Nombre de personnes âgées, a placé le vieillissement cérébral et ses pathologies associées dans lesdéfis majeurs de ce début de XXIème siècle. Ce travail de thèse consiste à étudier et quantifierl’impact de la consommation de cigarette sur le vieillissement morphologique cérébral au seind’une grande cohorte de volontaires sains, celle de l’étude 3 Cités. Nous nous sommes attachés àévaluer et comparer son impact, par rapport à d’autres facteurs accélérant le vieillissementcérébral, dans des études transversales et longitudinales. Il en ressort que le tabac à un effet,principalement global, plus important que les facteurs de risque cardiovasculaires inclus dans cetteétude, et de même ampleur que celui de l’âge. Nous montrons que cet effet est arrêté avec laconsommation, montrant qu’une prévention chez les personnes âgés pourrait s’avérer d’un bénéficemajeur pour la société. De plus, les analyses ont été réalisées en séparant les femmes et leshommes dans nos analyses. Cela nous a permit de mettre en évidence une influence différentiellede la consommation de tabac sur le vieillissement cérébral dans les deux sexes.Néanmoins, les résultats présentés ont pour la plupart jamais été montrés et cela demande laréplication de l’étude dans une autre population / The increase in life expectancy seen during the XXth century, followed by an increase in theproportion of elderly, placed the study of brain aging and of its accompanying diseases in thespotlight. This thesis had for goal the study and quantification of the impact of tobaccoconsumption on brain morphological aging in a large cohort of elderly subjects from the Three CitiesStudy. We focused to evaluate and compare its impact, in comparison with other factors known toinfluence brain aging, in longitudinals and cross-sectionals studies. We show that tobacco smokinghas an effect, mainly global, more important than the others cardiovascular risk factors included inthis study and as important as the effect of age. Also, we have found that this effect stops with theconsumption, showing that prevention among the elderly population might be of major interest forsociety. Moreover, analysis have been conducted in men and women separately, allowing us to finddifferential effects of tobacco consumption on the brain morphological aging in the two sexes.

The Lateral Habenula (LHb) have been implicated in both reward-seeking behavior and in depressive disorders due to its modulatory effects on dopamine rich areas. Excitatory projections from LHb target GABAergic interneurons of both ventral tegmental area (VTA) and rostromedial tegmental nucleus (RMTg) and consequently provide strong inhibition on VTA‟s dopaminergic neurons. These reward related signals are provided to LHb from distinct neuronal populations in internal Globus Pallidus (GPi). Here by using a dual viral combination of an adeno-associated helper virus (AAV) and a genetically modified rabies virus that displays specific transsynaptic retrograde spread we are providing anatomical evidence for a strong innervations of the LHb by VGLUT2+ glutaminergic and SOM+ GABAergic GPi neurons. Our results provide the first direct evidence for both an excitatory and an inhibitory projection m, from GPi to the LHb. Given the importance of the LHb as a modulatory nucleus of the dopaminergic system, the definition of its connectivity and function will give valuable insights in the understanding of both reward-seeking behavior and depressive disorders.

本研究は、先行研究で示唆されていた淡蒼球外節（GP）におけるニューロキニン１型受容体（NK-1R）の局在を、免疫染色と投射パターン、電気生理学の観点から示した。形態学的には、NK-1Rを持つ細胞がLhx6やPVを共発現し、線条体と視床下核の両方に投射するものの、FoxP2を発現する細胞とは共存しなかった。さらに、パッチクランプを用いてGP細胞の電気的性質を調べた後、NK-1Rアゴニストへの応答を観察した結果を合わせたところ、NK-1R細胞がPrototypicタイプに含まれる特定の集団であることが明らかになった。 / 博士(理学) / Doctor of Philosophy in Science / 同志社大学 / Doshisha University

In category learning, explicit processes function through the prefrontal cortex (PFC) and implicit processes function through the basal ganglia. Research suggested that these two systems compete with each other. The goal of this study was to shed light on this theory. 15 undergraduate subjects took part in an event-related experiment that required them to categorize computer-generated line-stimuli, which varied in length and/or angle depending on condition. Subjects participated in an explicit "rule-based" (RB) condition and an implicit "information-integration" (II) condition while connected to a functional near-infrared spectroscopy (fNIRS) apparatus, which measured the hemodynamic response (HR) in their PFC. Each condition contained 2 blocks. We hypothesized that the competition between explicit and implicit systems (COVIS) would be demonstrated if, by block 2, task-accuracy was approximately equal across conditions with PFC activity being comparatively higher in the II condition. This would indicate that subjects could learn the categorization task in both conditions but were only able to decipher an explicit rule in the RB condition; their PFC would struggle to do so in the II condition, resulting in perpetually high activation. In accordance with predictions, results revealed no difference in accuracy across conditions with significant difference in channel activation. There were channel trends (p < .1) which showed PFC activation decrease in the RB condition and increase in the II condition by block 2. While these results support our predictions, they are largely nonsignificant, which could be attributed to the event-related design. Future research should utilize a larger samples size for improved statistical power.

