The pyramidal cell of the sensorimotor cortex of the macaque monkey: Phenotypic variation

Recent studies have revealed striking differences in pyramidal cell structure among cortical regions involved in the processing of different functional modalities. For example, cells involved in visual processing show systematic variation, increasing in morphological complexity with rostral progression from V1 through extrastriate areas. Differences have also been identified between pyramidal cells in somatosensory, motor and prefrontal cortex, but the extent to which the pyramidal cell phenotype may vary between these functionally related cortical regions remains unknown. In the present study we investigated the structure of layer III pyramidal cells in somatosensory and motor areas 3b, 4, 5, 6 and 7b of the macaque monkey. Cells were intracellularly injected in fixed, flat-mounted cortical slices and analysed for morphometric parameters. The size of the basal dendritic arbours, the number of their branches and their spine density were found to vary systematically between areas. Namely, we found a trend for increasing complexity in dendritic arbour structure through areas 3b, 5 and 7b. A similar trend occurred through areas 4 and 6. The differences in arbour structure may determine the number of inputs received by neurons and may thus be an important factor in determining function at the cellular and systems level.

Expression of hNP22 is altered in the frontal cortex and hippocampus of the alcoholic human brain

Background: Human neuronal protein (hNP22) is a gene with elevated messenger RNA expression in the prefrontal cortex of the human alcoholic brain. hNP22 has high homology with a rat protein (rNP22). These proteins also share homology with a number of cytoskeleton-interacting proteins. Methods: A rabbit polyclonal antibody to an 18-amino acid epitope was produced for use in Western and immunohistochemical analysis. Samples from the human frontal and motor cortices were used for Western blots (n = 10), whereas a different group of frontal cortex and hippocampal samples were obtained for immunohistochemistry (n = 12). Results: The hNP22 antibody detected a single protein in both rat and human brain. Western blots revealed a significant increase in hNP22 protein levels in the frontal cortex but not the motor cortex of alcoholic cases. Immunohistochemical studies confirmed the increased hNP22 protein expression in all cortical layers. This is consistent with results previously obtained using Northern analysis. Immunohistochemical analysis also revealed a significant increase of hNP22 immunoreactivity in the CA3 and CA4 but not other regions of the hippocampus. Conclusions: It is possible that this protein may play a role in the morphological or plastic changes observed after chronic alcohol exposure and withdrawal, either as a cytoskeleton-interacting protein or as a signaling molecule.

Einfluss frühkindlicher Sozialerfahrung auf die funktionelle Reifung des anterioren cingulären Cortex der Strauchratte (Octodon degus)

Maternal separation, rodent, anterior cingulate, prefrontal cortex, spines, synapses, GABA, calbindin, parvalbumin, calretinin, CRH, CRF

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.

Immunodensity and mRNA expression of A2A adenosine, D2 dopamine, and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: effect of antipsychotic treatment.

RATIONALE: Dopamine D2 receptors are the main target of antipsychotic drugs. In the brain, D2 receptors coexpress with adenosine A2A and CB1 cannabinoid receptors, leading to functional interactions. OBJECTIVES: The protein and messenger RNA (mRNA) contents of A2A, D2, and CB1 receptors were quantified in postmortem prefrontal cortex of subjects with schizophrenia. MATERIALS AND METHODS: The study was performed in subjects suffering schizophrenia (n=31) who mainly died by suicide, matched with non-schizophrenia suicide victims (n=13) and non-suicide controls (n=33). The density of receptor proteins was evaluated by immunodetection techniques, and their relative mRNA expression was quantified by quantitative real-time polymerase chain reaction. RESULTS: In schizophrenia, the densities of A2A (90+/-6%, n=24) and D2-like receptors (95+/-5%, n=22) did not differ from those in controls (100%). Antipsychotic treatment did not induce changes in the protein expression. In contrast, the immunodensity of CB1 receptors was significantly decreased (71+/-7%, n=11; p<0.05) in antipsychotic-treated subjects with schizophrenia but not in drug-free subjects (104+/-13%, n=11). The relative mRNA amounts encoding for A2A, D2, and CB1 receptors were similar in brains of drug-free, antipsychotic-treated subjects with schizophrenia and controls. CONCLUSIONS: The findings suggest that antipsychotics induce down-regulation of CB1 receptors in brain. Since A2A, D2, and CB1 receptors coexpress on brain GABAergic neurons and reductions in markers of GABA neurotransmission have been identified in schizophrenia, a lower density of CB1 receptor induced by antipsychotics could represent an adaptative mechanism that reduces the endocannabinoid-mediated suppression of GABA release, contributing to the normalization of cognitive functions in the disorder.

