Doctor of Philosophy (PhD) / The investigation into the relationship between neural plasticity in the rat forebrain associated with opiate-induced behaviours yielded two major results. The major finding of the functional neuroanatomy of acute morphine dependence was that doses of naloxone that induced hyperalgesia following a brief exposure to morphine, in previously drug-naïve rats, caused a specific induction of the inducible transcription factor (itf) proteins c-Fos and zif268 in the extended amygdala. Moreover, doses of naloxone that caused a simple reversal in morphine analgesia failed to induce itf proteins in these same brain regions. This increase in itf proteins was specific to regions of the extended amygdala that receive and process nociceptive information relayed via the spino-parabrachio-amygdaloid pathway and was not observed in other regions that are involved in supraspinal pain modulation such as the rostral ventromedial medulla and the periaqueductal gray. We also found that acute morphine increased c-Fos protein in the basolateral amygdala and the major output nucleus of the central amygdala the medial subdivision. Acute morphine also up-regulated c-Fos protein in striatal, midbrain, and hypothalamic nuclei. A unique finding of the current study was that prolonged exposure to morphine was required to induce c-Fos in these brain regions, as the subsequent administration of naloxone 30-minutes after morphine either reversed or blocked this induction. These results indicate the potential role of the amygdala in analgesia following systemic morphine and in pain facilitation during acute morphine abstinence. Investigation into the neurons and circuitry that undergo long-term neuroplasticity in response to repeated morphine exposure revealed that network-level changes in the distribution of Fos protein in the nucleus accumbens and striatum predicted both tolerance to catalepsy and psychomotor sensitisation. Drug-naïve rats became profoundly cataleptic following morphine, an effect that rats with a drug-history became tolerant. Rats with a history of morphine exposure showed an increase in stereotyped behaviours compared to drug-naïve rats. The major finding of this study was that a shift in the induction of c-Fos protein from a matrix predominance in drug-naïve rats toward a patch predominance in drug-sensitised rats in the accumbens core predicted both tolerance to catalepsy and sensitisation of oral stereotyped behaviours. Acute injection of morphine in a drug-naïve rat induced catalepsy and increased the number of c-Fos-positive neurons in matrix striatopallidal projection neurons of the rostral accumbens core. An increase in activity of striatopallidal projection neurons, which give rise to the indirect pathway, could potentially increase inhibitory drive to the pedunculopontine nucleus (PPN). The PPN, long known as a site of termination for basal ganglia output, is thought to direct the outflow of incentive-motivational and sensorimotor information from the nucleus accumbens to pons, medullary, and spinal cord nuclei translating the incentive impact of the stimuli into appropriate motor, autonomic and emotive responses (Winn et al., 1997). Inhibition of this nucleus would cause the animal to be unable to initiate a movement and in effect lock up, which is precisely what cataleptic postures look like. In contrast c-Fos-positive neurons were decreased in the rostral matrix and increased in patch striatonigral projection neurons along the rostro-caudal extent of the accumbens core when morphine was administered to drug-sensitised rats. Striatonigral neurons located in the patch give rise to the direct pathway innervating the dopaminergic neurons in both substantia pars compacta and the dopamine rich islands in the substantia nigra pars reticulata (Berendse et al., 1992; Gerfen, 1992; Furuta et al., 2002). Activity of this pathway is thought to be involved in the initiation of movement (Gerfen, 1992; Gerfen and Wilson, 1996), however, when this pathway is overstimulated as is the case when morphine is injected in drug-sensitised rats this could potentially cause increased activity of PPN neurons leading to repetitive psychomotor behaviours or stereotypy. This data adds to the growing body of evidence that suggests that long-term neuroadaptations induced by drugs of abuse including morphine that lead to behavioural sensitisation involves the circuitry that includes the nucleus accumbens.

