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

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Movement is the key to animal behavior. From fighting off predators to reaching for food, our survival relies on movement. Losing the ability to move the body through the world in a purposeful way would be dire. We learn to perform a wide variety of actions, which require exact motor control. How are such skilled actions refined over time? The neural mechanism of motor learning has been posited to arise from integrating neuronal signals about motor commands, environmental context, and outcome through the cortico-basal ganglia-thalamic loop. Here, I investigate the role of two thalamic nuclei — the parafascicular (Pf) and ventroanterior/ventrolateral (VAL) —in the process of motor learning. In an introductory Chapter 1, I introduce some key behavioral signatures of motor learning and the distributed neural circuity for movement through the cortico-basal ganglia-thalamic network. Pf and VAL are at the center of this network. Both receive basal ganglia output but differ in primary projection patterns. Pf sends large excitatory projections directly to the striatum (the main input area of the basal ganglia), while VAL projects back to the cortex. Despite their critical place in the movement system, little is known about their changing roles in motor learning. In Chapter 2, I highlight a novel skilled forelimb joystick target task for mice; the JTT. In the JTT, head-fixed mice learn reaches to spatial targets in 2D space by moving an unrestricted joystick without visual feedback. This task allows for multiple windows of learning and refinement of various reaches in space. Over the learning of targeted reaching movements, mice increase their accuracy and individual trajectories become less variable, showing that they have learned the location of the target in space, and also refine the reaching movements. In Chapter 3, I use 2-photon calcium imaging of the forelimb-related areas of Pf and VAL to investigate how their activity changes over learning of forelimb reaching actions. Both Pf and VAL are highly engaged during movements. Neural population engagement of Pf decreases over time, suggesting a specific role early in learning. Additionally, the underlying neural dynamics of Pf and VAL shift and occupy different state spaces over learning, as shown through principal component analysis. To investigate if neural activity in Pf or VAL encodes behavioral information, we used a ridge regression model to predict the initial direction of movements from neural data. We were able to predict the initial direction from Pf activity on early training days, but not from VAL. In Chapter 4, I performed pre and post-learning lesions to Pf or VAL to investigate if they are needed for learning and/or performance of targeted reaches. Results show that Pf is needed for learning, but not the performance of accurate spatial reaches. VAL, on the other hand, does not affect the learning or performance of target reaches, but does affect the speed of movements. In a discussion-based Chapter 5, I summarize these above experiments, which suggest different roles for PF and VAL over learning of multiple targeted reaches, and reflect on future directions of my findings in the broader context of motor learning research in neuroscience. In particular, my findings highlight a novel and critical role for Pf in learning and processing directional information during early skill learning. This work demonstrates that the thalamus is an essential node of the brain networks involved in motor learning.

Rhythmic oscillations in neuronal activity display variations in amplitude (power) over a range of frequencies. Attention and cognitive performance correlate with increases in cortical gamma oscillations (40-70Hz) that are generated by the coordinated firing of glutamatergic pyramidal neurons and GABAergic interneurons, and are modulated by dopamine. In the medial prefrontal cortex (mPFC) of rats, gamma power increases during treadmill walking, or after administration of an acute subanesthetic dose of the NMDA receptor antagonist ketamine. Ketamine is also used to mimic symptoms of schizophrenia, including cognitive deficits, in healthy humans and rodents. Additionally, the ability of a drug to modify ketamine-induced gamma power has been proposed to predict its pro-cognitive therapeutic efficacy. However, the mechanism underlying ketamine-induced gamma oscillations is poorly understood. We hypothesized that gamma oscillations induced by walking and ketamine would be generated by a shared mechanism in the mPFC and one of its major sources of innervation, the mediodorsal thalamus (MD). Recordings from chronically implanted electrodes in rats showed that both treadmill walking and ketamine increased gamma power, firing rates, and spike-gamma LFP correlations in the mPFC. By contrast, in the MD, treadmill walking increased all three measures, but ketamine decreased firing rates and spike-gamma LFP correlations while increasing gamma power. Therefore, walking- and ketamine-induced gamma oscillations may arise from a shared circuit in the mPFC, but different circuits in the MD. Recent work in normal animals suggests that dopamine D4 receptors (D4Rs) synergize with the neuregulin/ErbB4 signaling pathway to modulate gamma oscillations and cognitive performance. Consequently, we hypothesized that drugs targeting the D4Rs and ErbB receptors would show pro-cognitive potential by reducing ketamine-induced gamma oscillations in mPFC. However, when injected before ketamine, neither the D4R agonist nor antagonist altered ketamine’s effects on gamma power or firing rates in the mPFC, but the pan-ErbB antagonist potentiated ketamine’s increase in gamma power, and prevented ketamine from increasing firing rates. This indicates that D4Rs and ErbB receptors influence gamma power via distinct mechanisms that interact with NMDA receptor antagonism differently. Our results highlight the value of using ketamine-induced changes in gamma power as a means of testing novel pharmaceutical agents.

Neocortical sensory areas have associated primary and secondary thalamic nuclei. While primary nuclei transmit sensory information to cortex, secondary nuclei remain poorly understood. I recorded juxtasomally from the secondary somatosensory (POm) and visual (LP) nuclei of awake mice. POm activity correlated with whisking, but not precise whisker kinematics. This movement modulation was not a result of sensory reafference, nor was it due to input from motor or somatosensory cortex, nor the superior colliculus. Whisking and pupil dilation were strongly correlated, reflecting arousal. Indeed LP, which is not part of the whisker system, tracked whisking equally well, indicating that POm activity does not encode whisker movement per se. The semblance of movement-related activity is likely instead a global effect of arousal on both nuclei. I then investigated how POm and LP may support feature-based attention. I trained head-fixed mice to attend to one sensory modality while ignoring a second modality. I used multielectrode arrays to record simultaneously from both regions. In mice trained to respond to tactile stimuli and ignore visual stimuli, POm was robustly activated by touch and largely unresponsive to visual stimuli. The reverse pattern was observed when mice were trained to respond to visual stimuli and ignore touch, with POm now more robustly activated during visual trials. This POm activity was not explained by differences in movements (i.e., whisking, licking) resulting from the two tasks. LP exhibited similar phenomena. I conclude that behavioral training reshapes activity in secondary thalamic nuclei. Secondary nuclei may respond to behaviorally relevant, reward-predicting stimuli regardless of stimulus modality.

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The optic tectum of the leopard frog has long been known to process visual information about prey and looming threats, stimuli characterized by their movement in the visual field. However, atectal frogs can still respond to the stationary visual environment, which therefore constitutes a separate visual subsystem in the frog. The present work seeks to characterize the stationary visual environment module in the leopard frog, beginning with the hypothesis that this module is located in the anterior thalamus, among two retinorecipient neuropil regions known as neuropil of Bellonci (NB) and corpus geniculatum (CG). First, the puzzle of how a stationary frog can see the stationary environment, in the absence of the eye movements necessary for persistence of vision, is resolved, as we show that whole-head movements caused by the frog's respiratory cycles keep the retinal image in motion. Next, the stationary visual environment system is evaluated along behavioral, anatomic, and physiological lines, and connections to other brain areas are elucidated. When the anterior thalamic visual center is disconnected, frogs show behavioral impairments in visually navigating the stationary world. Under electrophysiological probing, neurons in the NB/CG region show response properties consistent with their proposed role in processing information about the stationary visual environment: they respond to light/dark and color information, as well as reverse-engineered "stationary" stimuli (reproducing the movement on the retina of the visual backdrop caused by the frog's breathing movements), and they do not habituate. We show that there is no visuotopic map in the anterior thalamus but rather a nasal-ward constriction in the receptive fields of progressively more caudal cell groups in the NB/CG region. Furthermore, each side of the anterior thalamic visual region receives information from only the contralateral half of the visual field, as defined by the visual midline, resulting from a pattern of partial crossing over of optic nerve fibers that is also seen in the mammalian thalamic visual system, a commonality with unknown evolutionary implications. We show that the anterior thalamic visual region shares reciprocal connections with the same area on the opposite side of the brain, as well as with the posterior thalamus on both sides; there is also an anterograde ipsilateral projection from the NB/CG toward the medulla and presumably pre-motor areas. / Biology