Differential changes in synaptic proteins in the Alzheimer frontal cortex with marked increase in PSD-95 postsynaptic protein

We investigated how synaptic plasticity is related to the neurodegeneration process in the human dorsolateral prefrontal cortex. Pre- and postsynaptic proteins of Brodmann's area 9 from patients with Alzheimer's disease (AD) and age-matched controls were quantified by immunohistochemical methods and Western blots. The main finding was a significant increase in the expression of postsynaptic density protein PSD-95 in AD brains, revealed on both sections and immunoblots, while the expression of spinophilin, associated to spines, remained quantitatively unchanged despite qualitative changes with age and disease. Presynaptic protein alpha-synuclein indicated an increased immunohistochemical level, while synaptophysin remained unchanged. MAP2, a somatodendritic microtubule protein, as well as AD markers such as amyloid-beta protein and phosphorylated protein tau showed an increased expression on immunosections in AD. Altogether these changes suggest neuritic and synaptic reorganization in the process of AD. In particular, the significant increase in PSD-95 expression suggests a change in NMDA receptors trafficking and may represent a novel marker of functional significance for the disease.

Metabolic alterations in the cortex of a mouse model with glutathione deficit - relevance to schizophrenia

Background: Glutathione (GSH) is a major redox regulator and antioxidant and is decreased in cerebrospinal fluid and prefrontal cortex of schizophrenia patients [Do et al. (2000) Eur J Neurosci 12:3721]. The genes of the key GSH-synthesizing enzyme, glutamate- cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits, are associated with schizophrenia, suggesting that the deficit in GSH synthesis is of genetic origin [Gysin et al. (2007) PNAS 104:16621]. GCLM knock-out (KO) mice, which display an 80% decrease in brain GSH levels, have abnormal brain morphology and function [Do et al. (2009) Curr Opin Neurobiol 19:220]. Developmental redox deregulation by impaired GSH synthesis and environmental risk factors generating oxidative stress may have a central role in schizophrenia. Here, we used GCLM KO mice to investigate the impact of a genetically dysregulated redox system on the neurochemical profile of the developing brain. Methods: The neurochemical profile of the anterior and posterior cortical areas of male and female GCLM KO and wild-type mice was determined by in vivo 1H NMR spectroscopy on postnatal days 10, 20, 30, 60 and 90, under 1 to 1.5% isoflurane anaesthesia. Localised 1H NMR spectroscopy was performed on a 14.1 T, 26 cm VNMRS spectrometer (Varian, Magnex) using a home-built 8 mm diameter quadrature surface coil (used both for RF excitation and signal reception). Spectra were acquired using SPECIAL with TE of 2.8 ms and TR of 4 s from VOIs placed in anterior or posterior regions of the cortex [Mlynárik et al. (2006) MRM 56:965]. LCModel analysis allowed in vivo quantification of a neurochemical profile composed of 18 metabolites. Results: GCLM KO mice displayed nearly undetectable GSH levels as compared to WT mice, demonstrating their drastic redox deregulation. Depletion of GSH triggered alteration of metabolites related to its synthesis, namely increase of glycine and glutamate levels during development (P20 and P30). Concentrations of glutamine and aspartate that are produced from glutamate were also increased in GCLM KO animals relative to WT. In addition, GCLM KO mice also showed higher levels of N-acetylaspartate that originates from the acetylation of aspartate. These metabolites are particularly implicated in neurotransmission processes and in mitochondrial oxidative metabolism. Their increase may indicate impaired mitochondrial metabolism with concomitant accumulation of lactate in the adult mice (P60 and P90). In addition, the GSH depletion triggers reduction of GABA concentration in anterior cortex of the P60 mice, which is in accordance with known impairment of GABAergic interneurons in that area. Changes were generally more pronounced in males than in females at P60, which is consistent with earlier disease onset in male patients. Discussion: In conclusion, the observed metabolic alterations in the cortex of a mouse model of redox deregulation suggest impaired mitochondrial metabolism and altered neurotransmission. The results also highlight the age between P20 and P30 as a sensitive period during the development for these alterations.

