Augmentation sélective de l'expression protéique et de l'ARNm de la synthase du monoxyde d'azote dans les régions vulnérables du cerveau chez les rats déficients en thiamine

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Augmentation sélective de l'expression protéique et de l'ARNm de la synthase du monoxyde d'azote dans les régions vulnérables du cerveau chez les rats déficients en thiamine

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Depression in Parkinson`s disease: Convergence from voxel-based morphometry and functional magnetic resonance imaging in the limbic thalamus

Depression is the most frequent psychiatric disorder in Parkinson`s disease (PD). Although evidence Suggests that depression in PD is related to the degenerative process that underlies the disease, further studies are necessary to better understand the neural basis of depression in this population of patients. In order to investigate neuronal alterations underlying the depression in PD, we studied thirty-six patients with idiopathic PD. Twenty of these patients had the diagnosis of major depression disorder and sixteen did not. The two groups were matched for PD motor severity according to Unified Parkinson Disease Rating Scale (UPDRS). First we conducted a functional magnetic resonance imaging (fMRI) using an event-related parametric emotional perception paradigm with test retest design. Our results showed decreased activation in the left mediodorsal (MD) thalamus and in medial prefrontall cortex in PD patients with depression compared to those without depression. Based upon these results and the increased neuron count in MD thalamus found in previous studies, we conducted a region of interest (ROI) guided voxel-based morphometry (VBM) study comparing the thalamic volume. Our results showed an increased volume in mediodorsal thalamic nuclei bilaterally. Converging morphological changes and functional emotional processing in mediodorsal thalamus highlight the importance of limbic thalamus in PD depression. In addition this data supports the link between neurodegenerative alterations and mood regulation. (C) 2009 Elsevier Inc. All rights reserved.

Selective down-regulation of the astrocyte glutamate transporters GLT-1 and GLAST within the medial thalamus in experimental wernicke's encephalopathy

Although earlier studies on thiamine deficiency have reported increases in extracellular glutamate concentration in the thalamus, a vulnerable region of the brain in this disorder, the mechanism by which this occurs has remained unresolved. Treatment with pyrithiamine, a central thiamine antagonist, resulted in a 71 and 55% decrease in protein levels of the astrocyte glutamate transporters GLT-1 and GLAST, respectively, by immunoblotting in the medial thalamus of day 14 symptomatic rats at loss of righting reflexes. These changes occurred prior to the onset of convulsions and pannecrosis. Loss of both GLT-1 and GLAST transporter sites was also confirmed in this region of the thalamus at the symptomatic stage using immunohistochemical methods. In contrast, no change in either transporter protein was detected in the non-vulnerable frontal parietal cortex. These effects are selective; protein levels of the astrocyte GABA transporter GAT-3 were unaffected in the medial thalamus. In addition, astrocyte-specific glial fibrillary acidic protein (GFAP) content was unchanged in this brain region, suggesting that astrocytes are spared in this disorder. Loss of GLT-1 or GLAST protein was not observed on day 12 of treatment, indicating that down-regulation of these transporters occurs within 48 h prior to loss of righting reflexes. Finally, GLT-1 content was positively correlated with levels of the neurofilament protein alpha -internexin, suggesting that early neuronal drop-out may contribute to the down-regulation of this glutamate transporter and subsequent pannecrosis. A selective, focal loss of GLT-1 and GLAST transporter proteins provides a rational explanation for the increase in interstitial glutamate levels, and may play a major role in the selective vulnerability of thalamic structures to thiamine deficiency-induced cell death.

Projections from the substantia nigra pars reticulata to the motor thalamus of the rat: Single axon reconstructions and immunohistochemical study

This is a study in the rat of the distribution of specific neurotransmitters in neurones projecting from the substantia nigra reticulata (SNR) to the ventrolateral (VL) and ventromedial (VM) thalamic nuclei. Individual axons projecting from the SNR to these thalamic nuclei have also been reconstructed following small injection of the anterograde tracer dextran biotin into the the SNR. Analysis of reconstructions revealed two populations of SNR neurones projecting onto the VL and VM thalamic nuclei. One group projects directly onto the VM and VL, and the other projects to the VM/VL and to the parafascicular nucleus. In another set of experiments Fluoro-Gold was injected into the VL/VM to label SNR projection neurones retrogradely, and immunohistochemistry was performed to determine the distribution of choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), gamma -aminobutyric acid (GABA), and glutamate in Fluoro-Gold-labelled SNR projection neurones. Most SNR-VL/VM thalamic projection neurones were immunoreactive to acetylcholine or glutamate, whereas only 25% of the projection neurones were found to be immunoreactive to GABA. (C) 2001 Wiley-Liss, Inc.

Somatotopic organization and cortical projections of the ventrobasal complex of the flying fox: an "inverted" wing representation in the thalamus

The present study investigates the somatotopic representation in the somatosensory thalamus of a megachiropteran bat. Using standard microelectrode mapping techniques, representational maps were generated for the ventrobasal (Vb) and posterior (Po) thalamic complexes of the Grey-headed flying fox. Anatomical tracing from neocortical injections provided additional data confirming the somatotopy found physiologically. A full representation of the body surface innervated by the trigeminal and spinal nerves was found. However, in contrast with other mammals, the representations of the forelimb and adjacent thoracic trunk within the thalamus were inverted. This means that the distal portions of the wing membrane and the tips of the digits were represented dorsally in Vb, and the thoracic trunk was represented ventrally In Po the digit tips were represented in the ventral most portion and the thoracic trunk in the dorsal portion of the nucleus. These results are discussed in relation to similarities of megachiropteran somatosensory thalamic nuclei to those of other mammalian species and in relation to the formation of thalamic somatotopic maps and fiber sorting.

A role for the dominant thalamus in language? A linguistic comparison of two cases subsequent to unilateral thalamotomy procedures in the dominant and non-dominant hemispheres

Background: Thalamotomy has been reported to be successful in ameliorating the motor symptoms of tremor and/or rigidity in people with Parkinson's disease (PD), emphasising the bona fide contribution of this subcortical nucleus to the neural circuitry subserving motor function. Despite evidence of parallel yet segregated associative and motor cortico-subcortical-cortical circuits, comparatively few studies have investigated the effects of this procedure on cognitive functions. In particular, research pertaining to the impact of thalamotomy on linguistic processes is fundamentally lacking. Aims: The purpose of this research was to investigate the effects of thalamotomy in the language dominant and non-dominant hemispheres on linguistic functioning, relative to operative theoretical models of subcortical participation in language. This paper compares the linguistic profiles of two males with PD, aged 75 years (10 years of formal education) and 62 years (22 years of formal education), subsequent to unilateral thalamotomy procedures within the language dominant and non-dominant hemispheres, respectively. Methods & Procedures: Comprehensive linguistic profiles comprising general and high-level linguistic abilities in addition to on-line semantic processing skills were compiled up to 1 month prior to surgery and 3 months post-operatively, within perceived on'' periods (i.e., when optimally medicated). Pre- and post-operative language performances were compared within-subjects to a group of 16 non-surgical Parkinson's controls (NSPD) and a group of 16 non-neurologically impaired adults (NC). Outcomes & Results: The findings of this research suggest a laterality effect with regard to the contribution of the thalamus to high-level linguistic abilities and, potentially, the temporal processing of semantic information. This outcome supports the application of high-level linguistic assessments and measures of semantic processing proficiency to the clinical management of individuals with dominant thalamic lesions. Conclusions: The results reported lend support to contemporary theories of dominant thalamic participation in language, serving to further elucidate our current understanding of the role of subcortical structures in mediating linguistic processes, relevant to cortical hemispheric dominance.

Orexin/hypocretin (Orx/Hcrt) transmission and drug-seeking behavior: is the paraventricular nucleus of the thalamus (PVT) part of the drug seeking circuitry?

The orexin/hypocretin (Orx/Hcrt) system has long been considered to regulate a wide range of physiological processes, including feeding, energy metabolism, and arousal. More recently, concordant observations have demonstrated an important role for these peptides in the reinforcing properties of most drugs of abuse. Orx/Hcrt neurons arise in the lateral hypothalamus (LH) and project to all brain structures implicated in the regulation of arousal, stress, and reward. Although Orx/Hcrt neurons have been shown to massively project to the paraventricular nucleus of the thalamus (PVT), only recent evidence suggested that the PVT may be a key relay of Orx/Hcrt-coded reward-related communication between the LH and both the ventral and dorsal striatum. While this thalamic region was not thought to be part of the "drug addiction circuitry," an increasing amount of evidence demonstrated that the PVT-particularly PVT Orx/Hcrt transmission-was implicated in the modulation of reward function in general and several aspects of drug-directed behaviors in particular. The present review discusses recent findings that suggest that maladaptive recruitment of PVT Orx/Hcrt signaling by drugs of abuse may promote persistent compulsive drug-seeking behavior following a period of protracted abstinence and as such may represent a relevant target for understanding the long-term vulnerability to drug relapse after withdrawal.

The Ca(V)3.3 calcium channel is the major sleep spindle pacemaker in thalamus.

Low-threshold (T-type) Ca(2+) channels encoded by the Ca(V)3 genes endow neurons with oscillatory properties that underlie slow waves characteristic of the non-rapid eye movement (NREM) sleep EEG. Three Ca(V)3 channel subtypes are expressed in the thalamocortical (TC) system, but their respective roles for the sleep EEG are unclear. Ca(V)3.3 protein is expressed abundantly in the nucleus reticularis thalami (nRt), an essential oscillatory burst generator. We report the characterization of a transgenic Ca(V)3.3(-/-) mouse line and demonstrate that Ca(V)3.3 channels are indispensable for nRt function and for sleep spindles, a hallmark of natural sleep. The absence of Ca(V)3.3 channels prevented oscillatory bursting in the low-frequency (4-10 Hz) range in nRt cells but spared tonic discharge. In contrast, adjacent TC neurons expressing Ca(V)3.1 channels retained low-threshold bursts. Nevertheless, the generation of synchronized thalamic network oscillations underlying sleep-spindle waves was weakened markedly because of the reduced inhibition of TC neurons via nRt cells. T currents in Ca(V)3.3(-/-) mice were <30% compared with those in WT mice, and the remaining current, carried by Ca(V)3.2 channels, generated dendritic [Ca(2+)](i) signals insufficient to provoke oscillatory bursting that arises from interplay with Ca(2+)-dependent small conductance-type 2 K(+) channels. Finally, naturally sleeping Ca(V)3.3(-/-) mice showed a selective reduction in the power density of the σ frequency band (10-12 Hz) at transitions from NREM to REM sleep, with other EEG waves remaining unaltered. Together, these data identify a central role for Ca(V)3.3 channels in the rhythmogenic properties of the sleep-spindle generator and provide a molecular target to elucidate the roles of sleep spindles for brain function and development.

Dying neurons in thalamus of asphyxiated term newborns and rats are autophagic.

OBJECTIVE: Neonatal hypoxic-ischemic encephalopathy (HIE) still carries a high burden by its mortality and long-term neurological morbidity in survivors. Apart from hypothermia, there is no acknowledged therapy for HIE, reflecting the lack of mechanistic understanding of its pathophysiology. (Macro)autophagy, a physiological intracellular process of lysosomal degradation, has been proposed to be excessively activated in excitotoxic conditions such as HIE. The present study examines whether neuronal autophagy in the thalamus of asphyxiated human newborns or P7 rats is enhanced and related to neuronal death processes. METHODS: Neuronal autophagy and cell death were evaluated in the thalamus (frequently injured in severe HIE) of both human newborns who died after severe HIE (n = 5) and P7 hypoxic-ischemic rats (Rice-Vannuci model). Autophagic (LC3, p62), lysosomal (LAMP1, cathepsins), and cell death (TUNEL, caspase-3) markers were studied by immunohistochemistry in human and rat brain sections, and by additional methods in rats (immunoblotting, histochemistry, and electron microscopy). RESULTS: Following severe perinatal asphyxia in both humans and rats, thalamic neurons displayed up to 10-fold (p < 0.001) higher numbers of autophagosomes and lysosomes, implying an enhanced autophagic flux. The highly autophagic neurons presented strong features of apoptosis. These findings were confirmed and elucidated in more detail in rats. INTERPRETATION: These results show for the first time that autophagy is enhanced in severe HIE in dying thalamic neurons of human newborns, as in rats. Experimental neuroprotective strategies targeting autophagy could thus be a promising lead to follow for the development of future therapeutic approaches. Ann Neurol 2014;76:695-711.

