The early postnatal period is marked by the rapid acquisition of sensorimotor processing capabilities. Initially responding to a limited set of environmental stimuli with a restricted repertoire of behaviors, mammals exhibit a remarkable proliferation of sensorimotor abilities in the early postnatal period. Central to action selection, reinforcement, and contingency learning are a subcortical set of evolutionarily conserved nuclei called the basal ganglia. The striatum, which is the primary input nucleus of the basal ganglia, receives afferent innervation from throughout the CNS. Its projection neurons (SPNs) integrate these diverse inputs, regulating movement and encoding salient cue-outcome contingencies. Here, using electrophysiological, electrochemical, imaging, and behavioral approaches in mice, I will explore the postnatal maturation of the striatal cholinergic interneuron (ChI), a critical modulator of dopamine signaling, afferent excitation, and SPN excitability. In Chapter 1, I will set the stage for this exploration by reviewing the current literature on striatal postnatal development, including cellular physiology, axonal elaboration and synapse formation, and plasticity expression. I will survey striatal deficits observed in clinical neurodevelopmental conditions such as autism, ADHD, tic disorders, and substance use disorders. I will additionally summarize evidence that the striatum is uniquely vulnerable to physiological and immunological insult, as well as early life adversity. In Chapter 2, I turn my focus specifically to the striatal ChI, uncovering fundamental cell-intrinsic changes that occur postnatally in this population. I will also elaborate on the postnatal maturation of dopamine release properties and regulation thereof by cholinergic signaling from the ChI. In Chapter 3, I investigate the circuit connectivity and circuit-driven firing dynamics of ChIs as they mature postnatally. I utilize a brain slice preparation retaining thalmostriatal afferents in order to assay the ChI pause, a synchronized transient quiescence in ChIs thought to facilitate cue learning and behavioral flexibility. I find that the ChI pause is refined postnatally, dependent on developmental changes in thalamic input strength and the cell- intrinsic expression of specific ionic conductances. Finally, in Chapter 4, I present preliminary evidence that ChI circuit maturation as defined in preceding chapters is delayed by chronic stress exposure postnatally. Following the maternal separation model of early life stress, ChI intrinsic characteristics mature normally, but they retain heightened thalamic innervation and thalamus-driven pause expression.

Final publication is available at http://dx.doi.org/10.1111/ejn.12882 / 京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13040号 / 論医博第2115号 / 新制||医||1017(附属図書館) / 33032 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 影山 龍一郎, 教授 髙橋 良輔 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Cognitive deficits in first-episode psychosis (FEP) are well documented including deficits in cognitive control, but how sex may influence or impact these cognitive deficits is not well known. Cognitive deficits may impact multiple neural networks, including the fronto-parietal network (FPN). How sex may influence the structural integrity of regions in the FPN is also an important area of research in FEP that may provide further insight into the beginnings of the disease. The current study aimed to examine sexual dimorphisms in structural integrity of the frontoparietal network (FPN) and its role in cognitive control in FEP. A total of 111 FEP patients (68 male, 43 female) and 55 healthy control participants (35 male, 20 female) from the Human Connectome Project for Early Psychosis who underwent T1-weighted magnetic resonance imaging and neuropsychological testing were included in the study. Regions of interest (ROIs) included: left and right superior frontal gyrus, left and right middle frontal gyrus, left inferior frontal gyrus, left and right inferior parietal gyrus, right caudate and left thalamus. Using high-dimensional brain mapping procedures, surface shape of the right caudate and left thalamus was characterized using Large Deformation Diffeomorphic Metric Mapping, and cortical thickness of frontal and parietal regions was estimated using the FreeSurfer toolkit. Cognitive control was assessed using the Fluid Cognition Composite score from the NIH Toolbox Cognition Battery. Multivariate ANOVA models tested group differences, separated by sex, in cortical thickness ROIs, in addition to a whole-brain vertex-wise analysis. Vertex-wise statistical surface t-maps evaluated differences in subcortical surface shape, and Pearson correlations tested relationships between brain regions and Fluid Cognition performance. Results of deep brain region comparisons between schizophrenia males (SCZM) and schizophrenia females (SCZF) groups revealed significant outward deformation at the tail of the right caudate and significant inward deformation along the dorsal aspects of the right caudate. Additionally, significant inward deformation in multiple nuclei of the left thalamus were revealed. Significant negative relationships between Fluid Cognition and the left superior/middle frontal gyrus (r = -0.24, p = 0.05) in the male FEP group were observed. Additionally, significant positive relationships between Fluid Cognition and left inferior frontal gyrus (r = 0.35, p = 0.02) and left inferior parietal gyrus (r = 0.35, p = 0.02) in the female FEP group were found. Support vector machine models were trained using measures of cortical thickness and subcortical shape deformation values in all cohorts to classify participants based on diagnosis. Classification accuracy in all testing models ranged from 75-81%. Overall, findings revealed significant differences of subcortical structures, including smaller caudal and thalamic volume, in male FEP compared to female FEP, providing evidence of the importance to examine sex differences at the first episode. Increased consideration for the role of deep-brain structures in male and female FEP can aid in the clinical characterization of the early stages of the disease.

Leopard frogs (Rana pipiens) rely on vision to recognize behaviorally meaningful aspects of their environment. The optic tectum has been shown to mediate the frog's ability to recognize and respond to moving prey and looming objects. Nonetheless, atectal frogs are still able to appropriately respond to non-moving aspects of their environment. There appears to be independent visual systems operating in the frog: one system for recognizing moving objects; and another system for recognizing stationary objects. Little is known about the neural mechanisms mediating the recognition of stationary objects in frogs. Our laboratory showed that a retino-recipient area in the anterior lateral thalamus--the NB/CG zone--is involved in processing visual information concerning stationary aspects of the environment. This thesis aims to characterize the frog's responses to a range of stationary stimuli, and to elucidate the thalamic visual system that mediates those responses. I tested leopard frogs' responses to different stationary stimuli and found they respond in stereotypical ways. I discovered that leopard frogs are attracted to dark, stationary, opaque objects; and tested the extent of this attraction under different conditions. I found that frogs' preference to move toward a dark area versus a light source depends on the intensity of the light source relative to the intensity of ambient light. Unilateral lesions applied to the NB/CG zone of the anterior lateral thalamus resulted in temporary deficits in frogs' responses to stationary stimuli presented in the contralateral visual field. Deficits were observed in response to: dark objects, entrances to dark areas, light sources, and gaps between stationary barriers. However, responses to moving prey and looming stimuli were unaffected. Interestingly, these deficits tended to recover after about 6 days in most cases. Recovery time ranged from 2 - 28 days. The NB/CG zone is anatomically and functionally connected to a structure in the posterior thalamus called the "PMDT." The PMDT has no other connections in the brain. Thus, I have discovered a "satellite" of the NB/CG zone. Preliminary evidence suggests that the PMDT is another component of the visual system mediating stationary object recognition in the frog. / Biology

Axons of retinal ganglion cells (RGCs) send visual information to a number of retinorecipient regions in the brain. In rodents, visual thalamus receives dense innervations from RGC axons and is important for both image-forming and nonimage-forming visual functions. Retinal inputs invade visual thalamus during embryonic development, before the arrival of non-retinal inputs (such as local interneurons and axonal inputs from other brain regions). In this dissertation, I explore how early innervation of RGC axons affects circuitry in visual thalamus and the role of visual experience, neural activity, and molecular cues in the development. While the development of astrocytes in cortex has been well-described, they have been largely overlooked in visual thalamus. Using immunohistochemical, functional, and ultrastructural analysis, I show that astrocytes in visual thalamus reach adult-like morphological properties and functionality at retinogeniculate synapses early in development, by eye-opening and before visual experience. These studies reveal that while experience-dependent visual activity from RGC axons is critical for many aspects of visual thalamus development, astrocytic maturation occurs independent of that information about our visual environment. As with astrocytes, little progress has been made in understanding the development of interneurons in the visual thalamus. Here, I show that retinal inputs interact with thalamic astrocytes to influence the recruitment of GABAergic interneurons into visual thalamus. I found that this interaction between RGC axons and astrocytes is not dependent on neural activity of RGCs. Using transcriptomic analysis, in situ hybridization, and reporter lines, I observed thalamus-projecting RGCs express SHH and astrocytes in visual thalamus express SHH signaling molecules. My results reveal that SHH signaling between RGC axons and astrocytes is critical for astrocytic fibroblast growth factor 15 (FGF15) expression in developing visual thalamus. Ultimately, FGF15 serves as a potent