Intrahemispheric cortico-cortical connections of the human auditory cortex.

The human auditory cortex comprises the supratemporal plane and large parts of the temporal and parietal convexities. We have investigated the relevant intrahemispheric cortico-cortical connections using in vivo DSI tractography combined with landmark-based registration, automatic cortical parcellation and whole-brain structural connection matrices in 20 right-handed male subjects. On the supratemporal plane, the pattern of connectivity was related to the architectonically defined early-stage auditory areas. It revealed a three-tier architecture characterized by a cascade of connections from the primary auditory cortex to six adjacent non-primary areas and from there to the superior temporal gyrus. Graph theory-driven analysis confirmed the cascade-like connectivity pattern and demonstrated a strong degree of segregation and hierarchy within early-stage auditory areas. Putative higher-order areas on the temporal and parietal convexities had more widely spread local connectivity and long-range connections with the prefrontal cortex; analysis of optimal community structure revealed five distinct modules in each hemisphere. The pattern of temporo-parieto-frontal connectivity was partially asymmetrical. In conclusion, the human early-stage auditory cortical connectivity, as revealed by in vivo DSI tractography, has strong similarities with that of non-human primates. The modular architecture and hemispheric asymmetry in higher-order regions is compatible with segregated processing streams and lateralization of cognitive functions.

Fast oscillatory activity in the anterior cingulate cortex: dopaminergic modulation and effect of perineuronal net loss.

Dopamine release in the prefrontal cortex plays a critical role in cognitive function such as working memory, attention and planning. Dopamine exerts complex modulation on excitability of pyramidal neurons and interneurons, and regulates excitatory and inhibitory synaptic transmission. Because of the complexity of this modulation, it is difficult to fully comprehend the effect of dopamine on neuronal network activity. In this study, we investigated the effect of dopamine on local high-frequency oscillatory neuronal activity (in β band) in slices of the mouse anterior cingulate cortex (ACC). We found that dopamine enhanced the power of these oscillations induced by kainate and carbachol, but did not affect their peak frequency. Activation of D2R and in a lesser degree D1R increased the oscillation power, while activation of D4R had no effect. These high-frequency oscillations in the ACC relied on both phasic inhibitory and excitatory transmission and functional gap junctions. Thus, dopamine released in the ACC promotes high-frequency synchronized local cortical activity which is known to favor information transfer, fast selection and binding of distributed neuronal responses. Finally, the power of these oscillations was significantly enhanced after degradation of the perineuronal nets (PNNs) enwrapping most parvalbumin interneurons. This study provides new insights for a better understanding of the abnormal prefrontal gamma activity in schizophrenia (SZ) patients who display prefrontal anomalies of both the dopaminergic system and the PNNs.

Modulation de l'apprentissage visuel par stimulation électrique transcrânienne à courant direct du cortex préfrontal

Le traitement visuel répété d’un visage inconnu entraîne une suppression de l’activité neuronale dans les régions préférentielles aux visages du cortex occipito-temporal. Cette «suppression neuronale» (SN) est un mécanisme primitif hautement impliqué dans l’apprentissage de visages, pouvant être détecté par une réduction de l’amplitude de la composante N170, un potentiel relié à l’événement (PRE), au-dessus du cortex occipito-temporal. Le cortex préfrontal dorsolatéral (CPDL) influence le traitement et l’encodage visuel, mais sa contribution à la SN de la N170 demeure inconnue. Nous avons utilisé la stimulation électrique transcrânienne à courant direct (SETCD) pour moduler l’excitabilité corticale du CPDL de 14 adultes sains lors de l’apprentissage de visages inconnus. Trois conditions de stimulation étaient utilisées: inhibition à droite, excitation à droite et placebo. Pendant l’apprentissage, l’EEG était enregistré afin d’évaluer la SN de la P100, la N170 et la P300. Trois jours suivant l’apprentissage, une tâche de reconnaissance était administrée où les performances en pourcentage de bonnes réponses et temps de réaction (TR) étaient enregistrées. Les résultats indiquent que la condition d’excitation à droite a facilité la SN de la N170 et a augmentée l’amplitude de la P300, entraînant une reconnaissance des visages plus rapide à long-terme. À l’inverse, la condition d’inhibition à droite a causé une augmentation de l’amplitude de la N170 et des TR plus lents, sans affecter la P300. Ces résultats sont les premiers à démontrer que la modulation d’excitabilité du CPDL puisse influencer l’encodage visuel de visages inconnus, soulignant l’importance du CPDL dans les mécanismes d’apprentissage de base.

