-01

    diffusely thinned RPE layers (p=0.031) compared to controls. Conclusions Patients with untreated PDR exhibit inner retinal dysfunction, as evidenced by reduced contrast sensitivity and FDP performance, accompanied by alterations in inner and outer retinal structure. PRP-treated patients had more profound changes in outer retinal structure and function. Distinguishing the effects of PDR and PRP may guide the development of restorative vision therapies for patients with advanced diabetic retinopathy. PMID:25601533

  15. Association analysis reveals genetic variation altering bleomycin-induced pulmonary fibrosis in mice.

    PubMed

    Paun, Alexandra; Lemay, Anne-Marie; Tomko, Tomasz G; Haston, Christina K

    2013-03-01

    Pulmonary fibrosis is a disease of significant morbidity, with an incompletely defined genetic basis. Here, we combine linkage and association studies to identify genetic variations associated with pulmonary fibrosis in mice. Mice were treated with bleomycin by osmotic minipump, and pulmonary fibrosis was histologically assessed 6 weeks later. Fibrosis was mapped in C57BL6/J (fibrosis-susceptible) × A/J (fibrosis-resistant) F2 mice, and the major identified linkage intervals were evaluated in consomic mice. Genome-wide and linkage-interval genes were assessed for their association with fibrosis, using phenotypic data from 23 inbred strains and the murine single-nucleotide polymorphism map. Susceptibility to pulmonary fibrosis mapped to a locus on chromosome 17, which was verified with consomic mice, and to three additional suggestive loci that may interact with alleles on chromosome 17 to affect the trait in F2 mice. Two of the loci, including the region on chromosome 17, are homologous to previously mapped loci of human idiopathic fibrosis. Of the 23 phenotyped murine strains, four developed significant fibrosis, and the majority presented minimal disease. Genome-wide and linkage region-specific association studies revealed 11 pulmonary expressed genes (including the autophagy gene Cep55, and Masp2, which is a complement component) to contain polymorphisms significantly associated with bleomycin-induced fibrotic lung disease. In conclusion, genomic approaches were used to identify linkage intervals and specific genetic variations associated with pulmonary fibrosis in mice. The common loci and similarities in phenotype suggest these findings to be of relevance to clinical pulmonary fibrosis.

  16. Maternal stress predicts altered biogenesis and the profile of mitochondrial proteins in the frontal cortex and hippocampus of adult offspring rats.

    PubMed

    Głombik, Katarzyna; Stachowicz, Aneta; Ślusarczyk, Joanna; Trojan, Ewa; Budziszewska, Bogusława; Suski, Maciej; Kubera, Marta; Lasoń, Władysław; Wędzony, Krzysztof; Olszanecki, Rafał; Basta-Kaim, Agnieszka

    2015-10-01

    Currently, much attention is focused on the influence of mitochondrial disturbances at the onset of depression. The goal of this study was to investigate the impact of prenatal stress (an animal model of depression) on the mitochondrial biogenesis proteins and mitoproteome profile in the frontal cortex and hippocampus of adult 3-month-old male rats following a prenatal stress procedure. Our results show that rats that were exposed to prenatal stress stimuli displayed depression-like behaviors based on the sucrose preference and elevated plus maze tests. It has been found that the level of the PGC-1α protein was reduced in the frontal cortex and hippocampus of the adult offspring after the prenatal stress procedure. Moreover, in the frontal cortex, the level of the pro-apoptotic protein Bax was up-regulated. Two-dimensional electrophoresis coupled with mass spectrometry showed the statistically significant down-regulation of the mitochondrial ribosomal protein L12 (Mrpl12) and mitochondrial NADH dehydrogenase [ubiquinone] flavoprotein 2 (NDUFV2) as well as the up-regulation of the Tubulin Polymerization Promoting Proteins (Tppp/p25) in the frontal cortex. In contrast, in the hippocampus, the mitochondrial pyruvate dehydrogenase E1 component subunit beta, the voltage-dependent anion-selective channel protein 2 (VDAC2), and the GTP-binding nuclear protein RAN (RAN) were down-regulated and the expression of phosphatidylethanolamine-binding protein 1 (PEBP-1) was enhanced. These findings provide new evidence that stress during pregnancy may lead not only to behavioral deficits, but also to disturbances in the brain mitoproteome profile in adult rat offspring.

  17. Glucose or Altered Ceramide Biosynthesis Mediate Oxygen Deprivation Sensitivity Through Novel Pathways Revealed by Transcriptome Analysis in Caenorhabditis elegans

    PubMed Central

    Ladage, Mary L.; King, Skylar D.; Burks, David J.; Quan, Daniel L.; Garcia, Anastacia M.; Azad, Rajeev K.; Padilla, Pamela A.

    2016-01-01

    Individuals with type 2 diabetes display metabolic abnormalities, such as hyperglycemia, increased free fatty acids, insulin resistance, and altered ceramide levels, that contribute to vascular dysfunctions and compromised oxygen delivery. Caenorhabditis elegans fed a glucose-supplemented diet or with altered ceramide metabolism, due to a hyl-2 mutation, are sensitive to oxygen deprivation (anoxia). Our experiments showed that the combination of these factors further decreased the anoxia survival. RNA-sequencing analysis was performed to assess how a glucose-supplemented diet and/or a hyl-2 mutation altered the transcriptome. Comparison analysis of transcripts associated with anoxia-sensitive animals [hyl-2(tm2031) mutation or a glucose diet] revealed 199 common transcripts encoded by genes with known or predicted functions involving innate immunity, cuticle function (collagens), or xenobiotic and endobiotic phase I and II detoxification system. Use of RNA interference (RNAi) to target gene products of the xenobiotic and endobiotic phase I and II detoxification system (UDP-glycosyltransferase and Cytochrome p450 genes; ugt-15, ugt-18, ugt-19, ugt-41, ugt-63, cyp-13A12, cyp-25A1, and cyp-33C8) increased anoxia survival in wild-type animals fed a standard diet. Anoxia sensitivity of the hyl-2(tm2031) animals was suppressed by RNAi of cyp-25A1 or cyp-33C8 genes. A glucose diet fed to the P0 hermaphrodite decreased the anoxia survival of its F1 embryos; however, the RNAi of ugt-63 and cyp-33C8 suppressed anoxia sensitivity. These studies provide evidence that the detoxification system impacts oxygen deprivation responses and that C. elegans can be used to model the conserved detoxification system. PMID:27507791

  18. Comprehensive Plasma Metabolomic Analyses of Atherosclerotic Progression Reveal Alterations in Glycerophospholipid and Sphingolipid Metabolism in Apolipoprotein E-deficient Mice

    PubMed Central

    Dang, Vi T.; Huang, Aric; Zhong, Lexy H.; Shi, Yuanyuan; Werstuck, Geoff H.

    2016-01-01

    Atherosclerosis is the major underlying cause of most cardiovascular diseases. Despite recent advances, the molecular mechanisms underlying the pathophysiology of atherogenesis are not clear. In this study, comprehensive plasma metabolomics were used to investigate early-stage atherosclerotic development and progression in chow-fed apolipoprotein E-deficient mice at 5, 10 and 15 weeks of age. Comprehensive plasma metabolomic profiles, based on 4365 detected metabolite features, differentiate atherosclerosis-prone from atherosclerosis-resistant models. Metabolites in the sphingomyelin pathway were significantly altered prior to detectable lesion formation and at all subsequent time-points. The cytidine diphosphate-diacylglycerol pathway was up-regulated during stage I of atherosclerosis, while metabolites in the phosphatidylethanolamine and glycosphingolipid pathways were augmented in mice with stage II lesions. These pathways, involving glycerophospholipid and sphingolipid metabolism, were also significantly affected during the course of atherosclerotic progression. Our findings suggest that distinct plasma metabolomic profiles can differentiate the different stages of atherosclerotic progression. This study reveals that alteration of specific, previously unreported pathways of glycerophospholipid and sphingolipid metabolism are associated with atherosclerosis. The clear difference in the level of several metabolites supports the use of plasma lipid profiling as a diagnostic tool of atherogenesis. PMID:27721472

  19. Advances in the translational genomics of neuroblastoma: From improving risk stratification and revealing novel biology to identifying actionable genomic alterations.

    PubMed

    Bosse, Kristopher R; Maris, John M

    2016-01-01

    Neuroblastoma is an embryonal malignancy that commonly affects young children and is remarkably heterogenous in its malignant potential. Recently, the genetic basis of neuroblastoma has come into focus and not only has catalyzed a more comprehensive understanding of neuroblastoma tumorigenesis but also has revealed novel oncogenic vulnerabilities that are being therapeutically leveraged. Neuroblastoma is a model pediatric solid tumor in its use of recurrent genomic alterations, such as high-level MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog) amplification, for risk stratification. Given the relative paucity of recurrent, activating, somatic point mutations or gene fusions in primary neuroblastoma tumors studied at initial diagnosis, innovative treatment approaches beyond small molecules targeting mutated or dysregulated kinases will be required moving forward to achieve noticeable improvements in overall patient survival. However, the clonally acquired, oncogenic aberrations in relapsed neuroblastomas are currently being defined and may offer an opportunity to improve patient outcomes with molecularly targeted therapy directed toward aberrantly regulated pathways in relapsed disease. This review summarizes the current state of knowledge about neuroblastoma genetics and genomics, highlighting the improved prognostication and potential therapeutic opportunities that have arisen from recent advances in understanding germline predisposition, recurrent segmental chromosomal alterations, somatic point mutations and translocations, and clonal evolution in relapsed neuroblastoma.

  20. Longitudinal MRI reveals altered trajectory of brain development during childhood and adolescence in fetal alcohol spectrum disorders.

    PubMed

    Treit, Sarah; Lebel, Catherine; Baugh, Lauren; Rasmussen, Carmen; Andrew, Gail; Beaulieu, Christian

    2013-06-12

    Diffusion tensor imaging (DTI) of brain development in fetal alcohol spectrum disorders (FASD) has revealed structural abnormalities, but studies have been limited by the use of cross-sectional designs. Longitudinal scans can provide key insights into trajectories of neurodevelopment within individuals with this common developmental disorder. Here we evaluate serial DTI and T1-weighted volumetric MRI in a human sample of 17 participants with FASD and 27 controls aged 5-15 years who underwent 2-3 scans each, ∼2-4 years apart (92 scans total). Increases of fractional anisotropy and decreases of mean diffusivity (MD) were observed between scans for both groups, in keeping with changes expected of typical development, but mixed-models analysis revealed significant age-by-group interactions for three major white matter tracts: superior longitudinal fasciculus and superior and inferior fronto-occipital fasciculus. These findings indicate altered developmental progression in these frontal-association tracts, with the FASD group notably showing greater reduction of MD between scans. ΔMD is shown to correlate with reading and receptive vocabulary in the FASD group, with steeper decreases of MD in the superior fronto-occipital fasciculus and superior longitudinal fasciculus between scans correlating with greater improvement in language scores. Volumetric analysis revealed reduced total brain, white, cortical gray, and deep gray matter volumes and fewer significant age-related volume increases in the FASD group, although age-by-group interactions were not significant. Longitudinal DTI indicates delayed white matter development during childhood and adolescence in FASD, which may underlie persistent or worsening behavioral and cognitive deficits during this critical period.

  1. Urinary Metabolomics Reveals Alterations of Aromatic Amino Acid Metabolism of Alzheimer's Disease in the Transgenic CRND8 Mice.

    PubMed

    Tang, Zhi; Liu, Liangfeng; Li, Yongle; Dong, Jiyang; Li, Min; Huang, Jiandong; Lin, Shuhai; Cai, Zongwei

    2016-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with amyloid plaques accumulation as the key feature involved in its pathology. To date, however, the biochemical changes in AD have not been clearly characterized. Here, we present that urinary metabolomics based on high resolution mass spectrometry was employed for delineation of metabolic alterations in transgenic CRND8 mice. In this noninvasive approach, urinary metabolome reveals the biochemical changes in early onset of this AD mouse model. In virtue of comprehensive metabolite profiling and multivariate statistical analysis, a total of 73 differential metabolites of urine sample sets was identified in 12-week and 18-week transgenic mice compared to wild-type littermates, covering perturbations of aromatic amino acid metabolism, the Krebs cycle and one-carbon metabolism. Of particular interest is that divergent tryptophan metabolism, such as upregulation of serotonin pathway while downregulation of kynurenine pathway, was observed. Meanwhile, the accumulation of both N-acetylvanilalanine and 3-methoxytyrosine indicated aromatic L-amino acid decarboxylase deficiency. And the microbial metabolites derived from aromatic amino acid metabolism and drug-like phase II metabolic response via the glycine conjugation reactions were also highlighted, indicating that genetic modification in mouse brain not only alters genotype but also perturbs the gut microbiome. Together, our study demonstrated that the integrative approach employing mass spectrometry-based metabolomics and a transgenic mouse model for AD may provide new evidence for distinct metabolic signatures. The perturbations of metabolic pathways may have far-reaching implications for early diagnosis and intervention in AD. PMID:26825095

  2. Early continuous white noise exposure alters auditory spatial sensitivity and expression of GAD65 and GABAA receptor subunits in rat auditory cortex.

    PubMed

    Xu, Jinghong; Yu, Liping; Cai, Rui; Zhang, Jiping; Sun, Xinde

    2010-04-01

    Sensory experiences have important roles in the functional development of the mammalian auditory cortex. Here, we show how early continuous noise rearing influences spatial sensitivity in the rat primary auditory cortex (A1) and its underlying mechanisms. By rearing infant rat pups under conditions of continuous, moderate level white noise, we found that noise rearing markedly attenuated the spatial sensitivity of A1 neurons. Compared with rats reared under normal conditions, spike counts of A1 neurons were more poorly modulated by changes in stimulus location, and their preferred locations were distributed over a larger area. We further show that early continuous noise rearing induced significant decreases in glutamic acid decarboxylase 65 and gamma-aminobutyric acid (GABA)(A) receptor alpha1 subunit expression, and an increase in GABA(A) receptor alpha3 expression, which indicates a returned to the juvenile form of GABA(A) receptor, with no effect on the expression of N-methyl-D-aspartate receptors. These observations indicate that noise rearing has powerful adverse effects on the maturation of cortical GABAergic inhibition, which might be responsible for the reduced spatial sensitivity. PMID:19620619

  3. Severe Alterations in Lipid Composition of Frontal Cortex Lipid Rafts from Parkinson’s Disease and Incidental Parkinson’s Disease

    PubMed Central

    Fabelo, Noemí; Martín, Virginia; Santpere, Gabriel; Marín, Raquel; Torrent, Laia; Ferrer, Isidre; Díaz, Mario

    2011-01-01

    Lipid rafts are cholesterol- and sphingomyelin-enriched microdomains that provide a highly saturated and viscous physicochemical microenvironment to promote protein–lipid and protein–protein interactions. We purified lipid rafts from human frontal cortex from normal, early motor stages of Parkinson’s disease (PD) and incidental Parkinson’s disease (iPD) subjects and analyzed their lipid composition. We observed that lipid rafts from PD and iPD cortices exhibit dramatic reductions in their contents of n-3 and n-6 long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (22:6-n3) and arachidonic acid (20:4n-6). Also, saturated fatty acids (16:0 and 18:0) were significantly higher than in control brains. Paralleling these findings, unsaturation and peroxidability indices were considerably reduced in PD and iPD lipid rafts. Lipid classes were also affected in PD and iPD lipid rafts. Thus, phosphatidylserine and phosphatidylinositol were increased in PD and iPD, whereas cerebrosides and sulfatides and plasmalogen levels were considerably diminished. Our data pinpoint a dramatic increase in lipid raft order due to the aberrant biochemical structure in PD and iPD and indicate that these abnormalities of lipid rafts in the frontal cortex occur at early stages of PD pathology. The findings correlate with abnormal lipid raft signaling and cognitive decline observed during the development of these neurodegenerative disorders. PMID:21717034

  4. Compartmentation of the cerebellar cortex of hummingbirds (Aves: Trochilidae) revealed by the expression of zebrin II and phospholipase C beta 4.

    PubMed

    Iwaniuk, Andrew N; Marzban, Hassan; Pakan, Janelle M P; Watanabe, Masahiko; Hawkes, Richard; Wylie, Douglas R W

    2009-01-01

    The parasagittal organization of the mammalian cerebellar cortex into zones has been well characterized by immunohistochemical, hodological and physiological studies in recent years. The pattern of these parasagittal bands across the cerebellum is highly conserved across mammals, but whether a similar conservation of immunohistochemically defined parasagittal bands occurs within birds has remained uncertain. Here, we examine the compartmentation of the cerebellar cortex of a group of birds with unique cerebellar morphology-hummingbirds (Trochilidae). Immunohistochemical techniques were used to characterize the expression of zebrin II (aldolase C) and phospholipase C beta 4 (PLC beta 4) in the cerebellar cortex of two hummingbird species. A series of zebrin II immunopositive/immunonegative parasagittal stripes was apparent across most folia representing three major transverse zones: an anterior zone with a central stripe flanked by three lateral stripes on either side; a central zone of high/low immunopositive stripes; and a posterior zone with a central stripe flanked by four to six lateral stripes on either side. In addition, both folia I and X were uniformly immunopositive. The pattern of PLC beta 4 immunoreactivity was largely complementary-PLC beta 4 positive stripes were zebrin II negative and vice versa. The similarity of zebrin II expression between the hummingbirds and the pigeon indicates that the neurochemical compartmentation of the cerebellar cortex in birds is highly conserved, but species differences in the number and width of stripes do occur.

  5. Task and Resting-State fMRI Reveal Altered Salience Responses to Positive Stimuli in Patients with Major Depressive Disorder.

    PubMed

    Yang, Yang; Zhong, Ning; Imamura, Kazuyuki; Lu, Shengfu; Li, Mi; Zhou, Haiyan; Li, Huaizhou; Yang, Xiaojing; Wan, Zhijiang; Wang, Gang; Hu, Bin; Li, Kuncheng

    2016-01-01

    Altered brain function in patients with major depressive disorder (MDD) has been repeatedly demonstrated by task-based and resting-state studies, respectively. However, less is known concerning whether overlapped abnormalities in functional activities across modalities exist in MDD patients. To find out the answer, we implemented an fMRI experiment and collected both task and resting-state data from 19 MDD patients and 19 matched, healthy, controls. A distraction paradigm involving emotionally valenced pictures was applied to induce affective responses in subjects. As a result, concurrent deficits were found in arousing activation during a positive task in both the reward circuit and salience network (SN) that is composed of the dorsal part of anterior cingulate cortex (dACC) and bilateral anterior insulae (AI) in only the MDD group. Subsequent amplitude of low frequency fluctuations (ALFF) and functional connectivity analyses based on resting-state data exhibited consistent alterations in the bilateral AI of MDD patients, and indicated patients' difficulties in regulating the balance between central executive network (CEN) and default mode network (DMN) due to altered connectivity among the CEN, DMN, and SN. Our findings provide new evidence demonstrating impaired salience processing and resulting alterations in responses to positive stimuli in MDD patients. Furthermore, brain abnormalities synchronized across functional states in MDD patients can be evidenced by a combination of task and resting-state fMRI analyses.

  6. Task and Resting-State fMRI Reveal Altered Salience Responses to Positive Stimuli in Patients with Major Depressive Disorder

    PubMed Central

    Yang, Yang; Zhong, Ning; Imamura, Kazuyuki; Lu, Shengfu; Li, Mi; Zhou, Haiyan; Li, Huaizhou; Yang, Xiaojing; Wan, Zhijiang; Wang, Gang; Hu, Bin; Li, Kuncheng

    2016-01-01

    Altered brain function in patients with major depressive disorder (MDD) has been repeatedly demonstrated by task-based and resting-state studies, respectively. However, less is known concerning whether overlapped abnormalities in functional activities across modalities exist in MDD patients. To find out the answer, we implemented an fMRI experiment and collected both task and resting-state data from 19 MDD patients and 19 matched, healthy, controls. A distraction paradigm involving emotionally valenced pictures was applied to induce affective responses in subjects. As a result, concurrent deficits were found in arousing activation during a positive task in both the reward circuit and salience network (SN) that is composed of the dorsal part of anterior cingulate cortex (dACC) and bilateral anterior insulae (AI) in only the MDD group. Subsequent amplitude of low frequency fluctuations (ALFF) and functional connectivity analyses based on resting-state data exhibited consistent alterations in the bilateral AI of MDD patients, and indicated patients’ difficulties in regulating the balance between central executive network (CEN) and default mode network (DMN) due to altered connectivity among the CEN, DMN, and SN. Our findings provide new evidence demonstrating impaired salience processing and resulting alterations in responses to positive stimuli in MDD patients. Furthermore, brain abnormalities synchronized across functional states in MDD patients can be evidenced by a combination of task and resting-state fMRI analyses. PMID:27192082

  7. Directed Evolution Reveals Unexpected Epistatic Interactions That Alter Metabolic Regulation and Enable Anaerobic Xylose Use by Saccharomyces cerevisiae

    PubMed Central

    Tremaine, Mary; Hebert, Alexander S.; Myers, Kevin S.; Sardi, Maria; Dickinson, Quinn; Reed, Jennifer L.; Zhang, Yaoping; Coon, Joshua J.; Hittinger, Chris Todd; Gasch, Audrey P.; Landick, Robert

    2016-01-01

    The inability of native Saccharomyces cerevisiae to convert xylose from plant biomass into biofuels remains a major challenge for the production of renewable bioenergy. Despite extensive knowledge of the regulatory networks controlling carbon metabolism in yeast, little is known about how to reprogram S. cerevisiae to ferment xylose at rates comparable to glucose. Here we combined genome sequencing, proteomic profiling, and metabolomic analyses to identify and characterize the responsible mutations in a series of evolved strains capable of metabolizing xylose aerobically or anaerobically. We report that rapid xylose conversion by engineered and evolved S. cerevisiae strains depends upon epistatic interactions among genes encoding a xylose reductase (GRE3), a component of MAP Kinase (MAPK) signaling (HOG1), a regulator of Protein Kinase A (PKA) signaling (IRA2), and a scaffolding protein for mitochondrial iron-sulfur (Fe-S) cluster biogenesis (ISU1). Interestingly, the mutation in IRA2 only impacted anaerobic xylose consumption and required the loss of ISU1 function, indicating a previously unknown connection between PKA signaling, Fe-S cluster biogenesis, and anaerobiosis. Proteomic and metabolomic comparisons revealed that the xylose-metabolizing mutant strains exhibit altered metabolic pathways relative to the parental strain when grown in xylose. Further analyses revealed that interacting mutations in HOG1 and ISU1 unexpectedly elevated mitochondrial respiratory proteins and enabled rapid aerobic respiration of xylose and other non-fermentable carbon substrates. Our findings suggest a surprising connection between Fe-S cluster biogenesis and signaling that facilitates aerobic respiration and anaerobic fermentation of xylose, underscoring how much remains unknown about the eukaryotic signaling systems that regulate carbon metabolism. PMID:27741250

  8. Altered lacunar and vascular porosity in osteogenesis imperfecta mouse bone as revealed by synchrotron tomography contributes to bone fragility.

    PubMed

    Carriero, A; Doube, M; Vogt, M; Busse, B; Zustin, J; Levchuk, A; Schneider, P; Müller, R; Shefelbine, S J

    2014-04-01

    Osteogenesis imperfecta (brittle bone disease) is caused by mutations in the collagen genes and results in skeletal fragility. Changes in bone porosity at the tissue level indicate changes in bone metabolism and alter bone mechanical integrity. We investigated the cortical bone tissue porosity of a mouse model of the disease, oim, in comparison to a wild type (WT-C57BL/6), and examined the influence of canal architecture on bone mechanical performance. High-resolution 3D representations of the posterior tibial and the lateral humeral mid-diaphysis of the bones were acquired for both mouse groups using synchrotron radiation-based computed tomography at a nominal resolution of 700nm. Volumetric morphometric indices were determined for cortical bone, canal network and osteocyte lacunae. The influence of canal porosity architecture on bone mechanics was investigated using microarchitectural finite element (μFE) models of the cortical bone. Bright-field microscopy of stained sections was used to determine if canals were vascular. Although total cortical porosity was comparable between oim and WT bone, oim bone had more numerous and more branched canals (p<0.001), and more osteocyte lacunae per unit volume compared to WT (p<0.001). Lacunae in oim were more spherical in shape compared to the ellipsoidal WT lacunae (p<0.001). Histology revealed blood vessels in all WT and oim canals. μFE models of cortical bone revealed that small and branched canals, typical of oim bone, increase the risk of bone failure. These results portray a state of compromised bone quality in oim bone at the tissue level, which contributes to its deficient mechanical properties.

  9. High-throughput 16S rRNA gene sequencing reveals alterations of mouse intestinal microbiota after radiotherapy.

    PubMed

    Kim, Young Suk; Kim, Jinu; Park, Soo-Je

    2015-06-01

    The mammalian gastrointestinal tract harbors a highly complex microbial community that comprises hundreds of different types of bacterial cells. The gastrointestinal microbiota plays an important role in the function of the host intestine. Most cancer patients undergoing pelvic irradiation experience side effects such as diarrhea; however, little is currently known about the effects of irradiation on the microorganisms colonizing the mucosal surfaces of the gastrointestinal tract. The aim of this study was to investigate the effects of gamma irradiation on the compositions of the large and small intestinal microbiotas. The gut microbiotas in control mice and mice receiving irradiation treatment were characterized by high-throughput sequencing of the bacterial 16S rRNA gene. Irradiation treatment induced significant alterations in the bacterial compositions of the large and small intestines at the genus level. Unexpectedly, irradiation treatment increased the number of operational taxonomic units in the small intestine but not the large intestine. In particular, irradiation treatment increased the level of the genera Alistipes in the large intestine and increased the level of the genus Corynebacterium in the small intestine. By contrast, compared with that in the corresponding control group, the level of the genera Prevotella was lower in the irradiated large intestine, and the level of the genera Alistipes was lower in the irradiated small intestine. Overall, the data presented here reveal the potential microbiological effects of pelvic irradiation on the gastrointestinal tracts of cancer patients.

  10. Liquid Chromatography-Mass Spectrometry-Based In Vitro Metabolic Profiling Reveals Altered Enzyme Expressions in Eicosanoid Metabolism

    PubMed Central

    Lee, Su Hyeon; Kim, Eung Ju; Lee, Dong-Hyoung; Lee, Won-Yong; Chung, Bong Chul

    2016-01-01

    Background Eicosanoids are metabolites of arachidonic acid that are rapidly biosynthesized and degraded during inflammation, and their metabolic changes reveal altered enzyme expression following drug treatment. We developed an eicosanoid profiling method and evaluated their changes on drug treatment. Methods Simultaneous quantitative profiling of 32 eicosanoids in liver S9 fractions obtained from rabbits with carrageenan-induced inflammation was performed and validated by liquid chromatography-mass spectrometry coupled to anion-exchange solid-phase purification. Results The limit of quantification for the devised method ranged from 0.5 to 20.0 ng/mg protein, and calibration linearity was achieved (R2>0.99). The precision (% CV) and accuracy (% bias) ranged from 4.7 to 10.3% and 88.4 to 110.9%, respectively, and overall recoveries ranged from 58.0 to 105.3%. Our method was then applied and showed that epitestosterone treatment reduced the levels of all eicosanoids that were generated by cyclooxygenases and lipoxygenases. Conclusions Quantitative eicosanoid profiling combined with in vitro metabolic assays may be useful for evaluating metabolic changes affected by drugs during eicosanoid metabolism. PMID:27139607

  11. Global detection of molecular changes reveals concurrent alteration of several biological pathways in nonsmall cell lung cancer cells

    PubMed Central

    Ju, Z.; Kapoor, M.; Newton, K; Cheon, K.; Ramaswamy, A.; Lotan, R.; Strong, L. C.; Koo, J. S.

    2006-01-01

    To identify the molecular changes that occur in non-small cell lung carcinoma (NSCLC), we compared the gene expression profile of the NCI-H292 (H292) NSCLC cell line with that of normal human tracheobronchial epithelial (NHTBE) cells. The NHTBE cells were grown in a three-dimensional organotypic culture system that permits maintenance of the normal pseudostratified mucociliary phenotype characteristic of bronchial epithelium in vivo. Microarray analysis using the Affymetrix oligonucleotide chip U95Av2 revealed that 1,683 genes showed a > 1.5-fold change in expression in the H292 cell line relative to the NHTBE cells. Specifically, 418 genes were downregulated and 1,265 were upregulated in the H292 cells. The expression data for selected genes were validated in several different NSCLC cell lines using quantitative real-time PCR and Western analysis. Further analysis of the differentially expressed genes indicated that WNT responses, apoptosis, cell cycle regulation and cell proliferation were significantly altered in the H292 cells. Functional analysis using fluorescence-activated cell sorting confirmed concurrent changes in the activity of these pathways in the H292 line. These findings show that (1) NSCLC cells display deregulation of the WNT, apoptosis, proliferation and cell cycle pathways, as has been found in many other types of cancer cells, and (2) that organotypically cultured NHTBE cells can be used as a reference to identify genes and pathways that are differentially expressed in tumor cells derived from bronchogenic epithelium. PMID:16049682

  12. Single-molecule kinetics reveal microscopic mechanism by which High-Mobility Group B proteins alter DNA flexibility

    PubMed Central

    McCauley, Micah J.; Rueter, Emily M.; Rouzina, Ioulia; Maher, L. James; Williams, Mark C.

    2013-01-01

    Eukaryotic High-Mobility Group B (HMGB) proteins alter DNA elasticity while facilitating transcription, replication and DNA repair. We developed a new single-molecule method to probe non-specific DNA interactions for two HMGB homologs: the human HMGB2 box A domain and yeast Nhp6Ap, along with chimeric mutants replacing neutral N-terminal residues of the HMGB2 protein with cationic sequences from Nhp6Ap. Surprisingly, HMGB proteins constrain DNA winding, and this torsional constraint is released over short timescales. These measurements reveal the microscopic dissociation rates of HMGB from DNA. Separate microscopic and macroscopic (or local and non-local) unbinding rates have been previously proposed, but never independently observed. Microscopic dissociation rates for the chimeric mutants (∼10 s−1) are higher than those observed for wild-type proteins (∼0.1–1.0 s−1), reflecting their reduced ability to bend DNA through short-range interactions, despite their increased DNA-binding affinity. Therefore, transient local HMGB–DNA contacts dominate the DNA-bending mechanism used by these important architectural proteins to increase DNA flexibility. PMID:23143110

  13. Differential dynamics of amino acid release in the amygdala and olfactory cortex during odor fear acquisition as revealed with simultaneous high temporal resolution microdialysis.

