Each primary sensory cortex gets input from corresponding primary and secondary thalamic nuclei. While primary thalamic nuclei are characterized by their sensory responses, the degree to which secondary thalamus encodes sensory and non-sensory signals is unknown. In the whisker system, the primary nucleus is the ventral posterior nucleus (VPM) and the secondary nucleus is the posterior medial nucleus (POm). While VPM sends precise whisker touch signals to cortex, POm responses are not well understood. Unlike VPM, POm is interconnected with many cortical areas, including motor cortex and association areas. POm, as a recipient of both bottom-up whisker signals and top-down cortical signals, might integrate touch with contextual signals such as reward or movement. Using two-photon microscopy through a gradient index (GRIN) lens, I have assessed the POm response to touch with multi-whisker passive deflections of different velocities, to reward with water droplets, and to self-movement by measuring whisking and licking. POm activity had weak touch responses and was dominated by self-generated movements. My results suggest that POm is driven by self-movement or the internal state signals that accompany it, such as arousal. Next, I investigated whether these representations change when mice learn sensory-reward associations. I demonstrate that POm activity continues to be dominated by whisking and licking and does not acquire selectivity for reward-associated sensory stimuli. We propose a model in which the representation of movements within POm may facilitate learning sensory features in cortex by creating a window for plasticity around relevant stimuli.

Background: Primary progressive aphasia (PPA) is a clinical dementia syndrome characterized by impairments in language. The presence of Alzheimer disease (AD) neuropathology has been observed in approximately 40% of PPA cases. Cross-sectional and longitudinal features of cortical atrophy in PPA are emerging but less is known about the integrity of subcortical structures, particularly the thalamus. As a major relay station in the brain, the thalamus is implicated in language functioning given its reciprocal connections with perisylvian regions in the cortex. High-dimensional brain mapping was used to characterize thalamic morphology in individuals with and without non-semantic PPA. Further, shape differences were compared between PPA participants with suspected AD pathology (PPAAβ +) and those without suspected AD pathology (PPAAβ -) as determined by amyloid PET scans. The relationship between shape and specific language deficits were also investigated. Method: Thalamic integrity was examined in 57 PPA participants relative to cognitively healthy controls (N=44) with similar demographics. MR scans were acquired using high-resolution T1-weighted MPRAGE volumes following the ADNI protocol. Thalamic shape features were estimated using Large Deformation Diffeomorphic Metric Mapping. Thalamic nuclei of interest included mediodorsal, pulvinar, and anterior regions. General linear models compared differences in thalamic shape between groups. Pearson models characterized relationships between thalamic nuclei and language function. Results: After controlling for whole brain volume, thalamic volume did not differ between groups [F(1, 99)=0.80, p=0.80]. However, PPA participants exhibited significant bilateral inward shape deformation in dorsal and ventral regions that extended in an anterior to posterior fashion, and unilateral outward deformation in medial and lateral regions only in the left thalamus relative to controls [F(9, 91)=5.75, p<0.001, Wilk's Λ=0.64]. There were no shape differences between PPAAβ + and PPAAβ – groups. Pearson models revealed significant correlations between confrontation naming and shape deformation in the left pulvinar (r=0.59, p<0.01) and left anterior (r=0.55, p<0.01) thalamic nuclei for the PPAAβ + group only, such that lower language scores reflected greater localized volume loss. Conclusions: In the absence of volumetric differences, shape measures were able to capture unique aspects of localized morphologic differences in PPA that corresponded to worse naming performance only in those with suspected AD pathology. Thalamic changes appear to be a contributing and unrecognized component to the presentation and language characterization of PPA.

Huntington’s disease is an inherited neurodegenerative disease characterized by the degeneration of the cerebral cortex, thalamus, and striatum. The loss of neurons in the cerebral cortex and the thalamus may affect the synaptic circuitry in the striatum as these regions send glutamatergic projections (corticospinal & thalamostriatal) to neurons in the striatum. Prior studies have suggested the detrimental impact that the mutant Huntingtin protein (mHTT) may have on corticostriatal afferents, but less is known thalamic inputs to the dorsal striatum. In this study, we report a 50% reduction in thalamostriatal axospinous synapse density and significant reductions in dendritic spine volume at the ultrastructural level using electron microscopy. Additionally, dystrophic alterations to mitochondria size and morphology were also found. At the microcircuit level, we report a reduction in the spatial abundance of thalamostriatal axon terminals at the rostral, middle, and caudal levels of the dorsolateral striatum while an inverse distribution was observed for mHTT, suggesting a novel topographic distribution of thalamostriatal projections and mHTT along the rostral-caudal axis of the dorsolateral striatum. These findings are novel in the Q175 HD mouse model and supports the theory of an excitatory: inhibitory imbalance contributing to structural synaptic changes in the dorsal striatum. Further studies of the corticostriatal projections will determine the global extent of this imbalance.