No description available.

Cette thèse aborde la contribution des noyaux gris centraux (NGCs) au contrôle de trois activités motrices importantes que sont la locomotion non obstruée, le contrôle visuoguidé des modifications de la locomotion et celui des mouvements d’atteinte. Ce travail s’inscrit dans le cadre des études antérieures entreprises par notre laboratoire. Celles-ci ont détaillé l’activité de plusieurs aires corticales que nous supposons impliquées dans la planification des modifications locomotrices. De nombreuses cellules enregistrées dans ces études montrent des décharges similaires, quel que soit le membre qui franchit l’obstacle en premier (limb-independent). Ce signal pouvant être transformé en signal dépendant du membre, ou « limb-dependent », pour déterminer, entre autres, quel membre franchira l’obstacle en premier. Nous proposons que les NGCs soient impliqués dans cette transformation et qu’ils puissent contribuer à la fois à la sélection du membre qui enjambera l’obstacle en premier, et à l’initiation des modifications nécessaires à l’enjambement. Pour tester cette hypothèse, nous avons enregistré l’activité pallidale (i.e. noyau entopédonculaire et globus pallidus) de cinq chats lors de la marche sur tapis roulant et lors de l’enjambement des obstacles attachés à celui-ci. Nos résultats ont tout d’abord montré qu’une large population de cellules modulait son activité en accord avec le rythme locomoteur. Un grand nombre d’entre elles présentaient des modifications de leur activité de décharge avant l’initiation de l’enjambement, mais uniquement par rapport au membre controlatéral au site de l’enregistrement. Nous suggérons que ceci serait compatible avec une participation à la sélection du membre. De plus, d’autres cellules déchargeaient avec de brèves bouffées d’activité avant et pendant le franchissement et pourraient fournir les caractéristiques temporelles de celui-ci. La majorité des cellules ont montré des changements reliés à la phase de balancement du membre controlatéral, cependant quelques cellules déchargeaient en rapport avec l’activité de plusieurs membres menant à la suggestion de leur possible contribution à la régulation de la séquence d’activité dans les quatre membres. Pour déterminer si les mêmes cellules contribuaient au mouvement d’atteinte, leur activité a également été enregistrée, après le transfert du chat, sur un appareillage adjacent. La plupart des cellules déchargeaient lors de l’atteinte et pendant la locomotion. Dans certains cas, les modifications étaient très similaires, avec des cellules qui déchargeaient pendant la phase de balancement à la locomotion et pendant la phase de transport pendant l’atteinte. L’activité des autres était plus contrastée, suggérant un contrôle dépendant du contexte et possiblement l’existence de circuits séparés, dans le contrôle de différents mouvements. La tâche d’atteinte nous a aussi permis de corréler les décharges pallidales, avec les ajustements posturaux anticipateurs (APAs) qui précèdent le mouvement, ou avec le mouvement lui-même. Seules quelques cellules ont montré une meilleure corrélation avec les APAs, suggérant un rôle préférentiel du pallidum dans le mouvement spécifiquement, plutôt que dans les activités posturales qui le précèdent. En conclusion, nos résultats suggèrent que l’activité pallidale est étroitement corrélée à différents aspects des activités motrices et suggèrent que le pallidum est bien placé pour, en fonction du contexte, intégrer et transformer le signal cortical et participer au contrôle précis du déplacement et du positionnement du membre. Notons que puisque les plus importants changements d’activité prenaient la forme d’augmentations plutôt que des diminutions, nous discutons la possibilité que ces augmentations puissent sculpter l’activité thalamo-corticale plutôt que relâcher le thalamus de son inhibition. / This thesis addresses the issue of how the basal ganglia contribute to the control of three important motor activities: i) the control of non-obstructed locomotion, ii) the control of visually-guided gait modifications and iii) the control of visually-guided reaching movements. A major impetus for this work comes from previous studies from this laboratory that have detailed the activity of several cortical areas that we postulate are involved in the planning of gait modification. Many of the cells recorded in these studies show similar discharges regardless of which limb is the first to step over the obstacle (limb-independent). This signal therefore has to be transformed into a limb-dependent signal to determine, amongst other issues, which limb will be the first to step over the obstacle. We propose that the basal ganglia are involved in this transformation and that it might make a contribution both in selecting which limb will be the first to step over the obstacle as well as determining temporal aspects of the resulting step. To test this hypothesis, we recorded activity from the pallidum (i.e. globus pallidus and entopedoncular nucleus) of five cats trained to walk on a treadmill and to step over a moving obstacle attached to that treadmill. We showed that a large proportion of pallidal neurons modulated their discharge according to the locomotor rhythm. Many of these neurons discharged before the onset of the step over the obstacle, but only for the contralateral limb to the recording site, compatible with a bias toward selecting that limb. In addition, other cells discharged with brief bursts of activity before and during the step and might contribute to providing temporal information about the upcoming step. The majority of cells showed changes related to the swing phase of the contralateral limb but some cells discharged with respect to the activity in several limbs leading us to suggest a possible contribution to the regulation of the sequence of activity in the four limbs. To determine whether the same cells contributed to discrete reaches, neuronal activity was recorded from the same cells after the transfer of the cat from the treadmill to an adjacent apparatus. Most cells discharged during both behaviours and in some cases the discharges during gait modification and reaching were very similar. In particular, cells discharging during the swing phase of locomotion also discharged during the transport phase of the reach. In other cases, the activity was more disparate, suggesting a context-dependent control over the activity and perhaps the existence of separate circuits for the control of different movements. The reaching task allowed us to correlate the discharge with preparatory postural adjustments that precede movements. Only a few cells showed a better correlation with APAs in comparison with the movement, suggesting a preferential role of the pallidum in focal movements rather than in the preceding postural activities. In conclusion, our results suggest that the activity in the pallidum is tightly correlated with different aspects of motor activity, suggesting that the pallidum is well placed to integrate and transform cortical signals and participate in the precise control of limb displacement. It was noteworthy that the strongest and most frequent changes in activity were increases rather than decreases. We discuss the possibility that these increases in activity might sculpt thalamocortical activity rather than releasing the thalamus from inhibition.