Contrasting the functional properties of GABAergic axon terminals with single and multiple synapses in the thalamus

Diverse sources of GABAergic inhibition are a major feature of cortical networks, but distinct inhibitory input systems have not been systematically characterized in the thalamus. Here, we contrasted the properties of two independent GABAergic pathways in the posterior thalamic nucleus of rat, one input from the reticular thalamic nucleus (nRT), and one "extrareticular" input from the anterior pretectal nucleus (APT). The vast majority of nRT-thalamic terminals formed single synapses per postsynaptic target and innervated thin distal dendrites of relay cells. In contrast, single APT-thalamic terminals formed synaptic contacts exclusively via multiple, closely spaced synapses on thick relay cell dendrites. Quantal analysis demonstrated that the two inputs displayed comparable quantal amplitudes, release probabilities, and multiple release sites. The morphological and physiological data together indicated multiple, single-site contacts for nRT and multisite contacts for APT axons. The contrasting synaptic arrangements of the two pathways were paralleled by different short-term plasticities. The multisite APT-thalamic pathway showed larger charge transfer during 50-100 Hz stimulation compared with the nRT pathway and a greater persistent inhibition accruing during stimulation trains. Our results demonstrate that the two inhibitory systems are morpho-functionally distinct and suggest and that multisite GABAergic terminals are tailored for maintained synaptic inhibition even at high presynaptic firing rates. These data explain the efficacy of extrareticular inhibition in timing relay cell activity in sensory and motor thalamic nuclei. Finally, based on the classic nomenclature and the difference between reticular and extrareticular terminals, we define a novel, multisite GABAergic terminal type (F3) in the thalamus.

Postnatal expression pattern of calcium-binding proteins in organotypic thalamic cultures and in the dorsal thalamus in vivo.

The present study describes the postnatal expression of calbindin, calretinin and parvalbumin and glutamic acid decarboxylase (GAD) and microtubule-associated protein 2 (MAP2) in organotypic monocultures of rat dorsal thalamus compared to the thalamus in vivo. Cultures were maintained for up to 7 weeks. Cortex-conditioned medium improved the survival of thalamic cultures. MAP2-immunoreactive material was present in somata and dendrites of small and large-sized neurons throughout the cultures. Parvalbumin immunoreactivity was present in larger multipolar or bitufted neurons along the edge of a culture. These neurons also displayed strong parvalbumin mRNA and GAD mRNA expression, and GABA immunoreactivity. They likely corresponded to cells of the nucleus reticularis thalami. Parvalbumin mRNA, but neither parvalbumin protein nor GAD mRNA, was expressed in neurons with large somata within the explant. They likely represented relay cells. GAD mRNA, but not parvalbumin mRNA, was expressed in small neurons within the explants. Small neurons also displayed calbindin- and calretinin-immunoreactivity. The small neurons likely represented local circuit neurons. The time course of expression of the calcium-binding proteins revealed that all were present at birth with the predicted molecular weights. A low, but constant parvalbumin expression was observed in vitro without the developmental increase seen in vivo, which most likely represented parvalbumin from afferent sources. In contrast, the explantation transiently downregulated the calretinin and calbindin expression, but the neurons recovered the expression after 14 and 21 days, respectively. In conclusion, thalamic monocultures older than three weeks represent a stable neuronal network containing well differentiated neurons of the nucleus reticularis thalami, relay cells and local circuit neurons.