The anterior thalamic nuclei (ATN) are a critical part of an extended hippocampal system that supports key elements of episodic memory. Damage or disconnection of the ATN is a component of clinical conditions associated with severe anterograde amnesisa such as the Korsakoff’s syndrome, thalamic stroke, and neurodegenerative disorders. Previous studies have demonstrated that the ATN and hippocampus are often interdependent, and that ATN damage can result in ‘covert pathology’ in ostensibly healthy distal regions of the extended hippocampal system. Adult male rats with neurotoxic bilateral ATN lesions or sham surgery were post-operatively housed in an enriched environment or standard housing after a lesion-induced spatial working memory deficit had been established. These rats were retested on cross-maze and then trained in radial-arm maze spatial memory tasks. Other enriched rats received pseudo-training only after the enrichment period. The detailed neuromorphology of neurons was subsequently examined in the hippocampal CA1. Soma characteristics were also examined in the retrosplenial granular b cortex and the prelimbic cortex. In Experiment 1, ATN lesions produced clear deficits in both the cross-maze and radial-arm maze tasks and reduced hippocampal CA1 dendritic complexity, length, and spine density, while increasing the average diameter of the dendrites. Post-operative enrichment reversed the ATN lesion-induced deficits in the cross-maze and radial-arm maze, and returned CA1 basal and apical spine density to a level comparable to that of sham standard housed trained rats. The sham enriched rats exhibited improved radial-arm maze performance and increased CA1 branching complexity and spine density in both basal and apical arbors compared to sham standard housed rats. The neuromorphological changes observed in the enriched ATN and sham rats may be in part responsible for the spatial working memory improvements observed. Experiment 2 provided support for this contention by demonstrating that the CA1 spine changes were explicitly relevant to spatial learning and memory, because trained enriched sham and ATN rats had increased spines, particularly in the basal tree when compared to closely comparable pseudo-trained enriched rats. Interestingly, spatial memory training increased the numbers of both thin and mushroom spines, whereas enrichment was only associated with an increase in thin spines. In Experiment 3, ATN lesions increased cell body size in layer II of the retrosplenial granular b cortex, whereas enrichment decreased cell body size in layer V of this region. Neither ATN lesions nor enrichment had any effect on cell body morphology in the prelimbic cortex. The current research provides some of the strongest evidence to date of ATN and hippocampal interdependence within the extended hippocampal system, and provides the first evidence of neuromorphological correlates of recovery after ATN lesions.

Parkinson’s disease patients present with the highest risk of dementia development. The thalamus, integral to several functions and behaviours is involved in the pathophysiology of Parkinson’s disease. The aim of this thesis was to determine if anatomical abnormalities in the thalamus are associated with the development of dementia in Parkinson’s disease. We examined the thalamus using macro and microstructural techniques and the white matter pathways that connect the thalamus with areas of the surrounding cortex using diffusion tensor imaging (DTI) based tractography. T1-weighted magnetic resonance and DT images were collected in 56 Parkinson’s disease patients with no cognitive impairment, 19 patients with mild cognitive impairment, 17 patients with dementia and 25 healthy individuals who acted as control subjects. An established automated segmentation procedure (FIRST FSL) was used to delineate the thalamus and a modified k-means clustering algorithm applied to segment the thalamus into clusters assumed to represent thalamic nuclei. Fibre tracts were determined using DTI probabilistic tracking methods available in FIRST. Microstructural integrity was quantified by fractional anisotropy and mean diffusivity (MD) DTI measures. Results show that microstructural measures of thalamic integrity are more sensitive to cognitive dysfunction in PD than macrostructural measures. For the first time we showed a progressive worsening of cellular integrity (MD) in the groups who had greater levels of cognitive dysfunction. Thalamic degeneration was regionally specific and most advanced in the limbic thalamic nuclei which influenced executive function and attention, areas of cognition that are known to be affected in the earliest stages of PD. The integrity of the fibre tracts corresponding to these thalamic regions was also compromised. Degeneration of fibre tracts was most evident in the dementia group, indicating that they may be more protected against Lewy pathology than the nuclei of the thalamus. Our findings confirm previous histological, animal and lesion studies and provide a reliable estimate of cortical degeneration in PD that can be applied non-invasively and in vivo. A longitudinal study is needed to monitor the progression of cognitive decline in PD but we have provided the basis for further investigation into the predictive validity of thalamic degeneration for cognitive dysfunction. In the future, the microstructural changes of the thalamus could be used as biomarkers for the identification of individuals with a higher risk for dementia development and for the longitudinal monitoring of any interventions into cognitive decline.

Ce travail de thèse avait pour objectif d’étudier le rôle de l’hippocampe (HPC) ventral et des noyaux reuniens (Re) et rhomboïde (Rh) du thalamus dans les processus cognitifs qui sous-tendent la mémoire spatiale chez le Rat. Par l’utilisation d’approches complémentaires combinant l’imagerie cérébrale, la lésion excitotoxique, l’inactivation fonctionnelle réversible et des évaluations comportementales, nos résultats ont mis en évidence : (1) l’implication spécifique de l’HPC ventral uniquement dans le rappel d’informations spatiales ; (2) un rôle-clé des noyaux Re et Rh dans la persistance d’un souvenir spatial ; (3) l’implication des noyaux Re et Rh dans le labyrinthe du double-H, un nouveau test nécessitant d’une part, l’utilisation d’informations spatiales dépendant de l’intégrité de l’HPC dorsal, et d’autre part, une flexibilité comportementale, impliquant le cortex préfrontal médian. Ainsi, l’ensemble de ces résultats permet de proposer l’existence d’un circuit HPC-préfronto-thalamique impliqué dans divers aspects du traitement des informations spatiales. / The main objective of this thesis was to investigate the role of the ventral hippocampus (HPC) and the reuniens (Re) and rhomboid (Rh) thalamic nuclei in the cognitive processes underlying spatial memory in the Rat. If our results first confirmed, in the Morris water maze, the role of the dorsal HPC in the acquisition and retrieval of a spatial reference memory, we demonstrated the specific involvement of the ventral HPC only in the recall of spatial information. In addition, by using complementary approaches combining brain imaging, excitotoxic lesion and reversible functional inactivation, we were able to show for the first time a key role for the Re and Rh in the persistence of a spatial memory (25 days). Finally, the third set of experiments has highlighted the involvement of the Re and Rh in a mnemonic task performed in a new test, the double-H maze, which requires the use of spatial information depending on the integrity of the dorsal HPC, and a behavioral flexibility, involving the medial prefrontal cortex. Thus, taken together, these results suggest the involvement of a HPC-prefronto-thalamic network in various aspects of spatial information processing.

No description available.

Obsessive compulsive disorder (OCD) is one of the most disabling psychiatric disorder. About 10% of patients with OCD do not respond to pharmacological treatment. However, deep brain stimulation (DBS) has advanced as an alternative treatment. In 2002, two patients who suffered from co-morbidity of Parkinson’s disease (PD) and OCD were treated with DBS for their PD, with DBS-electrodes placed in the subthalamic nucleus (STN). Surprisingly, not only PD symptoms but also OCD symptoms were improved. This was the first time that patients with OCD were treated with DBS in STN and it was found to markedly improve their symptoms. When performing DBS in patients with OCD, as well as for treating PD, several side-effectshave been observed. The side-effects can be both physical and psychological. In this project,the aim is to investigate the efficiency and side-effects of DBS in OCD, correlated with the position of the electrode in, or near, the STN. To address the aim, 10 published reports were analysed. It was found that all electrode positions reported resulted in great improvement of OCD symptoms. In fact, 88% of patients had significant improvement. There was no clear correlation between position of the electrode and number or type of side-effect. However, there was a trend that patients with the electrode placed in associative/limbic STN suffered from more side-effects. In conclusion, this project demonstrates that there might be a correlation between target for electrode stimulation and side-effects. It would be interesting analyse this closer, including additional electrode target areas, but also consider other possible explanations for the variety of side-effects caused by DBS for OCD.

No description available.

Les ganglions de la base (GB) forment une boucle complexe avec le cortex et le thalamus qui est impliquée dans la sélection de l’action et le contrôle du mouvement. Les activités oscillatoires synchronisées dans le réseau des GB ont été proposées comme pouvant jouer un rôle essentiel dans la coordination du flux de l’information au sein de ces circuits neuronaux. Ainsi, leur dérégulation dans le temps et l’espace pourrait devenir pathologique. Dans la maladie de Parkinson (MP), l’expression anormalement élevée d’oscillations neuronales comprises dans les gammes de fréquences beta (β, 10-30 Hz) serait la cause des déficits moteurs (akinétique et bradykinétique) de cette maladie. Cependant, les réseaux neuronaux à l’origine des oscillations β et l’implication physiopathologique de celles-ci restent encore inconnus. Le noyau sous-thalamique (NST) est un carrefour anatomique des GB situé au centre de réseaux potentiellement impliqués dans l’émergence de ces états hyper-synchronisés. L’objectif de cette thèse était de déterminer le rôle causal des principales entrées du NST (i.e. le cortex moteur, le globus pallidus, et le noyau parafasciculaire du thalamus) dans le maintien et la propagation des oscillations β. Pour cela, nous avons développé des approches de manipulation optogénétique combinées à des enregistrements électrophysiologiques in vivo dans un modèle rongeur de la MP. L’ensemble de nos travaux démontre la contribution respective des différents circuits neuronaux interrogés et souligne l’importance du globus pallidus dans le contrôle de la propagation et du maintien des oscillations β dans l’ensemble de la boucle des GB. / The basal-ganglia (BG) form a complex loop with the cortex and the thalamus that is involved in action selection and movement control. Synchronized oscillatory activities in basal-ganglia neuronal circuits have been proposed to play a key role in coordinating information flow within this neuronal network. If synchronized oscillatory activities are important for normal motor function, their dysregulation in space and time could be pathological. Indeed, in Parkinson’s disease (PD), many studies have reported an abnormal increase in the expression level of neuronal oscillations contain in the beta (β) frequency range (15-30 Hz). These abnormal β oscillations have been correlated with two mains symptoms of PD: akinesia/bradykinesia. However, which BG neuronal circuits generate those abnormal β oscillations, and whether they play a causal role in PD motor dysfunction is not known. The subthalamic nucleus (STN) is a key nucleus in BG that receives converging inputs from the motor cortex, the parafascicular thalamic nucleus and the globus pallidus. Here, we used a rat model of PD combined with in vivo electrophysiological recordings and optogenetic silencing to investigate how selective manipulation of STN inputs causally influence BG network dynamic. Our data highlight the causal role of the globus pallidus in the generation and propagation mechanisms of abnormal β-oscillations.

<p><a></a><a>The visual system is capable of interpreting immense sensory complexity, allowing us to quickly identify behaviorally relevant stimuli in the environment. It performs this task with a hierarchical organization that works to detect, relay, and integrate visual stimulus features into an interpretable form. To understand the complexities of this system, visual neuroscientists have benefited from the many advantages of using mice as visual models. Despite their poor visual acuity, these animals possess surprisingly complex visual systems, and have been instrumental in understanding how visual features are processed in the primary visual cortex (V1). However, a growing body of literature has shown that primary sensory areas like V1 are capable of more than basic feature detection, but can express neural activity patterns related to learning, memory, categorization, and prediction. </a></p> <p>Visual experience fundamentally changes the encoding and perception of visual stimuli at many scales, and allows us to become familiar with environmental cues. However, the neural processes that govern visual familiarity are poorly understood. By exposing awake mice to repetitively presented visual stimuli over several days, we observed the emergence of low frequency oscillations in the primary visual cortex (V1). The oscillations emerged in population level responses known as visually evoked potentials (VEPs), as well as single-unit responses, and were not observed before the perceptual experience had occurred. They were also not evoked by novel visual stimuli, suggesting that they represent a new form of visual familiarity in the form of low frequency oscillations. The oscillations also required the muscarinic acetylcholine receptors (mAChRs) for their induction and expression, highlighting the importance of the cholinergic system in this learning and memory-based phenomenon. Ongoing visually evoked oscillations were also shown to increase the VEP amplitude of incoming visual stimuli if the stimuli were presented at the high excitability phase of the oscillations, demonstrating how neural activity with unique temporal dynamics can be used to influence visual processing.</p> <p>Given the necessity of perceptual experience for the strong expression of these oscillations and their dependence on the cholinergic system, it was clear we had discovered a phenomenon grounded in visual learning or memory. To further validate this, we characterized this response in a mouse model of Fragile X syndrome (FX), the most common inherited form of autism and a condition with known visual perceptual learning deficits. Using a multifaceted experimental approach, a number of neurophysiological differences were found in the oscillations displayed in FX mice. Extracellular recordings revealed shorter durations and lower power oscillatory activity in FX mice. Furthermore, we found that the frequency of peak oscillatory activity was significantly decreased in FX mice, demonstrating a unique temporal neural impairment not previously reported in FX. In collaboration with Dr. Christopher J. Quinn at Purdue, we performed functional connectivity analysis on the extracellularly recorded spikes from WT and FX mice. This analysis revealed significant impairments in functional connections from multiple layers in FX mice after the perceptual experience; some of which were validated by another graduate student (Qiuyu Wu) using Channelrhodopsin-2 assisted circuit mapping (CRACM). Together, these results shed new light on how visual stimulus familiarity is differentially encoded in FX via persistent oscillations, and allowed us to identify impairments in cross layer connectivity that may underlie these differences. </p> <p>Finally, we asked whether these oscillations are observable in other brain areas or are intrinsic to V1. Furthermore, we sought to determine if the oscillating unit populations in V1 possess uniform firing dynamics, or contribute differentially to the population level response. By performing paired recordings, we did not find prominent oscillatory activity in two visual thalamic nuclei (dLGN and LP) or a nonvisual area (RSC) connected to V1, suggesting the oscillations may not propagate with similar dynamics via cortico-thalamic connections or retrosplenial connections, <a>but may either be uniquely distributed across the visual hierarchy or predominantly</a> restricted to V1. Using K-means clustering on a large population of oscillating units in V1, we found unique temporal profiles of visually evoked responses, demonstrating distinct contributions of different unit sub-populations to the oscillation response dynamics.</p>

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal. / Parmi la multitude de fonctions que le système visuel effectue, la perception du mouvement est l'une des plus importantes. Il a été clairement démontré qu'il existe des sites cérébraux spécifiques pour la détection, l'analyse et l'intégration du mouvement. De façon classique, les mécanismes neurophysiologiques qui sous-tendent ces processus sont attribués aux aires corticales. Le thalamus quant à lui, est généralement considéré comme un « relais passif », c'est à dire qui transmet l'information sensorielle vers le cortex sans modifier le signal entrant. Le but de ce projet sera de préciser les mécanismes nerveux impliqués dans la perception et l'intégration du mouvement et plus précisément, la contribution des régions cérébrales sous-corticales et corticales intimement liés par des connexions réciproques. Ces régions sont: le complexe LP-pulvinar, situé dans le thalamus, l'aire extra-striée postero-médiane suprasylvienne (PMLS) et le cortex ectosylvien visuel antérieur (AEV); deux régions corticales ayant un rôle spécialisé dans l'analyse du mouvement. Les expériences ont été réalisées sur des chats adultes normaux anesthésiés. Une microélectrode d'enregistrement a été descendue dans ces trois sites afin d'enregistrer l'activité des neurones. Les réponses neuronales à des réseaux sinusoïdaux, des patrons texturés (« bruit visuel ») et des « plaids » ont été caractérisé pour étudier les mécanismes qui sous-tendent l'intégration du mouvement au niveau cellulaire. Afin de caractériser d'avantage ce lien, l'influence des aires corticales sur les propriétés thalamiques a été déterminée par inactivation locale réversible (i.e. micro-injection de l'acide y-aminobutyrique; GABA) ou par inactivation permanente plus vaste (i.e. ablation chirurgicale). Les résultats de cette étude se résument comme suit : 1) les propriétés des réponses neuronales du PMLS au bruit visuel sont similaires à celles du LP-pulvinar. Ce résultat suggère que les processus d'analyse impliquant une boucle cortico-thalamique PMLS-LP sont comparables au niveau cortical et sous-cortical. 2) les neurones du PMLS et du LP peuvent coder le mouvement relatif entre un objet et son arrièreplan. De plus, l'inactivation réversible du LP perturbe ces réponses au niveau du PMLS. Ces résultats sont essentiels dans l'établissement d'un lien fonctionnel entre ces deux régions quant à l'analyse de certains aspects du mouvement. 3) certains neurones du complexe LP-pulvinar sont capables d'intégrer l'information directionnelle telle que définie par des « plaids ». Ceci constitue la première démonstration de propriétés de haut-niveau en dehors du cortex. De plus, cette découverte suggère que le LP-pulvinar participe de façon parallèle et en coopération avec le cortex dans l'analyse de scènes visuelles complexes via l'exploitation des boucles cortico-thalamiques. Les résultats de cette étude sont importants non seulement pour appuyer des notions théoriques novatrices sur le rôle du thalamus, mais aussi dans le but de réévaluer et de préciser les mécanismes nerveux qui sous-tendent la perception du mouvement et l'intégration sensorielle en général. / Among the multitude of functions the visual system carries out, the perception of motion is one of the most important. It has been clearly demonstrated that the visual system contains numerous specialised areas implicated in the detection, analysis, and integration of motion. Classically, the neurophysiological mechanisms underlying these processes have been uniquely attributed to regions of the cerebral cortex. The thalamus for its part, has generally been regarded as a passive relay transferring information to the cortex without any modification of the sensory signal. The purpose of this study is to investigate the neurophysiological mechanisms implicated in the perception and integration of motion and more specifically, delineate the contribution of cortical and subcortical structures that are intimately related via reciprocal connections. These areas are: the LP-pulvinar complex; located in the thalamus, and the extrastriate posteromedial lateral suprasylvian (PMLS) and anterior ectosylvian visual (AEV) cortical areas; two regions whose role in motion analysis are well established. Experiments were carried out on normal adult anaesthetised cats. A recording microelectrode was descended in one of the aforementioned areas to record neuronal activity. Neuronal responses to drifting sine-wave gratings, moving texture patterns ("visual noise"), and "plaid patterns" were recorded in order to investigate the mechanisms underlying the integration of motion information at the neuronal level. As a continuation of the study, the influence of cortical motion areas on recorded thalannic responses will be determined by local reversible deactivation (i.e. microinjection of y-aminobutyric acid; GABA) or by irreversible deactivation (i.e. surgical ablation). The results of the study are as follows: 1) Response properties of PMLS neurons to moving texture patterns are similar to those found in the LP-pulvinar connplex. These results suggest that motion processing along both components of the PMLS-LP cortico-thalamic loop is carried out within a similar envelope of analysis. 2) Neurons in both PMLS and LP are able to code the relative motion of an object with respect to its background. Furthermore, reversible deactivation of LP disrupts these responses in PMLS. These results are important in establishing that both these areas are functionally linked in the analysis of specific aspects of motion. 3) The fact that pattern-selective responses to moving plaids can be found in the LP-pulvinar complex suggests that this area is capable of carrying out higher-order motion computations. The importance of this later results is two-fold. First, these findings represent the first demonstration that higher-order properties exists outside extrastriate cortical areas. Second, they further suggest that certain thalamic nuclei, via the establishment of cortico-thalamic loops, participate in parallel and in co-operation with the cortex in the analysis of complex visual scenes. The results of this study are important not only to reinforce current and novel theoretical notions regarding the role of the thalamus, but also in the re-evaluation of the neurophysiological mechanisms involved in motion perception and sensory integration as a whole.