Cognitive impairments are a hallmark of many, if not all, psychiatric disorders. They include deficits in working memory, attention, and cognitive flexibility. The prefrontal cortex (PFC) is essential for these cognitive functions and has been implicated in psychiatric disorders, including schizophrenia. The PFC receives reciprocal inputs from the thalamus, and this thalamo-PFC circuitry supports cognition. In patients with schizophrenia, who have impaired cognitive functioning, thalamo-PFC connectivity is disrupted. This finding is also seen in adolescents at high risk for the disorder, even before diagnosis.While impaired cortical maturation has been postulated as a mechanism in the etiology of schizophrenia, the postnatal development of thalamo-PFC circuitry is still poorly understood. In sensory cortex, activity relayed by the thalamus during a postnatal sensitive period is essential for proper cortical maturation. However, whether thalamic activity also shapes maturation of the PFC is unknown. Here, I will present evidence to support the hypothesis that adolescence represents a sensitive period, during which the PFC is susceptible to transient perturbations in thalamic input activity, resulting in persistent changes in circuitry. In Chapter 1, I present the existing literature on schizophrenia and our current understanding of its etiology. I then review the structure and connectivity of the PFC and its inputs, including the thalamus, in the context of schizophrenia and cognition. Next, I discuss the role of adolescence in the development of these structures and circuits. Finally, I introduce the concept of sensitive periods and outline the hypothesis that a similar process may occur in the context of the adolescent development of thalamo-PFC circuitry. To assess cognitive functioning in mouse models, I developed an operant-based working memory task. In Chapter 2, I describe this newly developed task and demonstrate that behavioral performance in the task is susceptible to PFC lesions. Thus, the task offers a new approach to studying PFC cognitive function. In Chapter 3, I discuss work done to address the hypothesis of adolescence as a sensitive period in the development of thalamo-PFC circuitry. I established an approach whereby I can transiently reduce activity in the thalamus during specific time windows. In this way, I compared the persistent effects of transient thalamic inhibition during adolescence and adulthood. I found that adolescent thalamic inhibition causes long-lasting deficits in cognitive behavioral performance, including the operant-based working memory task described in Chapter 2 and a cognitive flexibility task, decreased PFC cellular excitability, and reduced thalamo-PFC projection density. Meanwhile, adult thalamic inhibition has no persistent consequences on behavior or PFC excitability. Adolescent thalamic inhibition also results in disrupted PFC cellular cross-correlations and task outcome encoding during the cognitive flexibility task. Strikingly, exciting the thalamus in adulthood during the behavioral task rescues PFC cross-correlations, task outcome encoding, and the cognitive deficit. These data support the hypothesis that adolescence is a sensitive period in thalamo-PFC circuit maturation as adolescent thalamic inhibition has long-lasting consequences on PFC circuitry, while adult thalamic inhibition has no persistent effects. Moreover, these results highlight the role of the thalamus as a non-specific facilitator of PFC activity, expanding our understanding of this thalamic function to additional cognitive contexts. By supporting PFC network activity, boosting thalamic activity provides a potential therapeutic strategy for rescuing cognitive deficits in neurodevelopmental disorders. Finally, in Chapter 4, I conclude with a general discussion. I highlight major take-aways from this work as well as next steps in our exploration of these crucial neural circuits. Together, the findings outlined here offer new promise for early diagnosis and treatment options for patients with cognitive impairments and psychiatric disorders.

Propofol is one of the most commonly used general anesthetics in the world, and yet precisely how it enables loss of consciousness still eludes us. It exhibits rich spectral characteristics on electroencephalogram (EEG) recordings from human patients, including alpha oscillations (8-14 Hz) and Slow Wave Oscillations (SWO, 0.5-2.0 Hz). Additionally, these two oscillations are phase-amplitude coupled (PAC) in a dose-dependent manner: low doses cause “trough-max” coupling where alpha power is maximal during the trough of the SWO cycle, while high doses cause “peak-max” coupling where alpha power is maximal during the peak of the SWO cycle. These propofol rhythms occur at the same frequencies as sleep spindles and sleep SWO, and likely use the same well-studied thalamocortical circuitry. The study of anesthesia therefore represents a safe method for investigating both how our brains sleep and the much-debated components of consciousness. In this dissertation, I use Hodgkin-Huxley-style computational models of both the thalamus and cortex to explain how the direct and indirect effects of propofol can generate such spectral phenomena. In the first part of this dissertation, I discuss results from a thalamic model. I illustrate how GABAA potentiation by propofol can create sustained alpha oscillations in the hyperpolarized thalamus by utilizing the same mechanisms used by sleep spindles. I then show how the thalamus, under artificial SWO conditions, can output trough-max or peak-max PAC depending on background excitation, GABAA potentiation, and H-current conductance. In the second part of this dissertation, I discuss results from a thalamocortical model. My analysis reveals how, in a simulated EEG signal, trough-max PAC can arise from competition between thalamocortical and intracortical synaptic currents, while peak-max PAC can arise from their cooperation. Furthermore, the coherence of cortical SWO rhythms can directly control whether the system expresses trough-max or peak-max PAC, while the indirect effects of propofol on acetylcholine are required for both PAC states. This culmination of years of work reveals just how complex the inner workings of anesthesia can be in enabling its profound effects.

No description available.