    PubMed

    Hegoburu, Chloé; Sevelinges, Yannick; Thévenet, Marc; Gervais, Rémi; Parrot, Sandrine; Mouly, Anne-Marie

    2009-11-01

    Although the amygdala seems to be essential to the formation and storage of fear memories, it might store only some aspects of the aversive event and facilitate the storage of more specific sensory aspects in cortical areas. We addressed the time course of amygdala and cortical activation in the context of odor fear conditioning in rats. Using high temporal resolution (1-min sampling) intracerebral microdialysis, we investigated the dynamics of glutamate and GABA fluctuations simultaneously in basolateral amygdala (BLA) and posterior piriform cortex (pPCx) during the course of the acquisition session, which consisted of six odor (conditioned stimulus)-footshock (unconditioned stimulus) pairings. In BLA, we observed a transient increase in amino acid concentrations following the first odor-shock pairing, after which concentrations returned to baseline levels or slightly below. In pPCx, transient increases were seen after each pairing and were also observed after the last odor-shock pairing, corresponding to the predicted times of anticipated trials. Furthermore, we observed that for the first pairing, the increase in BLA occurred earlier than the increase in pPCx. These data suggest that the amygdala is engaged early during acquisition and precedes the activation of the olfactory cortex, which is maintained until the end of the session. In addition, our data raise the challenging idea that the olfactory cortex might store certain aspects of fear conditioning related to the timing of the associations.

  14. Chromosomal investigations of the Usubuchi sarcoma. II. Chromosomal alteration of the stem line cells revealed by differential staining techniques.

    PubMed

    Obara, Y; Sasaki, M; Shibasaki, Y; Okubo, M

    1982-11-01

    Stem line cells of the Usubuchi sarcoma (US) were karyologically investigated by means of G-, C-, and N-banding methods in ten samples from the 1,923rd to 2,081st transfer generations, with special attention to the structural alteration of marker-1 chromosome. The US cells showed wide variations in chromosome constitution and number, while the modal number of chromosomes was consistently 64 in all the generations examined. The chromosome constitutions varied widely even in cells with the modal number. In the early stage (1,923rd to 1,936th generations) the US contained two major stem lines characterized by marker combinations such as 1-2-3-4(1)-4(3)-8 and 2-3-4(1)-4(2)-4(3)-8, occurring with nearly similar frequency. From the middle to later transfer stages (from the 2,004th to the 2,081st generations), the 1-2-3-4(1)-4(3)-8 stem line rapidly declined and finally disappeared. In contrast, the 2-3-4(1)-4(2)-4(3)-8 line became a predominant part of the stem line. The G- and C-banding and population analyses of the stem line cells strongly suggested that marker 4(2) might have been derived from marker 1 by a deletion of the distal half of its long arm. The US studied contained a few stem lines and various types of sublines, each karyologically characteristic. G-Banding analysis revealed various types of intra- and interchromosomal rearrangements probably due to occasional chromosomal mutations either in markers or in nonmarkers in both stem lines and sublines. It seems likely that the stem line cells of the US are not always stable, but rather variable, in their chromosome makeup during the course of multiplication and successive transfers.

  15. A hierarchical analysis of transcriptome alterations in intrauterine growth restriction (IUGR) reveals common pathophysiological pathways in mammals.

    PubMed

    Buffat, C; Mondon, F; Rigourd, V; Boubred, F; Bessières, B; Fayol, L; Feuerstein, J-M; Gamerre, M; Jammes, H; Rebourcet, R; Miralles, F; Courbières, B; Basire, A; Dignat-Georges, F; Carbonne, B; Simeoni, U; Vaiman, D

    2007-11-01

    Intra-uterine growth restriction (IUGR) is a frequent disease, affecting up to 10% of human pregnancies and responsible for increased perinatal morbidity and mortality. Moreover, low birth weight is an important cause of the metabolic syndrome in the adult. Protein depletion during the gestation of rat females has been widely used as a model for human IUGR. By transcriptome analysis of control and protein-deprived rat placentas, we were able to identify 2543 transcripts modified more than 2.5 fold (1347 induced and 1196 repressed). Automatic functional classification enabled us to identify clusters of induced genes affecting chromosome structure, transcription, intracellular transport, protein modifications and apoptosis. In particular, we suggest the existence of a complex balance regulating apoptosis. Among repressed genes, we noted several groups of genes involved in immunity, signalling and degradation of noxious chemicals. These observations suggest that IUGR placentas have a decreased resistance to external aggression. The promoters of the most induced and most repressed genes were contrasted for their composition in putative transcription factor binding sites. There was an over-representation of Zn finger (ZNF) proteins and Pdx1 (pancreatic and duodenal homeobox protein 1) putative binding sites. Consistently, Pdx1 and a high proportion of ZNF genes were induced at the transcriptional level. A similar analysis of ZNF promoters showed an increased presence of putative binding sites for the Tata box binding protein (Tbp). Consistently again, we showed that the Tbp and TBP-associated factors (Tafs) were up-regulated in IUGR placentas. Also, samples of human IUGR and control placentas showed that human orthologous ZNFs and PDX1 were transcriptionally induced, especially in non-vascular IUGR. Immunohistochemistry revealed increased expression of PDX1 in IUGR human placentas. In conclusion, our approach permitted the proposition of hypotheses on a hierarchy of

  16. Upregulation of the rostral anterior cingulate cortex can alter the perception of emotions: fMRI-based neurofeedback at 3 and 7 T.

    PubMed

    Gröne, M; Dyck, M; Koush, Y; Bergert, S; Mathiak, K A; Alawi, E M; Elliott, M; Mathiak, K

    2015-03-01

    Recent advances in real-time functional magnetic resonance imaging (rt-fMRI) techniques enable online feedback about momentary brain activity from a localized region of interest. The anterior cingulate cortex (ACC) as a central hub for cognitive and emotional networks and its modulation has been suggested to elicit mood changes. In the presented real-time fMRI neurofeedback experiment at a 3 and a 7 T scanner we enabled participants to regulate ACC activity within one training session. The session consisted of three training runs of 8.5 min where subjects received online feedback about their current ACC activity. Before and after each run we presented emotional prosody. Subjects rated these stimuli according to their emotional valence and arousal, which served as an implicit mood measure. We found increases in ACC activation at 3 T (n = 15) and at 7 T (n = 9) with a higher activation success for the 3 T group. FMRI signal control of the rostral ACC depended on signal quality and predicted a valence bias in the rating of emotional prosody. Real-time fMRI neurofeedback of the ACC is feasible at different magnetic field strengths and can modulate localized ACC activity and emotion perception. It promises non-invasive therapeutic approaches for different psychiatric disorders characterized by impaired self-regulation.

  17. Alteration of imprinted Dlk1-Dio3 miRNA cluster expression in the entorhinal cortex induced by maternal immune activation and adolescent cannabinoid exposure

    PubMed Central

    Hollins, S L; Zavitsanou, K; Walker, F R; Cairns, M J

    2014-01-01

    A significant feature of the cortical neuropathology of schizophrenia is a disturbance in the biogenesis of short non-coding microRNA (miRNA) that regulate translation and stability of mRNA. While the biological origin of this phenomenon has not been defined, it is plausible that it relates to major environmental risk factors associated with the disorder such as exposure to maternal immune activation (MIA) and adolescent cannabis use. To explore this hypothesis, we administered the viral mimic poly I:C to pregnant rats and further exposed some of their maturing offsprings to daily injections of the synthetic cannabinoid HU210 for 14 days starting on postnatal day 35. Whole-genome miRNA expression analysis was then performed on the left and right hemispheres of the entorhinal cortex (EC), a region strongly associated with schizophrenia. Animals exposed to either treatment alone or in combination exhibited significant differences in the expression of miRNA in the left hemisphere, whereas the right hemisphere was less responsive. Hemisphere-associated differences in miRNA expression were greatest in the combined treatment and highly over-represented in a single imprinted locus on chromosome 6q32. This observation was significant as the syntenic 14q32 locus in humans encodes a large proportion of miRNAs differentially expressed in peripheral blood lymphocytes from patients with schizophrenia, suggesting that interaction of early and late environmental insults may affect miRNA expression, in a manner that is relevant to schizophrenia. PMID:25268256

  18. Jobelyn® Supplement Lowered Neuronal Degeneration: Significance of Altered p53 and ɤ-Enolase Protein Expressions in Prefrontal Cortex of Rat Exposed to Ethanol

    PubMed Central

    Charles, Oyinbo A.; Patrick, Igbigbi S.; Godwin, Avwioro O.

    2016-01-01

    Background Alcohol-induced neurodegeneration, a consequence of chronic ethanol exposure, is a neuroadaptation that drives the progression of alcohol use disorder (AUD). Unfortunately, conventional drugs for AUDs do not prevent neurodegeneration as part of their pharmacological repertoire. Multimodal neuroprotective therapeutic agents are hypothesized to have high therapeutic utility in the treatment of central nervous system. Interestingly, nutraceuticals by nature are multimodal in mechanisms of action. Purpose This study examined the neuroprotective potential of Jobelyn in prefrontal cortex (PFC) of a binge-alcohol rat model of AUD. Methods Three groups of rats were fed thrice daily through an orogastric tube with 5 g/kg ethanol (25% w/v), 5 g/kg ethanol (25% w/v) plus Jobelyn (4 mg/kg body weight), and 5 g/kg of a nutritionally complete diet (50% v/v), respectively. Cytoarchitectural study of the PFC was done in slides stained with haematoxylin and eosin. Immunohistochemical analyses were performed with mice monoclonal anti-p53 and anti-neuron specific enolase (NSE) antibodies to detect the degree of apoptosis and necrosis in the PFC. In addition, the degree of tissue damage and the level of lipid peroxidation were evaluated. Results Jobelyn supplementation significantly lowered the levels of histologic and biochemical indices of neurodegeneration, and caused an increased expression of p53 protein and a decreased expression of NSE immunoreactivity (NSE-IR). Conclusions Jobelyn supplementation ameliorates neurodegeneration in the PFC of AUD rats by reducing the oxidative stress, reducing the NSE-IR, and by increasing the expression of cellular tumor antigen p53 in the cortical neurons. PMID:27721582

  19. Regional and Duration of Illness Differences in the Alteration of NCAM-180 mRNA Expression within the Cortex of Subjects with Schizophrenia

    PubMed Central

    Gibbons, A. S.; Thomas, E. A.; Dean, B

    2009-01-01

    Schizophrenia has been proposed to have a neurodevelopmental aetiology. Neural Cell Adhesion Molecule 1 (NCAM1) is involved in several neurodevelopmental processes and abnormal expression of this gene has been associated in the pathology of schizophrenia and, thus, altered NCAM1 expression may be characteristic of the early stages of the illness. Alternative splicing of the NCAM1 transcript produces 3 major isoforms. Using qPCR we analysed mRNA expression of one of these isoforms; the 180 kDa isoform of NCAM1 (NCAM-180), in Brodmann Area (BA) 46, BA10 and BA17, postmortem, from 15 subjects with a short duration of illness of schizophrenia (<7 years) and 15 control subjects. NCAM-180 mRNA expression was increased in BA46 from subjects with schizophrenia compared to controls (P=0.013). By contrast, there were no significant differences in the expression of NCAM-180 mRNA in BA10 (P=0.575) or BA17 (P=0.772). We then analysed NCAM-180 mRNA expression in BA46 from 15 subjects with a longer duration of illness of schizophrenia (>22 years) and 15 controls. There was no significant difference in NCAM-180 mRNA expression in this second cohort. This data suggests NCAM-180 mRNA expression is altered in a regionally-specific manner in schizophrenia and these changes are associated with the early period following diagnosis. PMID:19411161

  20. Hyperthermia-induced seizures alter adenosine A1 and A2A receptors and 5'-nucleotidase activity in rat cerebral cortex.

    PubMed

    León-Navarro, David Agustín; Albasanz, José L; Martín, Mairena

    2015-08-01

    Febrile seizure is one of the most common convulsive disorders in children. The neuromodulator adenosine exerts anticonvulsant actions through binding adenosine receptors. Here, the impact of hyperthermia-induced seizures on adenosine A1 and A2A receptors and 5'-nucleotidase activity has been studied at different periods in the cerebral cortical area by using radioligand binding, real-time PCR, and 5'-nucleotidase activity assays. Hyperthermic seizures were induced in 13-day-old rats using a warmed air stream from a hair dryer. Neonates exhibited rearing and falling over associated with hindlimb clonus seizures (stage 5 on Racine scale criteria) after hyperthermic induction. A significant increase in A1 receptor density was observed using [(3) H]DPCPX as radioligand, and mRNA coding A1 was observed 48 h after hyperthermia-induced seizures. In contrast, a significant decrease in A2A receptor density was detected, using [(3) H]ZM241385 as radioligand, 48 h after hyperthermia-evoked convulsions. These short-term changes in A1 and A2A receptors were also accompanied by a loss of 5'-nucleotidase activity. No significant variations either in A1 or A2A receptor density or 5'-nucleotidase were observed 5 and 20 days after hyperthermic seizures. Taken together, both regulation of A1 and A2A receptors and loss of 5'-nucleotidase in the cerebral cortex suggest the existence of a neuroprotective mechanism against seizures. Febrile seizure is one of the most common convulsive disorders in children. The consequences of hyperthermia-induced seizures (animal model of febrile seizures) on adenosine A1 and A2A receptors and 5'-nucleotidase activity have been studied at different periods in cerebral cortical area. A significant increase in A1 receptor density and mRNA coding A1 was observed 48 h after hyperthermia-induced seizures. In contrast, a significant decrease in A2A receptor density and 5'-nucleotidase activity was detected 48 h after convulsions evoked by hyperthermia

  1. Targeted genomic sequencing of follicular dendritic cell sarcoma reveals recurrent alterations in NF-κB regulatory genes.

    PubMed

    Griffin, Gabriel K; Sholl, Lynette M; Lindeman, Neal I; Fletcher, Christopher D M; Hornick, Jason L

    2016-01-01

    Follicular dendritic cell sarcoma is a rare mesenchymal neoplasm with a variable and unpredictable clinical course. The genetic alterations that drive tumorigenesis in follicular dendritic cell sarcoma are largely unknown. One recent study performed BRAF sequencing and found V600E mutations in 5 of 27 (19%) cases. No other recurrent genetic alterations have been reported. The aim of the present study was to identify somatic alterations in follicular dendritic cell sarcoma by targeted sequencing of a panel of 309 known cancer-associated genes. DNA was isolated from formalin-fixed paraffin-embedded tissue from 13 cases of follicular dendritic cell sarcoma and submitted for hybrid capture-based enrichment and massively parallel sequencing with the Illumina HiSeq 2500 platform. Recurrent loss-of-function alterations were observed in tumor suppressor genes involved in the negative regulation of NF-κB activation (5 of 13 cases, 38%) and cell cycle progression (4 of 13 cases, 31%). Loss-of-function alterations in the NF-κB regulatory pathway included three cases with frameshift mutations in NFKBIA and two cases with bi-allelic loss of CYLD. Both cases with CYLD loss were metastases and carried concurrent alterations in at least one cell cycle regulatory gene. Alterations in cell cycle regulatory genes included two cases with bi-allelic loss of CDKN2A, one case with bi-allelic loss of RB1, and one case with a nonsense mutation in RB1. Last, focal copy-number gain of chromosome 9p24 including the genes CD274 (PD-L1) and PDCD1LG2 (PD-L2) was noted in three cases, which represents a well-described mechanism of immune evasion in cancer. These findings provide the first insight into the unique genomic landscape of follicular dendritic cell sarcoma and suggest shared mechanisms of tumorigenesis with a subset of other tumor types, notably B-cell lymphomas.

  2. Alterations in task-induced activity and resting-state fluctuations in visual and DMN areas revealed in long-term meditators.

    PubMed

    Berkovich-Ohana, Aviva; Harel, Michal; Hahamy, Avital; Arieli, Amos; Malach, Rafael

    2016-07-15

    Recently we proposed that the information contained in spontaneously emerging (resting-state) fluctuations may reflect individually unique neuro-cognitive traits. One prediction of this conjecture, termed the "spontaneous trait reactivation" (STR) hypothesis, is that resting-state activity patterns could be diagnostic of unique personalities, talents and life-styles of individuals. Long-term meditators could provide a unique experimental group to test this hypothesis. Using fMRI we found that, during resting-state, the amplitude of spontaneous fluctuations in long-term mindfulness meditation (MM) practitioners was enhanced in the visual cortex and significantly reduced in the DMN compared to naïve controls. Importantly, during a visual recognition memory task, the MM group showed heightened visual cortex responsivity, concomitant with weaker negative responses in Default Mode Network (DMN) areas. This effect was also reflected in the behavioral performance, where MM practitioners performed significantly faster than the control group. Thus, our results uncover opposite changes in the visual and default mode systems in long-term meditators which are revealed during both rest and task. The results support the STR hypothesis and extend it to the domain of local changes in the magnitude of the spontaneous fluctuations. PMID:27109713

  3. Alterations in task-induced activity and resting-state fluctuations in visual and DMN areas revealed in long-term meditators.

    PubMed

    Berkovich-Ohana, Aviva; Harel, Michal; Hahamy, Avital; Arieli, Amos; Malach, Rafael

    2016-07-15

    Recently we proposed that the information contained in spontaneously emerging (resting-state) fluctuations may reflect individually unique neuro-cognitive traits. One prediction of this conjecture, termed the "spontaneous trait reactivation" (STR) hypothesis, is that resting-state activity patterns could be diagnostic of unique personalities, talents and life-styles of individuals. Long-term meditators could provide a unique experimental group to test this hypothesis. Using fMRI we found that, during resting-state, the amplitude of spontaneous fluctuations in long-term mindfulness meditation (MM) practitioners was enhanced in the visual cortex and significantly reduced in the DMN compared to naïve controls. Importantly, during a visual recognition memory task, the MM group showed heightened visual cortex responsivity, concomitant with weaker negative responses in Default Mode Network (DMN) areas. This effect was also reflected in the behavioral performance, where MM practitioners performed significantly faster than the control group. Thus, our results uncover opposite changes in the visual and default mode systems in long-term meditators which are revealed during both rest and task. The results support the STR hypothesis and extend it to the domain of local changes in the magnitude of the spontaneous fluctuations.

  4. Dissociated roles of the anterior cingulate cortex in reward and conflict processing as revealed by the feedback error-related negativity and N200.

    PubMed

    Baker, Travis E; Holroyd, Clay B

    2011-04-01

    The reinforcement learning theory of the error-related negativity (ERN) holds that the impact of reward signals carried by the midbrain dopamine system modulates activity of the anterior cingulate cortex (ACC), alternatively disinhibiting and inhibiting the ACC following unpredicted error and reward events, respectively. According to a recent formulation of the theory, activity that is intrinsic to the ACC produces a component of the event-related brain potential (ERP) called the N200, and following unpredicted rewards, the N200 is suppressed by extrinsically applied positive dopamine reward signals, resulting in an ERP component called the feedback-ERN (fERN). Here we demonstrate that, despite extensive spatial and temporal overlap between the two ERP components, the functional processes indexed by the N200 (conflict) and the fERN (reward) are dissociable. These results point toward avenues for future investigation.

  5. Dissociated roles of the anterior cingulate cortex in reward and conflict processing as revealed by the feedback error-related negativity and N200.

    PubMed

    Baker, Travis E; Holroyd, Clay B

    2011-04-01

    The reinforcement learning theory of the error-related negativity (ERN) holds that the impact of reward signals carried by the midbrain dopamine system modulates activity of the anterior cingulate cortex (ACC), alternatively disinhibiting and inhibiting the ACC following unpredicted error and reward events, respectively. According to a recent formulation of the theory, activity that is intrinsic to the ACC produces a component of the event-related brain potential (ERP) called the N200, and following unpredicted rewards, the N200 is suppressed by extrinsically applied positive dopamine reward signals, resulting in an ERP component called the feedback-ERN (fERN). Here we demonstrate that, despite extensive spatial and temporal overlap between the two ERP components, the functional processes indexed by the N200 (conflict) and the fERN (reward) are dissociable. These results point toward avenues for future investigation. PMID:21295109

  6. Sound identification in human auditory cortex: Differential contribution of local field potentials and high gamma power as revealed by direct intracranial recordings.

    PubMed

    Nourski, Kirill V; Steinschneider, Mitchell; Rhone, Ariane E; Oya, Hiroyuki; Kawasaki, Hiroto; Howard, Matthew A; McMurray, Bob

    2015-09-01

    High gamma power has become the principal means of assessing auditory cortical activation in human intracranial studies, albeit at the expense of low frequency local field potentials (LFPs). It is unclear whether limiting analyses to high gamma impedes ability of clarifying auditory cortical organization. We compared the two measures obtained from posterolateral superior temporal gyrus (PLST) and evaluated their relative utility in sound categorization. Subjects were neurosurgical patients undergoing invasive monitoring for medically refractory epilepsy. Stimuli (consonant-vowel syllables varying in voicing and place of articulation and control tones) elicited robust evoked potentials and high gamma activity on PLST. LFPs had greater across-subject variability, yet yielded higher classification accuracy, relative to high gamma power. Classification was enhanced by including temporal detail of LFPs and combining LFP and high gamma. We conclude that future studies should consider utilizing both LFP and high gamma when investigating the functional organization of human auditory cortex.

  7. Abstinence from Cocaine and Sucrose Self-Administration Reveals Altered Mesocorticolimbic Circuit Connectivity by Resting State MRI

    PubMed Central

    Lu, Hanbing; Zou, Qihong; Chefer, Svetlana; Ross, Thomas J.; Vaupel, D. Bruce; Guillem, Karine; Rea, William P.; Yang, Yihong; Peoples, Laura L.

    2014-01-01

    Abstract Previous preclinical studies have emphasized that drugs of abuse, through actions within and between mesocorticolimbic (MCL) regions, usurp learning and memory processes normally involved in the pursuit of natural rewards. To distinguish MCL circuit pathobiological neuroadaptations that accompany addiction from general learning processes associated with natural reward, we trained two groups of rats to self-administer either cocaine (IV) or sucrose (orally) followed by an identically enforced 30 day abstinence period. These procedures are known to induce behavioral changes and neuroadaptations. A third group of sedentary animals served as a negative control group for general handling effects. We examined low-frequency spontaneous fluctuations in the functional magnetic resonance imaging (fMRI) signal, known as resting-state functional connectivity (rsFC), as a measure of intrinsic neurobiological interactions between brain regions. Decreased rsFC was seen in the cocaine-SA compared with both sucrose-SA and housing control groups between prelimbic (PrL) cortex and entopeduncular nucleus and between nucleus accumbens core (AcbC) and dorsomedial prefrontal cortex (dmPFC). Moreover, individual differences in cocaine SA escalation predicted connectivity strength only in the Acb-dmPFC circuit. These data provide evidence of fronto-striatal plasticity across the addiction trajectory, which are consistent with Acb-PFC hypoactivity seen in abstinent human drug addicts, indicating potential circuit level biomarkers that may inform therapeutic interventions. They further suggest that available data from cross-sectional human studies may reflect the consequence of rather a predispositional predecessor to their dependence. PMID:24999822

  8. Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia.

    PubMed

    Couch, Yvonne; Anthony, Daniel C; Dolgov, Oleg; Revischin, Alexander; Festoff, Barry; Santos, Ana Isabel; Steinbusch, Harry W; Strekalova, Tatyana

    2013-03-01

    A chronic stress paradigm comprising exposure to predation, tail suspension and restraint induces a depressive syndrome in C57BL/6J mice that occurs in some, but not all, animals. Here, we sought to extend our behavioural studies to investigate how susceptibility (sucrose preference<65%) or resilience (sucrose preference>65%) to stress-induced anhedonia affects the 5HT system and the expression of inflammation-related genes. All chronically stressed animals, displayed increased level of anxiety, but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions. These changes were not present in resilient or acutely stressed animals. Compared to resilient animals, susceptible mice showed elevated expression of tumour necrosis factor alpha (TNF) and the 5-HT transporter (SERT) in the pre-frontal area. Enhanced expression of 5HT(2A) and COX-1 in the pre-frontal area was observed in all stressed animals. In turn, indoleamine-2,3-dioxygenase (IDO) was significantly unregulated in the raphe of susceptible animals. At the cellular level, increased numbers of Iba-1-positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals. Consequently, the susceptible animals display a unique molecular profile when compared to resilient, but anxious, animals. Unexpectedly, this altered profile provides a rationale for exploring anti-inflammatory, and possibly, TNF-targeted therapy for major depression.

  9. Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia.

    PubMed

    Couch, Yvonne; Anthony, Daniel C; Dolgov, Oleg; Revischin, Alexander; Festoff, Barry; Santos, Ana Isabel; Steinbusch, Harry W; Strekalova, Tatyana

    2013-03-01

    A chronic stress paradigm comprising exposure to predation, tail suspension and restraint induces a depressive syndrome in C57BL/6J mice that occurs in some, but not all, animals. Here, we sought to extend our behavioural studies to investigate how susceptibility (sucrose preference<65%) or resilience (sucrose preference>65%) to stress-induced anhedonia affects the 5HT system and the expression of inflammation-related genes. All chronically stressed animals, displayed increased level of anxiety, but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions. These changes were not present in resilient or acutely stressed animals. Compared to resilient animals, susceptible mice showed elevated expression of tumour necrosis factor alpha (TNF) and the 5-HT transporter (SERT) in the pre-frontal area. Enhanced expression of 5HT(2A) and COX-1 in the pre-frontal area was observed in all stressed animals. In turn, indoleamine-2,3-dioxygenase (IDO) was significantly unregulated in the raphe of susceptible animals. At the cellular level, increased numbers of Iba-1-positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals. Consequently, the susceptible animals display a unique molecular profile when compared to resilient, but anxious, animals. Unexpectedly, this altered profile provides a rationale for exploring anti-inflammatory, and possibly, TNF-targeted therapy for major depression. PMID:23305936

  10. Assessment of the structural brain network reveals altered connectivity in children with unilateral cerebral palsy due to periventricular white matter lesions

    PubMed Central

    Pannek, Kerstin; Boyd, Roslyn N.; Fiori, Simona; Guzzetta, Andrea; Rose, Stephen E.

    2014-01-01

    Background Cerebral palsy (CP) is a term to describe the spectrum of disorders of impaired motor and sensory function caused by a brain lesion occurring early during development. Diffusion MRI and tractography have been shown to be useful in the study of white matter (WM) microstructure in tracts likely to be impacted by the static brain lesion. Aim The purpose of this study was to identify WM pathways with altered connectivity in children with unilateral CP caused by periventricular white matter lesions using a whole-brain connectivity approach. Methods Data of 50 children with unilateral CP caused by periventricular white matter lesions (5–17 years; manual ability classification system [MACS] I = 25/II = 25) and 17 children with typical development (CTD; 7–16 years) were analysed. Structural and High Angular Resolution Diffusion weighted Images (HARDI; 64 directions, b = 3000 s/mm2) were acquired at 3 T. Connectomes were calculated using whole-brain probabilistic tractography in combination with structural parcellation of the cortex and subcortical structures. Connections with altered fractional anisotropy (FA) in children with unilateral CP compared to CTD were identified using network-based statistics (NBS). The relationship between FA and performance of the impaired hand in bimanual tasks (Assisting Hand Assessment—AHA) was assessed in connections that showed significant differences in FA compared to CTD. Results FA was reduced in children with unilateral CP compared to CTD. Seven pathways, including the corticospinal, thalamocortical, and fronto-parietal association pathways were identified simultaneously in children with left and right unilateral CP. There was a positive relationship between performance of the impaired hand in bimanual tasks and FA within the cortico-spinal and thalamo-cortical pathways (r2 = 0.16–0.44; p < 0.05). Conclusion This study shows that network-based analysis of structural connectivity can identify alterations

  11. Alterations in regional shape on ipsilateral and contralateral cortex contrast in children with unilateral cerebral palsy and are predictive of multiple outcomes.

    PubMed

    Pagnozzi, Alex M; Dowson, Nicholas; Fiori, Simona; Doecke, James; Bradley, Andrew P; Boyd, Roslyn N; Rose, Stephen

    2016-10-01

    Congenital brain lesions result in a wide range of cerebral tissue alterations observed in children with cerebral palsy (CP) that are associated with a range of functional impairments. The relationship between injury severity and functional outcomes, however, remains poorly understood. This research investigates the differences in cortical shape between children with congenital brain lesions and typically developing children (TDC) and investigates the correlations between cortical shape and functional outcome in a large cohort of patients diagnosed with unilateral CP. Using 139 structural magnetic resonance images, including 95 patients with clinically diagnosed CP and 44 TDC, cortical segmentations were obtained using a modified expectation maximization algorithm. Three shape characteristics (cortical thickness, curvature, and sulcal depth) were computed within a number of cortical regions. Significant differences in these shape measures compared to the TDC were observed on both the injured hemisphere of children with CP (P < 0.004), as well as on the apparently uninjured hemisphere, illustrating potential compensatory mechanisms in these children. Furthermore, these shape measures were significantly correlated with several functional outcomes, including motor, cognition, vision, and communication (P < 0.012), with three out of these four models performing well on test set validation. This study highlights that cortical neuroplastic effects may be quantified using MR imaging, allowing morphological changes to be studied longitudinally, including any influence of treatment. Ultimately, such approaches could be used for the long term prediction of outcomes and the tailoring of treatment to individuals. Hum Brain Mapp 37:3588-3603, 2016. © 2016 Wiley Periodicals, Inc.

  12. Biophysical alterations in lipid rafts from human cerebral cortex associate with increased BACE1/AβPP interaction in early stages of Alzheimer's disease.

    PubMed

    Díaz, Mario; Fabelo, Noemí; Martín, Virginia; Ferrer, Isidre; Gómez, Tomás; Marín, Raquel

    2015-01-01

    In the present study, we have assessed the biophysical properties of lipid rafts from different brain areas in subjects exhibiting early neuropathological stages of Alzheimer's disease (AD). By means of steady-state fluorescence polarization analyses using two environment-sensitive fluorescent probes, we demonstrate that lipid rafts from cerebellum, and frontal and entorhinal cortices, exhibit different biophysical behaviors depending on the stage of the disease. Thus, while membrane anisotropies were similar in the cerebellum along stages, lipid rafts from frontal and entorhinal cortices at AD stages I/II and AD III were significantly more liquid-ordered than in control subjects, both at the aqueous interface and hydrophobic core of the raft membrane. Thermotropic analyses demonstrated the presence of Arrhenius breakpoints between 28.3-32.0 °C, which were not influenced by the disease stage. However, analyses of membrane microviscosity (ηapp) demonstrate that frontal and entorhinal lipid rafts are notably more viscous and liquid-ordered all across the membrane from early stages of the disease. These physicochemical alterations in lipid rafts do not correlate with changes in cholesterol or sphingomyelin levels, but to reduced unsaturation index and increased saturate/polyunsaturated ratios in phospholipid acyl chains. Moreover, we demonstrate that β-secretase/AβPP (amyloid-β protein precursor) interaction and lipid raft microviscosity are strongly, and positively, correlated in AD frontal and entorhinal cortices. These observations strengthens the hypothesis that physical properties of these microdomains modulate the convergence of amyloidogenic machinery toward lipid rafts, and also points to a critical role of polyunsaturated fatty acids in amyloidogenic processing of AβPP.

  13. Cognition without Cortex.

    PubMed

    Güntürkün, Onur; Bugnyar, Thomas

    2016-04-01

    Assumptions on the neural basis of cognition usually focus on cortical mechanisms. Birds have no cortex, but recent studies in parrots and corvids show that their cognitive skills are on par with primates. These cognitive findings are accompanied by neurobiological discoveries that reveal avian and mammalian forebrains are homologous, and show similarities in connectivity and function down to the cellular level. But because birds have a large pallium, but no cortex, a specific cortical architecture cannot be a requirement for advanced cognitive skills. During the long parallel evolution of mammals and birds, several neural mechanisms for cognition and complex behaviors may have converged despite an overall forebrain organization that is otherwise vastly different. PMID:26944218

  14. Similarity-Based Fusion of MEG and fMRI Reveals Spatio-Temporal Dynamics in Human Cortex During Visual Object Recognition

    PubMed Central

    Cichy, Radoslaw Martin; Pantazis, Dimitrios; Oliva, Aude

    2016-01-01

    Every human cognitive function, such as visual object recognition, is realized in a complex spatio-temporal activity pattern in the brain. Current brain imaging techniques in isolation cannot resolve the brain's spatio-temporal dynamics, because they provide either high spatial or temporal resolution but not both. To overcome this limitation, we developed an integration approach that uses representational similarities to combine measurements of magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) to yield a spatially and temporally integrated characterization of neuronal activation. Applying this approach to 2 independent MEG–fMRI data sets, we observed that neural activity first emerged in the occipital pole at 50–80 ms, before spreading rapidly and progressively in the anterior direction along the ventral and dorsal visual streams. Further region-of-interest analyses established that dorsal and ventral regions showed MEG–fMRI correspondence in representations later than early visual cortex. Together, these results provide a novel and comprehensive, spatio-temporally resolved view of the rapid neural dynamics during the first few hundred milliseconds of object vision. They further demonstrate the feasibility of spatially unbiased representational similarity-based fusion of MEG and fMRI, promising new insights into how the brain computes complex cognitive functions. PMID:27235099

  15. Similarity-Based Fusion of MEG and fMRI Reveals Spatio-Temporal Dynamics in Human Cortex During Visual Object Recognition.

    PubMed

    Cichy, Radoslaw Martin; Pantazis, Dimitrios; Oliva, Aude

    2016-08-01

    Every human cognitive function, such as visual object recognition, is realized in a complex spatio-temporal activity pattern in the brain. Current brain imaging techniques in isolation cannot resolve the brain's spatio-temporal dynamics, because they provide either high spatial or temporal resolution but not both. To overcome this limitation, we developed an integration approach that uses representational similarities to combine measurements of magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) to yield a spatially and temporally integrated characterization of neuronal activation. Applying this approach to 2 independent MEG-fMRI data sets, we observed that neural activity first emerged in the occipital pole at 50-80 ms, before spreading rapidly and progressively in the anterior direction along the ventral and dorsal visual streams. Further region-of-interest analyses established that dorsal and ventral regions showed MEG-fMRI correspondence in representations later than early visual cortex. Together, these results provide a novel and comprehensive, spatio-temporally resolved view of the rapid neural dynamics during the first few hundred milliseconds of object vision. They further demonstrate the feasibility of spatially unbiased representational similarity-based fusion of MEG and fMRI, promising new insights into how the brain computes complex cognitive functions.

  16. Similarity-Based Fusion of MEG and fMRI Reveals Spatio-Temporal Dynamics in Human Cortex During Visual Object Recognition.

    PubMed

    Cichy, Radoslaw Martin; Pantazis, Dimitrios; Oliva, Aude

    2016-08-01

    Every human cognitive function, such as visual object recognition, is realized in a complex spatio-temporal activity pattern in the brain. Current brain imaging techniques in isolation cannot resolve the brain's spatio-temporal dynamics, because they provide either high spatial or temporal resolution but not both. To overcome this limitation, we developed an integration approach that uses representational similarities to combine measurements of magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) to yield a spatially and temporally integrated characterization of neuronal activation. Applying this approach to 2 independent MEG-fMRI data sets, we observed that neural activity first emerged in the occipital pole at 50-80 ms, before spreading rapidly and progressively in the anterior direction along the ventral and dorsal visual streams. Further region-of-interest analyses established that dorsal and ventral regions showed MEG-fMRI correspondence in representations later than early visual cortex. Together, these results provide a novel and comprehensive, spatio-temporally resolved view of the rapid neural dynamics during the first few hundred milliseconds of object vision. They further demonstrate the feasibility of spatially unbiased representational similarity-based fusion of MEG and fMRI, promising new insights into how the brain computes complex cognitive functions. PMID:27235099

  17. Quantitative shotgun proteomics reveals extensive changes to the proteome of the orbitofrontal cortex in rats that are hyperactive following withdrawal from a high sugar diet.

    PubMed

    Franklin, Jane L; Mirzaei, Mehdi; Wearne, Travis A; Sauer, Melanie K; Homewood, Judi; Goodchild, Ann K; Haynes, Paul A; Cornish, Jennifer L

    2016-02-01

    In most Westernized societies, there has been an alarming increase in the consumption of sugar-sweetened drinks. For many adults these drinks represent a substantial proportion of their total daily caloric intake. Here we investigated whether extended exposure to sugar changes behavior and protein expression in the orbitofrontal cortex (OFC). Male adult Sprague-Dawley rats (n = 8 per group) were treated for 26 days with either water or a 10% sucrose solution. Locomotor behavior was measured on the first and last day of treatment, then 1 week after treatment. Following the 1-week period free from treatment, sucrose treated rats were significantly more active than the control. Two hours following final behavioral testing, brains were rapidly removed and prepared for proteomic analysis of the OFC. Label free quantitative shotgun proteomic analyses of three rats from each group found 290 proteins were differentially expressed in the sucrose treated group when compared to the control group. Major changes in the proteome were seen in proteins related to energy metabolism, mitochondrial function and the cellular response to stress. This research does not seek to suggest that sugar will cause specific neurological disorders, however similar changes in proteins have been seen in neurological disorders such as Alzheimer's disease, Parkinson's disease and schizophrenia. PMID:26621205

  18. Lateral frontal cortex oxygenation changes during translation and language switching revealed by non-invasive near-infrared multi-point measurements.

    PubMed

    Quaresima, Valentina; Ferrari, Marco; van der Sluijs, Marco C P; Menssen, Jan; Colier, Willy N J M

    2002-11-30

    The organisation of language in the brain of multilingual people remains controversial. Using a high temporal resolution 12-channel near-infrared continuous wave spectroscopy system, we have demonstrated that it is possible to monitor non-invasively, comfortably and, without the interferences due to intrinsic limitations of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), cortical oxygenation changes in the Broca's area in response to translation of short sentences and language switching. Eight Dutch students proficient in English translated aloud from their native language into English or vice versa or alternating (switching) short visually presented sentences. These tasks provoked, in the left inferior frontal cortex which includes the Broca's area, a consistent and incremental rise in oxyhaemoglobin accompanied by a smaller decrease in deoxyhaemoglobin. The investigated cortical areas surrounding the Broca's area showed no uniform and consistent oxygenation changes upon the three different translation tasks. These results confirm that Broca's area is involved in the translation process and its so called activation is unaffected by the direction of the translation. In addition, these results strengthen the role of near-infrared multi-point measurements as a powerful tool for investigating the spatial and temporal features of the cortical oxygenation changes during language processing.

  19. Quantitative Proteomic Analysis of the Orbital Frontal Cortex in Rats Following Extended Exposure to Caffeine Reveals Extensive Changes to Protein Expression: Implications for Neurological Disease.

    PubMed

    Franklin, Jane L; Mirzaei, Mehdi; Wearne, Travis A; Homewood, Judi; Goodchild, Ann K; Haynes, Paul A; Cornish, Jennifer L

    2016-05-01

    Caffeine is a plant-derived psychostimulant and a common additive found in a wide range of foods and pharmaceuticals. The orbitofrontal cortex (OFC) is rapidly activated by flavours, integrates gustatory and olfactory information, and plays a critical role in decision-making, with dysfunction contributing to psychopathologies and neurodegenerative conditions. This study investigated whether long-term consumption of caffeine causes changes to behavior and protein expression in the OFC. Male adult Sprague-Dawley rats (n = 8 per group) were treated for 26 days with either water or a 0.6 g/L caffeine solution. Locomotor behavior was measured on the first and last day of treatment, then again after 9 days treatment free following exposure to a mild stressor. When tested drug free, caffeine-treated animals were hyperactive compared to controls. Two hours following final behavioral testing, brains were rapidly removed and prepared for proteomic analysis of the OFC. Label free shotgun proteomics found 157 proteins differentially expressed in the caffeine-drinking rats compared to control. Major proteomic effects were seen for cell-to-cell communication, cytoskeletal regulation, and mitochondrial function. Similar changes have been observed in neurological disorders including Alzheimer's disease, Parkinson's disease, and schizophrenia.

  20. Somatic and dendritic perforated-patch recordings reveal b-adrenergic receptor-induced depolarization in medial prefrontal cortex pyramidal neurons.

    PubMed

    Szulczyk, Bartłomiej

    2016-01-01

    The aim of this perforated-patch study was to test the effect of isoproterenol on the membrane potential in mPFC (medial prefrontal cortex) pyramidal neurons. Isoproterenol depolarized the membrane potential recorded from the soma. This effect was absent in the presence of metoprolol, suggesting the involvement of beta1-adrenergic receptors. The adenylate cyclase activator forskolin also depolarized the membrane potential. Moreover, the effect of isoproterenol was abolished by the adenylate cyclase inhibitor SQ 22536. This suggested that adenylate cyclase was involved in mediating the effect of the beta-adrenergic receptor agonist. The isoproterenol-induced depolarization persisted after inhibition of protein kinase A with H-89. The effect of beta-adrenergic receptor activation on the membrane potential was dependent on Ih channels because it was abolished in the presence of the Ih channel inhibitor ZD 7288. Dendritic recordings were also performed. In the dendritic segments between 100 microm and 150 microm from the soma and between 200 microm and 250 microm from the soma, isoproterenol also depolarized the membrane potential. The magnitude of the beta-adrenergic receptor-stimulated depolarization was the same in the soma and in both dendritic localizations. The depolarization exerted by isoproterenol may influence PFC cognitive functions. PMID:27373953

  1. Killing two birds with one stone: the potential role of aripiprazole for patients with comorbid major depressive disorder and nicotine dependence via altering brain activity in the anterior cingulate cortex.

    PubMed

    Chu, Che-Sheng; Tzeng, Nian-Sheng; Chang, Hsin-An; Chang, Chuan-Chia; Chen, Tien-Yu

    2014-09-01

    The high comorbidity between major depressive disorder (MDD) and nicotine dependence (ND) is well recognized. Patients with comorbid MDD and ND often have increased suicidal risk and poor outcomes. A dysfunctional dopaminergic brain reward system might be a neurobiological link between MDD and ND. Aripiprazole has been considered as a dopamine stabilizer and was the first atypical antipsychotic agent approved by the US Food and Drug Administration as an adjunctive to the treatment of unipolar MDD. Bupropion is well known as a dual norepinephrine and dopamine reuptake inhibitor, and has been shown to be effective in smoking cessation. One reason bupropion is useful in treating ND is that it enhances the level of dopamine in the brain. Aripiprazole might act as a dopamine agonist similar to the way that bupropion does because of its partial dopamine D2 agonist and 30% intrinsic dopaminergic activity. Several recent studies have applied the unique pharmacodynamic characteristics of aripiprazole to treat patients with ND. Based on neuroimaging findings, aripiprazole can reduce substance cravings by altering brain activity, particularly in the brain regions of the anterior cingulate cortex. Therefore, we hypothesize that adjunctive aripiprazole with antidepressant may be an effective treatment for patients with MDD and ND comorbidity. A new drug invention that combines an antidepressant with an adequate dose of aripiprazole thus should be considered. The neurobiological basis for this combination to treat patients with MDD and ND comorbidity deserves further study.

  2. Alterations in binding site density of dopamine transporter in the striatum, orbitofrontal cortex, and amygdala in early Parkinson's disease: compartment analysis for beta-CFT binding with positron emission tomography.

    PubMed

    Ouchi, Y; Yoshikawa, E; Okada, H; Futatsubashi, M; Sekine, Y; Iyo, M; Sakamoto, M

    1999-05-01

    We investigated changes in the kinetics in the binding of the dopamine transporter probe 2-beta-carbomethoxy-3beta-(4-[11C]fluorophenyl)tropane (beta-CFT) in living brain by compartmental analysis, using positron emission tomography in unmedicated patients with Parkinson's disease (PD) (Hoehn and Yahr stages I-II). With dynamic positron emission tomographic data from 90-minute acquisitions and metabolite-corrected arterial input functions, binding potentials (k3/k4) were calculated by using estimated rate constants (K1 - k4). In this analysis, the magnitude of the distribution volume (K1/k2) measured in the cerebellum, in which specific binding is negligible, was used as a constrained value for fitting in binding regions. Statistics showed that k3/k4 values in the striatum, the orbitofrontal cortex, and the amygdala were significantly lower in PD patients than in normal controls, whereas there were no differences in K1/k2 ratios and structural volumes between the groups. Correlation analysis showed that the putaminal and orbitofrontal binding levels were correlated positively with motor and mentation scores, respectively, of the Unified Parkinson's Disease Rating Scale. These results indicated that not only the striatal but also the orbitofrontal and amygdalar presynaptic dopaminergic functions were altered in early PD. The reductions in these mesocortical/mesolimbic functions might contribute to the mental and behavioral impairment observed in PD.

  3. Methylome analysis reveals alterations in DNA methylation in the regulatory regions of left ventricle development genes in human dilated cardiomyopathy.

    PubMed

    Jo, Bong-Seok; Koh, In-Uk; Bae, Jae-Bum; Yu, Ho-Yeong; Jeon, Eun-Seok; Lee, Hae-Young; Kim, Jae-Joong; Choi, Murim; Choi, Sun Shim

    2016-08-01

    Dilated cardiomyopathy (DCM) is one of the main causes of heart failure (called cardiomyopathies) in adults. Alterations in epigenetic regulation (i.e., DNA methylation) have been implicated in the development of DCM. Here, we identified a total of 1828 differentially methylated probes (DMPs) using the Infinium 450K HumanMethylation Bead chip by comparing the methylomes between 18 left ventricles and 9 right ventricles. Alterations in DNA methylation levels were observed mainly in lowly methylated regions corresponding to promoter-proximal regions, which become hypermethylated in severely affected left ventricles. Subsequent mRNA microarray analysis showed that the effect of DNA methylation on gene expression regulation is not unidirectional but is controlled by the functional sub-network context. DMPs were significantly enriched in the transcription factor binding sites (TFBSs) we tested. Alterations in DNA methylation were specifically enriched in the cis-regulatory regions of cardiac development genes, the majority of which are involved in ventricular development (e.g., TBX5 and HAND1).

  4. Transcriptomics Profiling of Alzheimer's Disease Reveal Neurovascular Defects, Altered Amyloid-β Homeostasis, and Deregulated Expression of Long Noncoding RNAs.

    PubMed

    Magistri, Marco; Velmeshev, Dmitry; Makhmutova, Madina; Faghihi, Mohammad Ali

    2015-01-01

    The underlying genetic variations of late-onset Alzheimer's disease (LOAD) cases remain largely unknown. A combination of genetic variations with variable penetrance and lifetime epigenetic factors may converge on transcriptomic alterations that drive LOAD pathological process. Transcriptome profiling using deep sequencing technology offers insight into common altered pathways regardless of underpinning genetic or epigenetic factors and thus represents an ideal tool to investigate molecular mechanisms related to the pathophysiology of LOAD. We performed directional RNA sequencing on high quality RNA samples extracted from hippocampi of LOAD and age-matched controls. We further validated our data using qRT-PCR on a larger set of postmortem brain tissues, confirming downregulation of the gene encoding substance P (TAC1) and upregulation of the gene encoding the plasminogen activator inhibitor-1 (SERPINE1). Pathway analysis indicates dysregulation in neural communication, cerebral vasculature, and amyloid-β clearance. Beside protein coding genes, we identified several annotated and non-annotated long noncoding RNAs that are differentially expressed in LOAD brain tissues, three of them are activity-dependent regulated and one is induced by Aβ(1-42) exposure of human neural cells. Our data provide a comprehensive list of transcriptomics alterations in LOAD hippocampi and warrant holistic approach including both coding and non-coding RNAs in functional studies aimed to understand the pathophysiology of LOAD.

  5. Neuregulin-1 (Nrg1) signaling has a preventive role and is altered in the frontal cortex under the pathological conditions of Alzheimer's disease.

    PubMed

    Jiang, Qiong; Chen, Shuangxi; Hu, Chengliang; Huang, Peizhi; Shen, Huifan; Zhao, Weijiang

    2016-09-01

    Alzheimer's disease (AD), one of the neurodegenerative disorders that may develop in the elderly, is characterized by the deposition of β‑amyloid protein (Aβ) and extensive neuronal cell death in the brain. Neuregulin‑1 (Nrg1)‑mediated intercellular and intracellular communication via binding to ErbB receptors regulates a diverse set of biological processes involved in the development of the nervous system. In the present study, a linear correlation was identified between Nrg1 and phosphorylated ErbB (pNeu and pErbB4) receptors in a human cortical tissue microarray. In addition, increased expression levels of Nrg1, but reduced pErbB receptor levels, were detected in the frontal lobe of a patient with AD. Western blotting and immunofluorescence staining were subsequently performed to uncover the potential preventive role of Nrg1 in cortical neurons affected by the neurodegenerative processes of AD. It was observed that the expression of Nrg1 increased as the culture time of the cortical neurons progressed. In addition, H2O2 and Aβ1‑42, two inducers of oxidative stress and neuronal damage, led to a dose‑dependent decrease in Nrg1 expression. Recombinant Nrg1β, however, was revealed to exert a pivotal role in preventing oxidative stress and neuronal damage from occurring in the mouse cortical neurons. Taken together, these results suggest that changes in Nrg1 signaling may influence the pathological development of AD, and exogenous Nrg1 may serve as a potential candidate for the prevention and treatment of AD. PMID:27486021

  6. Neuregulin-1 (Nrg1) signaling has a preventive role and is altered in the frontal cortex under the pathological conditions of Alzheimer's disease

    PubMed Central

    Jiang, Qiong; Chen, Shuangxi; Hu, Chengliang; Huang, Peizhi; Shen, Huifan; Zhao, Weijiang

    2016-01-01

    Alzheimer's disease (AD), one of the neurodegenerative disorders that may develop in the elderly, is characterized by the deposition of β-amyloid protein (Aβ) and extensive neuronal cell death in the brain. Neuregulin-1 (Nrg1)-mediated intercellular and intracellular communication via binding to ErbB receptors regulates a diverse set of biological processes involved in the development of the nervous system. In the present study, a linear correlation was identified between Nrg1 and phosphorylated ErbB (pNeu and pErbB4) receptors in a human cortical tissue microarray. In addition, increased expression levels of Nrg1, but reduced pErbB receptor levels, were detected in the frontal lobe of a patient with AD. Western blotting and immunofluorescence staining were subsequently performed to uncover the potential preventive role of Nrg1 in cortical neurons affected by the neurodegenerative processes of AD. It was observed that the expression of Nrg1 increased as the culture time of the cortical neurons progressed. In addition, H2O2 and Aβ1–42, two inducers of oxidative stress and neuronal damage, led to a dose-dependent decrease in Nrg1 expression. Recombinant Nrg1β, however, was revealed to exert a pivotal role in preventing oxidative stress and neuronal damage from occurring in the mouse cortical neurons. Taken together, these results suggest that changes in Nrg1 signaling may influence the pathological development of AD, and exogenous Nrg1 may serve as a potential candidate for the prevention and treatment of AD. PMID:27486021

  7. Cell-attached single-channel recordings in intact prefrontal cortex pyramidal neurons reveal compartmentalized D1/D5 receptor modulation of the persistent sodium current

    PubMed Central

    Gorelova, Natalia; Seamans, Jeremy K.

    2015-01-01

    The persistent Na+ current (INap) is believed to be an important target of dopamine modulation in prefrontal cortex (PFC) neurons. While past studies have tested the effects of dopamine on INap, the results have been contradictory largely because of difficulties in measuring INap using somatic whole-cell recordings. To circumvent these confounds we used the cell-attached patch-clamp technique to record single Na+ channels from the soma, proximal dendrite (PD) or proximal axon (PA) of intact prefrontal layer V pyramidal neurons. Under baseline conditions, numerous well resolved Na+ channel openings were recorded that exhibited an extrapolated reversal potential of 73 mV, a slope conductance of 14–19 pS and were blocked by tetrodotoxin (TTX). While similar in most respects, the propensity to exhibit prolonged bursts lasting >40 ms was many fold greater in the axon than the soma or dendrite. Bath application of the D1/D5 receptor agonist SKF81297 shifted the ensemble current activation curve leftward and increased the number of late events recorded from the PD but not the soma or PA. However, the greatest effect was on prolonged bursting where the D1/D5 receptor agonist increased their occurrence 3 fold in the PD and nearly 7 fold in the soma, but not at all in the PA. As a result, D1/D5 receptor activation equalized the probability of prolonged burst occurrence across the proximal axosomatodendritic region. Therefore, D1/D5 receptor modulation appears to be targeted mainly to Na+ channels in the PD/soma and not the PA. By circumventing the pitfalls of previous attempts to study the D1/D5 receptor modulation of INap, we demonstrate conclusively that D1/D5 receptor activation can increase the INap generated proximally, however questions still remain as to how D1/D5 receptor modulates Na+ currents in the more distal initial segment where most of the INap is normally generated. PMID:25729354

  8. Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves.

    PubMed

    Huang, Hong-Lei; Cendan, Cruz-Miguel; Roza, Carolina; Okuse, Kenji; Cramer, Rainer; Timms, John F; Wood, John N

    2008-01-01

    Neuropathic pain may arise following peripheral nerve injury though the molecular mechanisms associated with this are unclear. We used proteomic profiling to examine changes in protein expression associated with the formation of hyper-excitable neuromas derived from rodent saphenous nerves. A two-dimensional difference gel electrophoresis (2D-DIGE) profiling strategy was employed to examine protein expression changes between developing neuromas and normal nerves in whole tissue lysates. We found around 200 proteins which displayed a >1.75-fold change in expression between neuroma and normal nerve and identified 55 of these proteins using mass spectrometry. We also used immunoblotting to examine the expression of low-abundance ion channels Nav1.3, Nav1.8 and calcium channel alpha2delta-1 subunit in this model, since they have previously been implicated in neuronal hyperexcitability associated with neuropathic pain. Finally, S35methionine in vitro labelling of neuroma and control samples was used to demonstrate local protein synthesis of neuron-specific genes. A number of cytoskeletal proteins, enzymes and proteins associated with oxidative stress were up-regulated in neuromas, whilst overall levels of voltage-gated ion channel proteins were unaffected. We conclude that altered mRNA levels reported in the somata of damaged DRG neurons do not necessarily reflect levels of altered proteins in hyper-excitable damaged nerve endings. An altered repertoire of protein expression, local protein synthesis and topological re-arrangements of ion channels may all play important roles in neuroma hyper-excitability. PMID:18700027

  9. Exome capture sequencing of adenoma reveals genetic alterations in multiple cellular pathways at the early stage of colorectal tumorigenesis.

    PubMed

    Zhou, Donger; Yang, Liu; Zheng, Liangtao; Ge, Weiting; Li, Dan; Zhang, Yong; Hu, Xueda; Gao, Zhibo; Xu, Jinghong; Huang, Yanqin; Hu, Hanguang; Zhang, Hang; Zhang, Hao; Liu, Mingming; Yang, Huanming; Zheng, Lei; Zheng, Shu

    2013-01-01

    Most of colorectal adenocarcinomas are believed to arise from adenomas, which are premalignant lesions. Sequencing the whole exome of the adenoma will help identifying molecular biomarkers that can predict the occurrence of adenocarcinoma more precisely and help understanding the molecular pathways underlying the initial stage of colorectal tumorigenesis. We performed the exome capture sequencing of the normal mucosa, adenoma and adenocarcinoma tissues from the same patient and sequenced the identified mutations in additional 73 adenomas and 288 adenocarcinomas. Somatic single nucleotide variations (SNVs) were identified in both the adenoma and adenocarcinoma by comparing with the normal control from the same patient. We identified 12 nonsynonymous somatic SNVs in the adenoma and 42 nonsynonymous somatic SNVs in the adenocarcinoma. Most of these mutations including OR6X1, SLC15A3, KRTHB4, RBFOX1, LAMA3, CDH20, BIRC6, NMBR, GLCCI1, EFR3A, and FTHL17 were newly reported in colorectal adenomas. Functional annotation of these mutated genes showed that multiple cellular pathways including Wnt, cell adhesion and ubiquitin mediated proteolysis pathways were altered genetically in the adenoma and that the genetic alterations in the same pathways persist in the adenocarcinoma. CDH20 and LAMA3 were mutated in the adenoma while NRXN3 and COL4A6 were mutated in the adenocarcinoma from the same patient, suggesting for the first time that genetic alterations in the cell adhesion pathway occur as early as in the adenoma. Thus, the comparison of genomic mutations between adenoma and adenocarcinoma provides us a new insight into the molecular events governing the early step of colorectal tumorigenesis. PMID:23301059

  10. Connectivity and tissue microstructural alterations in right and left temporal lobe epilepsy revealed by diffusion spectrum imaging.

    PubMed

    Lemkaddem, Alia; Daducci, Alessandro; Kunz, Nicolas; Lazeyras, François; Seeck, Margitta; Thiran, Jean-Philippe; Vulliémoz, Serge

    2014-01-01

    Focal epilepsy is increasingly recognized as the result of an altered brain network, both on the structural and functional levels and the characterization of these widespread brain alterations is crucial for our understanding of the clinical manifestation of seizure and cognitive deficits as well as for the management of candidates to epilepsy surgery. Tractography based on Diffusion Tensor Imaging allows non-invasive mapping of white matter tracts in vivo. Recently, diffusion spectrum imaging (DSI), based on an increased number of diffusion directions and intensities, has improved the sensitivity of tractography, notably with respect to the problem of fiber crossing and recent developments allow acquisition times compatible with clinical application. We used DSI and parcellation of the gray matter in regions of interest to build whole-brain connectivity matrices describing the mutual connections between cortical and subcortical regions in patients with focal epilepsy and healthy controls. In addition, the high angular and radial resolution of DSI allowed us to evaluate also some of the biophysical compartment models, to better understand the cause of the changes in diffusion anisotropy. Global connectivity, hub architecture and regional connectivity patterns were altered in TLE patients and showed different characteristics in RTLE vs LTLE with stronger abnormalities in RTLE. The microstructural analysis suggested that disturbed axonal density contributed more than fiber orientation to the connectivity changes affecting the temporal lobes whereas fiber orientation changes were more involved in extratemporal lobe changes. Our study provides further structural evidence that RTLE and LTLE are not symmetrical entities and DSI-based imaging could help investigate the microstructural correlate of these imaging abnormalities.

  11. Comparative genomic hybridization array analysis and real-time PCR reveals genomic copy number alteration for lung adenocarcinomas.

    PubMed

    Choi, Jin Soo; Zheng, Long Tai; Ha, Eunyoung; Lim, Yun Jeong; Kim, Yeul Hong; Wang, Young-Pil; Lim, Young

    2006-01-01

    Genomic alterations in lung cancer tissues have been observed in various studies. To analyze the aberrations in the genome of lung cancer patients, we used array comparative genomic hybridization (array CGH) in 15 lung adenocarcinoma (AdC) tissues. Copy number gains and losses in chromosomal regions were detected and corresponding genes were confirmed by real-time polymerase chain reaction (PCR). As for the results, several frequently altered loci, including gain of 16p (46% of samples), were found, and the most common losses were found in 14q32.33 (26% of samples). High-level DNA amplifications (> 0.8 log(2) ratio) were detected at 1p, 5p, 7p, 9p, 11p, 11q, 12q, 14q, 16p, 17q, 19q, 20p, 21q, and 22q. A subset of genes, gained or lost, was checked for over- or underrepresentation by means of real-time PCR. The degree of fold change was highest in ECGF1 (22q13.33), HOXA9 (7p15.2), MAFG (17q25.3), TSC2 (16p13.3), and ICAM1 (19p13.2) genes and the 16p chromosome terminal region (16p13.3pter). Taken together, these results show that array CGH could be used as a powerful tool for identification of genomic alteration for lung cancer, and the above-mentioned genes may represent potential candidate genes in the study of lung cancer pathogenesis and diagnosis.