Restless legs syndrome (RLS) is a sensory-motor disorder characterized by abnormal circadian rhythm with an increase in the severity of sensory and motor symptoms at night. Even though many neurological diseases have shown a strong nexus between motor and cognitive symptoms, to date, cognitive functions especially cognitive control in RLS has been poorly understood. Given that cognitive control is a key to leading a self-serving and successful life, including many aspects of employment, social life, and attaining long-term goals, this thesis aimed to examine cognitive control and the underlying mechanisms in RLS. Thalamic gamma aminobutyric acid (GABA), which has been linked to RLS sensory-motor symptoms, also plays an important role in cognitive control. Therefore, the potential relationship between thalamic GABA level and cognitive control in RLS was examined (Study I). RLS patients displayed reduced working memory-based control performances as compared to healthy controls. Elevated thalamic GABA was found to attenuate the observed control deficits in RLS, even though changes in thalamic GABA levels might not be the ultimate causes of these deficits. According to the modulatory effect of thalamic GABA on thalamic activity and thalamo-cortical connectivity, relatively higher GABA levels may have helped RLS patients compensate for their pathological changes such as thalamic hyperactivity and hypoconnectivity, which may underpin the observed control deficits. The critical feature of RLS, abnormal circadian rhythm is thought to be related to nocturnal striatal dopamine deficiency. Concerning the dopaminergic modulation of cognitive control, the circadian variation of cognitive control processes has been investigated (Study II & III). RLS patients displayed reduced attentional control (Study II) and automatic response activation (Study III) at night, which resulted from decreased activation within the extra-striate visual cortex, the superior parietal cortex, and the premotor cortex. As there were no activity changes within the prefrontal cortex, it is likely that cortico-basal ganglia cognitive loops were less prone to RLS. Instead, striatal dopamine deficiency at night may have influenced the cortico-cortical functional connectivity and cortico-basal ganglia motor loops in RLS. These findings not only shed light on the underlying mechanisms of cognitive control, but also advance early clinical treatment possibilities for cognitive changes in RLS patients. Furthermore, recent insights into daytime-related cognition may help patients develop a suitable daytime schedule to minimize the detrimental effects induced by cognitive deficits.