To successfully navigate daily life, organisms must be able to identify stimuli that are predictive of beneficial outcomes. A key thalamic nucleus involved in this process is the mediodorsal thalamus (MD), which bidirectionally communicates with the prefrontal cortex, facilitating cognitive and decision-making functions. Despite the MD's involvement in higher-order relays, the precise mechanisms underlying its astrocytic activity, its contribution to synaptic plasticity, and the subsequent effects on cognitive processing remain poorly understood. Emerging data highlights the pivotal role of astrocytes in regulating synaptic transmission, with astrocytic calcium activity being linked to gliotransmitter release. Abnormalities in astrocytic calcium activity have been found to impair learning and memory, thus insights into their mechanism during cognitive processes in the MD could reveal novel targets for investigating cognitive disorders. In this study, we investigated astrocytic activity during a cue-based learning task, uncovering notable differences in the timing of astrocytic calcium release between early and late stages of the task. To investigate plasticity-related changes between early and late stages, the density of astrocytes, glutamatergic nerve terminals, and astrocyte glutamate transporter proteins will be examined. We found that MD astrocytic calcium activity responds to the initial cue and the reward, suggesting that this activity mediates the temporal dynamics of synaptic plasticity, influencing how thalamic circuits adjust to both cues and outcomes during learning. / Master of Science / Cognitive abilities are highly regulated by activity present in the mediodorsal thalamus, which is an area of the brain largely responsible for learning and decision making. Cognition has been primarily studied in the context of specific neuronal pathways. However, neurons are supplemented by other cell types in the brain called glia, the most abundant of which are astrocytes. Astrocytes help connect specific neurons together to form synapses. During the process of learning, new synapses can make new connections in a phenomenon called synaptic plasticity which is highly mediated by astrocytes. This activity of astrocytes in the mediodorsal thalamus has not been studied sufficiently. We measured the MD-specific astrocytic activity in real time during a cue-based learning task using a technique called fiber photometry. We also recorded instances of reward seeking behavior characterized by a light cue signaling an upcoming reward. We found that during early learning, astrocytic activity peaked around the onset of the light cue whereas during late learning, astrocytic activity peaked after reward onset. We began to visualize the thalamus excised from animals that completed 0-10 days of the learning task. Our goal with this data is to determine if the number of astrocytes and other proteins that are involved in synaptic plasticity increase with increased learning experience. We are able to suggest that astrocyte activity in the mediodorsal thalamus regulates the changes in patterns of synaptic activity, thereby impacting the ability to learn.

Le traçage rétrograde des voies corticales chez le singe a permis d’étudier deux sujets liés. En premier lieu, des injections dans 40 aires d'un atlas cortical de 91 aires ont permis de constituer une base de données cohérente sur la connectivité corticale à l’échelle de l’hémisphère. Les structures sous-corticales favorisant la communication corticale via la formation de boucles cortico-sous-cortico-corticales ont été examinées. Nous montrons que la force des projections du claustrum (considéré comme ayant une affiliation étroite avec le cortex) vers chaque aire explorée est exceptionnelle. De plus, un chevauchement des neurones marqués dans le claustrum a été observé suite à des paires d'injections dans des aires largement éloignées, y compris dépourvues de connexions cortico-corticales directes. A l’aide d’outils de la théorie des graphes, nous avons examiné la centralité des 40 aires et du claustrum dans le réseau cortical. En particulier, le claustrum est le meilleur exemple d’une aire pouvant prétendre au statut de « hub ». Ces résultats soulignent l'importance d'étudier les principes organisationnels du cortex via l'analyse de la topologie de son réseau. En second lieu, nous avons étudié le développement de la voie corticospinale par laquelle le cortex influence la planification, l'exécution et le contrôle de la motricité fine. Nous montrons que la topologie des projections corticospinales chez l’adulte émerge suite à un processus développemental de raffinement des projections ipsi- et controlatérale étendues. Ces résultats suggèrent que le développement de la connectivité corticale pourrait être régulé de manière dynamique et spécifique aux primates / The retrograde tracing experiments in macaque cortex in this thesis had two related objectives. Firstly, injections in 40 cortical areas (from a 91-area atlas) allowed the construction of a hemisphere-wide consistent database of cortical connectivity. We examined which subcortical structures promote cortical communication via the formation of cortico-subcortical-cortical loops. The claustrum, which we argue has a tight affiliation with the cortex, showed uniquely strong outputs to every cortical area. Widely separated injection pairs led to overlapping labelled neurons in the claustrum including those pairs lacking direct cortico-cortical connections. Using graph theoretic tools, we examined how central the 40 areas and claustrum are in the cortical network, specifically with respect to hub status. This showed that the claustrum is, beyond doubt, the prime hub of the cortex. These findings emphasise the importance of studying the organizational principles of the cortex via the analysis of its network topology. Secondly, we investigated the development of the corticospinal pathway, a route over which the cortex directly influences the planning, execution and control of fine voluntary movements. We show that the adult pattern of corticospinal projections emerges via a developmental process from a widespread ipsi- and contralateral distribution. These findings suggest that the developmental refinement of cortical connectivity might be dynamically regulated and primate specific