We perceive the environment via sensor arrays and interact with it through motor outputs. The work of this thesis concerns how the brain selects actions given the information about the perceived state of the world and how it learns and adapts these selections to changes in this environment. Reinforcement learning theories suggest that an action will be more or less likely to be selected if the outcome has been better or worse than expected. A group of subcortical structures, the basal ganglia (BG), is critically involved in both the selection and the reward prediction. We developed and investigated a computational model of the BG. We implemented a Bayesian-Hebbian learning rule, which computes the weights between two units based on the probability of their activations. We were able test how various configurations of the represented pathways impacted the performance in several reinforcement learning and conditioning tasks. Then, following the development of a more biologically plausible version with spiking neurons, we simulated lesions in the different pathways and assessed how they affected learning and selection. We observed that the evolution of the weights and the performance of the models resembled qualitatively experimental data. The absence of an unique best way to configure the model over all the learning paradigms tested indicates that an agent could dynamically configure its action selection mode, mainly by including or not the reward prediction values in the selection process. We present hypotheses on possible biological substrates for the reward prediction pathway. We base these on the functional requirements for successful learning and on an analysis of the experimental data. We further simulate a loss of dopaminergic neurons similar to that reported in Parkinson’s disease. We suggest that the associated motor symptoms are mostly causedby an impairment of the pathway promoting actions, while the pathway suppressing them seems to remain functional. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.</p><p> </p>

Earlier human and animal studies have indicated abnormal striatal GABAergic interneurons relating to autism spectrum disorder’s (ASD) core features such as stereotypic repetitive behaviors, impaired language and motor skills, and social interactions. Purkinje cells (PCs) in the cerebellum are of great interest in ASD; earlier research has reported a loss of PCs, irregularities within deep cerebellar nuclei, a lower level of GAD67 (glutamic acid decarboxylase) mRNA expressed on PCs, and reduced parvalbumin (PV)-positive interneurons in cortex and hippocampus. In this study, in-situ hybridization was used to quantify the levels of PV mRNA in PCs in post-mortem human autism and control cerebellum sections. Two-tailed t-test analysis of the data showed a significant decrease (p<0.05) in PV mRNA level on PCs in autism compared to control sections. In addition, when comparing two groups (seizure and no seizure) in autism sections, no statistical significance was observed. Post-mortem interval (PMI) and age was compared between the PV mRNA levels in autism and control. Only weak negative correlation was found among age and PV mRNA levels in both groups. This report of decreased PV mRNA level in autism cases further supported previous research findings related to PCs and also confirmed interference with the inhibitory function of PCs to deep cerebellar nuclei and the cortex resulting in behavioral and motor impairments in ASD.

Dopamine (DA) is a key neuromodulator in the striatum, and is important for action selection and reinforcement learning. Dysfunctions in striatal DA signalling contribute to numerous disorders including Parkinson’s disease (PD) and drug addiction. Midbrain DA neurons switch from low to high frequency firing in response to reward-related events, which is proposed to increase striatal DA release. However, in addition to DA neuron firing pattern, striatal DA signalling depends upon the short-term plasticity of DA release, which is controlled by presynaptic and local network factors. This thesis uses fast-scan cyclic voltammetry, in murine striatal slices, to detect subsecond changes in extracellular DA, and investigate the presynaptic control of striatal DA release and release plasticity. Acetylcholine from striatal cholinergic interneurons, acting at nicotinic receptors (nAChRs) on DA terminals, is one factor that strongly influences DA release. This thesis particularly explores how presynaptic factors interact with nAChRs to control DA release. Firstly, release probability, a key determinant of release plasticity at many synapses, was found to be only weakly related to DA release plasticity, and only when nAChRs are inactive. Secondly, a direct role of the DA uptake transporter (DAT) in controlling DA release plasticity was identified, when nAChRs are inactive. Thirdly, regional differences were identified in the role of the DAT in controlling DA release via control of D2 receptor activation, when nAChRs are active. Finally, mutant α-synuclein, which causes PD in humans, was found to only subtly affect striatal DA release. These data suggest that the control of striatal DA release differs substantially from other central transmitters. Release probability and α-synuclein play only minor roles, but nAChRs and the DAT significantly control DA release plasticity. These findings review our understanding of striatal DA release and may have implications for understanding the actions of drugs of abuse and early PD pathogenesis.

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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.

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.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13570号 / 論医博第2296号 / 新制||医||1069(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 花川 隆, 教授 渡邉 大, 教授 高橋 淳 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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