Le système des noyaux de la base est principalement impliqué dans le contrôle et l'apprentissage moteur.Le rôle de la voie cortico-striatale a été et est toujours fortement étudié mais le striatum reçoit aussides afférences excitatrices du thalamus, souvent considéré comme un simple relais entre les noyaux dela base et le cortex, formant ainsi des boucles de structures sous-corticales. Les principales afférencesthalamostriatales glutamatergiques proviennent des noyaux thalamiques intralaminaires et forment descontacts synaptiques avec les deux types de neurones efférents GABAergiques du striatum (i- et d-MSNs) et les interneurones cholinergiques (INCs). Le complexe thalamique intralaminaire peut sedistinguer en une partie rostrale (ILTr) contenant les noyaux centrolatéral (CL), paracentral (PC) etcentral médial (CeM) et une partie caudale (ILTc) formée du noyau parafasciculaire (Pf) chez lerongeur (équivalent du complexe parafasciculaire-centromedian chez le primate). Le complexe thalamiqueintralaminaire est souvent considéré comme une structure fonctionnelle homogène, cependant de plus enplus d’études mettent en évidence des différences anatomiques, électrophysiologiques et fonctionnelles desparties rostrales et caudales de l’intralaminaire. Le noyau intralaminaire caudal est de mieux en mieuxdécrit et sa projection striatale se montre impliquée principalement dans la réponse aux stimuli sensorielsainsi que dans la flexibilité motrice. Des données obtenues par Marco Diana et collaborateurs à l’EcoleNationale Supérieure (Paris) apportent un éclairage nouveau sur l'importance du noyau intralaminairerostral, en particulier le noyau centrolatéral, dans le contrôle du mouvement, en montrant que la stimulationoptogénétique de la projection glycinergique/GABAergique ponto-intralaminaire thalamique inhibe les neu-rones thalamiques et provoque une hypolocomotion. Ces résultats indiquent que la suppression de laprojection thalamique sur le striatum mène à une perturbation de la fonction des ganglions de la base.Cette dernière décennie se caractérise par une explosion de nouvelles techniques aussi bien dans lesdomaines d’imagerie que dans les techniques de manipulation génique d’animaux permettant de répondreà certaines questions qui ne pouvaient techniquement pas trouver de réponse jusqu’ici. Ce travail dethèse a pour but de mieux comprendre l’importance des afférences du thalamus intralaminaire sur lestriatum, en particulier sa partie rostrale, qui, de manière surprenante, sont très mal caractérisées. Deplus, les noyaux thalamiques intralaminaires sont un relais entre le cervelet et le striatum, par conséquent,l'analyse de ces connexions pourrait améliorer notre compréhension des maladies neurodégénératives tellesque la maladie de Parkinson impliquant à la fois les noyaux gris centraux et le cervelet, mais dont lesinteractions fonctionnelles n'ont pas encore été décryptées.La première partie de ce travail de thèse consiste en une étude anatomique détaillée des projections duthalamus intralaminaire sur le striatum, en particulier sur ses principales sous-populations (d- et i-MSNs,INCs) et sous-régions (dorso-latéral=DLS, dorso-médian=DMS), par l’utilisation combinée d’un marquagerétrograde monosynaptique et d’une technique de transparisation (« clearing ») permettant par la suitede réaliser une imagerie complète du cerveau à l’aide d’un microscope à feuille de lumière. Les analysesanatomiques réalisées ont permis de confirmer l’existence de projections directes des noyaux thalamiquesintralaminaires sur le striatum dorsal, celles-ci présentant un pattern d’innervation préférentiel pour lesINCs (DMS>DLS) suivi par les dMSNs (DLS>DMS). Les cibles postsynaptiques des projectionsthalamostriatales sont similaires aux projections dopaminergiques, suggérant une interaction étroite entreces afférences.La seconde partie de cette thèse, vise a mieux comprendre l’importance fonctionnelle des connexionsthalamostriatales mises en évidence précédemment dans la locomotion spontanée. Pour cela deux ap-proches seront utilisées: une approche modifiant l’activité de ces neurones par l’utilisation de techniquescomme l’optogénétique et la chémogénétique et une approche descriptive par une technique d’imageriecalcique permettant d’enregistrer l’activité neuronale en temps réel sur des animaux libres de se mouvoir.Les résultats obtenus montrent que l’inhibition de l’ensemble des neurones de l’ILTr est nécessaire pourobserver un phénotype moteur d’hypolocomotion. La mise en place d’un système de détection de motricitéfine et l’enregistrement de l’activité calcique des neurones striataux, nous permettront, à l’avenir, de mieux identifier le type de comportement moteur impliqué dans cette hypolocomotion ainsi que d’évaluer l’impactde cette inhibition thalamique sur l’activité des neurones striataux. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13142号 / 論医博第2142号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊佐 正, 教授 野田 亮, 教授 岩田 想 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20790号 / 医博第4290号 / 新制||医||1025(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 高橋 淳, 教授 井上 治久, 教授 林 康紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13156号 / 論医博第2143号 / 新制||医||1028(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 林 康紀, 教授 渡邉 大, 教授 影山 龍一郎 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM