Neuroendocrine, behavioral and macrophage activity changes induced by picrotoxin effects in mice

The relevance and property of studies related to stress effects on immune function are undisputable. All studies conducted on stress-immune relationships, however, provide from physical and/or psychological stressors. Indeed, as far as it is of our knowledge brain-innate immune responses were not analyzed after anxiogenic-like drugs use. The present experiment was then undertaken to analyze the effects of picrotoxin (0.3, 0.6 and 1.0 mg/kg doses) on behavior, macrophage activity, serum corticosterone and noradrenaline (NE) levels and turnover in the brain of adult mice. Results showed that picrotoxin treatment in mice: (1) decreased motor and rearing activities in an open-field; (2) decreased the number of entries into the plus-maze open-arms and decreased the time spent in the exploration of the plus-maze open-arms; (3) decreased both motor activity and the level of holes exploration in the hole-board; (4) increased the levels of serum corticosterone in dose-dependent way; (5) increased noradrenaline (NE) and MHPG levels and NE turnover in the hypothalamus; and (6) increased Staphylococcus aureus and PMA-induced macrophage oxidative burst. However, and contrary to that reported after physical or psychological stress, this drug induced no effects on macrophage phagocytosis and NE levels and turnover in the frontal cortex. The present results are thus showing that picrotoxin induces some but not all neuro-innate immunity changes previously reported for inescapable foot-shock and psychological stressors in mice. These facts suggest that this chemical stressor triggers CNS pathways that might be somehow different from those fired by inescapable foot-shock and psychological stressors, leading to different neuro-innate immune responses. (C) 2007 Elsevier Ltd. All fights reserved.

5-HT1A, but not 5-HT2 and 5-HT7, receptors in the nucleus raphe magnus modulate hypoxia-induced hyperpnoea

Aim: In the present study, we assessed the role of 5-hydroxytryptamine (5-HT) receptors (5-HT1A, 5-HT2 and 5-HT7) in the nucleus raphe magnus (NRM) on the ventilatory and thermoregulatory responses to hypoxia. Methods: To this end, pulmonary ventilation (V-E) and body temperature (T-b) of male Wistar rats were measured in conscious rats, before and after a 0.1 mu L microinjection of WAY-100635 (5-HT1A receptor antagonist, 3 mu g 0.1 mu L-1, 56 mM), ketanserin (5-HT2 receptor antagonist, 2 mu g 0.1 mu L-1, 36 mM) and SB269970 (5-HT7 receptor antagonist, 4 mu g 0.1 mu L-1, 103 mM) into the NRM, followed by 60 min of severe hypoxia exposure (7% O-2). Results: Intra-NMR microinjection of vehicle (control rats) or 5-HT antagonists did not affect V-E or T-b during normoxic conditions. Exposure of rats to 7% O-2 evoked a typical hypoxia-induced anapyrexia after vehicle microinjections, which was not affected by microinjection of WAY-100635, SB269970 or ketanserin. The hypoxia-induced hyperpnoea was not affected by SB269970 and ketanserin intra-NMR. However, the treatment with WAY-100635 intra-NRM attenuated the hypoxia-induced hyperpnoea. Conclusion: These data suggest that 5-HT acting on 5-HT1A receptors in the NRM increases the hypoxic ventilatory response.

Imitation, mirror neurons and autism

Various deficits in the cognitive functioning of people with autism have been documented in recent years but these provide only partial explanations for the condition. We focus instead on an imitative disturbance involving difficulties both in copying actions and in inhibiting more stereotyped mimicking, such as echolalia. A candidate for the neural basis of this disturbance may be found in a recently discovered class of neurons in frontal cortex, 'mirror neurons' (MNs). These neurons show activity in relation both to specific actions performed by self and matching actions performed by others, providing a potential bridge between minds. MN systems exist in primates without imitative and 'theory of mind' abilities and we suggest that in order for them to have become utilized to perform social cognitive functions, sophisticated cortical neuronal systems have evolved in which MNs function as key elements. Early developmental failures of MN systems are likely to result in a consequent cascade of developmental impairments characterised by the clinical syndrome of autism. Crown Copyright (C) 2001 Published by Elsevier Science Ltd. All rights reserved.