Étude du cortex prémoteur et préfrontal lors de la prise de décision pendant l'intégration temporelle des informations

Une variété de modèles sur le processus de prise de décision dans divers contextes présume que les sujets accumulent les évidences sensorielles, échantillonnent et intègrent constamment les signaux pour et contre des hypothèses alternatives. L'intégration continue jusqu'à ce que les évidences en faveur de l'une des hypothèses dépassent un seuil de critère de décision (niveau de preuve exigé pour prendre une décision). De nouveaux modèles suggèrent que ce processus de décision est plutôt dynamique; les différents paramètres peuvent varier entre les essais et même pendant l’essai plutôt que d’être un processus statique avec des paramètres qui ne changent qu’entre les blocs d’essais. Ce projet de doctorat a pour but de démontrer que les décisions concernant les mouvements d’atteinte impliquent un mécanisme d’accumulation temporelle des informations sensorielles menant à un seuil de décision. Pour ce faire, nous avons élaboré un paradigme de prise de décision basée sur un stimulus ambigu afin de voir si les neurones du cortex moteur primaire (M1), prémoteur dorsal (PMd) et préfrontal (DLPFc) démontrent des corrélats neuronaux de ce processus d’accumulation temporelle. Nous avons tout d’abord testé différentes versions de la tâche avec l’aide de sujets humains afin de développer une tâche où l’on observe le comportement idéal des sujets pour nous permettre de vérifier l’hypothèse de travail. Les données comportementales chez l’humain et les singes des temps de réaction et du pourcentage d'erreurs montrent une augmentation systématique avec l'augmentation de l'ambigüité du stimulus. Ces résultats sont cohérents avec les prédictions des modèles de diffusion, tel que confirmé par une modélisation computationnelle des données. Nous avons, par la suite, enregistré des cellules dans M1, PMd et DLPFc de 2 singes pendant qu'ils s'exécutaient à la tâche. Les neurones de M1 ne semblent pas être influencés par l'ambiguïté des stimuli mais déchargent plutôt en corrélation avec le mouvement exécuté. Les neurones du PMd codent la direction du mouvement choisi par les singes, assez rapidement après la présentation du stimulus. De plus, l’activation de plusieurs cellules du PMd est plus lente lorsque l'ambiguïté du stimulus augmente et prend plus de temps à signaler la direction de mouvement. L’activité des neurones du PMd reflète le choix de l’animal, peu importe si c’est une bonne réponse ou une erreur. Ceci supporte un rôle du PMd dans la prise de décision concernant les mouvements d’atteinte. Finalement, nous avons débuté des enregistrements dans le cortex préfrontal et les résultats présentés sont préliminaires. Les neurones du DLPFc semblent beaucoup plus influencés par les combinaisons des facteurs de couleur et de position spatiale que les neurones du PMd. Notre conclusion est que le cortex PMd est impliqué dans l'évaluation des évidences pour ou contre la position spatiale de différentes cibles potentielles mais assez indépendamment de la couleur de celles-ci. Le cortex DLPFc serait plutôt responsable du traitement des informations pour la combinaison de la couleur et de la position des cibles spatiales et du stimulus ambigu nécessaire pour faire le lien entre le stimulus ambigu et la cible correspondante.

Right ventromedial and dorsolateral prefrontal cortices mediate adaptive decisions under ambiguity by integrating choice utility and outcome evaluation.