motogen that is essential for thalamic interneuron migration. These data identify a novel morphogen-dependent and activity-independent mechanism that mediates crosstalk between RGCs and astrocytes to facilitate the recruitment of interneurons into the developing visual thalamus. / Doctor of Philosophy / The most dominant sense in human is the sight, which we need to interact with our environment efficiently. The retina takes up the information about our visual world and sends it to the brain, which ultimately puts everything together, for us to see properly. The visual information from the retina goes to the brain via nerves (which are essentially cables/wires of brain cells). These nerves from the retina go to many places in the brain, including a region called visual thalamus, which is the focus of my PhD work. For the past five years, I have been trying to understanding if nerves from the retina play a role in the brain formation during early development. To study this, I have used mice as a model system, as their brain regions that process visual information have very similar structural architecture to those in humans. My research shows that retinal nerves are indeed important for the development of visual thalamus. Here, I show that information from the eye is critical for migration (a process during development where brain cells move from their place of origin to their final location) of cells in visual thalamus. Discoveries made in this dissertation are important because they highlight how different cells in the central nervous system communicate with each other at the level of molecules and how these interactions are important for building circuits that are important for vision.

La ligne directrice de nos expériences a été l'hypothèse que l'apparition et/ou la persistance des fluctuations de longue durée entre les états silencieux et actifs dans les réseaux néocorticaux et une excitabilité neuronale modifiée sont les facteurs principaux de l'épileptogenèse, menant aux crises d’épilepsie avec expression comportementale. Nous avons testé cette hypothèse dans deux modèles expérimentaux différents. La déafférentation corticale chronique a essayé de répliquer la déafférentation physiologique du neocortex observée pendant le sommeil à ondes lentes. Dans ces conditions, caractérisées par une diminution de la pression synaptique et par une incidence augmentée de périodes silencieuses dans le système cortico-thalamique, le processus de plasticité homéostatique augmente l’excitabilité neuronale. Par conséquent, le cortex a oscillé entre des périodes actives et silencieuses et, également, a développé des activités hyper-synchrones, s'étendant de l’hyperexcitabilité cellulaire à l'épileptogenèse focale et à des crises épileptiques généralisées. Le modèle de stimulation sous-liminale chronique (« kindling ») du cortex cérébral a été employé afin d'imposer au réseau cortical une charge synaptique supérieure à celle existante pendant les états actifs naturels - état de veille ou sommeil paradoxal (REM). Dans ces conditions un mécanisme différent de plasticité qui s’est exprimé dans le système thalamo-corticale a imposé pour des longues périodes de temps des oscillations continuelles entre les époques actives et silencieuses, que nous avons appelées des activités paroxysmiques persistantes. Indépendamment du mécanisme sous-jacent de l'épileptogenèse les crises d’épilepsie ont montré certaines caractéristiques similaires : une altération dans l’excitabilité neuronale mise en évidence par une incidence accrue des décharges neuronales de type bouffée, une tendance constante vers la généralisation, une propagation de plus en plus rapide, une synchronie augmentée au cours du temps, et une modulation par les états de vigilance (facilitation pendant le sommeil à ondes lentes et barrage pendant le sommeil REM). Les états silencieux, hyper-polarisés, de neurones corticaux favorisent l'apparition des bouffées de potentiels d’action en réponse aux événements synaptiques, et l'influence post-synaptique d'une bouffée de potentiels d’action est beaucoup plus importante par rapport à l’impacte d’un seul potentiel d’action. Nous avons également apporté des évidences que les neurones néocorticaux de type FRB sont capables à répondre avec des bouffées de potentiels d’action pendant les