Application of DNA microarrays to study human alcoholism

An emerging idea is that long-term alcohol abuse results in changes in gene expression in the brain and that these changes are responsible at least partly for alcohol tolerance, dependence and neurotoxicity, The overall goal of our research is to identify genes which are differentia[ly expressed in the brains of well-characterized human alcoholics as compared with non-alcoholics. This should identify as-yet-unknown alcohol-responsive genes, and may well confirm changes in the expression of genes which have been delineated in animal models of alcohol abuse. Cases were carefully selected and samples pooled on the basis of relevant criteria; differential expression was monitored by microarray hybridization. The inherent diversity of human alcoholics can be exploited to identify genes associated with specific pathological processes, as well as to assess the effects of concomitant disease, severity of brain damage, drinking behavior, and factors such as gender and smoking history. initial results show selective changes in gene expression in alcoholics; of particular importance is a coordinated reduction in genes coding for myelin components, Copyright (C) 2001 National Science Council, ROC and S. Karger AG, Basel.

Glutamate(NMDA) receptor NR1 subunit mRNA expression in Alzheimer's disease

We analyzed the expression profile of two NMDAR1 mRNA isoform subsets. NR1(0xx) and NR1(1xx), in discrete regions of human cerebral cortex. The subsets are characterized by the absence or presence of a 21-amino acid N-terminal cassette. Reverse transcription polymerase chain reaction for NR1 isoforms was performed on total RNA preparations from spared and susceptible regions from 10 pathologically confirmed Alzheimer's disease (AD) cases and 10 matched controls. Primers spanning the splice insert yielded two bands, 342 bp (NR1(0xx)) and 405 bp (NR1(1xx)), on agarose gel electrophoresis. The bands were visualized with ethidium and quantified by densitometry. NR1(1xx) transcript expression was calculated as a proportion of the NR1(1xx) + NR1(0xx) total. Values were significantly lower in AD cases than in controls in mid-cingulate cortex, p < 0.01, superior temporal cortex, p < 0.01 and hippocampus, p similar to 0.05. Cortical proportionate NR1(1xx) transcript expression was invariant over the range of ages acid areas of controls tested, at similar to 50%. This was also true for AD motor and occipital cortex. Proportionate NR1(1xx) expression in AD cingulate and temporal cortex was lower at younger ages and increased with age: this regression was significantly different from that in the homotropic areas of controls. Variations in NR1 N-terminal cassette expression may underlie the local vulnerability to excitotoxic damage of some areas in the AD brain. Alternatively, changes in NR1 mRNA expression may arise as a consequence of the AD disease process.

The pyramidal cell in cognition: A comparative study in human and monkey

Here we present evidence that the pyramidal cell phenotype varies markedly in the cortex of different anthropoid species. Regional and species differences in the size of, number of bifurcations in, and spine density of the basal dendritic arbors cannot be explained by brain size. Instead, pyramidal cell morphology appears to accord with the specialized cortical function these cells perform. Cells in the prefrontal cortex of humans are more branched and more spinous than those in the temporal and occipital lobes. Moreover, cells in the prefrontal cortex of humans are more branched and more spinous than those in the prefrontal cortex of macaque and marmoset monkeys. These results suggest that highly spinous, compartmentalized, pyramidal cells (and the circuits they form) are required to perform complex cortical functions such as comprehension, perception, and planning.

Brain activity during the encoding, retention, and retrieval of stimulus representations

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

Orthographic/phonological facilitation of naming responses in the picture-word task: An event-related fMRI study using overt vocal responding