  12. Comprehensive genomic profiling of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations.

    PubMed

    Ross, Jeffrey S; Ali, Siraj M; Wang, Kai; Khaira, Depinder; Palma, Norma A; Chmielecki, Juliann; Palmer, Gary A; Morosini, Deborah; Elvin, Julia A; Fernandez, Sandra V; Miller, Vincent A; Stephens, Philip J; Cristofanilli, Massimo

    2015-11-01

    Inflammatory breast cancer (IBC) is a distinct clinicopathologic entity that carries a worse prognosis relative to non-IBC breast cancer even when matched for standard biomarkers (ER/PR/HER2). The objective of this study was to identify opportunities for benefit from targeted therapy, which are not currently identifiable in the standard workup for advanced breast cancer. Comprehensive genomic profiling on 53 IBC formalin-fixed paraffin-embedded specimens (mean, 800× + coverage) using the hybrid capture-based FoundationOne assay. Academic and community oncology clinics. From a series of 2208 clinical cases of advanced/refractory invasive breast cancers, 53 cases with IBC were identified. The presence of clinically relevant genomic alterations (CRGA) in IBC and responses to targeted therapies. CRGA were defined as genomic alterations (GA) associated with on label targeted therapies and targeted therapies in mechanism-driven clinical trials. For the 44 IBCs with available biomarker data, 19 (39 %) were ER-/PR-/HER2- (triple-negative breast cancer, TNBC). For patients in which the clinical HER2 status was known, 11 (25 %) were HER2+ with complete (100 %) concordance with ERBB2 (HER2) amplification detected by the CGP assay. The 53 sequenced IBC cases harbored a total of 266 GA with an average of 5.0 GA/tumor (range 1-15). At least one alteration associated with an FDA approved therapy or clinical trial was identified in 51/53 (96 %) of cases with an average of 2.6 CRGA/case. The most frequently altered genes were TP53 (62 %), MYC (32 %), PIK3CA (28 %), ERBB2 (26 %), FGFR1 (17 %), BRCA2 (15 %), and PTEN (15 %). In the TNBC subset of IBC, 8/19 (42 %) showed MYC amplification (median copy number 8X, range 7-20) as compared to 9/32 (28 %) in non-TNBC IBC (median copy number 7X, range 6-21). Comprehensive genomic profiling uncovered a high frequency of GA in IBC with 96 % of cases harboring at least 1 CRGA. The clinical benefit of selected targeted

  13. cDNA microarray reveals the alterations of cytoskeleton-related genes in osteoblast under high magneto-gravitational environment.

    PubMed

    Qian, Airong; Di, Shengmeng; Gao, Xiang; Zhang, Wei; Tian, Zongcheng; Li, Jingbao; Hu, Lifang; Yang, Pengfei; Yin, Dachuan; Shang, Peng

    2009-07-01

    The diamagnetic levitation as a novel ground-based model for simulating a reduced gravity environment has been widely applied in many fields. In this study, a special designed superconducting magnet, which can produce three apparent gravity levels (0, 1, and 2 g), namely high magneto-gravitational environment (HMGE), was used to simulate space gravity environment. The effects of HMGE on osteoblast gene expression profile were investigated by microarray. Genes sensitive to diamagnetic levitation environment (0 g), gravity changes, and high magnetic field changes were sorted on the basis of typical cell functions. Cytoskeleton, as an intracellular load-bearing structure, plays an important role in gravity perception. Therefore, 13 cytoskeleton-related genes were chosen according to the results of microarray analysis, and the expressions of these genes were found to be altered under HMGE by real-time PCR. Based on the PCR results, the expressions of WASF2 (WAS protein family, member 2), WIPF1 (WAS/WASL interacting protein family, member 1), paxillin, and talin 1 were further identified by western blot assay. Results indicated that WASF2 and WIPF1 were more sensitive to altered gravity levels, and talin 1 and paxillin were sensitive to both magnetic field and gravity changes. Our findings demonstrated that HMGE can affect osteoblast gene expression profile and cytoskeleton-related genes expression. The identification of mechanosensitive genes may enhance our understandings to the mechanism of bone loss induced by microgravity and may provide some potential targets for preventing and treating bone loss or osteoporosis.

  14. Sensory experience modifies feature map relationships in visual cortex

    PubMed Central

    Cloherty, Shaun L; Hughes, Nicholas J; Hietanen, Markus A; Bhagavatula, Partha S

    2016-01-01

    The extent to which brain structure is influenced by sensory input during development is a critical but controversial question. A paradigmatic system for studying this is the mammalian visual cortex. Maps of orientation preference (OP) and ocular dominance (OD) in the primary visual cortex of ferrets, cats and monkeys can be individually changed by altered visual input. However, the spatial relationship between OP and OD maps has appeared immutable. Using a computational model we predicted that biasing the visual input to orthogonal orientation in the two eyes should cause a shift of OP pinwheels towards the border of OD columns. We then confirmed this prediction by rearing cats wearing orthogonally oriented cylindrical lenses over each eye. Thus, the spatial relationship between OP and OD maps can be modified by visual experience, revealing a previously unknown degree of brain plasticity in response to sensory input. DOI: http://dx.doi.org/10.7554/eLife.13911.001 PMID:27310531

  15. Sensory experience modifies feature map relationships in visual cortex.

    PubMed

    Cloherty, Shaun L; Hughes, Nicholas J; Hietanen, Markus A; Bhagavatula, Partha S; Goodhill, Geoffrey J; Ibbotson, Michael R

    2016-01-01

    The extent to which brain structure is influenced by sensory input during development is a critical but controversial question. A paradigmatic system for studying this is the mammalian visual cortex. Maps of orientation preference (OP) and ocular dominance (OD) in the primary visual cortex of ferrets, cats and monkeys can be individually changed by altered visual input. However, the spatial relationship between OP and OD maps has appeared immutable. Using a computational model we predicted that biasing the visual input to orthogonal orientation in the two eyes should cause a shift of OP pinwheels towards the border of OD columns. We then confirmed this prediction by rearing cats wearing orthogonally oriented cylindrical lenses over each eye. Thus, the spatial relationship between OP and OD maps can be modified by visual experience, revealing a previously unknown degree of brain plasticity in response to sensory input. PMID:27310531

  16. Genome-wide DNA methylation analysis of neuroblastic tumors reveals clinically relevant epigenetic events and large-scale epigenomic alterations localized to telomeric regions.

    PubMed

    Buckley, Patrick G; Das, Sudipto; Bryan, Kenneth; Watters, Karen M; Alcock, Leah; Koster, Jan; Versteeg, Rogier; Stallings, Raymond L

    2011-05-15

    The downregulation of specific genes through DNA hypermethylation is a major hallmark of cancer, although the extent and genomic distribution of hypermethylation occurring within cancer genomes is poorly understood. We report on the first genome-wide analysis of DNA methylation alterations in different neuroblastic tumor subtypes and cell lines, revealing higher order organization and clinically relevant alterations of the epigenome. The methylation status of 33,485 discrete loci representing all annotated CpG islands and RefSeq gene promoters was assessed in primary neuroblastic tumors and cell lines. A comparison of genes that were hypermethylated exclusively in the clinically favorable ganglioneuroma/ganglioneuroblastoma tumors revealed that nine genes were associated with poor clinical outcome when overexpressed in the unfavorable neuroblastoma (NB) tumors. Moreover, an integrated DNA methylation and copy number analysis identified 80 genes that were recurrently concomitantly deleted and hypermethylated in NB, with 37 reactivated by 5-aza-deoxycytidine. Lower expression of four of these genes was correlated with poor clinical outcome, further implicating their inactivation in aggressive disease pathogenesis. Analysis of genome-wide hypermethylation patterns revealed 70 recurrent large-scale blocks of contiguously hypermethylated promoters/CpG islands, up to 590 kb in length, with a distribution bias toward telomeric regions. Genome-wide hypermethylation events in neuroblastic tumors are extensive and frequently occur in large-scale blocks with a significant bias toward telomeric regions, indicating that some methylation alterations have occurred in a coordinated manner. Our results indicate that methylation contributes toward the clinicopathological features of neuroblastic tumors, revealing numerous genes associated with poor patient survival in NB.

  17. Microarray analysis reveals higher gestational folic Acid alters expression of genes in the cerebellum of mice offspring-a pilot study.

    PubMed

    Barua, Subit; Kuizon, Salomon; Chadman, Kathryn K; Brown, W Ted; Junaid, Mohammed A

    2015-01-01

    Folate is a water-soluble vitamin that is critical for nucleotide synthesis and can modulate methylation of DNA by altering one-carbon metabolism. Previous studies have shown that folate status during pregnancy is associated with various congenital defects including the risk of aberrant neural tube closure. Maternal exposure to a methyl supplemented diet also can alter DNA methylation and gene expression, which may influence the phenotype of offspring. We investigated if higher gestational folic acid (FA) in the diet dysregulates the expression of genes in the cerebellum of offspring in C57BL/6 J mice. One week before gestation and throughout the pregnancy, groups of dams were supplemented with FA either at 2 mg/kg or 20 mg/kg of diet. Microarray analysis was used to investigate the genome wide gene expression profile in the cerebellum from day old pups. Our results revealed that exposure to the higher dose FA diet during gestation dysregulated expression of several genes in the cerebellum of both male and female pups. Several transcription factors, imprinted genes, neuro-developmental genes and genes associated with autism spectrum disorder exhibited altered expression levels. These findings suggest that higher gestational FA potentially dysregulates gene expression in the offspring brain and such changes may adversely alter fetal programming and overall brain development. PMID:25629700

  18. Integrated Proteomic and Glycoproteomic Analyses of Prostate Cancer Cells Reveal Glycoprotein Alteration in Protein Abundance and Glycosylation.

    PubMed

    Shah, Punit; Wang, Xiangchun; Yang, Weiming; Toghi Eshghi, Shadi; Sun, Shisheng; Hoti, Naseruddin; Chen, Lijun; Yang, Shuang; Pasay, Jered; Rubin, Abby; Zhang, Hui

    2015-10-01

    Prostate cancer is the most common cancer among men in the U.S. and worldwide, and androgen-deprivation therapy remains the principal treatment for patients. Although a majority of patients initially respond to androgen-deprivation therapy, most will eventually develop castration resistance. An increased understanding of the mechanisms that underline the pathogenesis of castration resistance is therefore needed to develop novel therapeutics. LNCaP and PC3 prostate cancer cell lines are models for androgen-dependence and androgen-independence, respectively. Herein, we report the comparative analysis of these two prostate cancer cell lines using integrated global proteomics and glycoproteomics. Global proteome profiling of the cell lines using isobaric tags for relative and absolute quantitation (iTRAQ) labeling and two- dimensional (2D) liquid chromatography-tandem MS (LC-MS/MS) led to the quantification of 8063 proteins. To analyze the glycoproteins, glycosite-containing peptides were isolated from the same iTRAQ-labeled peptides from the cell lines using solid phase extraction followed by LC-MS/MS analysis. Among the 1810 unique N-linked glycosite-containing peptides from 653 identified N-glycoproteins, 176 glycoproteins were observed to be different between the two cell lines. A majority of the altered glycoproteins were also observed with changes in their global protein expression levels. However, alterations in 21 differentially expressed glycoproteins showed no change at the protein abundance level, indicating that the glycosylation site occupancy was different between the two cell lines. To determine the glycosylation heterogeneity at specific glycosylation sites, we further identified and quantified 1145 N-linked glycopeptides with attached glycans in the same iTRAQ-labeled samples. These intact glycopeptides contained 67 glycan compositions and showed increased fucosylation in PC3 cells in several of the examined glycosylation sites. The increase in

  19. Integrated Proteomic and Glycoproteomic Analyses of Prostate Cancer Cells Reveal Glycoprotein Alteration in Protein Abundance and Glycosylation.

    PubMed

    Shah, Punit; Wang, Xiangchun; Yang, Weiming; Toghi Eshghi, Shadi; Sun, Shisheng; Hoti, Naseruddin; Chen, Lijun; Yang, Shuang; Pasay, Jered; Rubin, Abby; Zhang, Hui

    2015-10-01

    Prostate cancer is the most common cancer among men in the U.S. and worldwide, and androgen-deprivation therapy remains the principal treatment for patients. Although a majority of patients initially respond to androgen-deprivation therapy, most will eventually develop castration resistance. An increased understanding of the mechanisms that underline the pathogenesis of castration resistance is therefore needed to develop novel therapeutics. LNCaP and PC3 prostate cancer cell lines are models for androgen-dependence and androgen-independence, respectively. Herein, we report the comparative analysis of these two prostate cancer cell lines using integrated global proteomics and glycoproteomics. Global proteome profiling of the cell lines using isobaric tags for relative and absolute quantitation (iTRAQ) labeling and two- dimensional (2D) liquid chromatography-tandem MS (LC-MS/MS) led to the quantification of 8063 proteins. To analyze the glycoproteins, glycosite-containing peptides were isolated from the same iTRAQ-labeled peptides from the cell lines using solid phase extraction followed by LC-MS/MS analysis. Among the 1810 unique N-linked glycosite-containing peptides from 653 identified N-glycoproteins, 176 glycoproteins were observed to be different between the two cell lines. A majority of the altered glycoproteins were also observed with changes in their global protein expression levels. However, alterations in 21 differentially expressed glycoproteins showed no change at the protein abundance level, indicating that the glycosylation site occupancy was different between the two cell lines. To determine the glycosylation heterogeneity at specific glycosylation sites, we further identified and quantified 1145 N-linked glycopeptides with attached glycans in the same iTRAQ-labeled samples. These intact glycopeptides contained 67 glycan compositions and showed increased fucosylation in PC3 cells in several of the examined glycosylation sites. The increase in

  20. Altered pre-reflective sense of agency in autism spectrum disorders as revealed by reduced intentional binding.

    PubMed

    Sperduti, Marco; Pieron, Marie; Leboyer, Marion; Zalla, Tiziana

    2014-02-01

    Autism spectrum disorders (ASDs) are neurodevelopmental conditions that severely affect social interaction, communication and several behavioural and cognitive functions, such as planning and monitoring motor actions. A renewed interest in intrapersonal cognition has recently emerged suggesting a putative dissociation between impaired declarative processes, such as autobiographical memory, and spared implicit processes, such as the sense of agency (SoA) in ASDs. However, so far only a few studies have investigated the integrity of SoA using tasks exclusively tapping reflective mechanisms. Since pre-reflective processes of SoA are based on the same predictive internal models that are involved in planning and monitoring actions, we hypothesized that pre-reflective aspects of SoA, as measured by the intentional binding effect, would be altered in adults with high functioning autism spectrum disorders, relative to volunteers with typical development. Here, in accordance with our hypothesis, we report reduced IB in participants with ASDs. PMID:23881092

  1. cDNA microarray reveals the alterations of cytoskeleton-related genes in osteoblast under high magneto-gravitational environment.

    PubMed

    Qian, Airong; Di, Shengmeng; Gao, Xiang; Zhang, Wei; Tian, Zongcheng; Li, Jingbao; Hu, Lifang; Yang, Pengfei; Yin, Dachuan; Shang, Peng

    2009-07-01

    The diamagnetic levitation as a novel ground-based model for simulating a reduced gravity environment has been widely applied in many fields. In this study, a special designed superconducting magnet, which can produce three apparent gravity levels (0, 1, and 2 g), namely high magneto-gravitational environment (HMGE), was used to simulate space gravity environment. The effects of HMGE on osteoblast gene expression profile were investigated by microarray. Genes sensitive to diamagnetic levitation environment (0 g), gravity changes, and high magnetic field changes were sorted on the basis of typical cell functions. Cytoskeleton, as an intracellular load-bearing structure, plays an important role in gravity perception. Therefore, 13 cytoskeleton-related genes were chosen according to the results of microarray analysis, and the expressions of these genes were found to be altered under HMGE by real-time PCR. Based on the PCR results, the expressions of WASF2 (WAS protein family, member 2), WIPF1 (WAS/WASL interacting protein family, member 1), paxillin, and talin 1 were further identified by western blot assay. Results indicated that WASF2 and WIPF1 were more sensitive to altered gravity levels, and talin 1 and paxillin were sensitive to both magnetic field and gravity changes. Our findings demonstrated that HMGE can affect osteoblast gene expression profile and cytoskeleton-related genes expression. The identification of mechanosensitive genes may enhance our understandings to the mechanism of bone loss induced by microgravity and may provide some potential targets for preventing and treating bone loss or osteoporosis. PMID:19578720

  2. Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors.

    PubMed

    Metcalf, Talibah U; Cubas, Rafael A; Ghneim, Khader; Cartwright, Michael J; Grevenynghe, Julien Van; Richner, Justin M; Olagnier, David P; Wilkinson, Peter A; Cameron, Mark J; Park, Byung S; Hiscott, John B; Diamond, Michael S; Wertheimer, Anne M; Nikolich-Zugich, Janko; Haddad, Elias K

    2015-06-01

    Aging leads to dysregulation of multiple components of the immune system that results in increased susceptibility to infections and poor response to vaccines in the aging population. The dysfunctions of adaptive B and T cells are well documented, but the effect of aging on innate immunity remains incompletely understood. Using a heterogeneous population of peripheral blood mononuclear cells (PBMCs), we first undertook transcriptional profiling and found that PBMCs isolated from old individuals (≥ 65 years) exhibited a delayed and altered response to stimulation with TLR4, TLR7/8, and RIG-I agonists compared to cells obtained from adults (≤ 40 years). This delayed response to innate immune agonists resulted in the reduced production of pro-inflammatory and antiviral cytokines and chemokines including TNFα, IL-6, IL-1β, IFNα, IFNγ, CCL2, and CCL7. While the major monocyte and dendritic cell subsets did not change numerically with aging, activation of specific cell types was altered. PBMCs from old subjects also had a lower frequency of CD40+ monocytes, impaired up-regulation of PD-L1 on monocytes and T cells, and increased expression of PD-L2 and B7-H4 on B cells. The defective immune response to innate agonists adversely affected adaptive immunity as TLR-stimulated PBMCs (minus CD3 T cells) from old subjects elicited significantly lower levels of adult T-cell proliferation than those from adult subjects in an allogeneic mixed lymphocyte reaction (MLR). Collectively, these age-associated changes in cytokine, chemokine and interferon production, as well as co-stimulatory protein expression could contribute to the blunted memory B- and T-cell immune responses to vaccines and infections. PMID:25728020

  3. Glutamate and glutathione interplay in a motor neuronal model of amyotrophic lateral sclerosis reveals altered energy metabolism.

    PubMed

    D'Alessandro, Giuseppina; Calcagno, Eleonora; Tartari, Silvia; Rizzardini, Milena; Invernizzi, Roberto William; Cantoni, Lavinia

    2011-08-01

    Impairment of mitochondrial function might contribute to oxidative stress associated with neurodegeneration in amyotrophic lateral sclerosis (ALS). Glutamate levels in tissues of ALS patients are sometimes altered. In neurons, mitochondrial metabolism of exogenous glutamine is mainly responsible for the net synthesis of glutamate, which is a neurotransmitter, but it is also necessary for the synthesis of glutathione, the main endogenous antioxidant. We investigated glutathione synthesis and glutamine/glutamate metabolism in a motor neuronal model of familial ALS. In standard culture conditions (with glutamine) or restricting glutamine or cystine, the level of glutathione was always lower in the cell line expressing the mutant (G93A) human Cu, Zn superoxide dismutase (G93ASOD1) than in the line expressing wild-type SOD1. With glutamine the difference in glutathione was associated with a lower glutamate and impairment of the glutamine/glutamate metabolism as evidenced by lower glutaminase and cytosolic malate dehydrogenase activity. d-β-hydroxybutyrate, as an alternative to glutamine as energy substrate in addition to glucose, reversed the decreases of cytosolic malate dehydrogenase activity and glutamate and glutathione. However, in the G93ASOD1 cell line, in all culture conditions the expression of pyruvate dehydrogenase kinase l protein, which down-regulates pyruvate dehydrogenase activity, was induced, together with an increase in lactate release in the medium. These findings suggest that the glutathione decrease associated with mutant SOD1 expression is due to mitochondrial dysfunction caused by the reduction of the flow of glucose-derived pyruvate through the TCA cycle; it implies altered glutamate metabolism and depends on the different mitochondrial energy substrates. PMID:21530659

  4. Altered dendritic distribution of dopamine D2 receptors and reduction in mitochondrial number in parvalbumin-containing interneurons in the medial prefrontal cortex of cannabinoid-1 (CB1) receptor knockout mice

    PubMed Central

    Fitzgerald, Megan L.; Chan, June; Mackie, Kenneth; Lupica, Carl R.; Pickel, Virginia M.

    2013-01-01

    The prelimbic prefrontal cortex (PL) is a brain region integral to complex behaviors that are highly influenced by cannabinoids and by dopamine D2 receptor (D2R)-mediated regulation of fast-firing parvalbumin-containing interneurons. We have recently shown that constitutive deletion of the cannabinoid CB1 receptor (CB1R) greatly reduces parvalbumin levels in these neurons. The effects of CB1R deletion on PL parvalbumin interneurons may be ascribed to loss of CB1R-mediated retrograde signaling on mesocortical dopamine transmission, and, in turn, altered expression and/or subcellular distribution of the D2R in the PL. Furthermore, diminished parvalbumin expression could indicate metabolic changes in fast-firing interneurons that may be reflected in changes in mitochondrial density in this population. We therefore comparatively examined electron microscopic dual labeling of the D2R and parvalbumin in CB1 (−/−) and CB1 (+/+) mice to test the hypothesis that absence of the CB1R produces changes in D2R localization and mitochondrial distribution in parvalbumin-containing interneurons of the PL. CB1 (−/−) mice had a significantly lower density of cytoplasmic D2R-immunogold particles in medium parvalbumin-labeled dendrites and a concomitant increase in the density of these particles in small dendrites. These dendrites received both excitatory and inhibitory-type synapses from unlabeled terminals and contained many mitochondria, whose numbers were significantly reduced in the CB1 (−/−) mice. Non-parvalbumin containing dendrites showed no between-group differences in either D2R distribution or mitochondrial number. These results suggest that cannabinoid signaling provides an important determinant of dendritic D2 receptor distribution and mitochondrial availability in fast-spiking interneurons. PMID:22592925

  5. Sex-specific effects of cytotoxic chemotherapy agents cyclophospha-mide and mitomycin C on gene expression, oxidative DNA damage, and epigenetic alterations in the prefrontal cortex and hippocampus – an aging connection

    PubMed Central

    Kovalchuk, Anna; Rodriguez-Juarez, Rocio; Ilnytskyy, Yaroslav; Byeon, Boseon; Shpyleva, Svitlana; Melnyk, Stepan; Pogribny, Igor; Kolb, Bryan; Kovalchuk, Olga

    2016-01-01

    Recent research shows that chemotherapy agents can be more toxic to healthy brain cells than to the target cancer cells. They cause a range of side effects, including memory loss and cognitive dysfunction that can persist long after the completion of treatment. This condition is known as chemo brain. The molecular and cellular mechanisms of chemo brain remain obscure. Here, we analyzed the effects of two cytotoxic chemotherapy drugs—cyclophosphamide (CPP) and mitomycin C (MMC) - on transcriptomic and epigenetic changes in the murine prefrontal cortex (PFC) and hippocampal regions. We for the first time showed that CPP and MMC treatments led to profound sex- and brain region-specific alterations in gene expression profiles. Gene expression changes were most prominent in the PFC tissues of female mice 3 weeks after MMC treatment, and the gene expression response was much greater for MCC than CPP exposure. MMC exposure resulted in oxidative DNA damage, evidenced by accumulation of 8-oxo-2′-deoxyguanosine (8-oxodG) and a decrease in the level of 8-oxodG repair protein OGG1 in the PFC of female animals 3 weeks after treatment. MMC treatment decreased global DNA methylation and increased DNA hydroxymethylation in the PFC tissues of female mice. The majority of the changes induced by chemotherapy in the PFC tissues of female mice resembled those that occur during the brain's aging processes. Therefore, our study suggests a link between chemotherapy-induced chemo brain and brain aging, and provides an important roadmap for future analysis. PMID:27032448

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

    PubMed Central

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

    2014-01-01

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

  7. Bone marrow cell transcripts from Fanconi anaemia patients reveal in vivo alterations in mitochondrial, redox and DNA repair pathways.

    PubMed

    Pagano, Giovanni; Talamanca, Annarita Aiello; Castello, Giuseppe; d'Ischia, Marco; Pallardó, Federico V; Petrović, Sandra; Porto, Beatriz; Tiano, Luca; Zatterale, Adriana

    2013-08-01

    Fanconi anaemia (FA) is a genetic cancer predisposition disorder associated with cytogenetic instability, bone marrow failure and a pleiotropic cellular phenotype, including low thresholds of responses to oxidative stress, cross-linking agents and selected cytokines. This study was aimed at defining the scope of abnormalities in gene expression using the publicly available FA Transcriptome Consortium (FTC) database (Gene Expression Omnibus, 2009 and publicly available as GSE16334). We evaluated the data set that included transcriptomal analyses on RNA obtained from low-density bone marrow cells (BMC) from 20 patients with FA and 11 healthy volunteers, by seeking to identify changes in expression of over 22,000 genes, including a set of genes involved in: (i) bioenergetic pathways; (ii) antioxidant activities; (iii) response to stress and metal-chelating proteins; (iv) inflammation-related cytokines and (v) DNA repair. Ontological analysis of genes expressed at magnitudes of 1.5-fold or greater demonstrated significant suppression of genes in the categories of (i) energy metabolism; (ii) antioxidant activities; and (iii) stress and chelating proteins. Enhanced expression was found for 16 of 26 genes encoding inflammatory cytokines. A set of 20 of 21 transcripts for DNA repair activities were down-regulated; four of these transcripts related to type II topoisomerase. The data provide evidence for alterations in gene regulation of bioenergetic activities, redox-related activities, stress and metal-chelating proteins, and of some selected DNA repair activities in patients with FA.

  8. Combinational losses of synucleins reveal their differential requirements for compensating age-dependent alterations in motor behavior and dopamine metabolism.

    PubMed

    Connor-Robson, Natalie; Peters, Owen M; Millership, Steven; Ninkina, Natalia; Buchman, Vladimir L

    2016-10-01

    Synucleins are involved in multiple steps of the neurotransmitter turnover, but the largely normal synaptic function in young adult animals completely lacking synucleins suggests their roles are dispensable for execution of these processes. Instead, they may be utilized for boosting the efficiency of certain molecular mechanisms in presynaptic terminals, with a deficiency of synuclein proteins sensitizing to or exacerbating synaptic malfunction caused by accumulation of mild alterations, which are commonly associated with aging. Although functional redundancy within the family has been reported, it is unclear whether the remaining synucleins can fully compensate for the deficiency of a lost family member or whether some functions are specific for a particular member. We assessed several structural and functional characteristics of the nigrostriatal system of mice lacking members of the synuclein family in every possible combination and demonstrated that stabilization of the striatal dopamine level depends on the presence of α-synuclein and cannot be compensated by other family members, whereas β-synuclein is required for efficient maintenance of animal's balance and coordination in old age. PMID:27614017

  9. An integrated approach to reveal miRNAs' impacts on the functional consequence of copy number alterations in cancer.

    PubMed

    Li, Kening; Liu, Yongjing; Zhou, Yuanshuai; Zhang, Rui; Zhao, Ning; Yan, Zichuang; Zhang, Qiang; Zhang, Shujuan; Qiu, Fujun; Xu, Yan

    2015-01-01

    Copy number alteration (CNA) is known to induce gene expression changes mainly through dosage effect, and therefore affect the initiation and progression of tumor. However, tumor samples exhibit heterogeneity in gene dosage sensitivity due to the complicated mechanisms of transcriptional regulation. Currently, no high-throughput method has been available for identifying the regulatory factors affecting the functional consequences of CNA, and determining their effects on cancer. In view of the important regulatory role of miRNA, we investigated the influence of miRNAs on the dosage sensitivities of genes within the CNA regions. By integrating copy number, mRNA expression, miRNA expression profiles of three kinds of cancer, we observed a tendency for high dosage-sensitivity genes to be more targeted by miRNAs in cancer, and identified the miRNAs regulating the dosage sensitivity of amplified/deleted target genes. The results show that miRNAs can modulate oncogenic biological functions by regulating the genes within the CNA regions, and thus play a role as a trigger or balancer in cancer, affecting cancer processes, even survival. This work provided a framework for analyzing the regulation of dosage effect, which will shed a light on understanding the oncogenic and tumor suppressive mechanisms of CNA. Besides, new cancer-related miRNAs were identified. PMID:26099552

  10. Gentamicin differentially alters cellular metabolism of cochlear hair cells as revealed by NAD(P)H fluorescence lifetime imaging

    NASA Astrophysics Data System (ADS)

    Zholudeva, Lyandysha V.; Ward, Kristina G.; Nichols, Michael G.; Smith, Heather Jensen

    2015-05-01

    Aminoglycoside antibiotics are implicated as culprits of hearing loss in more than 120,000 individuals annually. Research has shown that the sensory cells, but not supporting cells, of the cochlea are readily damaged and/or lost after use of such antibiotics. High-frequency outer hair cells (OHCs) show a greater sensitivity to antibiotics than high- and low-frequency inner hair cells (IHCs). We hypothesize that variations in mitochondrial metabolism account for differences in susceptibility. Fluorescence lifetime microscopy was used to quantify changes in NAD(P)H in sensory and supporting cells from explanted murine cochleae exposed to mitochondrial uncouplers, inhibitors, and an ototoxic antibiotic, gentamicin (GM). Changes in metabolic state resulted in a redistribution of NAD(P)H between subcellular fluorescence lifetime pools. Supporting cells had a significantly longer lifetime than sensory cells. Pretreatment with GM increased NAD(P)H intensity in high-frequency sensory cells, as well as the NAD(P)H lifetime within IHCs. GM specifically increased NAD(P)H concentration in high-frequency OHCs, but not in IHCs or pillar cells. Variations in NAD(P)H intensity in response to mitochondrial toxins and GM were greatest in high-frequency OHCs. These results demonstrate that GM rapidly alters mitochondrial metabolism, differentially modulates cell metabolism, and provides evidence that GM-induced changes in metabolism are significant and greatest in high-frequency OHCs.

  11. Transcriptional Analysis of Vitiligo Skin Reveals the Alteration of WNT Pathway: A Promising Target for Repigmenting Vitiligo Patients.

    PubMed

    Regazzetti, Claire; Joly, Florence; Marty, Carine; Rivier, Michel; Mehul, Bruno; Reiniche, Pascale; Mounier, Carine; Rival, Yves; Piwnica, David; Cavalié, Marine; Chignon-Sicard, Bérengère; Ballotti, Robert; Voegel, Johannes; Passeron, Thierry

    2015-12-01

    Vitiligo affects 1% of the worldwide population. Halting disease progression and repigmenting the lesional skin represent the two faces of therapeutic challenge in vitiligo. We performed transcriptome analysis on lesional, perilesional, and non-depigmented skin from vitiligo patients and on matched skin from healthy subjects. We found a significant increase in CXCL10 in non-depigmented and perilesional vitiligo skin compared with levels in healthy control skin; however, neither CXCL10 nor other immune factors were deregulated in depigmented vitiligo skin. Interestingly, the WNT pathway, which is involved in melanocyte differentiation, was altered specifically in vitiligo skin. We demonstrated that oxidative stress decreases WNT expression/activation in keratinocytes and melanocytes. We developed an ex vivo skin model and confirmed the decrease activation of the WNT pathway in human skin subjected to oxidative stress. Finally, using pharmacological agents that activate the WNT pathway, we treated ex vivo depigmented skin from vitiligo patients and successfully induced differentiation of resident stem cells into pre-melanocytes. Our results shed light on the previously unrecognized role of decreased WNT activation in the prevention of melanocyte differentiation in depigmented vitiligo skin. Furthermore, these results support further clinical exploration of WNT agonists to repigment vitiligo lesions.

  12. Comparative analysis of somatic copy-number alterations across different human cancer types reveals two distinct classes of breakpoint hotspots

    PubMed Central

    Li, Yudong; Zhang, Li; Ball, Robyn L.; Liang, Xinle; Li, Jianrong; Lin, Zhenguo; Liang, Han

    2012-01-01

    Somatic copy-number alterations (SCNAs) play a crucial role in the development of human cancer. However, it is not well understood what evolutionary mechanisms contribute to the global patterns of SCNAs in cancer genomes. Taking advantage of data recently available through The Cancer Genome Atlas, we performed a systematic analysis on genome-wide SCNA breakpoint data for eight cancer types. First, we observed a high degree of overall similarity among the SCNA breakpoint landscapes of different cancer types. Then, we compiled 19 genomic features and evaluated their effects on the observed SCNA patterns. We found that evolutionary indel and substitution rates between species (i.e. humans and chimpanzees) consistently show the strongest correlations with breakpoint frequency among all the surveyed features; whereas the effects of some features are quite cancer-type dependent. Focusing on SCNA breakpoint hotspots, we found that cancer-type-specific breakpoint hotspots and common hotspots show distinct patterns. Cancer-type-specific hotspots are enriched with known cancer genes but are poorly predicted from genomic features; whereas common hotspots show the opposite patterns. This contrast suggests that explaining high-frequency SCNAs in cancer may require different evolutionary models: positive selection driven by cancer genes, and non-adaptive evolution related to an intrinsically unstable genomic context. Our results not only present a systematic view of the effects of genetic factors on genome-wide SCNA patterns, but also provide deep insights into the evolutionary process of SCNAs in cancer. PMID:22899649

  13. An integrated approach to reveal miRNAs’ impacts on the functional consequence of copy number alterations in cancer

    PubMed Central

    Li, Kening; Liu, Yongjing; Zhou, Yuanshuai; Zhang, Rui; Zhao, Ning; Yan, Zichuang; Zhang, Qiang; Zhang, Shujuan; Qiu, Fujun; Xu, Yan

    2015-01-01

    Copy number alteration (CNA) is known to induce gene expression changes mainly through dosage effect, and therefore affect the initiation and progression of tumor. However, tumor samples exhibit heterogeneity in gene dosage sensitivity due to the complicated mechanisms of transcriptional regulation. Currently, no high-throughput method has been available for identifying the regulatory factors affecting the functional consequences of CNA, and determining their effects on cancer. In view of the important regulatory role of miRNA, we investigated the influence of miRNAs on the dosage sensitivities of genes within the CNA regions. By integrating copy number, mRNA expression, miRNA expression profiles of three kinds of cancer, we observed a tendency for high dosage-sensitivity genes to be more targeted by miRNAs in cancer, and identified the miRNAs regulating the dosage sensitivity of amplified/deleted target genes. The results show that miRNAs can modulate oncogenic biological functions by regulating the genes within the CNA regions, and thus play a role as a trigger or balancer in cancer, affecting cancer processes, even survival. This work provided a framework for analyzing the regulation of dosage effect, which will shed a light on understanding the oncogenic and tumor suppressive mechanisms of CNA. Besides, new cancer-related miRNAs were identified. PMID:26099552

  14. Bifunctional Probes of Cathepsin Protease Activity and pH Reveal Alterations in Endolysosomal pH during Bacterial Infection.

    PubMed

    Sanman, Laura E; van der Linden, Wouter A; Verdoes, Martijn; Bogyo, Matthew

    2016-07-21

    Cysteine cathepsins are lysosomal proteases involved in regulation of both normal cellular processes and disease. Biochemical studies with peptide substrates indicate that cathepsins have optimal activity at acidic pH and highly attenuated activity at neutral pH. In contrast, there is mounting evidence that cathepsins have biological roles in environments that have non-acidic pH. To further define the specific pH environments where cathepsins act, we designed bifunctional activity-based probes (ABPs) that allow simultaneous analysis of cathepsin protease activity and pH. We use these probes to analyze the steady-state environment of cathepsin activity in macrophages and to measure dynamic changes in activity and pH upon stimulation. We show that Salmonella typhimurium induces a change in lysosomal pH that ultimately impairs cathepsin activity in both infected cells and a fraction of bystander cells, highlighting a mechanism by which Salmonella can simultaneously flourish within host cells and alter the behavior of nearby uninfected cells.

  15. Metabonomic Analysis Reveals Efficient Ameliorating Effects of Acupoint Stimulations on the Menopause-caused Alterations in Mammalian Metabolism

    NASA Astrophysics Data System (ADS)

    Zhang, Limin; Wang, Yulan; Xu, Yunxiang; Lei, Hehua; Zhao, Ying; Li, Huihui; Lin, Xiaosheng; Chen, Guizhen; Tang, Huiru

    2014-01-01

    Acupoint stimulations are effective in ameliorating symptoms of menopause which is an unavoidable ageing consequence for women. To understand the mechanistic aspects of such treatments, we systematically analyzed the effects of acupoint laser-irradiation and catgut-embedding on the ovariectomy-induced rat metabolic changes using NMR and GC-FID/MS methods. Results showed that ovariectomization (OVX) caused comprehensive metabolic changes in lipid peroxidation, glycolysis, TCA cycle, choline and amino acid metabolisms. Both acupoint laser-irradiation and catgut-embedding ameliorated the OVX-caused metabonomic changes more effectively than hormone replacement therapy (HRT) with nilestriol. Such effects of acupoint stimulations were highlighted in alleviating lipid peroxidation, restoring glucose homeostasis and partial reversion of the OVX-altered amino acid metabolism. These findings provided new insights into the menopause effects on mammalian biochemistry and beneficial effects of acupoint stimulations in comparison with HRT, demonstrating metabonomics as a powerful approach for potential applications in disease prognosis and developments of effective therapies.

  16. Differential cysteine labeling and global label-free proteomics reveals an altered metabolic state in skeletal muscle aging.

    PubMed

    McDonagh, Brian; Sakellariou, Giorgos K; Smith, Neil T; Brownridge, Philip; Jackson, Malcolm J

    2014-11-01

    The molecular mechanisms underlying skeletal muscle aging and associated sarcopenia have been linked to an altered oxidative status of redox-sensitive proteins. Reactive oxygen and reactive nitrogen species (ROS/RNS) generated by contracting skeletal muscle are necessary for optimal protein function, signaling, and adaptation. To investigate the redox proteome of aging gastrocnemius muscles from adult and old male mice, we developed a label-free quantitative proteomic approach that includes a differential cysteine labeling step. The approach allows simultaneous identification of up- and downregulated proteins between samples in addition to the identification and relative quantification of the reversible oxidation state of susceptible redox cysteine residues. Results from muscles of adult and old mice indicate significant changes in the content of chaperone, glucose metabolism, and cytoskeletal regulatory proteins, including Protein DJ-1, cAMP-dependent protein kinase type II, 78 kDa glucose regulated protein, and a reduction in the number of redox-responsive proteins identified in muscle of old mice. Results demonstrate skeletal muscle aging causes a reduction in redox-sensitive proteins involved in the generation of precursor metabolites and energy metabolism, indicating a loss in the flexibility of the redox energy response. Data is available via ProteomeXchange with identifier PXD001054.

  17. CX-516 Cortex pharmaceuticals.

    PubMed

    Danysz, Wojciech

    2002-07-01

    CX-516 is one of a series of AMPA modulators under development by Cortex, in collaboration with Shire and Servier, for the potential treatment of Alzheimer's disease (AD), schizophrenia and mild cognitive impairment (MCI) [234221]. By June 2001, CX-516 was in phase II trials for both schizophrenia and attention deficit hyperactivity disorder (ADHD) [412513]. A phase II trial in fragile X syndrome and autism was expected to start in May 2002 [449861]. In October 2001, Cortex was awarded a Phase II SBIR grant of $769,818 from the National Institutes of Mental Health to investigate the therapeutic potential of AMPAkines in schizophrenia. This award was to support a phase IIb study of CX-516 as a combination therapy in schizophrenia patients concomitantly treated with olanzapine. The trial was to enroll 80 patients and employ a randomized, double-blind, placebo-controlled design in which the placebo group was to receive olanzapine plus placebo and the active group was to receive olanzapine plus CX-516 [425982]. In April 2000, Shire and Cortex signed an option agreement in which Shire was to evaluate CX-516for the treatment of ADHD. Under the terms of the agreement, Shire would undertake a double-blind, placebo-controlled evaluation of CX-516 involving ADHD patients. If the study proved effective, Shire would have the right to convert its option into an exclusive worldwide license for the AMPAkines for ADHD under a development and licensing agreement. Should Shire elect to execute this agreement, Shire would bear all future developmental costs [363618]. By February 2002, Cortex and Servier had revealed their intention to begin enrolment for an international study of an AMPAkine compound as a potential treatment for MCI in the near future. Assuming enrollment proceeded as anticipated, results were expected during the second quarter of 2003 [439301]. By May 2002, phase II trials were underway [450134]. In March 2002, Cortex was awarded extended funding under the

  18. PhyloChip microarray analysis reveals altered gastrointestinal microbial communities in a rat model of colonic hypersensitivity

    SciTech Connect

    Nelson, T.A.; Holmes, S.; Alekseyenko, A.V.; Shenoy, M.; DeSantis, T.; Wu, C.H.; Andersen, G.L.; Winston, J.; Sonnenburg, J.; Pasricha, P.J.; Spormann, A.

    2010-12-01

    Irritable bowel syndrome (IBS) is a chronic, episodic gastrointestinal disorder that is prevalent in a significant fraction of western human populations; and changes in the microbiota of the large bowel have been implicated in the pathology of the disease. Using a novel comprehensive, high-density DNA microarray (PhyloChip) we performed a phylogenetic analysis of the microbial community of the large bowel in a rat model in which intracolonic acetic acid in neonates was used to induce long lasting colonic hypersensitivity and decreased stool water content and frequency, representing the equivalent of human constipation-predominant IBS. Our results revealed a significantly increased compositional difference in the microbial communities in rats with neonatal irritation as compared with controls. Even more striking was the dramatic change in the ratio of Firmicutes relative to Bacteroidetes, where neonatally irritated rats were enriched more with Bacteroidetes and also contained a different composition of species within this phylum. Our study also revealed differences at the level of bacterial families and species. The PhyloChip is a useful and convenient method to study enteric microflora. Further, this rat model system may be a useful experimental platform to study the causes and consequences of changes in microbial community composition associated with IBS.

  19. Genetic alterations and their clinical implications in gastric cancer peritoneal carcinomatosis revealed by whole-exome sequencing of malignant ascites

    PubMed Central

    Kim, Jeong-Hwan; Kwon, Woo Sun; Lee, Won Seok; Kim, Jeong Min; Park, Jun Yong; Kim, Hyo Song; Park, Kyu Hyun; Kim, Tae Soo; Park, Jong-Lyul; Chung, Hyun Cheol; Rha, Sun Young; Kim, Seon-Young

    2016-01-01

    Peritoneal carcinomatosis accompanied by malignant ascites is a major cause of death of advanced gastric cancer (GC). To comprehensively characterize the underlying genomic events involved in GC peritoneal carcinomatosis, we analyzed whole-exome sequences of normal gastric tissues, primary tumors, and malignant ascites from eight GC patients. We identified a unique mutational signature biased toward C-to-A substitutions in malignant ascites. In contrast, the patients who received treatment of adjuvant chemotherapy showed a high rate of C-to-T substitutions along with hypermutation in malignant ascites. Comparative analysis revealed several candidate mutations for GC peritoneal carcinomatosis: recurrent mutations in COL4A6, INTS2, and PTPN13; mutations in druggable genes including TEP1, PRKCD, BRAF, ERBB4, PIK3CA, HDAC9, FYN, FASN, BIRC2, FLT3, ROCK1, CD22, and PIK3C2B; and mutations in metastasis-associated genes including TNFSF12, L1CAM, DIAPH3, ROCK1, TGFBR1, MYO9B, NR4A1, and RHOA. Notably, gene ontology analysis revealed the significant enrichment of mutations in the Rho-ROCK signaling pathway-associated biological processes in malignant ascites. At least four of the eight patients acquired somatic mutations in the Rho-ROCK pathway components, suggesting the possible relevance of this pathway to GC peritoneal carcinomatosis. These results provide a genome-wide molecular understanding of GC peritoneal carcinomatosis and its clinical implications, thereby facilitating the development of effective therapeutics. PMID:26811494

  20. Genetic alterations and their clinical implications in gastric cancer peritoneal carcinomatosis revealed by whole-exome sequencing of malignant ascites.

    PubMed

    Lim, Byungho; Kim, Chan; Kim, Jeong-Hwan; Kwon, Woo Sun; Lee, Won Seok; Kim, Jeong Min; Park, Jun Yong; Kim, Hyo Song; Park, Kyu Hyun; Kim, Tae Soo; Park, Jong-Lyul; Chung, Hyun Cheol; Rha, Sun Young; Kim, Seon-Young

    2016-02-16

    Peritoneal carcinomatosis accompanied by malignant ascites is a major cause of death of advanced gastric cancer (GC). To comprehensively characterize the underlying genomic events involved in GC peritoneal carcinomatosis, we analyzed whole-exome sequences of normal gastric tissues, primary tumors, and malignant ascites from eight GC patients. We identified a unique mutational signature biased toward C-to-A substitutions in malignant ascites. In contrast, the patients who received treatment of adjuvant chemotherapy showed a high rate of C-to-T substitutions along with hypermutation in malignant ascites. Comparative analysis revealed several candidate mutations for GC peritoneal carcinomatosis: recurrent mutations in COL4A6, INTS2, and PTPN13; mutations in druggable genes including TEP1, PRKCD, BRAF, ERBB4, PIK3CA, HDAC9, FYN, FASN, BIRC2, FLT3, ROCK1, CD22, and PIK3C2B; and mutations in metastasis-associated genes including TNFSF12, L1CAM, DIAPH3, ROCK1, TGFBR1, MYO9B, NR4A1, and RHOA. Notably, gene ontology analysis revealed the significant enrichment of mutations in the Rho-ROCK signaling pathway-associated biological processes in malignant ascites. At least four of the eight patients acquired somatic mutations in the Rho-ROCK pathway components, suggesting the possible relevance of this pathway to GC peritoneal carcinomatosis. These results provide a genome-wide molecular understanding of GC peritoneal carcinomatosis and its clinical implications, thereby facilitating the development of effective therapeutics. PMID:26811494

  1. Isotropic 3D Nuclear Morphometry of Normal, Fibrocystic and Malignant Breast Epithelial Cells Reveals New Structural Alterations

    PubMed Central

    Nandakumar, Vivek; Kelbauskas, Laimonas; Hernandez, Kathryn F.; Lintecum, Kelly M.; Senechal, Patti; Bussey, Kimberly J.; Davies, Paul C. W.; Johnson, Roger H.; Meldrum, Deirdre R.

    2012-01-01

    Background Grading schemes for breast cancer diagnosis are predominantly based on pathologists' qualitative assessment of altered nuclear structure from 2D brightfield microscopy images. However, cells are three-dimensional (3D) objects with features that are inherently 3D and thus poorly characterized in 2D. Our goal is to quantitatively characterize nuclear structure in 3D, assess its variation with malignancy, and investigate whether such variation correlates with standard nuclear grading criteria. Methodology We applied micro-optical computed tomographic imaging and automated 3D nuclear morphometry to quantify and compare morphological variations between human cell lines derived from normal, benign fibrocystic or malignant breast epithelium. To reproduce the appearance and contrast in clinical cytopathology images, we stained cells with hematoxylin and eosin and obtained 3D images of 150 individual stained cells of each cell type at sub-micron, isotropic resolution. Applying volumetric image analyses, we computed 42 3D morphological and textural descriptors of cellular and nuclear structure. Principal Findings We observed four distinct nuclear shape categories, the predominant being a mushroom cap shape. Cell and nuclear volumes increased from normal to fibrocystic to metastatic type, but there was little difference in the volume ratio of nucleus to cytoplasm (N/C ratio) between the lines. Abnormal cell nuclei had more nucleoli, markedly higher density and clumpier chromatin organization compared to normal. Nuclei of non-tumorigenic, fibrocystic cells exhibited larger textural variations than metastatic cell nuclei. At p<0.0025 by ANOVA and Kruskal-Wallis tests, 90% of our computed descriptors statistically differentiated control from abnormal cell populations, but only 69% of these features statistically differentiated the fibrocystic from the metastatic cell populations. Conclusions Our results provide a new perspective on nuclear structure variations

  2. Array comparative genomic hybridization reveals frequent alterations of G1/S checkpoint genes in undifferentiated pleomorphic sarcoma of bone.

    PubMed

    Niini, Tarja; Lahti, Leo; Michelacci, Francesca; Ninomiya, Shinsuke; Hattinger, Claudia Maria; Guled, Mohamed; Böhling, Tom; Picci, Piero; Serra, Massimo; Knuutila, Sakari

    2011-05-01

    Undifferentiated pleomorphic sarcoma of bone (UPSb) is a rare tumor often difficult to differentiate from fibrosarcoma of bone (FSb), diagnostically. We applied array comparative genomic hybridization (array CGH) to screen for genes with potential importance in the tumor and compared the results with alterations seen in FSb. Twenty-two fresh frozen tissue specimens from 20 patients (18 primary tumors and 4 local recurrences) with UPSb were studied. DNA was isolated and hybridized onto Agilent 244K CGH oligoarrays. The hybridization data were analyzed using Agilent DNA Analytics Software. The number of changes ranged from 2 to 168 (average = 66). Losses were most frequently seen at 8p, 9p, 10, 13q, and 18q, and gains at 4q, 5p, 6p, 7p, 8q, 12p, 14q, 17q, 19p, 20q, 22q, and X. Homozygous deletions of CDKN2A, RB1, TP53, and ING1 were seen in 8/20, 7/20, 3/20, and 2/20 cases, respectively. Hypermethylation of both p16(INK4a) and p14(ARF) was found in two cases with loss at CDKN2A. Inactivation either of CDKN2A, RB1, or TP53 was detected in 18/20 cases. One case showed high level gains of CDK4 and MDM2. Frequent gains were seen at MYC, PDGFRA, KIT, and KDR. Immunohistochemical positivity of KIT, PDGFRA, KDR, and PDGFRB was found in 8/14, 5/14, 4/14, and 4/14 cases, respectively. The regions most significantly discriminating between UPSb and FSb included RB1 and MYC. No homozygous deletions of RB1 were found in FSb. In conclusion, our analysis showed the disruption of G1/S checkpoint regulation to be crucial for the oncogenesis of UPSb.

  3. Transcriptomic profiling revealed the signatures of intestinal barrier alteration and pathogen entry in turbot (Scophthalmus maximus) following Vibrio anguillarum challenge.

    PubMed

    Gao, Chengbin; Fu, Qiang; Su, Baofeng; Zhou, Shun; Liu, Fengqiao; Song, Lin; Zhang, Min; Ren, Yichao; Dong, Xiaoyu; Tan, Fenghua; Li, Chao

    2016-12-01

    The mucosal immune system serves as the frontline barriers of host defense against pathogen infection, especially for the fishes, which are living in the pathogen rich aquatic environment. The intestine constitutes the largest surface body area in constantly contact with the external pathogens, and plays a vital role in the immune defense against inflammation and pathogen infection. Previous studies have revealed that fish intestine might serves as the portal of entry for Vibrio anguillarum. To characterize the immune actors and their associated immune activities in turbot intestine barrier during bacterial infection, here we examined the gene expression profiles of turbot intestine at three time points following experimental infection with V. anguillarum utilizing RNA-seq technology. A total of 122 million reads were assembled into 183,101 contigs with an average length of 1151 bp and the N50 size of 2302 bp. Analysis of differential gene expression between control and infected samples at 1 h, 4 h, and 12 h revealed 2079 significantly expressed genes. Enrichment and pathway analysis of the differentially expressed genes showed the centrality of the pathogen attachment and recognition, antioxidant/apoptosis, mucus barrier modification and immune activation/inflammation in the pathogen entry and host immune responses. The present study reported the novel gene expression patterns in turbot mucosal immunity, which were overlooked in previous studies. Our results can help to understand the mechanisms of turbot host defense, and may also provide foundation to identify the biomarkers for future selection of disease-resistant broodstock and evaluation of disease prevention and treatment options. PMID:27431928

  4. Training improves multitasking performance by increasing the speed of information processing in human prefrontal cortex.

    PubMed

    Dux, Paul E; Tombu, Michael N; Harrison, Stephenie; Rogers, Baxter P; Tong, Frank; Marois, René

    2009-07-16

    Our ability to multitask is severely limited: task performance deteriorates when we attempt to undertake two or more tasks simultaneously. Remarkably, extensive training can greatly reduce such multitasking costs. While it is not known how training alters the brain to solve the multitasking problem, it likely involves the prefrontal cortex given this brain region's purported role in limiting multitasking performance. Here, we show that the reduction of multitasking interference with training is not achieved by diverting the flow of information processing away from the prefrontal cortex or by segregating prefrontal cells into independent task-specific neuronal ensembles, but rather by increasing the speed of information processing in this brain region, thereby allowing multiple tasks to be processed in rapid succession. These results not only reveal how training leads to efficient multitasking, they also provide a mechanistic account of multitasking limitations, namely the poor speed of information processing in human prefrontal cortex.

  5. RNA Sequencing Reveals the Alteration of the Expression of Novel Genes in Ethanol-Treated Embryoid Bodies.

    PubMed

    Mandal, Chanchal; Kim, Sun Hwa; Chai, Jin Choul; Oh, Seon Mi; Lee, Young Seek; Jung, Kyoung Hwa; Chai, Young Gyu

    2016-01-01

    Fetal alcohol spectrum disorder is a collective term representing fetal abnormalities associated with maternal alcohol consumption. Prenatal alcohol exposure and related anomalies are well characterized, but the molecular mechanism behind this phenomenon is not well characterized. In this present study, our aim is to profile important genes that regulate cellular development during fetal development. Human embryonic carcinoma cells (NCCIT) are cultured to form embryoid bodies and then treated in the presence and absence of ethanol (50 mM). We employed RNA sequencing to profile differentially expressed genes in the ethanol-treated embryoid bodies from NCCIT vs. EB, NCCIT vs. EB+EtOH and EB vs. EB+EtOH data sets. A total of 632, 205 and 517 differentially expressed genes were identified from NCCIT vs. EB, NCCIT vs. EB+EtOH and EB vs. EB+EtOH, respectively. Functional annotation using bioinformatics tools reveal significant enrichment of differential cellular development and developmental disorders. Furthermore, a group of 42, 15 and 35 transcription factor-encoding genes are screened from all of the differentially expressed genes obtained from NCCIT vs. EB, NCCIT vs. EB+EtOH and EB vs. EB+EtOH, respectively. We validated relative gene expression levels of several transcription factors from these lists by quantitative real-time PCR. We hope that our study substantially contributes to the understanding of the molecular mechanism underlying the pathology of alcohol-mediated anomalies and ease further research.

  6. Genome Alignment Spanning Major Poaceae Lineages Reveals Heterogeneous Evolutionary Rates and Alters Inferred Dates for Key Evolutionary Events.

    PubMed

    Wang, Xiyin; Wang, Jingpeng; Jin, Dianchuan; Guo, Hui; Lee, Tae-Ho; Liu, Tao; Paterson, Andrew H

    2015-06-01

    Multiple comparisons among genomes can clarify their evolution, speciation, and functional innovations. To date, the genome sequences of eight grasses representing the most economically important Poaceae (grass) clades have been published, and their genomic-level comparison is an essential foundation for evolutionary, functional, and translational research. Using a formal and conservative approach, we aligned these genomes. Direct comparison of paralogous gene pairs all duplicated simultaneously reveal striking variation in evolutionary rates among whole genomes, with nucleotide substitution slowest in rice and up to 48% faster in other grasses, adding a new dimension to the value of rice as a grass model. We reconstructed ancestral genome contents for major evolutionary nodes, potentially contributing to understanding the divergence and speciation of grasses. Recent fossil evidence suggests revisions of the estimated dates of key evolutionary events, implying that the pan-grass polyploidization occurred ∼96 million years ago and could not be related to the Cretaceous-Tertiary mass extinction as previously inferred. Adjusted dating to reflect both updated fossil evidence and lineage-specific evolutionary rates suggested that maize subgenome divergence and maize-sorghum divergence were virtually simultaneous, a coincidence that would be explained if polyploidization directly contributed to speciation. This work lays a solid foundation for Poaceae translational genomics.

  7. 520-d Isolation and confinement simulating a flight to Mars reveals heightened immune responses and alterations of leukocyte phenotype.

    PubMed

    Yi, B; Rykova, M; Feuerecker, M; Jäger, B; Ladinig, C; Basner, M; Hörl, M; Matzel, S; Kaufmann, I; Strewe, C; Nichiporuk, I; Vassilieva, G; Rinas, K; Baatout, S; Schelling, G; Thiel, M; Dinges, D F; Morukov, B; Choukèr, A

    2014-08-01

    During interplanetary exploration, chronic stress caused by long term isolation and confinement in the spacecraft is one of the major concerns of physical and psychological health of space travelers. And for human on Earth, more and more people live in an isolated condition, which has become a common social problem in modern western society. Collective evidences have indicated prolonged chronic stress could bring big influence to human immune function, which may lead to a variety of health problems. However, to what extent long-term isolation can affect the immune system still remains largely unknow. A simulated 520-d Mars mission provided an extraordinary chance to study the effect of prolonged isolation. Six healthy males participated in this mission and their active neuroendocrine and immune conditions were studied with saliva and blood samples from all participants on chosen time points during the isolation period. As a typical neuroendocrine parameter, stress hormone cortisol was measured in the morning saliva samples. Immune phenotype changes were monitored through peripheral leukocyte phenotype analysis. Using an ex vivo viral infection simulation assay we assessed the immune response changes characterized by the ability to produce representative endogenous pro-inflammatory cytokines. The results of this study revealed elevated cortisol levels, increased lymphocyte amount and heightened immune responses, suggesting that prolonged isolation acting as chronic stressors are able to trigger leukocyte phenotype changes and poorly controlled immune responses.

  8. 520-d Isolation and confinement simulating a flight to Mars reveals heightened immune responses and alterations of leukocyte phenotype.

    PubMed

    Yi, B; Rykova, M; Feuerecker, M; Jäger, B; Ladinig, C; Basner, M; Hörl, M; Matzel, S; Kaufmann, I; Strewe, C; Nichiporuk, I; Vassilieva, G; Rinas, K; Baatout, S; Schelling, G; Thiel, M; Dinges, D F; Morukov, B; Choukèr, A

    2014-08-01

    During interplanetary exploration, chronic stress caused by long term isolation and confinement in the spacecraft is one of the major concerns of physical and psychological health of space travelers. And for human on Earth, more and more people live in an isolated condition, which has become a common social problem in modern western society. Collective evidences have indicated prolonged chronic stress could bring big influence to human immune function, which may lead to a variety of health problems. However, to what extent long-term isolation can affect the immune system still remains largely unknow. A simulated 520-d Mars mission provided an extraordinary chance to study the effect of prolonged isolation. Six healthy males participated in this mission and their active neuroendocrine and immune conditions were studied with saliva and blood samples from all participants on chosen time points during the isolation period. As a typical neuroendocrine parameter, stress hormone cortisol was measured in the morning saliva samples. Immune phenotype changes were monitored through peripheral leukocyte phenotype analysis. Using an ex vivo viral infection simulation assay we assessed the immune response changes characterized by the ability to produce representative endogenous pro-inflammatory cytokines. The results of this study revealed elevated cortisol levels, increased lymphocyte amount and heightened immune responses, suggesting that prolonged isolation acting as chronic stressors are able to trigger leukocyte phenotype changes and poorly controlled immune responses. PMID:24704568

  9. Transcriptomics and physiological analyses reveal co-ordinated alteration of metabolic pathways in Jatropha curcas drought tolerance.

    PubMed

    Sapeta, Helena; Lourenço, Tiago; Lorenz, Stefan; Grumaz, Christian; Kirstahler, Philipp; Barros, Pedro M; Costa, Joaquim Miguel; Sohn, Kai; Oliveira, M Margarida

    2016-02-01

    Jatropha curcas, a multipurpose plant attracting a great deal of attention due to its high oil content and quality for biofuel, is recognized as a drought-tolerant species. However, this drought tolerance is still poorly characterized. This study aims to contribute to uncover the molecular background of this tolerance, using a combined approach of transcriptional profiling and morphophysiological characterization during a period of water-withholding (49 d) followed by rewatering (7 d). Morphophysiological measurements showed that J. curcas plants present different adaptation strategies to withstand moderate and severe drought. Therefore, RNA sequencing was performed for samples collected under moderate and severe stress followed by rewatering, for both roots and leaves. Jatropha curcas transcriptomic analysis revealed shoot- and root-specific adaptations across all investigated conditions, except under severe stress, when the dramatic transcriptomic reorganization at the root and shoot level surpassed organ specificity. These changes in gene expression were clearly shown by the down-regulation of genes involved in growth and water uptake, and up-regulation of genes related to osmotic adjustments and cellular homeostasis. However, organ-specific gene variations were also detected, such as strong up-regulation of abscisic acid synthesis in roots under moderate stress and of chlorophyll metabolism in leaves under severe stress. Functional validation further corroborated the differential expression of genes coding for enzymes involved in chlorophyll metabolism, which correlates with the metabolite content of this pathway.

  10. Transcriptomics and physiological analyses reveal co-ordinated alteration of metabolic pathways in Jatropha curcas drought tolerance.

    PubMed

    Sapeta, Helena; Lourenço, Tiago; Lorenz, Stefan; Grumaz, Christian; Kirstahler, Philipp; Barros, Pedro M; Costa, Joaquim Miguel; Sohn, Kai; Oliveira, M Margarida

    2016-02-01

    Jatropha curcas, a multipurpose plant attracting a great deal of attention due to its high oil content and quality for biofuel, is recognized as a drought-tolerant species. However, this drought tolerance is still poorly characterized. This study aims to contribute to uncover the molecular background of this tolerance, using a combined approach of transcriptional profiling and morphophysiological characterization during a period of water-withholding (49 d) followed by rewatering (7 d). Morphophysiological measurements showed that J. curcas plants present different adaptation strategies to withstand moderate and severe drought. Therefore, RNA sequencing was performed for samples collected under moderate and severe stress followed by rewatering, for both roots and leaves. Jatropha curcas transcriptomic analysis revealed shoot- and root-specific adaptations across all investigated conditions, except under severe stress, when the dramatic transcriptomic reorganization at the root and shoot level surpassed organ specificity. These changes in gene expression were clearly shown by the down-regulation of genes involved in growth and water uptake, and up-regulation of genes related to osmotic adjustments and cellular homeostasis. However, organ-specific gene variations were also detected, such as strong up-regulation of abscisic acid synthesis in roots under moderate stress and of chlorophyll metabolism in leaves under severe stress. Functional validation further corroborated the differential expression of genes coding for enzymes involved in chlorophyll metabolism, which correlates with the metabolite content of this pathway. PMID:26602946

  11. Expression profiling of the RPE in zebrafish smarca4 mutant revealed altered signals that potentially affect RPE and retinal differentiation

    PubMed Central

    Ma, Ping; Collery, Ross; Trowbridge, Sara; Zhong, Wenxuan; Leung, Yuk Fai

    2014-01-01

    Purpose The purpose of this study was to develop a framework for analyzing retinal pigment epithelium (RPE) expression profiles from zebrafish eye mutants. Methods The fish model we used was SWI/SNF-related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (smarca4), a retinal dystrophic mutant with a previously described retinal phenotype and expression profiles. Histological and Affymetrix GeneChip analyses were conducted to characterize the RPE defects and underlying differential expression, respectively. Results Histological analysis revealed that smarca4 RPE was formed, but its differentiation was abnormal. In particular, ultrastructural analysis of smarca4 RPE by transmission electron microscopy demonstrated several defects in melanogenesis. The nature of these defects also suggests that the cytoskeletal dynamics, which are tightly linked with melanogenesis, were impaired in smarca4 RPE. To compare the expression profile of normal wild-type (WT) and smarca4 RPE, the gene expression profiles of microdissected retinas and RPE-attached retinas were measured with Affymetrix GeneChip analysis. The RPE expression values were then estimated from these samples by subtracting the retinal expression values from the expression values of the RPE-attached retinas. A factorial analysis was conducted using the expression values of the RPE, retinal, and whole-embryo samples. Specific rules (contrasts) were built using the coefficients of the resulting fitted models to select for three groups of genes: 1) smarca4-regulated RPE genes, 2) smarca4-regulated retinal genes, and 3) smarca4-regulated RPE genes that are not differentially expressed in the retina. Interestingly, the third group consists of 39 genes that are highly related to cytoskeletal dynamics, melanogenesis, and paracrine and intracellular signal transduction. Conclusions Our analytical framework provides an experimental approach to identify differentially-regulated genes in the

  12. Morphological and metabolic changes in the cortex of mice lacking the functional presynaptic active zone protein bassoon: a combined 1H-NMR spectroscopy and histochemical study.

    PubMed

    Angenstein, Frank; Hilfert, Liane; Zuschratter, Werner; Altrock, Wilko D; Niessen, Heiko G; Gundelfinger, Eckart D

    2008-04-01

    Mice lacking functional presynaptic active zone protein Bassoon are characterized by an enlarged cerebral cortex and an altered cortical activation pattern. This morphological and functional phenotype is associated with defined metabolic distortions as detected by a metabonomic approach using high-field (14.1 T) high-resolution 1H-nuclear magnetic resonance spectroscopy (MRS) in conjunction with statistical pattern recognition. Within the cortex but not in the cerebellum, concentrations of N-acetyl aspartate, glutamine, and glutamate are significantly reduced, whereas the majority of all other detectable low molecular metabolites are unchanged. The reduction of the neuron-specific metabolite N-acetyl aspartate in the cortex coincides with a significant decrease in neuronal density in cortical layer V. Comparing the neuron with glia cell densities across the cortex reveals cortex layer-dependent alterations in the ratio between both cell types. Whereas the ratio shifts significantly toward neurons in the cortical input layers IV, the ratio is reversed in cortical layer V. Consequently, the previously observed altered neuronal activation pattern in the cortex is reflected not only in defined cytoarchitectural anomalies but also in metabolic disturbances in the glutamine-glutamate and N-acetyl aspartate metabolism.

  13. Metabolic profiling reveals altered nitrogen nutrient regimes have diverse effects on the metabolism of hydroponically-grown tomato (Solanum lycopersicum) plants.

    PubMed

    Urbanczyk-Wochniak, Ewa; Fernie, Alisdair R

    2005-01-01

    The role of inorganic nitrogen assimilation in the production of amino acids is one of the most important biochemical processes in plants. For this reason, a detailed broad-range characterization of the metabolic response of tomato (Solanum lycopersicum) leaves to the alteration of nitrate level was performed. Tomato plants were grown hydroponically in liquid culture under three different nitrate regimes: saturated (8 mM NO3-), replete (4 mM NO3-) and deficient (0.4 mM NO3-). All treatments were performed under varied light intensity, with leaf samples being collected after 7, 14, and 21 d. In addition, the short-term response (after 1, 24, 48, and 94 h) to varying nutrient status was evaluated at the higher light intensity. GC-MS analysis of the levels of amino acids, tricarboxylic acid cycle intermediates, sugars, sugar alcohols, and representative compounds of secondary metabolism revealed substantial changes under the various growth regimes applied. The data presented here suggest that nitrate nutrition has wide-ranging effects on plant leaf metabolism with nitrate deficiency resulting in decreases in many amino and organic acids and increases in the level of several carbohydrates and phosphoesters, as well as a handful of secondary metabolites. These results are compared with previously reported transcript profiles of altered nitrogen regimes and discussed within the context of current models of carbon nitrogen interaction.

  14. Insular cortex and neuropsychiatric disorders: a review of recent literature.

    PubMed

    Nagai, M; Kishi, K; Kato, S

    2007-09-01

    The insular cortex is located in the centre of the cerebral hemisphere, having connections with the primary and secondary somatosensory areas, anterior cingulate cortex, amygdaloid body, prefrontal cortex, superior temporal gyrus, temporal pole, orbitofrontal cortex, frontal and parietal opercula, primary and association auditory cortices, visual association cortex, olfactory bulb, hippocampus, entorhinal cortex, and motor cortex. Accordingly, dense connections exist among insular cortex neurons. The insular cortex is involved in the processing of visceral sensory, visceral motor, vestibular, attention, pain, emotion, verbal, motor information, inputs related to music and eating, in addition to gustatory, olfactory, visual, auditory, and tactile data. In this article, the literature on the relationship between the insular cortex and neuropsychiatric disorders was summarized following a computer search of the Pub-Med database. Recent neuroimaging data, including voxel based morphometry, PET and fMRI, revealed that the insular cortex was involved in various neuropsychiatric diseases such as mood disorders, panic disorders, PTSD, obsessive-compulsive disorders, eating disorders, and schizophrenia. Investigations of functions and connections of the insular cortex suggest that sensory information including gustatory, olfactory, visual, auditory, and tactile inputs converge on the insular cortex, and that these multimodal sensory information may be integrated there.

  15. Reduced Anterior Cingulate Cortex Glutamatergic Concentrations in Childhood Major Depression

    ERIC Educational Resources Information Center

    Mirza, Yousha; Tang, Jennifer; Russell, Aileen; Banerjee, S. Preeya; Bhandari, Rashmi; Ivey, Jennifer; Rose, Michelle; Moore, Gregory J.; Rosenberg, David R.

    2004-01-01

    Objective: To examine in vivo glutamatergic neurochemical alterations in the anterior cingulate cortex of children with major depressive disorder (MDD). Method: Single-voxel proton magnetic resonance spectroscopic ([.sup.1]H-MRS) examinations of the anterior cingulate cortex were conducted in 13 psychotropic-naive children and adolescents with MDD…

  16. Traveling waves in visual cortex.

    PubMed

    Sato, Tatsuo K; Nauhaus, Ian; Carandini, Matteo

    2012-07-26

    Electrode recordings and imaging studies have revealed that localized visual stimuli elicit waves of activity that travel across primary visual cortex. Traveling waves are present also during spontaneous activity, but they can be greatly reduced by widespread and intensive visual stimulation. In this Review, we summarize the evidence in favor of these traveling waves. We suggest that their substrate may lie in long-range horizontal connections and that their functional role may involve the integration of information over large regions of space.

  17. Alteration in Nuclear Factor-KappaB Pathway and Functionality of Estrogen via Receptors Promote Neuroinflammation in Frontal Cortex after 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Treatment

    PubMed Central

    Mitra, Soham; Ghosh, Nabanita; Sinha, Priyobrata; Chakrabarti, Nilkanta; Bhattacharyya, Arindam

    2015-01-01

    The MPTP mediated neurodegeneration in substantia nigra has been well studied, but not the status of frontal cortex. The novelty of the present study is to explore the sex difference of frontal cortex during MPTP intoxication and to investigate the role of estrogen and its receptors in presence of glial cells in a time chase experiment; to identify which pathway of NF-kappaB exist to proceed the neuroinflammation; to investigate the estrogen binding with its nuclear or cytosolic receptors and whether any direct relation exists between estrogen receptor (ER) -beta and NF-kappaB molecules p65 and RelB. The progression of neurodegeneration occurred with the association of glial cells and functional (via its nuclear and cytosolic receptors) estrogen level. Both the canonical and/or non canonical pathways of NF-kappaB exist in frontal cortex of both the sexes after MPTP treatment. The homodimeric or heterodimeric form of ER-beta binds with NF-kappaB molecules p65 and RelB differently, but the canonical or non canonical pathways of NF-kappaB molecules could not be stopped or may be promoted. The changes in the molecular and cellular pattern in frontal cortex of both sexes during MPTP intoxication depends on the estrogen function via its nuclear or cytosolic estrogen receptors. PMID:26365888

  18. Construction of a subtractive library from hexavalent chromium treated winter flounder (Pseudopleuronectes americanus) reveals alterations in non-selenium glutathione peroxidases.

    PubMed

    Chapman, Laura M; Roling, Jonathan A; Bingham, Lacey K; Herald, Matt R; Baldwin, William S

    2004-04-14

    Chromium is released during several industrial processes and has accumulated in some estuarine areas. Its effects on mammals have been widely studied, but relatively little information is available on its effects on fish. Gene expression changes are useful biomarkers that can provide information about toxicant exposure and effects, as well as the health of an organism and its ability to adapt to its surroundings. Therefore, we investigated the effects of Cr(VI) on gene expression in the sediment dwelling fish, winter flounder (Pseudopleuronectes americanus). Winter flounder ranging from 300 to 360 g were injected i.p. with Cr(VI) as chromium oxide at 25 microg/kg chromium in 0.15N KCl. Twenty-four hours following injections, winter flounder were euthanized with MS-222 and the livers were excised. Half of the livers were used to make cytosol and the other half were used to isolate mRNA for subtractive hybridization. Subtractive clones obtained were spotted onto nylon filters, which revealed several genes with potentially altered expression due to Cr(VI), including an alpha class GST, 1-Cys peroxiredoxin (a non-selenium glutathione peroxidase), a P-450 2X subfamily member, two elongation factors (EF-1 gamma and EF-2), and complement component C3. Semi-quantitative RT-PCR was performed and confirmed that Cr(VI) down-regulated complement component C3, an EST, and two potential glutathione peroxidases, GSTA3 and 1-Cys peroxiredoxin. In addition, cytosolic GSH peroxidase activity was reduced, and silver stained SDS-PAGE gels from glutathione-affinity purified cytosol demonstrated that a 27.1 kDa GSH-binding protein was down-regulated greater than 50%. Taken together, Cr(VI) significantly altered the expression of several genes including two potential glutathione peroxidases in winter flounder. PMID:15003702

  19. Disturbed Dreaming and the Instability of Sleep: Altered Nonrapid Eye Movement Sleep Microstructure in Individuals with Frequent Nightmares as Revealed by the Cyclic Alternating Pattern

    PubMed Central

    Simor, Péter; Bódizs, Róbert; Horváth, Klára; Ferri, Raffaele

    2013-01-01

    Study Objectives: Nightmares are disturbing mental experiences during sleep that usually result in abrupt awakenings. Frequent nightmares are associated with poor subjective sleep quality, and recent polysomnographic data suggest that nightmare sufferers exhibit impaired sleep continuity during nonrapid eye movement (NREM) sleep. Because disrupted sleep might be related to abnormal arousal processes, the goal of this study was to examine polysomnographic arousal-related activities in a group of nightmare sufferers and a healthy control group. Design: Sleep microstructure analysis was carried out by scoring the cyclic alternating pattern (CAP) in NREM sleep and the arousal index in rapid eye movement (REM) sleep on the second night of the polysomnographic examination. Setting: Hospital-based sleep research laboratory. Participants: There were 17 in the nightmare (NMs) group and 23 in the healthy control (CTLs) group. Interventions: N/A. Measurements and Results: The NMs group exhibited reduced amounts of CAP A1 subtype and increased CAP A2 and A3 subtypes, as well as longer duration of CAP A phases in comparison with CTLs. Moreover, these differences remained significant after controlling for the confounding factors of anxious and depressive symptoms. The absolute number and frequency of REM arousals did not differ significantly between the two groups. Conclusions: The results of our study indicate that NREM sleep microstructure is altered during nonsymptomatic nights of nightmares. Disrupted sleep in the NMs group seems to be related to abnormal arousal processes, specifically an imbalance in sleep-promoting and arousing mechanisms during sleep. Citation: Simor P; Bódizs R; Horváth K; Ferri R. Disturbed dreaming and the instability of sleep: altered nonrapid eye movement sleep microstructure in individuals with frequent nightmares as revealed by the cyclic alternating pattern. SLEEP 2013;36(3):413-419. PMID:23449753

  20. Optical Cryoimaging Reveals a Heterogeneous Distribution of Mitochondrial Redox State in ex vivo Guinea Pig Hearts and Its Alteration During Ischemia and Reperfusion.

    PubMed

    Ranji, Mahsa; Motlagh, Mohammad Masoudi; Salehpour, Fahimeh; Sepehr, Reyhaneh; Heisner, James S; Dash, Ranjan K; Camara, Amadou K S

    2016-01-01

    Oxidation of substrates to generate ATP in mitochondria is mediated by redox reactions of NADH and FADH2. Cardiac ischemia and reperfusion (IR) injury compromises mitochondrial oxidative phosphorylation. We hypothesize that IR alters the metabolic heterogeneity of mitochondrial redox state of the heart that is only evident in the 3-D optical cryoimaging of the perfused heart before, during, and after IR. The study involved four groups of hearts: time control (TC: heart perfusion without IR), global ischemia (Isch), global ischemia followed by reperfusion (IR) and TC with PCP (a mitochondrial uncoupler) perfusion. Mitochondrial NADH and FAD autofluorescence signals were recorded spectrofluorometrically online in guinea pig ex vivo-perfused hearts in the Langendorff mode. At the end of each specified protocol, hearts were rapidly removed and snap frozen in liquid N2 for later 3-D optical cryoimaging of the mitochondrial NADH, FAD, and NADH/FAD redox ratio (RR). The TC hearts revealed a heterogeneous spatial distribution of NADH, FAD, and RR. Ischemia and IR altered the spatial distribution and caused an overall increase and decrease in the RR by 55% and 64%, respectively. Uncoupling with PCP resulted in the lowest level of the RR (73% oxidation) compared with TC. The 3-D optical cryoimaging of the heart provides novel insights into the heterogeneous distribution of mitochondrial NADH, FAD, RR, and metabolism from the base to the apex during ischemia and IR. This 3-D information of the mitochondrial redox state in the normal and ischemic heart was not apparent in the dynamic spectrofluorometric data. PMID:27574574

  1. Genomic profiling of microRNAs and proteomics reveals an early molecular alteration associated with tumorigenesis induced by MC-LR in mice.

    PubMed

    Zhao, Yanyan; Xie, Ping; Fan, Huihui

    2012-01-01

    Studies have demonstrated that microcystins (MCs) can act as potential carcinogens and have caused serious risk to public environmental health. The molecular mechanisms of MC-induced susceptibility to carcinogenesis are largely unknown. In this study, we performed for the first time a comprehensive analysis of changes in microRNAs (miRNAs) and proteins expression in livers of mice treated with MC-LR. Utilizing microarray and two-dimensional gel electrophoresis (2-DE) analysis, we identified 37 miRNAs and 42 proteins significantly altered. Many aberrantly expressed miRNAs were related to various cancers (e.g., miR-125b, hepatocellular carcinoma; miR-21, leukemia; miR-16, chronic lymphocytic leukemia; miR-192, pituitary adenomas; miR-199a-3p, ovarian cancer; miR-34a, pancreatic cancer). Several miRNAs (e.g., miR-34a, miR-21) and proteins (e.g., TGM2, NDRG2) that play crucial roles in liver tumorigenesis were first found to be affected by MC-LR in mouse liver. MC-LR also altered the expression of a number of miRNAs and proteins involved in several pathways related to tumorigenesis, such as glutathione metabolism, VEGF signaling, and MAPK signaling pathway. Integration of post-transcriptomics, proteomics, and transcriptomics reveals that the networks miRNAs and their potential target genes and proteins involved in had a close association with carcinogenesis. These results provide an early molecular mechanism for liver tumorigenesis induced by MCs.

  2. Optical Cryoimaging Reveals a Heterogeneous Distribution of Mitochondrial Redox State in ex vivo Guinea Pig Hearts and Its Alteration During Ischemia and Reperfusion

    PubMed Central

    Motlagh, Mohammad Masoudi; Salehpour, Fahimeh; Sepehr, Reyhaneh; Heisner, James S.; Dash, Ranjan K.; Camara, Amadou K. S.

    2016-01-01

    Oxidation of substrates to generate ATP in mitochondria is mediated by redox reactions of NADH and FADH2. Cardiac ischemia and reperfusion (IR) injury compromises mitochondrial oxidative phosphorylation. We hypothesize that IR alters the metabolic heterogeneity of mitochondrial redox state of the heart that is only evident in the 3-D optical cryoimaging of the perfused heart before, during, and after IR. The study involved four groups of hearts: time control (TC: heart perfusion without IR), global ischemia (Isch), global ischemia followed by reperfusion (IR) and TC with PCP (a mitochondrial uncoupler) perfusion. Mitochondrial NADH and FAD autofluorescence signals were recorded spectrofluorometrically online in guinea pig ex vivo-perfused hearts in the Langendorff mode. At the end of each specified protocol, hearts were rapidly removed and snap frozen in liquid N2 for later 3-D optical cryoimaging of the mitochondrial NADH, FAD, and NADH/FAD redox ratio (RR). The TC hearts revealed a heterogeneous spatial distribution of NADH, FAD, and RR. Ischemia and IR altered the spatial distribution and caused an overall increase and decrease in the RR by 55% and 64%, respectively. Uncoupling with PCP resulted in the lowest level of the RR (73% oxidation) compared with TC. The 3-D optical cryoimaging of the heart provides novel insights into the heterogeneous distribution of mitochondrial NADH, FAD, RR, and metabolism from the base to the apex during ischemia and IR. This 3-D information of the mitochondrial redox state in the normal and ischemic heart was not apparent in the dynamic spectrofluorometric data. PMID:27574574

  3. Cochlear Injury and Adaptive Plasticity of the Auditory Cortex

    PubMed Central

    Fetoni, Anna Rita; Troiani, Diana; Petrosini, Laura; Paludetti, Gaetano

    2015-01-01

    Growing evidence suggests that cochlear stressors as noise exposure and aging can induce homeostatic/maladaptive changes in the central auditory system from the brainstem to the cortex. Studies centered on such changes have revealed several mechanisms that operate in the context of sensory disruption after insult (noise trauma, drug-, or age-related injury). The oxidative stress is central to current theories of induced sensory-neural hearing loss and aging, and interventions to attenuate the hearing loss are based on antioxidant agent. The present review addresses the recent literature on the alterations in hair cells and spiral ganglion neurons due to noise-induced oxidative stress in the cochlea, as well on the impact of cochlear damage on the auditory cortex neurons. The emerging image emphasizes that noise-induced deafferentation and upward spread of cochlear damage is associated with the altered dendritic architecture of auditory pyramidal neurons. The cortical modifications may be reversed by treatment with antioxidants counteracting the cochlear redox imbalance. These findings open new therapeutic approaches to treat the functional consequences of the cortical reorganization following cochlear damage. PMID:25698966

  4. Analysis of parotid glands of primary Sjögren's syndrome patients using proteomic technology reveals altered autoantigen composition and novel antigenic targets

    PubMed Central

    Stea, E A; Routsias, J G; Samiotaki, M; Panayotou, G; Papalambros, E; Moutsopoulos, H M; Tzioufas, A G

    2007-01-01

    Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration, destruction of the salivary and lacrimal glands and production of autoantibodies against a variety of cellular proteins. The aberrant immune response against these autoantigens may begin or extend to other proteins that are not yet defined. Several studies have shown that autoantibody production is taking place in the affected salivary glands. In the present study, using proteomic approaches, we aimed to: (a) identify new autoantigens in the salivary glands of primary SS (pSS) patients and (b) evaluate the epigenetic changes of known autoantigens. Total parotid gland extracts of pSS patients were analysed using two-dimensional gel electrophoresis, sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot with pSS patients' sera or purified autoantibodies and immunoprecipitation using homologous IgG. Identification of the unknown proteins was performed using mass spectrometry (MS). Immunoblot analysis on two-dimensional gels using purified anti-La/SSB antibodies revealed that pSS salivary glands contain high levels of post-translationally modified La/SSB autoantigen, while the native form of the protein is recognized faintly, in contrast to normal controls. Moreover, salivary glands of pSS patients contain post-translationally modified actin that becomes immunogenic in the microenviroment of the affected tissue. The alteration of the physicochemical properties of self-proteins could thus contribute to the break of immune tolerance against them. PMID:17177966

  5. Dyslexic children lack word selectivity gradients in occipito-temporal and inferior frontal cortex

    PubMed Central

    Olulade, O.A.; Flowers, D.L.; Napoliello, E.M.; Eden, G.F.

    2015-01-01

    fMRI studies using a region-of-interest approach have revealed that the ventral portion of the left occipito-temporal cortex, which is specialized for orthographic processing of visually presented words (and includes the so-called “visual word form area”, VWFA), is characterized by a posterior-to-anterior gradient of increasing selectivity for words in typically reading adults, adolescents, and children (e.g. Brem et al., 2006, 2009). Similarly, the left inferior frontal cortex (IFC) has been shown to exhibit a medial-to-lateral gradient of print selectivity in typically reading adults (Vinckier et al., 2007). Functional brain imaging studies of dyslexia have reported relative underactivity in left hemisphere occipito-temporal and inferior frontal regions using whole-brain analyses during word processing tasks. Hence, the question arises whether gradient sensitivities in these regions are altered in dyslexia. Indeed, a region-of-interest analysis revealed the gradient-specific functional specialization in the occipito-temporal cortex to be disrupted in dyslexic children (van der Mark et al., 2009). Building on these studies, we here (1) investigate if a word-selective gradient exists in the inferior frontal cortex in addition to the occipito-temporal cortex in normally reading children, (2) compare typically reading with dyslexic children, and (3) examine functional connections between these regions in both groups. We replicated the previously reported anterior-to-posterior gradient of increasing selectivity for words in the left occipito-temporal cortex in typically reading children, and its absence in the dyslexic children. Our novel finding is the detection of a pattern of increasing selectivity for words along the medial-to-lateral axis of the left inferior frontal cortex in typically reading children and evidence of functional connectivity between the most lateral aspect of this area and the anterior aspects of the occipito-temporal cortex. We report

  6. Protein kinase A alterations in adrenocortical tumors.

    PubMed

    Espiard, S; Ragazzon, B; Bertherat, J

    2014-11-01

    Stimulation of the cAMP pathway by adrenocorticotropin (ACTH) is essential for adrenal cortex maintenance, glucocorticoid and adrenal androgens synthesis, and secretion. Various molecular and cellular alterations of the cAMP pathway have been observed in endocrine tumors. Protein kinase A (PKA) is a central key component of the cAMP pathway. Molecular alterations of PKA subunits have been observed in adrenocortical tumors. PKA molecular defects can be germline in hereditary disorders or somatic in sporadic tumors. Heterozygous germline inactivating mutations of the PKA regulatory subunit RIα gene (PRKAR1A) can be observed in patients with ACTH-independent Cushing's syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD). PRKAR1A is considered as a tumor suppressor gene. Interestingly, these mutations can also be observed as somatic alterations in sporadic cortisol-secreting adrenocortical adenomas. Germline gene duplication of the catalytic subunits Cα (PRKACA) has been observed in patients with PPNAD. Furthermore, exome sequencing revealed recently activating somatic mutations of PRKACA in about 40% of cortisol-secreting adrenocortical adenomas. In vitro and in vivo functional studies help in the progress to understand the mechanisms of adrenocortical tumors development due to PKA regulatory subunits alterations. All these alterations are observed in benign oversecreting tumors and are mimicking in some way cAMP pathway constitutive activation. On the long term, unraveling these alterations will open new strategies of pharmacological treatment targeting the cAMP pathway in adrenal tumors and cortisol-secretion disorders. PMID:25105543

  7. Focal thinning of the cerebral cortex in multiple sclerosis.

    PubMed

    Sailer, Michael; Fischl, Bruce; Salat, David; Tempelmann, Claus; Schönfeld, Mircea Ariel; Busa, Evelina; Bodammer, Nils; Heinze, Hans-Jochen; Dale, Anders

    2003-08-01

    Brain atrophy as determined by quantitative MRI can be used to characterize disease progression in multiple sclerosis. Many studies have addressed white matter (WM) alterations leading to atrophy, while changes of the cerebral cortex have been studied to a lesser extent. In vivo, the cerebral cortex has been difficult to study due to its complex structure and regional variability. Measurement of cerebral cortex thickness at different disease stages may provide new insights into grey matter (GM) pathology. In the present investigation, we evaluated in vivo cortical thickness and its relationship to disability, disease duration, WM T2 hyper-intense and T1 hypo-intense lesion volumes. High-resolution MRI brain scans were obtained in 20 patients with clinically definite multiple sclerosis and 15 age-matched normal subjects. A novel method of automated surface reconstruction yielded measurements of the cortical thickness for each subject's entire brain and computed cross-subject statistics based on the cortical anatomy. Statistical thickness difference maps were generated by performing t-tests between patient and control groups and individual thickness measures were submitted to analyses of variance to investigate the relationship between cortical thickness and clinical variables. The mean overall thickness of the cortical ribbon was reduced in multiple sclerosis patients compared with controls [2.30 mm (SD 0.14) versus 2.48 mm (SD 0.11)], showing a significant main effect of group (controls versus patients). In patients, we found significant main effects for disability, disease duration, T2 and T1 lesion volumes. The visualization of statistical difference maps of the cortical GM thickness on inflated brains across the cortical surface revealed a distinct distribution of significant focal thinning of the cerebral cortex in addition to the diffuse cortical atrophy. Focal cortical thinning in frontal [2.37 mm (SD 0.17) versus 2.73 mm (SD 0.25)] and in temporal [2.65 mm

  8. Cross-Species Integrative Functional Genomics in GeneWeaver Reveals a Role for Pafah1b1 in Altered Response to Alcohol.

    PubMed

    Bubier, Jason A; Wilcox, Troy D; Jay, Jeremy J; Langston, Michael A; Baker, Erich J; Chesler, Elissa J

    2016-01-01

    Identifying the biological substrates of complex neurobehavioral traits such as alcohol dependency pose a tremendous challenge given the diverse model systems and phenotypic assessments used. To address this problem we have developed a platform for integrated analysis of high-throughput or genome-wide functional genomics studies. A wealth of such data exists, but it is often found in disparate, non-computable forms. Our interactive web-based software system, Gene Weaver (http://www.geneweaver.org), couples curated results from genomic studies to graph-theoretical tools for combinatorial analysis. Using this system we identified a gene underlying multiple alcohol-related phenotypes in four species. A search of over 60,000 gene sets in GeneWeaver's database revealed alcohol-related experimental results including genes identified in mouse genetic mapping studies, alcohol selected Drosophila lines, Rattus differential expression, and human alcoholic brains. We identified highly connected genes and compared these to genes currently annotated to alcohol-related behaviors and processes. The most highly connected gene not annotated to alcohol was Pafah1b1. Experimental validation using a Pafah1b1 conditional knock-out mouse confirmed that this gene is associated with an increased preference for alcohol and an altered thermoregulatory response to alcohol. Although this gene has not been previously implicated in alcohol-related behaviors, its function in various neural mechanisms makes a role in alcohol-related phenomena plausible. By making diverse cross-species functional genomics data readily computable, we were able to identify and confirm a novel alcohol-related gene that may have implications for alcohol use disorders and other effects of alcohol.

  9. Cross-Species Integrative Functional Genomics in GeneWeaver Reveals a Role for Pafah1b1 in Altered Response to Alcohol.

    PubMed

    Bubier, Jason A; Wilcox, Troy D; Jay, Jeremy J; Langston, Michael A; Baker, Erich J; Chesler, Elissa J

    2016-01-01

    Identifying the biological substrates of complex neurobehavioral traits such as alcohol dependency pose a tremendous challenge given the diverse model systems and phenotypic assessments used. To address this problem we have developed a platform for integrated analysis of high-throughput or genome-wide functional genomics studies. A wealth of such data exists, but it is often found in disparate, non-computable forms. Our interactive web-based software system, Gene Weaver (http://www.geneweaver.org), couples curated results from genomic studies to graph-theoretical tools for combinatorial analysis. Using this system we identified a gene underlying multiple alcohol-related phenotypes in four species. A search of over 60,000 gene sets in GeneWeaver's database revealed alcohol-related experimental results including genes identified in mouse genetic mapping studies, alcohol selected Drosophila lines, Rattus differential expression, and human alcoholic brains. We identified highly connected genes and compared these to genes currently annotated to alcohol-related behaviors and processes. The most highly connected gene not annotated to alcohol was Pafah1b1. Experimental validation using a Pafah1b1 conditional knock-out mouse confirmed that this gene is associated with an increased preference for alcohol and an altered thermoregulatory response to alcohol. Although this gene has not been previously implicated in alcohol-related behaviors, its function in various neural mechanisms makes a role in alcohol-related phenomena plausible. By making diverse cross-species functional genomics data readily computable, we were able to identify and confirm a novel alcohol-related gene that may have implications for alcohol use disorders and other effects of alcohol. PMID:26834590

  10. Cross-Species Integrative Functional Genomics in GeneWeaver Reveals a Role for Pafah1b1 in Altered Response to Alcohol

    PubMed Central

    Bubier, Jason A.; Wilcox, Troy D.; Jay, Jeremy J.; Langston, Michael A.; Baker, Erich J.; Chesler, Elissa J.

    2016-01-01

    Identifying the biological substrates of complex neurobehavioral traits such as alcohol dependency pose a tremendous challenge given the diverse model systems and phenotypic assessments used. To address this problem we have developed a platform for integrated analysis of high-throughput or genome-wide functional genomics studies. A wealth of such data exists, but it is often found in disparate, non-computable forms. Our interactive web-based software system, Gene Weaver (http://www.geneweaver.org), couples curated results from genomic studies to graph-theoretical tools for combinatorial analysis. Using this system we identified a gene underlying multiple alcohol-related phenotypes in four species. A search of over 60,000 gene sets in GeneWeaver's database revealed alcohol-related experimental results including genes identified in mouse genetic mapping studies, alcohol selected Drosophila lines, Rattus differential expression, and human alcoholic brains. We identified highly connected genes and compared these to genes currently annotated to alcohol-related behaviors and processes. The most highly connected gene not annotated to alcohol was Pafah1b1. Experimental validation using a Pafah1b1 conditional knock-out mouse confirmed that this gene is associated with an increased preference for alcohol and an altered thermoregulatory response to alcohol. Although this gene has not been previously implicated in alcohol-related behaviors, its function in various neural mechanisms makes a role in alcohol-related phenomena plausible. By making diverse cross-species functional genomics data readily computable, we were able to identify and confirm a novel alcohol-related gene that may have implications for alcohol use disorders and other effects of alcohol. PMID:26834590

  11. [The involvement of the cerebral cortex, hypothalamus, pituitary and adrenal cortex in the development of periodontosis].

    PubMed

    Usineviciu, A; Ursan, G; Vitebski, V; Dorofteiu, M

    1989-01-01

    The authors emphasized in parodontosis patients functional alterations of hypothalamic centres with phagocytosis-stimulatory, vasomotor and neurotrophic functions and disturbances of the functional relationship between the hypothalamus (H), the ascendent reticular formation (RF) and the cerebral cortex (CC). Stimulatory therapy of this areas, especially by direct stimulation of the H improves the hypothalamic functions, the relationship between H and the RF and all the clinical status of parodontosis patients. In rabbits with experimental parodontosis have been found functional and histological alterations in cerebral cortex, and especially in hypothalamus, together with lesions in the hypothalamo-posthypophyso-neurosecretoric system, in the anterior pituitary (P) cells (for ACTH, TSH and FSH) as well as in zona fasciculares of the adrenal cortex (AC). This data, together with findings of other authors, prove that parodontosis is a diencephalopathy involving a whole system: CC-H-P-AC.

  12. Decreased Premotor Cortex Volume in Victims of Urban Violence with Posttraumatic Stress Disorder

    PubMed Central

    Rocha-Rego, Vanessa; Pereira, Mirtes G.; Oliveira, Leticia; Mendlowicz, Mauro V.; Fiszman, Adriana; Marques-Portella, Carla; Berger, William; Chu, Carlton; Joffily, Mateus; Moll, Jorge; Mari, Jair J.; Figueira, Ivan; Volchan, Eliane

    2012-01-01

    Background Studies addressing posttraumatic stress disorder (PTSD) have demonstrated that PTSD patients exhibit structural abnormalities in brain regions that relate to stress regulation and fear responses, such as the hippocampus, amygdala, anterior cingulate cortex, and ventromedial prefrontal cortex. Premotor cortical areas are involved in preparing to respond to a threatening situation and in representing the peripersonal space. Urban violence is an important and pervasive cause of human suffering, especially in large urban centers in the developing world. Violent events, such as armed robbery, are very frequent in certain cities, and these episodes increase the risk of PTSD. Assaultive trauma is characterized by forceful invasion of the peripersonal space; therefore, could this traumatic event be associated with structural alteration of premotor areas in PTSD? Methodology/Principal Findings Structural magnetic resonance imaging scans were acquired from a sample of individuals that had been exposed to urban violence. This sample consisted of 16 PTSD patients and 16 age- and gender-matched controls. Psychometric questionnaires differentiated PTSD patients from trauma-exposed controls with regard to PTSD symptoms, affective, and resilience predispositions. Voxel-based morphometric analysis revealed that, compared with controls, the PTSD patients presented significant reductions in gray matter volume in the ventral premotor cortex and in the pregenual anterior cingulate cortex. Conclusions Volume reduction in the premotor cortex that is observed in victims of urban violence with PTSD may be associated with a disruption in the dynamical modulation of the safe space around the body. The finding that PTSD patients presented a smaller volume of pregenual anterior cingulate cortex is consistent with the results of other PTSD neuroimaging studies that investigated different types of traumatic events. PMID:22952599

  13. Sensory-related neural activity regulates the structure of vascular networks in the cerebral cortex

    PubMed Central

    Lacoste, Baptiste; Comin, Cesar H.; Ben-Zvi, Ayal; Kaeser, Pascal S.; Xu, Xiaoyin; Costa, Luciano da F.; Gu, Chenghua

    2014-01-01

    SUMMARY Neurovascular interactions are essential for proper brain function. While the effect of neural activity on cerebral blood flow has been extensively studied, whether neural activity influences vascular patterning remains elusive. Here, we demonstrate that neural activity promotes the formation of vascular networks in the early postnatal mouse barrel cortex. Using a combination of genetics, imaging, and computational tools to allow simultaneous analysis of neuronal and vascular components, we found that vascular density and branching were decreased in the barrel cortex when sensory input was reduced by either a complete deafferentation, a genetic impairment of neurotransmitter release at thalamocortical synapses, or a selective reduction of sensory-related neural activity by whisker plucking. In contrast, enhancement of neural activity by whisker stimulation led to an increase in vascular density and branching. The finding that neural activity is necessary and sufficient to trigger alterations of vascular networks reveals a novel feature of neurovascular interactions. PMID:25155955

  14. Neural circuit remodeling and structural plasticity in the cortex during chronic pain

    PubMed Central

    Kim, Woojin

    2016-01-01

    Damage in the periphery or spinal cord induces maladaptive plastic changes along the somatosensory nervous system from the periphery to the cortex, often leading to chronic pain. Although the role of neural circuit remodeling and structural synaptic plasticity in the 'pain matrix' cortices in chronic pain has been thought as a secondary epiphenomenon to altered nociceptive signaling in the spinal cord, progress in whole brain imaging studies on human patients and animal models has suggested a possibility that plastic changes in cortical neural circuits may actively contribute to chronic pain symptoms. Furthermore, recent development in two-photon microscopy and fluorescence labeling techniques have enabled us to longitudinally trace the structural and functional changes in local circuits, single neurons and even individual synapses in the brain of living animals. These technical advances has started to reveal that cortical structural remodeling following tissue or nerve damage could rapidly occur within days, which are temporally correlated with functional plasticity of cortical circuits as well as the development and maintenance of chronic pain behavior, thereby modifying the previous concept that it takes much longer periods (e.g. months or years). In this review, we discuss the relation of neural circuit plasticity in the 'pain matrix' cortices, such as the anterior cingulate cortex, prefrontal cortex and primary somatosensory cortex, with chronic pain. We also introduce how to apply long-term in vivo two-photon imaging approaches for the study of pathophysiological mechanisms of chronic pain. PMID:26807017

  15. Complex regional pain syndrome type I affects brain structure in prefrontal and motor cortex.

    PubMed

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

    2014-01-01

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

  16. Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma.

    PubMed

    Ryall, Scott; Krishnatry, Rahul; Arnoldo, Anthony; Buczkowicz, Pawel; Mistry, Matthew; Siddaway, Robert; Ling, Cino; Pajovic, Sanja; Yu, Man; Rubin, Joshua B; Hukin, Juliette; Steinbok, Paul; Bartels, Ute; Bouffet, Eric; Tabori, Uri; Hawkins, Cynthia

    2016-01-01

    Paediatric brain tumours arising in the thalamus present significant diagnostic and therapeutic challenges to physicians due to their sensitive midline location. As such, genetic analysis for biomarkers to aid in the diagnosis, prognosis and treatment of these tumours is needed. Here, we identified 64 thalamic gliomas with clinical follow-up and characterized targeted genomic alterations using newly optimized droplet digital and NanoString-based assays. The median age at diagnosis was 9.25 years (range, 0.63-17.55) and median survival was 6.43 (range, 0.01-27.63) years. Our cohort contained 42 and 22 tumours reviewed as low and high grade gliomas, respectively. Five (12 %) low grade and 11 (50 %) high grade gliomas were positive for the H3F3A/HIST1H3B K27M (H3K27M) mutation. Kaplan-Meier survival analysis revealed significantly worse overall survival for patients harbouring the H3K27M mutation versus H3F3A/HIST1H3B wild type (H3WT) samples (log-rank p < 0.0001) with a median survival of 1.02 vs. 9.12 years. Mitogen-activated protein kinase (MAPK) pathway activation via BRAF or FGFR1 hotspot mutations or fusion events were detected in 44 % of patients, and was associated with long-term survival in the absence of H3K27M (log-rank p < 0.0001). Multivariate analysis demonstrated H3K27M status and high grade histology to be the most significant independent predictors of poor overall survival with hazard ratios of 6.945 and 7.721 (p < 0.0001), respectively. In contrast, MAPK pathway activation is a predictor of favourable patient outcome, although not independent of other clinical factors. Importantly, we show that low grade malignancies may harbour H3K27M mutations and that these tumours show a dismal survival compared to low grade H3WT cases. Our data strongly supports the inclusion of targeted genetic testing in childhood thalamic tumours to most accurately stratify patients into appropriate risk groups. PMID:27577993

  17. A Pilot Study of Mindfulness-Based Exposure Therapy in OEF/OIF Combat Veterans with PTSD: Altered Medial Frontal Cortex and Amygdala Responses in Social–Emotional Processing

    PubMed Central

    King, Anthony P.; Block, Stefanie R.; Sripada, Rebecca K.; Rauch, Sheila A. M.; Porter, Katherine E.; Favorite, Todd K.; Giardino, Nicholas; Liberzon, Israel

    2016-01-01

    Combat-related posttraumatic stress disorder (PTSD) is common among returning veterans, and is a serious and debilitating disorder. While highly effective treatments involving trauma exposure exist, difficulties with engagement and early drop may lead to sub-optimal outcomes. Mindfulness training may provide a method for increasing emotional regulation skills that may improve engagement in trauma-focused therapy. Here, we examine potential neural correlates of mindfulness training and in vivo exposure (non-trauma focused) using a novel group therapy [mindfulness-based exposure therapy (MBET)] in Afghanistan (OEF) or Iraq (OIF) combat veterans with PTSD. OEF/OIF combat veterans with PTSD (N = 23) were treated with MBET (N = 14) or a comparison group therapy [Present-centered group therapy (PCGT), N = 9]. PTSD symptoms were assessed at pre- and post-therapy with Clinician Administered PTSD scale. Functional neuroimaging (3-T fMRI) before and after therapy examined responses to emotional faces (angry, fearful, and neutral faces). Patients treated with MBET had reduced PTSD symptoms (effect size d = 0.92) but effect was not significantly different from PCGT (d = 0.43). Improvement in PTSD symptoms from pre- to post-treatment in both treatment groups was correlated with increased activity in rostral anterior cingulate cortex, dorsal medial prefrontal cortex (mPFC), and left amygdala. The MBET group showed greater increases in amygdala and fusiform gyrus responses to Angry faces, as well as increased response in left mPFC to Fearful faces. These preliminary findings provide intriguing evidence that MBET group therapy for PTSD may lead to changes in neural processing of social–emotional threat related to symptom reduction. PMID:27703434

  18. Comparative Proteomic Analysis of Carbonylated Proteins from the Striatum and Cortex of Pesticide-Treated Mice

    PubMed Central

    Coughlan, Christina; Walker, Douglas I.; Lohr, Kelly M.; Richardson, Jason R.; Saba, Laura M.; Caudle, W. Michael; Fritz, Kristofer S.; Roede, James R.

    2015-01-01

    Epidemiological studies indicate exposures to the herbicide paraquat (PQ) and fungicide maneb (MB) are associated with increased risk of Parkinson's disease (PD). Oxidative stress appears to be a premier mechanism that underlies damage to the nigrostriatal dopamine system in PD and pesticide exposure. Enhanced oxidative stress leads to lipid peroxidation and production of reactive aldehydes; therefore, we conducted proteomic analyses to identify carbonylated proteins in the striatum and cortex of pesticide-treated mice in order to elucidate possible mechanisms of toxicity. Male C57BL/6J mice were treated biweekly for 6 weeks with saline, PQ (10 mg/kg), MB (30 mg/kg), or the combination of PQ and MB (PQMB). Treatments resulted in significant behavioral alterations in all treated mice and depleted striatal dopamine in PQMB mice. Distinct differences in 4-hydroxynonenal-modified proteins were observed in the striatum and cortex. Proteomic analyses identified carbonylated proteins and peptides from the cortex and striatum, and pathway analyses revealed significant enrichment in a variety of KEGG pathways. Further analysis showed enrichment in proteins of the actin cytoskeleton in treated samples, but not in saline controls. These data indicate that treatment-related effects on cytoskeletal proteins could alter proper synaptic function, thereby resulting in impaired neuronal function and even neurodegeneration. PMID:26345149

  19. Experience-dependent gene expression in adult visual cortex.

    PubMed

    Chen, Jiabin; Yamahachi, Homare; Gilbert, Charles D

    2010-03-01

    Experience-dependent plasticity of the adult visual cortex underlies perceptual learning and recovery of function following central nervous system lesions. To reveal the signal transduction cascades involved in adult cortical plasticity, we utilized a model of remapping of cortical topography following binocular retinal lesions. In this model, the lesion projection zone (LPZ) of primary visual cortex (V1) recovers visually driven activity by the sprouting of horizontal axonal connections originating from the cells in the surrounding region. To explore the molecular mechanism underlying this process, we used gene microarrays from an expression library prepared from Macaque V1. By microarray analysis of gene expression levels in the LPZ and the surrounding region, and subsequent confirmation with Quantitative Real-Time polymerase chain reaction and in situ hybridization, the participation of a number of genes was observed, including the Rho GTPase family. Its role in regulation of cytoskeleton assembly provides a possible link between the alteration of neural activity and cortical functional reorganization. PMID:19571270

  20. Orbitofrontal cortex and representation of incentive value in associative learning.

    PubMed

    Gallagher, M; McMahan, R W; Schoenbaum, G

    1999-08-01

    Clinical evidence indicates that damage to ventromedial prefrontal cortex disrupts goal-directed actions that are guided by motivational and emotional factors. As a consequence, patients with such damage characteristically engage in maladaptive behaviors. Other research has shown that neurons in the corresponding orbital region of prefrontal cortex in laboratory animals encode information regarding the incentive properties of goals or expected events. The present study investigates the effect of neurotoxic orbitofrontal cortex (OFC) lesions in the rat on responses that are normally influenced by associations between a conditioned stimulus (CS) and the incentive value of reinforcement. Rats were first trained to associate a visual CS with delivery of food pellets to a food cup. As a consequence of learning, rats approached the food cup during the CS in anticipation of reinforcement. In a second training phase, injection of LiCl followed consumption of the food unconditioned stimulus (US) in the home cage, a procedure used to alter the incentive value of the US. Subsequently, rats were returned to the conditioning chamber, and their responding to the CS in the absence of the food US was tested. Lesions of OFC did not affect either the initial acquisition of a conditioned response to the light CS in the first training phase or taste aversion learning in the second training phase. In the test for devaluation, however, OFC rats exhibited no change in conditioned responding to the visual CS. This outcome contrasts with the behavior of control rats; after devaluation of the US a significant decrease occurred in approach to the food cup during presentation of the CS. The results reveal an inability of a cue to access representational information about the incentive value of associated reinforcement after OFC damage. PMID:10414988

  1. The neural representation of Arabic digits in visual cortex

    PubMed Central

    Peters, Lien; De Smedt, Bert; Op de Beeck, Hans P.

    2015-01-01

    In this study, we investigated how Arabic digits are represented in the visual cortex, and how their representation changes throughout the ventral visual processing stream, compared to the representation of letters. We probed these questions with two functional magnetic resonance imaging (fMRI) experiments. In Experiment 1, we explored whether we could find brain regions that were more activated for digits than for number words in a subtraction task. One such region was detected in lateral occipital cortex. However, the activity in this region might have been confounded by string length—number words contain more characters than digits. We therefore conducted a second experiment in which string length was systematically controlled. Experiment 2 revealed that the findings of the first experiment were task dependent (as it was only observed in a task in which numerosity was relevant) or stimulus dependent (as it was only observed when the number of characters of a stimulus was not controlled). We further explored the characteristics of the activation patterns for digit and letter strings across the ventral visual processing stream through multi-voxel pattern analyses. We found an alteration in representations throughout the ventral processing stream from clustering based on amount of visual information in primary visual cortex (V1) towards clustering based on symbolic stimulus category higher in the visual hierarchy. The present findings converge to the conclusion that in the ventral visual system, as far as can be detected with fMRI, the distinction between Arabic digits and letter strings is represented in terms of distributed patterns rather than separate regions. PMID:26441613

  2. Alterations of Hippocampal Projections in Adult Macaques with Neonatal Hippocampal Lesions: A Diffusion Tensor Imaging Study

    PubMed Central

    Meng, Yuguang; Payne, Christa; Li, Longchuan; Hu, Xiaoping; Zhang, Xiaodong; Bachevalier, Jocelyne

    2014-01-01

    Neuropsychological and brain imaging studies have demonstrated persistent deficits in memory functions and structural changes after neonatal neurotoxic hippocampal lesion in monkeys. However, the relevant microstructural changes in the white matter of affected brain regions following this early insult remain unknown. This study assessed white matter integrity in the main hippocampal projections of adult macaque monkeys with neonatal hippocampal lesions, by diffusion tensor imaging (DTI). Data analysis was performed using tract-based spatial statistics (TBSS) and compared with volume of interest statistics. Alterations of fractional anisotropy (FA) and diffusivity indices were observed in fornix, temporal stem, ventromedial prefrontal cortex and optical radiations. To further validate the lesion effects on the prefrontal cortex, probabilistic diffusion tractography was used to examine the integrity of the fiber connections between hippocampus and ventromedial prefrontal cortex, and alterations were found in these connections. In addition, increased radial diffusivity in the left ventromedial prefrontal cortex correlated negatively with the severity of deficits in working memory in the same monkeys. The findings revealed microstructural changes due to neonatal hippocampal lesion, and confirmed that neonatal neurotoxic hippocampal lesions resulted in significant and enduring functional alterations in the hippocampal projection system. PMID:25204865

  3. Rhyolite genesis at the Picabo Volcanic Center of the Snake River Plain: Progressive recycling of hydrothermally altered rhyolites revealed by high resolution analysis of individual zircons

    NASA Astrophysics Data System (ADS)

    Drew, D.; Bindeman, I. N.; Watts, K. E.; Schmitt, A. K.; McCurry, M. O.

    2012-12-01

    The Picabo eruptive center of the Snake River Plain (SRP) produced a series of normal and low δ18O rhyolites from 10.44 Ma to 6.62 Ma, providing the first evidence of progressive recycling of hydrothermally altered rhyolites during the formation of a caldera complex. In this study we present a characterization of ignimbrites and associated lavas based on U-Pb ages and δ18O compositions of individual zircon cores measured by ion microprobe, phenocryst δ18O values measured by laser fluorination, whole rock 87Sr/86Sr and 143Nd/144Nd compositions, and whole rock geochemistry. Our data define rhyolite genesis at the Picabo volcanic center through time and have implications for the transition between volcanic centers. Caldera complex evolution at Picabo began with eruption of the 10.44 ± 0.27 Ma Tuff of Arbon Valley (TAV), a chemically zoned unit with a normal δ18Omelt value (8.15‰), very high 87Sr/86Sr (up to 0.734430) and very low ɛNd (-18). Eruptions continued with the ~9.1 Ma Two-and-a-Half-Mile Rhyolite (Kellogg et al., 1988), a unit significant in that it has an even lower ɛNd than the TAV and a normal δ18Omelt value (8.10‰). This low ɛNd of -23, of the Two-and-a-Half-Mile Rhyolite, reveals that greater than 40% of Archean crust was assimilated. These normal δ18O eruptions were followed by a series of lower δ18O eruptions distinguishable by Sr and Nd isotopes and whole rock chemistry. The 8.25 ± 0.26 Ma Rhyolite of West Pocatello has the lowest δ18Omelt value (3.34‰) of these eruptions, and based on nearly identical age, 87Sr/86Sr, 143Nd/144Nd, and whole rock chemistry, we correlate it to a 1,000 m thick intracaldera tuff (present in the INEL drillcore). Along with a distinct decrease in δ18O, from the TAV to the Rhyolite of West Pocatello, there is a corresponding increase in δ18Ozircon heterogeneity from the TAV (1‰ variation) to the low δ18O units with the greatest δ18Ozircon diversity (up to 5‰). Although morphological evidence for

  4. Targeted Lipidomics of Fontal Cortex and Plasma Diacylglycerols (DAG) in Mild Cognitive Impairment and Alzheimer's Disease: Validation of DAG Accumulation Early in the Pathophysiology of Alzheimer's Disease.

    PubMed

    Wood, Paul L; Medicherla, Srikanth; Sheikh, Naveen; Terry, Bradley; Phillipps, Aaron; Kaye, Jeffrey A; Quinn, Joseph F; Woltjer, Randall L

    2015-01-01

    Previous studies have demonstrated augmented levels of diacylglycerols (DAG) in the frontal cortex and plasma of Alzheimer's disease (AD) patients. We extended these findings from non-targeted lipidomics studies to design a lipidomics platform to interrogate DAGs and monoacylglycerols (MAG) in the frontal cortex and plasma of MCI subjects. Control subjects included both aged normal controls and controls with normal cognition, but AD pathology at autopsy, individuals termed non-demented AD neuropathology. DAGs with saturated, unsaturated, and polyunsaturated fatty acid substituents were found to be elevated in MCI frontal cortex and plasma. Tandem mass spectrometry of the DAGs did not reveal any differences in the distributions of the fatty acid substitutions between MCI and control subjects. While triacylglycerols were not altered in MCI subjects there were increases in MAG levels both in the frontal cortex and plasma. In toto, increased levels of DAGs and MAGs appear to occur early in AD pathophysiology and require both further validation in a larger patient cohort and elucidation of the lipidomics alteration(s) that lead to the accumulation of DAGs in MCI subjects. PMID:26402017

  5. Targeted Lipidomics of Fontal Cortex and Plasma Diacylglycerols (DAG) in Mild Cognitive Impairment and Alzheimer's Disease: Validation of DAG Accumulation Early in the Pathophysiology of Alzheimer's Disease.

    PubMed

    Wood, Paul L; Medicherla, Srikanth; Sheikh, Naveen; Terry, Bradley; Phillipps, Aaron; Kaye, Jeffrey A; Quinn, Joseph F; Woltjer, Randall L

    2015-01-01

    Previous studies have demonstrated augmented levels of diacylglycerols (DAG) in the frontal cortex and plasma of Alzheimer's disease (AD) patients. We extended these findings from non-targeted lipidomics studies to design a lipidomics platform to interrogate DAGs and monoacylglycerols (MAG) in the frontal cortex and plasma of MCI subjects. Control subjects included both aged normal controls and controls with normal cognition, but AD pathology at autopsy, individuals termed non-demented AD neuropathology. DAGs with saturated, unsaturated, and polyunsaturated fatty acid substituents were found to be elevated in MCI frontal cortex and plasma. Tandem mass spectrometry of the DAGs did not reveal any differences in the distributions of the fatty acid substitutions between MCI and control subjects. While triacylglycerols were not altered in MCI subjects there were increases in MAG levels both in the frontal cortex and plasma. In toto, increased levels of DAGs and MAGs appear to occur early in AD pathophysiology and require both further validation in a larger patient cohort and elucidation of the lipidomics alteration(s) that lead to the accumulation of DAGs in MCI subjects.

  6. Mescaline-induced changes of brain-cortex ribosomes. Effect of mescaline on the stability of brain-cortex ribosomes.

    PubMed

    Datta, R K; Ghosh, J J

    1970-05-01

    1. During the action of mescaline sulphate on goat brain-cortex slices the ribosomal particles become susceptible to breakdown, releasing protein, RNA, acidsoluble nucleotides and ninhydrin-positive materials, resulting in loss of ribosomal enzyme activities. 2. Ribosomes of the mescaline-treated cortex slices undergo rapid degradation in the presence of trypsin and ribonuclease. 3. Mescaline does not alter the chemical and nucleotide compositions or the u.v.-absorption characteristics of ribosomal particles, however.

  7. Altered brain arginine metabolism in schizophrenia

    PubMed Central

    Liu, P; Jing, Y; Collie, N D; Dean, B; Bilkey, D K; Zhang, H

    2016-01-01

    Previous research implicates altered metabolism of l-arginine, a versatile amino acid with a number of bioactive metabolites, in the pathogenesis of schizophrenia. The present study, for we believe the first time, systematically compared the metabolic profile of l-arginine in the frontal cortex (Brodmann's area 8) obtained post-mortem from schizophrenic individuals and age- and gender-matched non-psychiatric controls (n=20 per group). The enzyme assays revealed no change in total nitric oxide synthase (NOS) activity, but significantly increased arginase activity in the schizophrenia group. Western blot showed reduced endothelial NOS protein expression and increased arginase II protein level in the disease group. High-performance liquid chromatography and liquid chromatography/mass spectrometric assays confirmed significantly reduced levels of γ-aminobutyric acid (GABA), but increased agmatine concentration and glutamate/GABA ratio in the schizophrenia cases. Regression analysis indicated positive correlations between arginase activity and the age of disease onset and between l-ornithine level and the duration of illness. Moreover, cluster analyses revealed that l-arginine and its main metabolites l-citrulline, l-ornithine and agmatine formed distinct groups, which were altered in the schizophrenia group. The present study provides further evidence of altered brain arginine metabolism in schizophrenia, which enhances our understanding of the pathogenesis of schizophrenia and may lead to the future development of novel preventions and/or therapeutics for the disease. PMID:27529679

  8. Melanogenesis stimulation in B16-F10 melanoma cells induces cell cycle alterations, increased ROS levels and a differential expression of proteins as revealed by proteomic analysis

    SciTech Connect

    Cunha, Elizabeth S.; Kawahara, Rebeca; Kadowaki, Marina K.; Amstalden, Hudson G.; Noleto, Guilhermina R.; Cadena, Silvia Maria S.C.; Winnischofer, Sheila M.B.; Martinez, Glaucia R.

    2012-09-10

    Considering that stimulation of melanogenesis may lead to alterations of cellular responses, besides melanin production, our main goal was to study the cellular effects of melanogenesis stimulation of B16-F10 melanoma cells. Our results show increased levels of the reactive oxygen species after 15 h of melanogenesis stimulation. Following 48 h of melanogenesis stimulation, proliferation was inhibited (by induction of cell cycle arrest in the G1 phase) and the expression levels of p21 mRNA were increased. In addition, melanogenesis stimulation did not induce cellular senescence. Proteomic analysis demonstrated the involvement of proteins from other pathways besides those related to the cell cycle, including protein disulfide isomerase A3, heat-shock protein 70, and fructose biphosphate aldolase A (all up-regulated), and lactate dehydrogenase (down-regulated). In RT-qPCR experiments, the levels of pyruvate kinase M2 mRNA dropped, whereas the levels of ATP synthase (beta-F1) mRNA increased. These data indicate that melanogenesis stimulation of B16-F10 cells leads to alterations in metabolism and cell cycle progression that may contribute to an induction of cell quiescence, which may provide a mechanism of resistance against cellular injury promoted by melanin synthesis. -- Highlights: Black-Right-Pointing-Pointer Melanogenesis stimulation by L-tyrosine+NH{sub 4}Cl in B16-F10 melanoma cells increases ROS levels. Black-Right-Pointing-Pointer Melanogenesis inhibits cell proliferation, and induced cell cycle arrest in the G1 phase. Black-Right-Pointing-Pointer Proteomic analysis showed alterations in proteins of the cell cycle and glucose metabolism. Black-Right-Pointing-Pointer RT-qPCR analysis confirmed alterations of metabolic targets after melanogenesis stimulation.

  9. Comparative transcriptomic analysis reveals the oncogenic fusion protein PAX3-FOXO1 globally alters mRNA and miRNA to enhance myoblast invasion

    PubMed Central

    Loupe, J M; Miller, P J; Bonner, B P; Maggi, E C; Vijayaraghavan, J; Crabtree, J S; Taylor, C M; Zabaleta, J; Hollenbach, A D

    2016-01-01

    Rhabdomyosarcoma, one of the most common childhood sarcomas, is comprised of two main subtypes, embryonal and alveolar (ARMS). ARMS, the more aggressive subtype, is primarily characterized by the t(2;13)(p35;p14) chromosomal translocation, which fuses two transcription factors, PAX3 and FOXO1 to generate the oncogenic fusion protein PAX3-FOXO1. Patients with PAX3-FOXO1-postitive tumors have a poor prognosis, in part due to the enhanced local invasive capacity of these cells, which leads to the increased metastatic potential for this tumor. Despite this knowledge, little is known about the role that the oncogenic fusion protein has in this increased invasive potential. In this report we use large-scale comparative transcriptomic analyses in physiologically relevant primary myoblasts to demonstrate that the presence of PAX3-FOXO1 is sufficient to alter the expression of 70 mRNA and 27 miRNA in a manner predicted to promote cellular invasion. In contrast the expression of PAX3 alters 60 mRNA and 23 miRNA in a manner predicted to inhibit invasion. We demonstrate that these alterations in mRNA and miRNA translate into changes in the invasive potential of primary myoblasts with PAX3-FOXO1 increasing invasion nearly 2-fold while PAX3 decreases invasion nearly 4-fold. Taken together, these results allow us to build off of previous reports and develop a more expansive molecular model by which the presence of PAX3-FOXO1 alters global gene regulatory networks to enhance the local invasiveness of cells. Further, the global nature of our observed changes highlights the fact that instead of focusing on a single-gene target, we must develop multi-faceted treatment regimens targeting multiple genes of a single oncogenic phenotype or multiple genes that target different oncogenic phenotypes for tumor progression. PMID:27454080

  10. Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene.