The Iowa gambling task (IGT) is one of the most influential behavioral paradigms in reward-related decision making and has been, most notably, associated with ventromedial prefrontal cortex function. However, performance in the IGT relies on a complex set of cognitive subprocesses, in particular integrating information about the outcome of choices into a continuously updated decision strategy under ambiguous conditions. The complexity of the task has made it difficult for neuroimaging studies to disentangle the underlying neurocognitive processes. In this study, we used functional magnetic resonance imaging in combination with a novel adaptation of the task, which allowed us to examine separately activation associated with the moment of decision or the evaluation of decision outcomes. Importantly, using whole-brain regression analyses with individual performance, in combination with the choice/outcome history of individual subjects, we aimed to identify the neural overlap between areas that are involved in the evaluation of outcomes and in the progressive discrimination of the relative value of available choice options, thus mapping the two fundamental cognitive processes that lead to adaptive decision making. We show that activation in right ventromedial and dorsolateral prefrontal cortex was predictive of adaptive performance, in both discriminating disadvantageous from advantageous decisions and confirming negative decision outcomes. We propose that these two prefrontal areas mediate shifting away from disadvantageous choices through their sensitivity to accumulating negative outcomes. These findings provide functional evidence of the underlying processes by which these prefrontal subregions drive adaptive choice in the task, namely through contingency-sensitive outcome evaluation.

Prolonged neglect following unilateral disruption of a prefrontal cortical-dorsal striatal system.

We investigated the potential function of the system formed by connections between the medial prefrontal cortex and the dorsomedial striatum in aspects of attentional function in the rat. It has been reported previously that disconnection of the same corticostriatal circuit produced marked deficits in performance of a serial, choice reaction-time task while sparing the acquisition of an appetitive Pavlovian approach behaviour in an autoshaping task (Christakou et al., 2001). Here, we hypothesized that unilateral disruption of the same circuit would lead to hemispatial inattention, contrasting with the global attention deficit following complete disconnection of the system. Combined unilateral lesions of the medial prefrontal cortex (mPFC) and the medial caudate-putamen (mCPu) within the same hemisphere produced a severe and long-lasting contralesional neglect syndrome while sparing the acquisition of autoshaping. These results provide further evidence for the involvement of the medial prefrontal-dorsomedial striatal circuit in aspects of attentional function, as well as insight into the nature of neglect deficits following lesions at different levels within corticostriatal circuitry.

Prefrontal cortical-ventral striatal interactions involved in affective modulation of attentional performance: implications for corticostriatal circuit function

Anatomically segregated systems linking the frontal cortex and the striatum are involved in various aspects of cognitive, affective, and motor processing. In this study, we examined the effects of combined unilateral lesions of the medial prefrontal cortex (mPFC) and the core subregion of the nucleus accumbens (AcbC) in opposite hemispheres (disconnection) on a continuous performance, visual attention test [five-choice serial reaction-time task (5CSRTT)]. The disconnection lesion produced a set of specific changes in performance of the 5CSRTT, resembling changes that followed bilateral AcbC lesions while, in addition, comprising a subset of the behavioral changes after bilateral mPFC lesions previously reported using the same task. Specifically, both mPFC/AcbC disconnection and bilateral AcbC lesions markedly affected aspects of response control related to affective feedback, as indexed by perseverative responding in the 5CSRTT. These effects were comparable, although not identical, to those in animals with either bilateral AcbC or mPFC/AcbC disconnection lesions. The mPFC/AcbC disconnection resulted in a behavioral profile largely distinct from that produced by disconnection of a similar circuit described previously, between the mPFC and the dorsomedial striatum, which were shown to form a functional network underlying aspects of visual attention and attention to action. This distinction provides an insight into the functional specialization of corticostriatal circuits in similar behavioral contexts.

Functional disconnection of a prefrontal cortical-dorsal striatal system disrupts choice reaction time performance: implications for attentional function

This series of experiments investigated the role of a prefrontal cortical-dorsal striatal circuit in attention, using a continuous performance task of sustained and spatially divided visual attention. A unilateral excitotoxic lesion of the medial prefrontal cortex and a contralateral lesion of the medial caudate-putamen were used to "disconnect" the circuit. Control groups of rats with unilateral lesions of either structure were tested in the same task. Behavioral controls included testing the effects of the disconnection lesion on Pavlovian discriminated approach behavior. The disconnection lesion produced a significant reduction in the accuracy of performance in the attentional task but did not impair Pavlovian approach behavior or affect locomotor or motivational variables, providing evidence for the involvement of this medial prefrontal corticostriatal system in aspects of visual attentional function.