In the picture-word interference task, naming responses are facilitated when a distractor word is orthographically and phonologically related to the depicted object as compared to an unrelated word. We used event-related functional magnetic resonance imaging (fMRI) to investigate the cerebral hemodynamic responses associated with this priming effect. Serial (or independent-stage) and interactive models of word production that explicitly account for picture-word interference effects assume that the locus of the effect is at the level of retrieving phonological codes, a role attributed recently to the left posterior superior temporal cortex (Wernicke's area). This assumption was tested by randomly presenting participants with trials from orthographically related and unrelated distractor conditions and acquiring image volumes coincident with the estimated peak hemodynamic response for each trial. Overt naming responses occurred in the absence of scanner noise, allowing reaction time data to be recorded. Analysis of this data confirmed the priming effect. Analysis of the fMRI data revealed blood oxygen level-dependent signal decreases in Wernicke's area and the right anterior temporal cortex, whereas signal increases were observed in the anterior cingulate, the right orbitomedial prefrontal, somatosensory, and inferior parietal cortices, and the occipital lobe. The results are interpreted as supporting the locus for the facilitation effect as assumed by both classes of theoretical model of word production. In addition, our results raise the possibilities that, counterintuitively, picture-word interference might be increased by the presentation of orthographically related distractors, due to competition introduced by activation of phonologically related word forms, and that this competition requires inhibitory processes to be resolved. The priming effect is therefore viewed as being sufficient to offset the increased interference. We conclude that information from functional imaging studies might be useful for constraining theoretical models of word production. (C) 2002 Elsevier Science (USA).

Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down syndrome: Effects of environmental enrichment

Mental retardation in individuals with Down syndrome (DS) is thought to result from anomalous development and function of the brain; however, the underlying neuropathological processes have yet to be determined. Early implementation of special care programs result in limited, and temporary, cognitive improvements in DS individuals. In the present study, we investigated the possible neural correlates of these limited improvements. More specifically, we studied cortical pyramidal cells in the frontal cortex of Ts65Dn mice, a partial trisomy of murine chromosome 16 (MMU16) model characterized by cognitive deficits, hyperactivity, behavioral disruption and reduced attention levels similar to those observed in DS, and their control littermates. Animals were raised either in a standard or in an enriched environment. Environmental enrichment had a marked effect on pyramidal cell structure in control animals. Pyramidal cells in environmentally enriched control animals were significantly more branched and more spinous than non-enriched controls. However, environmental enrichment had little effect on pyramidal cell structure in Ts65Dn mice. As each dendritic spine receives at least one excitatory input, differences in the number of spines found in the dendritic arbors of pyramidal cells in the two groups reflect differences in the number of excitatory inputs they receive and, consequently, complexity in cortical circuitry. The present results suggest that behavioral deficits demonstrated in the Ts65Dn model could be attributed to abnormal circuit development.

Stress affects theta activity in limbic networks and impairs novelty-induced exploration and familiarization

Exposure to a novel environment triggers the response of several brain areas that regulate emotional behaviors. Here, we studied theta oscillations within the hippocampus (HPC)-amygdala (AMY)-medial prefrontal cortex (mPFC) network in exploration of a novel environment and subsequent familiarization through repeated exposures to that same environment; in addition, we assessed how concomitant stress exposure could disrupt this activity and impair both behavioral processes. Local field potentials were simultaneously recorded from dorsal and ventral hippocampus (dHPC and vHPC respectively), basolateral amygdala (BLA) and mPFC in freely behaving rats while they were exposed to a novel environment, then repeatedly re-exposed over the course of 3 weeks to that same environment and, finally, on re-exposure to a novel unfamiliar environment. A longitudinal analysis of theta activity within this circuit revealed a reduction of vHPC and BLA theta power and vHPC-BLA theta coherence through familiarization which was correlated with a return to normal exploratory behavior in control rats. In contrast, a persistent over-activation of the same brain regions was observed in stressed rats that displayed impairments in novel exploration and familiarization processes. Importantly, we show that stress also affected intra-hippocampal synchrony and heightened the coherence between vHPC and BLA. In summary, we demonstrate that modulatory theta activity in the aforementioned circuit, namely in the vHPC and BLA, is correlated with the expression of anxiety in novelty-induced exploration and familiarization in both normal and pathological conditions.