phases hyper-polarisées de l'oscillation lente, propriété qui peut jouer un rôle très important dans l’analyse de l’information dans le cerveau normal et dans l'épileptogenèse. Finalement, nous avons rapporté un troisième mécanisme de plasticité dans les réseaux corticaux après les crises d’épilepsie - une diminution d’amplitude des potentiels post-synaptiques excitatrices évoquées par la stimulation corticale après les crises - qui peut être un des facteurs responsables des déficits comportementaux observés chez les patients épileptiques. Nous concluons que la transition incessante entre des états actifs et silencieux dans les circuits cortico-thalamiques induits par disfacilitation (sommeil à ondes lentes), déafférentation corticale (épisodes ictales à 4-Hz) ou par une stimulation sous-liminale chronique (activités paroxysmiques persistantes) crée des circonstances favorables pour le développement de l'épileptogenèse. En plus, l'augmentation de l’incidence des bouffées de potentiels d’actions induisant une excitation post-synaptique anormalement forte, change l'équilibre entre l'excitation et l'inhibition vers une supra-excitation menant a l’apparition des crises d’épilepsie. / The guiding line in our experiments was the hypothesis that the occurrence and / or the persistence of long-lasting fluctuations between silent and active states in the neocortical networks, together with a modified neuronal excitability are the key factors of epileptogenesis, leading to behavioral seizures. We addressed this hypothesis in two different experimental models. The chronic cortical deafferentation replicated the physiological deafferentation of the neocortex observed during slow-wave sleep (SWS). Under these conditions of decreased synaptic input and increased incidence of silent periods in the corticothalamic system the process of homeostatic plasticity up-regulated cortical cellular and network mechanisms and leaded to an increased excitability. Therefore, the deafferented cortex was able to oscillate between active and silent epochs for long periods of time and, furthermore, to develop highly synchronized activities, ranging from cellular hyperexcitability to focal epileptogenesis and generalized seizures. The kindling model was used in order to impose to the cortical network a synaptic drive superior to the one naturally occurring during the active states - wake or rapid eye movements (REM) sleep. Under these conditions a different plasticity mechanism occurring in the thalamo-cortical system imposed long-lasting oscillatory pattern between active and silent epochs, which we called outlasting activities. Independently of the mechanism of epileptogenesis seizures showed some analogous characteristics: alteration of the neuronal firing pattern with increased bursts probability, a constant tendency toward generalization, faster propagation and increased synchrony over the time, and modulation by the state of vigilance (overt during SWS and completely abolished during REM sleep). Silent, hyperpolarized, states of cortical neurons favor the induction of burst firing in response to depolarizing inputs, and the postsynaptic influence of a burst is much stronger as compared to a single spike. Furthermore, we brought evidences that a particular type of neocortical neurons - fast rhythmic bursting (FRB) class - is capable to consistently respond with bursts during the hyperpolarized phase of the slow oscillation, fact that may play a very important role in both normal brain processing and in epileptogenesis. Finally, we reported a third plastic mechanism in the cortical network following seizures - a decreasing amplitude of cortically evoked excitatory post-synaptic potentials (EPSP) following seizures - which may be one of the factors responsible for the behavioral deficits observed in patients with epilepsy. We conclude that incessant transitions between active and silent states in cortico-thalamic circuits induced either by disfacilitation (sleep), cortical deafferentation (4-Hz ictal episodes) and by kindling (outlasting activities) create favorable circumstances for epileptogenesis. The increase in burst-firing, which further induce abnormally strong postsynaptic excitation, shifts the balance of excitation and inhibition toward overexcitation leading to the onset of seizures.