    PubMed

    Schmidt, Janine; Gong, Shunyou; Marafioti, Teresa; Mankel, Barbara; Gonzalez-Farre, Blanca; Balagué, Olga; Mozos, Ana; Cabeçadas, José; van der Walt, Jon; Hoehn, Daniela; Rosenwald, Andreas; Ott, German; Dojcinov, Stefan; Egan, Caoimhe; Nadeu, Ferran; Ramis-Zaldívar, Joan Enric; Clot, Guillem; Bárcena, Carmen; Pérez-Alonso, Vanesa; Endris, Volker; Penzel, Roland; Lome-Maldonado, Carmen; Bonzheim, Irina; Fend, Falko; Campo, Elias; Jaffe, Elaine S; Salaverria, Itziar; Quintanilla-Martinez, Leticia

    2016-08-25

    Pediatric-type follicular lymphoma (PTFL) is a variant of follicular lymphoma (FL) with distinctive clinicopathological features. Patients are predominantly young males presenting with localized lymphadenopathy; the tumor shows high-grade cytology and lacks both BCL2 expression and t(14;18) translocation. The genetic alterations involved in the pathogenesis of PTFL are unknown. Therefore, 42 PTFL (40 males and 2 females; mean age, 16 years; range, 5-31) were genetically characterized. For comparison, 11 cases of conventional t(14:18)(-) FL in adults were investigated. Morphologically, PTFL cases had follicular growth pattern without diffuse areas and characteristic immunophenotype. All cases showed monoclonal immunoglobulin (IG) rearrangement. PTFL displays low genomic complexity when compared with t(14;18)(-) FL (mean, 0.77 vs 9 copy number alterations per case; P <001). Both groups presented 1p36 alterations including TNFRSF14, but copy-number neutral loss of heterozygosity (CNN-LOH) of this locus was more frequently observed in PTFL (40% vs 9%; P =075). TNFRSF14 was the most frequently affected gene in PTFL (21 mutations and 2 deletions), identified in 54% of cases, followed by KMT2D mutations in 16%. Other histone-modifying genes were rarely affected. In contrast, t(14;18)(-) FL displayed a mutational profile similar to t(14;18)(+) FL. In 8 PTFL cases (19%), no genetic alterations were identified beyond IG monoclonal rearrangement. The genetic landscape of PTFL suggests that TNFRSF14 mutations accompanied by CNN-LOH of the 1p36 locus in over 70% of mutated cases, as additional selection mechanism, might play a key role in the pathogenesis of this disease. The genetic profiles of PTFL and t(14;18)(-) FL in adults indicate that these are two different disorders. PMID:27257180

  11. Transcriptomics Profiling of Alzheimer’s Disease Reveal Neurovascular Defects, Altered Amyloid-β Homeostasis, and Deregulated Expression of Long Noncoding RNAs

    PubMed Central

    Magistri, Marco; Velmeshev, Dmitry; Makhmutova, Madina; Faghihi, Mohammad Ali

    2015-01-01

    Abstract The underlying genetic variations of late-onset Alzheimer’s disease (LOAD) cases remain largely unknown. A combination of genetic variations with variable penetrance and lifetime epigenetic factors may converge on transcriptomic alterations that drive LOAD pathological process. Transcriptome profiling using deep sequencing technology offers insight into common altered pathways regardless of underpinning genetic or epigenetic factors and thus represents an ideal tool to investigate molecular mechanisms related to the pathophysiology of LOAD. We performed directional RNA sequencing on high quality RNA samples extracted from hippocampi of LOAD and age-matched controls. We further validated our data using qRT-PCR on a larger set of postmortem brain tissues, confirming downregulation of the gene encoding substance P (TAC1) and upregulation of the gene encoding the plasminogen activator inhibitor-1 (SERPINE1). Pathway analysis indicates dysregulation in neural communication, cerebral vasculature, and amyloid-β clearance. Beside protein coding genes, we identified several annotated and non-annotated long noncoding RNAs that are differentially expressed in LOAD brain tissues, three of them are activity-dependent regulated and one is induced by Aβ1 - 42 exposure of human neural cells. Our data provide a comprehensive list of transcriptomics alterations in LOAD hippocampi and warrant holistic approach including both coding and non-coding RNAs in functional studies aimed to understand the pathophysiology of LOAD. PMID:26402107

  12. RNA-seq Analysis of δ9-Tetrahydrocannabinol-treated T Cells Reveals Altered Gene Expression Profiles That Regulate Immune Response and Cell Proliferation.

    PubMed

    Yang, Xiaoming; Bam, Marpe; Nagarkatti, Prakash S; Nagarkatti, Mitzi

    2016-07-22

    Marijuana has drawn significant public attention and concern both for its medicinal and recreational use. Δ9-Tetrahydrocannabinol (THC), which is the main bioactive component in marijuana, has also been shown to possess potent anti-inflammatory properties by virtue of its ability to activate cannabinoid receptor-2 (CB-2) expressed on immune cells. In this study, we used RNA-seq to quantify the transcriptomes and transcript variants that are differentially regulated by THC in super antigen-activated lymph node cells and CD4(+) T cells. We found that the expressions of many transcripts were altered by THC in both total lymph node cells and CD4(+) T cells. Furthermore, the abundance of many miRNA precursors and long non-coding RNAs was dramatically altered in THC-treated mice. For example, the expression of miR-17/92 cluster and miR-374b/421 cluster was down-regulated by THC. On the other hand miR-146a, which has been shown to induce apoptosis, was up-regulated by THC. Long non-coding RNAs that are expressed from the opposite strand of CD27 and Appbp2 were induced by THC. In addition, THC treatment also caused alternative promoter usage and splicing. The functions of those altered transcripts were mainly related to immune response and cell proliferation. PMID:27268054

  13. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors

    PubMed Central

    Shern, Jack F.; Chen, Li; Chmielecki, Juliann; Wei, Jun S.; Patidar, Rajesh; Rosenberg, Mara; Ambrogio, Lauren; Auclair, Daniel; Wang, Jianjun; Song, Young K.; Tolman, Catherine; Hurd, Laura; Liao, Hongling; Zhang, Shile; Bogen, Dominik; Brohl, Andrew S.; Sindiri, Sivasish; Catchpoole, Daniel; Badgett, Thomas; Getz, Gad; Mora, Jaume; Anderson, James R.; Skapek, Stephen X.; Barr, Frederic G.; Meyerson, Matthew; Hawkins, Douglas S.; Khan, Javed

    2015-01-01

    Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma (RMS) remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs. Two genotypes are evident in RMS tumors; those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in RMS is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations of NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, we found novel recurrent mutations in FBXW7, and BCOR providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of cases providing a framework for genomics directed therapies that might improve outcomes for RMS patients. PMID:24436047

  14. Epigenetic Profiling of H3K4Me3 Reveals Herbal Medicine Jinfukang-Induced Epigenetic Alteration Is Involved in Anti-Lung Cancer Activity.

    PubMed

    Lu, Jun; Zhang, Xiaoli; Shen, Tingting; Ma, Chao; Wu, Jun; Kong, Hualei; Tian, Jing; Shao, Zhifeng; Zhao, Xiaodong; Xu, Ling

    2016-01-01

    Traditional Chinese medicine Jinfukang (JFK) has been clinically used for treating lung cancer. To examine whether epigenetic modifications are involved in its anticancer activity, we performed a global profiling analysis of H3K4Me3, an epigenomic marker associated with active gene expression, in JFK-treated lung cancer cells. We identified 11,670 genes with significantly altered status of H3K4Me3 modification following JFK treatment (P < 0.05). Gene Ontology analysis indicates that these genes are involved in tumor-related pathways, including pathway in cancer, basal cell carcinoma, apoptosis, induction of programmed cell death, regulation of transcription (DNA-templated), intracellular signal transduction, and regulation of peptidase activity. In particular, we found that the levels of H3K4Me3 at the promoters of SUSD2, CCND2, BCL2A1, and TMEM158 are significantly altered in A549, NCI-H1975, NCI-H1650, and NCI-H2228 cells, when treated with JFK. Collectively, these findings provide the first evidence that the anticancer activity of JFK involves modulation of histone modification at many cancer-related gene loci. PMID:27087825

  15. Epigenetic Profiling of H3K4Me3 Reveals Herbal Medicine Jinfukang-Induced Epigenetic Alteration Is Involved in Anti-Lung Cancer Activity.

    PubMed

    Lu, Jun; Zhang, Xiaoli; Shen, Tingting; Ma, Chao; Wu, Jun; Kong, Hualei; Tian, Jing; Shao, Zhifeng; Zhao, Xiaodong; Xu, Ling

    2016-01-01

    Traditional Chinese medicine Jinfukang (JFK) has been clinically used for treating lung cancer. To examine whether epigenetic modifications are involved in its anticancer activity, we performed a global profiling analysis of H3K4Me3, an epigenomic marker associated with active gene expression, in JFK-treated lung cancer cells. We identified 11,670 genes with significantly altered status of H3K4Me3 modification following JFK treatment (P < 0.05). Gene Ontology analysis indicates that these genes are involved in tumor-related pathways, including pathway in cancer, basal cell carcinoma, apoptosis, induction of programmed cell death, regulation of transcription (DNA-templated), intracellular signal transduction, and regulation of peptidase activity. In particular, we found that the levels of H3K4Me3 at the promoters of SUSD2, CCND2, BCL2A1, and TMEM158 are significantly altered in A549, NCI-H1975, NCI-H1650, and NCI-H2228 cells, when treated with JFK. Collectively, these findings provide the first evidence that the anticancer activity of JFK involves modulation of histone modification at many cancer-related gene loci.

  16. Altered ARA2 (RABA1a) expression in Arabidopsis reveals the involvement of a Rab/YPT family member in auxin-mediated responses.

    PubMed

    Koh, Eun-Ji; Kwon, Ye-Rim; Kim, Kang-Il; Hong, Suk-Whan; Lee, Hojoung

    2009-05-01

    Ras super family proteins serve as molecular switches regulating many different cellular processes. However, given the large number of family members, sequence information has provided little insight into the function of individual proteins. This study examined phenotypic alterations in an Arabidopsis ara2 mutant, in which a Ras super family member-encoding gene is disrupted by a T-DNA insertion. Although one mutant line (Salk_013811) was hypersensitive to auxin, its T-DNA insertion was in the 5'-UTR of ARA2. Thus, we examined a true ARA2 knock-out mutant (Salk_077747) which contains an insertion in the first exon of ARA2. We found that ARA2 expression is responsive to auxin and at low concentrations, ara2 mutant plants exhibit increased numbers of lateral roots. ARA2 overexpression causes plants to exhibit hypersensitivity to auxin, due to altered expression of auxin-responsive genes, and these plants exhibited reduced numbers of lateral roots. A GFP-ARA2 fusion protein localized to the endosomes, suggesting that ARA2 may play a role in vesicle trafficking of components involved in polar auxin transport. Taken together, these results show that ARA2 is an essential component of a pathway that couples auxin signaling to plant growth and development.

  17. Epigenetic Profiling of H3K4Me3 Reveals Herbal Medicine Jinfukang-Induced Epigenetic Alteration Is Involved in Anti-Lung Cancer Activity

    PubMed Central

    Lu, Jun; Zhang, Xiaoli; Shen, Tingting; Ma, Chao; Wu, Jun; Kong, Hualei; Tian, Jing; Shao, Zhifeng; Zhao, Xiaodong; Xu, Ling

    2016-01-01

    Traditional Chinese medicine Jinfukang (JFK) has been clinically used for treating lung cancer. To examine whether epigenetic modifications are involved in its anticancer activity, we performed a global profiling analysis of H3K4Me3, an epigenomic marker associated with active gene expression, in JFK-treated lung cancer cells. We identified 11,670 genes with significantly altered status of H3K4Me3 modification following JFK treatment (P < 0.05). Gene Ontology analysis indicates that these genes are involved in tumor-related pathways, including pathway in cancer, basal cell carcinoma, apoptosis, induction of programmed cell death, regulation of transcription (DNA-templated), intracellular signal transduction, and regulation of peptidase activity. In particular, we found that the levels of H3K4Me3 at the promoters of SUSD2, CCND2, BCL2A1, and TMEM158 are significantly altered in A549, NCI-H1975, NCI-H1650, and NCI-H2228 cells, when treated with JFK. Collectively, these findings provide the first evidence that the anticancer activity of JFK involves modulation of histone modification at many cancer-related gene loci. PMID:27087825

  18. Tomato plants overexpressing cryptochrome 2 reveal altered expression of energy and stress-related gene products in response to diurnal cues.

    PubMed

    Lopez, Loredana; Carbone, Fabrizio; Bianco, Linda; Giuliano, Giovanni; Facella, Paolo; Perrotta, Gaetano

    2012-05-01

    In order to sense and respond to the fluctuating light conditions, higher plants possess several families of photoreceptors, such as phytochromes (PHYs), cryptochromes (CRYs) and phototropins. CRYs are responsible for photomorphogenesis and play a role in circadian, developmental and adaptive growth regulation of plants. In tomato (Solanum lycopersicum), CRY2 controls vegetative development, flowering time, fruit antioxidant content as well as the diurnal transcription of several other photoreceptor genes. We applied large-scale molecular approaches to identify altered transcripts and proteins in tomato wild-type (WT) versus a CRY2 overexpressing transgenic genotype, under a diurnal rhythm. Our results showed that tomato CRY2 profoundly affects both gene and protein expression in response to daily light cycle. Particularly altered molecular pathways are related to biotic/abiotic stress, photosynthesis, including components of the light and dark reactions and of starch and sucrose biosynthesis, as well as to secondary metabolism, such as phenylpropanoid, phenolic and flavonoid/anthocyanin biosynthesis pathways. One of the most interesting results is the coordinated up-regulation, in the transgenic genotype, of a consistent number of transcripts and proteins involved in photorespiration and photosynthesis. It is conceivable that light modulates the energetic metabolism of tomato through a fine CRY2-mediated transcriptional control.

  19. Neural correlates of the LSD experience revealed by multimodal neuroimaging.

    PubMed

    Carhart-Harris, Robin L; Muthukumaraswamy, Suresh; Roseman, Leor; Kaelen, Mendel; Droog, Wouter; Murphy, Kevin; Tagliazucchi, Enzo; Schenberg, Eduardo E; Nest, Timothy; Orban, Csaba; Leech, Robert; Williams, Luke T; Williams, Tim M; Bolstridge, Mark; Sessa, Ben; McGonigle, John; Sereno, Martin I; Nichols, David; Hellyer, Peter J; Hobden, Peter; Evans, John; Singh, Krish D; Wise, Richard G; Curran, H Valerie; Feilding, Amanda; Nutt, David J

    2016-04-26

    Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD's marked effects on the visual cortex did not significantly correlate with the drug's other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of "ego-dissolution" and "altered meaning," implying the importance of this particular circuit for the maintenance of "self" or "ego" and its processing of "meaning." Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others. PMID:27071089

  20. Neural correlates of the LSD experience revealed by multimodal neuroimaging.

    PubMed

    Carhart-Harris, Robin L; Muthukumaraswamy, Suresh; Roseman, Leor; Kaelen, Mendel; Droog, Wouter; Murphy, Kevin; Tagliazucchi, Enzo; Schenberg, Eduardo E; Nest, Timothy; Orban, Csaba; Leech, Robert; Williams, Luke T; Williams, Tim M; Bolstridge, Mark; Sessa, Ben; McGonigle, John; Sereno, Martin I; Nichols, David; Hellyer, Peter J; Hobden, Peter; Evans, John; Singh, Krish D; Wise, Richard G; Curran, H Valerie; Feilding, Amanda; Nutt, David J

    2016-04-26

    Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD's marked effects on the visual cortex did not significantly correlate with the drug's other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of "ego-dissolution" and "altered meaning," implying the importance of this particular circuit for the maintenance of "self" or "ego" and its processing of "meaning." Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.

  1. Neural correlates of the LSD experience revealed by multimodal neuroimaging

    PubMed Central

    Carhart-Harris, Robin L.; Muthukumaraswamy, Suresh; Roseman, Leor; Kaelen, Mendel; Droog, Wouter; Murphy, Kevin; Tagliazucchi, Enzo; Schenberg, Eduardo E.; Nest, Timothy; Orban, Csaba; Leech, Robert; Williams, Luke T.; Williams, Tim M.; Bolstridge, Mark; Sessa, Ben; McGonigle, John; Sereno, Martin I.; Nichols, David; Hobden, Peter; Evans, John; Singh, Krish D.; Wise, Richard G.; Curran, H. Valerie; Feilding, Amanda; Nutt, David J.

    2016-01-01

    Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD’s marked effects on the visual cortex did not significantly correlate with the drug’s other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of “ego-dissolution” and “altered meaning,” implying the importance of this particular circuit for the maintenance of “self” or “ego” and its processing of “meaning.” Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others. PMID:27071089

  2. Aging without Apolipoprotein D: Molecular and cellular modifications in the hippocampus and cortex.

    PubMed

    Sanchez, Diego; Bajo-Grañeras, Raquel; Del Caño-Espinel, Manuela; Garcia-Centeno, Rosa; Garcia-Mateo, Nadia; Pascua-Maestro, Raquel; Ganfornina, Maria D

    2015-07-01

    A detailed knowledge of the mechanisms underlying brain aging is fundamental to understand its functional decline and the baseline upon which brain pathologies superimpose. Endogenous protective mechanisms must contribute to the adaptability and plasticity still present in the healthy aged brain. Apolipoprotein D (ApoD) is one of the few genes with a consistent and evolutionarily conserved up-regulation in the aged brain. ApoD protecting roles upon stress or injury are well known, but a study of the effects of ApoD expression in the normal aging process is still missing. Using an ApoD-knockout mouse we analyze the effects of ApoD on factors contributing to the functional maintenance of the aged brain. We focused our cellular and molecular analyses in the cortex and hippocampus at an age representing the onset of senescence where mortality risks are below 25%, avoiding bias towards long-lived animals. Lack of ApoD causes a prematurely aged brain without altering lifespan. Age-dependent hyperkinesia and memory deficits are accompanied by differential molecular effects in the cortex and hippocampus. Transcriptome analyses reveal distinct effects of ApoD loss on the molecular age-dependent patterns of the cortex and hippocampus, with different cell-type contributions to age-regulated gene expression. Markers of glial reactivity, proteostasis, and oxidative and inflammatory damage reveal early signs of aging and enhanced brain deterioration in the ApoD-knockout brain. The lack of ApoD results in an age-enhanced significant reduction in neuronal calcium-dependent functionality markers and signs of early reduction of neuronal numbers in the cortex, thus impinging upon parameters clearly differentiating neurodegenerative conditions from healthy brain aging. Our data support the hypothesis that the physiological increased brain expression of ApoD represents a homeostatic anti-aging mechanism.

  3. Retained fetal adrenal cortex in a cynomolgus macaque (Macaca fascicularis).

    PubMed

    Radi, Zaher; Evans, Mark

    2014-10-01

    An incidental, bilateral, retained fetal adrenal cortex was detected in a male cynomolgus macaque (age, approximately 2.4 y) used in a 4-week toxicology study. Microscopic examination of the adrenal gland cortex zone revealed the presence of additional solid sheets and columns of cells supported by vascular capillary bed and composed of large polyhedral cells with abundant eosinophilic, slightly finely vacuolated cytoplasm that surrounded the entire circumference of the medulla. Nuclei were vesicular, round to oval with prominent small nucleoli. There was no evidence for inflammation or cellular degeneration. Based on the microscopic examination, a diagnosis of retained fetal cortex of the adrenal gland was made. This morphologic change resembles fetal cortex in human infants. To our knowledge, this case description is the first report of a cynomolgus macaque with the rare entity of retained fetal cortex, which should not be misinterpreted as a test article-related change.

  4. A systematic review of non-motor rTMS induced motor cortex plasticity

    PubMed Central

    Nordmann, Grégory; Azorina, Valeriya; Langguth, Berthold; Schecklmann, Martin

    2015-01-01

    Motor cortex excitability can be measured by single- and paired-pulse transcranial magnetic stimulation (TMS). Repetitive transcranial magnetic stimulation (rTMS) can induce neuroplastic effects in stimulated and in functionally connected cortical regions. Due to its ability to non-invasively modulate cortical activity, rTMS has been investigated for the treatment of various neurological and psychiatric disorders. However, such studies revealed a high variability of both clinical and neuronal effects induced by rTMS. In order to better elucidate this meta-plasticity, rTMS-induced changes in motor cortex excitability have been monitored in various studies in a pre-post stimulation design. Here, we give a literature review of studies investigating motor cortex excitability changes as a neuronal marker for rTMS effects over non-motor cortical areas. A systematic literature review in April 2014 resulted in 29 articles in which motor cortex excitability was assessed before and after rTMS over non-motor areas. The majority of the studies focused on the stimulation of one of three separate cortical areas: the prefrontal area (17 studies), the cerebellum (8 studies), or the temporal cortex (3 studies). One study assessed the effects of multi-site rTMS. Most studies investigated healthy controls but some also stimulated patients with neuropsychiatric conditions (e.g., affective disorders, tinnitus). Methods and findings of the identified studies were highly variable showing no clear systematic pattern of interaction of non-motor rTMS with measures of motor cortex excitability. Based on the available literature, the measurement of motor cortex excitability changes before and after non-motor rTMS has only limited value in the investigation of rTMS related meta-plasticity as a neuronal state or as a trait marker for neuropsychiatric diseases. Our results do not suggest that there are systematic alterations of cortical excitability changes during rTMS treatment, which calls

  5. Multiplexed quantitative high content screening reveals that cigarette smoke condensate induces changes in cell structure and function through alterations in cell signaling pathways in human bronchial cells.

    PubMed

    Carter, Charleata A; Hamm, Jonathan T

    2009-07-10

    Human bronchial cells are one of the first cell types exposed to environmental toxins. Toxins often activate nuclear factor-kappaB (NF-kappaB) and protein kinase C (PKC). We evaluated the hypothesis that cigarette smoke condensate (CSC), the particulate fraction of cigarette smoke, activates PKC-alpha and NF-kappaB, and concomitantly disrupts the F-actin cytoskeleton, induces apoptosis and alters cell function in BEAS-2B human bronchial epithelial cells. Compared to controls, exposure of BEAS-2B cells to doses of 30mug/ml CSC significantly activated PKC-alpha, while CSC doses above 20mug/ml CSC significantly activated NF-kappaB. As NF-kappaB was activated, cell number decreased. CSC treatment of BEAS-2B cells induced a decrease in cell size and an increase in cell surface extensions including filopodia and lamellipodia. CSC treatment of BEAS-2B cells induced F-actin rearrangement such that stress fibers were no longer prominent at the cell periphery and throughout the cells, but relocalized to perinuclear regions. Concurrently, CSC induced an increase in the focal adhesion protein vinculin at the cell periphery. CSC doses above 30mug/ml induced a significant increase in apoptosis in BEAS-2B cells evidenced by an increase in activated caspase 3, an increase in mitochondrial mass and a decrease in mitochondrial membrane potential. As caspase 3 increased, cell number decreased. CSC doses above 30mug/ml also induced significant concurrent changes in cell function including decreased cell spreading and motility. CSC initiates a signaling cascade in human bronchial epithelial cells involving PKC-alpha, NF-kappaB and caspase 3, and consequently decreases cell spreading and motility. These CSC-induced alterations in cell structure likely prevent cells from performing their normal function thereby contributing to smoke-induced diseases.

  6. Genome-Wide Expression Profiling Deciphers Host Responses Altered during Dengue Shock Syndrome and Reveals the Role of Innate Immunity in Severe Dengue

    PubMed Central

    Devignot, Stéphanie; Bergon, Aurélie; Rihet, Pascal; Ong, Sivuth; Lorn, Patrich T.; Chroeung, Norith; Ngeav, Sina; Tolou, Hugues J.; Buchy, Philippe; Couissinier-Paris, Patricia

    2010-01-01

    Background Deciphering host responses contributing to dengue shock syndrome (DSS), the life-threatening form of acute viral dengue infections, is required to improve both the differential prognosis and the treatments provided to DSS patients, a challenge for clinicians. Methodology/Principal Findings Based on a prospective study, we analyzed the genome-wide expression profiles of whole blood cells from 48 matched Cambodian children: 19 progressed to DSS while 16 and 13 presented respectively classical dengue fever (DF) or dengue hemorrhagic fever grades I/II (DHF). Using multi-way analysis of variance (ANOVA) and adjustment of p-values to control the False Discovery Rate (FDR<10%), we identified a signature of 2959 genes differentiating DSS patients from both DF and DHF, and showed a strong association of this DSS-gene signature with the dengue disease phenotype. Using a combined approach to analyse the molecular patterns associated with the DSS-gene signature, we provide an integrative overview of the transcriptional responses altered in DSS children. In particular, we show that the transcriptome of DSS children blood cells is characterized by a decreased abundance of transcripts related to T and NK lymphocyte responses and by an increased abundance of anti-inflammatory and repair/remodeling transcripts. We also show that unexpected pro-inflammatory gene patterns at the interface between innate immunity, inflammation and host lipid metabolism, known to play pathogenic roles in acute and chronic inflammatory diseases associated with systemic vascular dysfunction, are transcriptionnally active in the blood cells of DSS children. Conclusions/Significance We provide a global while non exhaustive overview of the molecular mechanisms altered in of DSS children and suggest how they may interact to lead to final vascular homeostasis breakdown. We suggest that some mechanisms identified should be considered putative therapeutic targets or biomarkers of progression to DSS

  7. Blood Pressure is Associated With Cerebral Blood Flow Alterations in Patients With T2DM as Revealed by Perfusion Functional MRI.

    PubMed

    Xia, Wenqing; Rao, Hengyi; Spaeth, Andrea M; Huang, Rong; Tian, Sai; Cai, Rongrong; Sun, Jie; Wang, Shaohua

    2015-12-01

    Type 2 diabetes mellitus (T2DM) and hypertension are both associated with cognitive impairment and brain function abnormalities. We investigated whether abnormal cerebral blood flow (CBF) patterns exists in T2DM patients and possible relationships between aberrant CBF and cognitive performance. Furthermore, we examined the influence of hypertension on CBF alterations in T2DM patients. T2DM patients (n = 38) and non-T2DM subjects (n = 40) were recruited from clinics, hospitals, and normal community health screenings. Cerebral blood flow images were collected and analyzed using arterial spin labeling perfusion functional magnetic resonance imaging (fMRI). Regions with major CBF differences between T2DM patients and non-T2DM controls were detected via 1-way ANOVA. The interaction effects between hypertension and T2DM for CBF alterations were also examined. Correlation analyses illustrated the association between CBF values and cognitive performance and between CBF and blood pressure. Compared with non-T2DM controls, T2DM patients exhibited decreased CBF, primarily in the visual area and the default mode network (DMN); decreased CBF in these regions was correlated with cognitive performance. There was a significant interaction effect between hypertension and diabetes for CBF in the precuneus and the middle occipital gyrus. Additionally, blood pressure correlated negatively with CBF in T2DM patients.T2DM patients exhibited reduced CBF in the visual area and DMN. Hypertension may facilitate a CBF decrease in the setting of diabetes. T2DM patients may benefit from blood pressure control to maintain their brain perfusion through CBF preservation. PMID:26632913

  8. High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients.

    PubMed

    Frémont, Marc; Coomans, Danny; Massart, Sebastien; De Meirleir, Kenny

    2013-08-01

    Human intestinal microbiota plays an important role in the maintenance of host health by providing energy, nutrients, and immunological protection. Intestinal dysfunction is a frequent complaint in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients, and previous reports suggest that dysbiosis, i.e. the overgrowth of abnormal populations of bacteria in the gut, is linked to the pathogenesis of the disease. We used high-throughput 16S rRNA gene sequencing to investigate the presence of specific alterations in the gut microbiota of ME/CFS patients from Belgium and Norway. 43 ME/CFS patients and 36 healthy controls were included in the study. Bacterial DNA was extracted from stool samples, PCR amplification was performed on 16S rRNA gene regions, and PCR amplicons were sequenced using Roche FLX 454 sequencer. The composition of the gut microbiota was found to differ between Belgian controls and Norwegian controls: Norwegians showed higher percentages of specific Firmicutes populations (Roseburia, Holdemania) and lower proportions of most Bacteroidetes genera. A highly significant separation could be achieved between Norwegian controls and Norwegian patients: patients presented increased proportions of Lactonifactor and Alistipes, as well as a decrease in several Firmicutes populations. In Belgian subjects the patient/control separation was less pronounced, however some abnormalities observed in Norwegian patients were also found in Belgian patients. These results show that intestinal microbiota is altered in ME/CFS. High-throughput sequencing is a useful tool to diagnose dysbiosis in patients and could help designing treatments based on gut microbiota modulation (antibiotics, pre and probiotics supplementation).

  9. Prenatal exposure to the CB1 and CB2 cannabinoid receptor agonist WIN 55,212-2 alters migration of early-born glutamatergic neurons and GABAergic interneurons in the rat cerebral cortex.

    PubMed

    Saez, Trinidad M M; Aronne, María P; Caltana, Laura; Brusco, Alicia H

    2014-05-01

    The endocannabinoid system, composed of cannabinoid receptors, endocannabinoids, and synthesis and degradation enzymes, is present since early stages of brain development. During this period, the endocannabinoid system is involved in the regulation of neural progenitor proliferation and specification as well as the migration and differentiation of pyramidal neurons and interneurons. Marijuana consumption during pregnancy represents a serious risk in relation to the fetal brain development since Δ(9) -tetrahidrocannabinol, the main active compound of cannabis, can reach the fetus through placenta and hemato-encephalic barrier. Cohort studies performed on children and adolescents of mothers who consumed marijuana during pregnancy reported cognitive and comportamental abnormalities. In the present study, we examined the expression of the cannabinoid receptor CB1 R during corticogenesis in radially and tangentially migrating post-mitotic neurons. We found that prenatal exposure to WIN impaired tangential and radial migration of post-mitotic neurons in the dorsal pallium. In addition, we described alterations of two transcription factors associated with proliferating and newly post-mitotic glutamatergic cells in the dorsal pallium, Tbr1 and Tbr2, and disruption in the number of Cajal-Retzius cells. The present results contribute to the knowledge of neurobiological substrates that determine neuro-comportamental changes that will persist through post-natal life.

  10. Perinatal asphyxia results in changes in presynaptic bouton number in stri