Past/present and future worries: na fMRI study

For the past decade, numerous imaging techniques gave rise to remarka-ble progresses in the understanding of brain’s structure and function. Amongst the wide variety of studies onto the field of neuroscience, neuropsychiatric re-searches with resource to neuroimaging have attracted increasing attention. The present study will focus on the identification of brain areas recruited while normative subjects read sentences related to past/present or future wor-ries. Our main aim was to accurately characterize these brain areas while providing them with a time-stamp that would hopefully help us understand the implications of past/present memories and future envisioning in worrying episodes. With that purpose, functional magnetic resonance imaging data was collected from ten healthy individuals. The obtained data was processed and statistically treated using the General Linear Model and both Fixed and Ran-dom Effects Analysis for group-level results. Thereafter, a Multi-Voxel Pattern Analysis with Searchlight Mapping was performed in order to find patterns of activation that allow differentiation between conditions. The obtained results indicate higher brain activation while reading sen-tences related to past/present worries when compared to future worry or neu-tral sentences. The main areas include frontal cortex, posterior parietal, occipital and temporal areas. Worrying, per se, was characterized by activation of the medial posterior parietal cortex, left posterior occipital lobe and left central temporal lobe. With the searchlight mapping approach we were able to further identify patterns of distinction between conditions, which were located in the parietal, limbic and frontal lobes.

Pathological Reorganization of NMDA Receptors Subunits and Postsynaptic Protein PSD-95 Distribution in Alzheimer's Disease.

In Alzheimer's disease (AD), synaptic alterations play a major role and are often correlated with cognitive changes. In order to better understand synaptic modifications, we compared alterations in NMDA receptors and postsynaptic protein PSD-95 expression in the entorhinal cortex (EC) and frontal cortex (FC; area 9) of AD and control brains. We combined immunohistochemical and image analysis methods to quantify on consecutive sections the distribution of PSD-95 and NMDA receptors GluN1, GluN2A and GluN2B in EC and FC from 25 AD and control cases. The density of stained receptors was analyzed using multivariate statistical methods to assess the effect of neurodegeneration. In both regions, the number of neuronal profiles immunostained for GluN1 receptors subunit and PSD-95 protein was significantly increased in AD compared to controls (3-6 fold), while the number of neuronal profiles stained for GluN2A and GluN2B receptors subunits was on the contrary decreased (3-4 fold). The increase in marked neuronal profiles was more prominent in a cortical band corresponding to layers 3 to 5 with large pyramidal cells. Neurons positive for GluN1 or PSD-95 staining were often found in the same localization on consecutive sections and they were also reactive for the anti-tau antibody AD2, indicating a neurodegenerative process. Differences in the density of immunoreactive puncta representing neuropile were not statistically significant. Altogether these data indicate that GluN1 and PSD-95 accumulate in the neuronal perikarya, but this is not the case for GluN2A and GluN2B, while the neuropile compartment is less subject to modifications. Thus, important variations in the pattern of distribution of the NMDA receptors subunits and PSD-95 represent a marker in AD and by impairing the neuronal network, contribute to functional deterioration.

Influence of the in vivo deregulation of the expression of ntrk3 (trkc) on cortical development of a murine model of panic/anxiety disorder

Alteracions durant el desenvolupament cerebral produirien canvis en la connectivitat neuronal i la bioquímica cel•lular que podrien resultar en una disfunció cognitiva i/o emocional, desembocant a trastorns psiquiàtrics. Les neurotrofines intervenen en els processos del neurodesenvolupament i en la funcionalitat del cervell adult i, conseqüentment, serien bons candidats com a factors de predisposició en diverses malalties mentals. S’ha suggerit la implicació del receptor de la neurotrofina 3, TrkC, en el trastorn de pànic. Nosaltres proposem que la sobreexpressió del gen NTRK3 (TrkC) és un mediador comú dels desencadenants genètics i ambientals d’aquest trastorn. Concretament, la seva desregulació podria produir canvis estructurals i funcionals a l’escorça cerebral dels pacients pel seu paper durant l’establiment dels circuïts corticals i la neuroplasticitat a l’adult, probablement esdevenint elements de predisposició a patir atacs de pànic. Els objectius principals d’aquest treball han estat: 1/determinar la contribució específica del gen NTRK3 a les alteracions de l’escorça cerebral observades en pacients, utilitzant un model murí modificat genèticament (TgNTRK3), i 2/analitzar l’impacte específic de la sobreexpressió de NTRK3 sobre la corticogènesi durant estadis embrionaris o postnatals estudiant la neurogènesi i la neuritogènesi. Els resultats indiquen que la sobreexpressió de NTRK3 als ratolins produeix una reducció del gruix de l’escorça frontal, recapitulant la hipofrontalitat dels pacients, que comportaria una menor inhibició dels nuclis subcorticals del sistema límbic com l’amígdala, i alteracions citoarquitectòniques a l’escorça prefrontal medial que recolzen la hipòtesi del seu mal funcionament. Tanmateix, els ratolins TgNTRK3 presenten canvis estructurals a l’escorça somatosensorial, suggerint que el processament de la informació sensorial podria estar alterat, el que encara no s’ha explorat en pacients. La sobreexpressió de NTRK3 també afecta la neuritogènesi en cultius primaris corticals i modifica la resposta de les neurones a l’estimulació amb neurotrofines. Per tant, el fenotip cortical adult dels TgNTRK3 podria dependre d’alteracions durant la corticogènesi.

Differential prefrontal-like deficit in children after cerebellar astrocytoma and medulloblastoma tumor

BACKGROUND This study was realized thanks to the collaboration of children and adolescents who had been resected from cerebellar tumors. The medulloblastoma group (CE+, n = 7) in addition to surgery received radiation and chemotherapy. The astrocytoma group (CE, n = 13) did not receive additional treatments. Each clinical group was compared in their executive functioning with a paired control group (n = 12). The performances of the clinical groups with respect to controls were compared considering the tumor's localization (vermis or hemisphere) and the affectation (or not) of the dentate nucleus. Executive variables were correlated with the age at surgery, the time between surgery-evaluation and the resected volume. METHODS The executive functioning was assessed by means of WCST, Complex Rey Figure, Controlled Oral Word Association Test (letter and animal categories), Digits span (WISC-R verbal scale) and Stroop test. These tests are very sensitive to dorsolateral PFC and/or to medial frontal cortex functions. The scores for the non-verbal Raven IQ were also obtained. Direct scores were corrected by age and transformed in standard scores using normative data. The neuropsychological evaluation was made at 3.25 (SD = 2.74) years from surgery in CE group and at 6.47 (SD = 2.77) in CE+ group. RESULTS The Medulloblastoma group showed severe executive deficit (frontal-like deficit due to cerebellar lesions and/or cerebellar-frontal diaschisis, as indicate the results in astrocytoma group (without treatments), that also can be generated and/or increased by treatments in the medulloblastoma group. The need for differential rehabilitation strategies for specific clinical groups is remarked. The results are also discussed in the context of the Cerebellar Cognitive Affective Syndrome.

Multispectral brain morphometry in Tourette syndrome persisting into adulthood.

Tourette syndrome is a childhood-onset neuropsychiatric disorder with a high prevalence of attention deficit hyperactivity and obsessive-compulsive disorder co-morbidities. Structural changes have been found in frontal cortex and striatum in children and adolescents. A limited number of morphometric studies in Tourette syndrome persisting into adulthood suggest ongoing structural alterations affecting frontostriatal circuits. Using cortical thickness estimation and voxel-based analysis of T1- and diffusion-weighted structural magnetic resonance images, we examined 40 adults with Tourette syndrome in comparison with 40 age- and gender-matched healthy controls. Patients with Tourette syndrome showed relative grey matter volume reduction in orbitofrontal, anterior cingulate and ventrolateral prefrontal cortices bilaterally. Cortical thinning extended into the limbic mesial temporal lobe. The grey matter changes were modulated additionally by the presence of co-morbidities and symptom severity. Prefrontal cortical thickness reduction correlated negatively with tic severity, while volume increase in primary somatosensory cortex depended on the intensity of premonitory sensations. Orbitofrontal cortex volume changes were further associated with abnormal water diffusivity within grey matter. White matter analysis revealed changes in fibre coherence in patients with Tourette syndrome within anterior parts of the corpus callosum. The severity of motor tics and premonitory urges had an impact on the integrity of tracts corresponding to cortico-cortical and cortico-subcortical connections. Our results provide empirical support for a patho-aetiological model of Tourette syndrome based on developmental abnormalities, with perturbation of compensatory systems marking persistence of symptoms into adulthood. We interpret the symptom severity related grey matter volume increase in distinct functional brain areas as evidence of ongoing structural plasticity. The convergence of evidence from volume and water diffusivity imaging strengthens the validity of our findings and attests to the value of a novel multimodal combination of volume and cortical thickness estimations that provides unique and complementary information by exploiting their differential sensitivity to structural change.