Ce travail s’est focalisé sur l’implication, longtemps négligée, du complexe centremédian/parafasciculaire (CM/Pf) du thalamus dans le fonctionnement physiopathologique des ganglions de la base (GB), avec pour objectif principal d’évaluer le potentiel thérapeutique du ciblage de ce noyau dans le traitement chirurgical par stimulation cérébrale profonde (SCP) des mouvements anormaux. Notre étude a porté dans un premier temps sur un modèle de la maladie de Parkinson (MP) chez le rat. La SCP à haute fréquence (SHF) du CM/Pf réduit différents troubles parkinsoniens (akinésie et négligence sensorimotrice) ainsi que les dyskinésies L‐Dopa induites. Cependant, la mise en évidence d’une action négative du traitement dopaminergique sur les effets anti‐parkinsoniens de cette stimulation compromet l’intérêt de cette cible dans le cadre de la MP dont la L‐Dopa reste le traitement de référence. Au niveau cellulaire, la SHF‐CM/Pf interfère très largement avec les effets de la lésion dopaminergique dans le réseau des GB, confirmant la position clé de ce complexe dans la modulation de l’activité des GB. De plus, la comparaison des effets comportementaux et cellulaires de la SHF de cette cible avec celle du noyau subthalamique, cible actuellement privilégiée dans le traitement de la MP, montre des spécificités en relation notamment avec une action sélective de la manipulation du CM/Pf sur le noyau entopédonculaire (EP), homologue chez le rongeur du globus pallidus interne dont l’implication dans les dyskinésies est bien documentée. Notre étude électrophysiologique in vivo confirme la relation entre activité du Pf et manifestation des dyskinésies en mettant en évidence une réactivité du Pf au traitement chronique à la L‐Dopa. Nous avons également montré que la lésion dopaminergique entraine une diminution de l’expression d’un marqueur métabolique de l’activité neuronale dans le Pf qui est complètement normalisée par la SHF, suggérant pour la première fois que la SHF pourrait corriger une diminution d’activité du noyau ciblé. Enfin, la relation étroite entre l’EP et le CM/Pf nous a encouragé à évaluer les effets de la SCP du Pf sur les dystonies sachant que celles‐ci sont traitées par SCP du globus pallidus interne. Nous avons montré, sur le modèle de hamster dtsz, que l’induction des dystonies est favorisée par la SCP à basse fréquence du Pf alors qu’elle est retardée par la SHF appliquée de façon subchronique (9 jour), ce qui met en évidence l’implication du CM/Pf dans cette autre affection motrice liée aux GB. / The involvement of the centremedian/parafascicular (CM/Pf) thalamic complex has long been neglected in the pathophysiological functioning of basal ganglia (BG). However, this complex forms a functional loop with the BG suggesting that it could be a new target for the surgical treatment by deep brain stimulation (DBS) of BG‐related disorders such as Parkinson's disease (PD). In this context, we evaluated the therapeutic potential of CM/Pf‐DBS in a rat PD model. DBS at high frequency (HFS) of CM/Pf alleviates PD symptoms (akinesia, sensorimotor neglect) as well as L‐Dopa‐induced dyskinesias. However, our observation that chronic L‐Dopa suppresses the antiparkinsonian benefits provided by CM/Pf‐HFS compromises the interest of this target for PD. At cellular level, CM/Pf‐HFS widely impacts the dopaminergic denervation‐induced changes in the BG, showing that CM/Pf is a key node for modulating BG function. Comparison of the behavioral and cellular effects of HFS of CM/Pf versus subthalamic nucleus, the currently preferred target for PD treatment, led us to suggest that their differential impact on akinesia and dyskinesia may be due to a selective action of CM/Pf‐HFS on entopeduncular nucleus (EP), the rodent homologous of internal globus pallidus, whose involvement in dyskinesia is already documented. In vivo electrophysiological recordings of CM/Pf neurons provided further support for the relationship between CM/Pf and dyskinesia. We also showed that the dopaminergic lesion resulted in a decreased gene expression of a metabolic marker of neuronal activity in the CM/Pf, which is completely normalized by HFS, providing the first evidence that HFS may be able to correct a decrease in activity of the targeted nucleus. Finally, given the close relationship between EP and CM/Pf and knowing that internal globus pallidus is a target for DBS in dystonia, we evaluated the effects of CM/Pf‐DBS in an animal model of this disorder, the dtsz hamster. We found that the stress induction of dystonia in this model is delayed by subchronic CM/Pf HFS whereas it is favored by low frequency stimulation providing evidence forthe involvement of CM/Pf in another BG‐related movement disorder.