The basal ganglia are the key circuitry controlling movement and reward behavior. Both locomotion and reward-related behavior are also modified by dopaminergic input from the substantia nigra and the ventral tegmental area (VTA). If the basal ganglia are severed by lesion or in disease, such as in Parkinson’s disease, the affected individuals suffer from severe motor impairments and often of affective and reward-related symptoms. The subthalamic nucleus (STN) is a glutamatergic key area of the basal ganglia and a common target for deep brain stimulation in Parkinson’s disease to alleviate motor symptoms. The STN serves not only motoric, but also limbic and cognitive functions, which is often attributed to a tripartite anatomical subdivision. However, the functional output of both VTA and STN may rely more on intermingled subpopulations than on a strictly anatomical subdivision. In this doctoral thesis, the role of subpopulations within and associated with the basal ganglia is addressed from both a genetic and a behavioral angle. The identification of a genetically defined subpopulation within the STN, co-expressing Paired-like homeodomain transcription factor 2 (Pitx2) and Vesicular glutamate transport 2 (Vglut2), made it possible to conditionally reduce glutamatergic transmission from this subgroup of neurons and to investigate its influence on locomotion and motivational behavior, giving interesting insights into the mechanisms possibly underlying deep brain stimulation therapy and its side-effects. We address the strong influence of the Pitx2-Vglut2 subpopulation on movement, as well as the more subtle changes in reward-related behavior and the impact of the alterations on the reward-related dopaminergic circuitry. We also further elucidate the genetic composition of the STN by finding new markers for putative STN subpopulations, thereby opening up new possibilities to target those cells genetically and optogenetically. This will help in future to examine both STN development, function in the adult central nervous system and defects caused by specific deletion. Eventually identifying and characterizing subpopulations of the STN can contribute to the optimization of deep brain stimulation and help to reduce its side-effects, or even open up possibilities for genetic or optogenetic therapy approaches.

Based on the belief that it is a locomotor control structure, the pedunculopontine tegmental nucleus (PPTg) has been considered a potential target for deep brain stimulation (DBS) for Parkinson's disease (PD) patients with symptoms refractory to medication and/or stimulation of established target sites. To date, a number of patients have been implanted with PPTg electrodes with mostly disappointing results. Exact target site in PPTg, possible mechanisms of PPTg-DBS and likely potential benefits need to be systematically explored before consideration of further clinical application. The research described here approaches these questions by (i) investigating the role of the PPTg in gait per se; (ii) developing a refined model of PD that mimics the underlying pathophysiology by including partial loss of the PPTg itself; (iii) adapting a wireless device to let rats move freely while receiving DBS; and (iv) investigating the effect of DBS at different sites in the PPTg on gait and posture in the traditional and refined model of PD. Underlining the concern that understanding the PPTg as a locomotor control structure is inadequate, the experiments showed that neither partial nor complete lesions of PPTg caused gait deficits. The refined model showed hardly any differences compared to the standard one, but the effect of DBS in each was very different, highlighting the need to take degeneration in the PPTg into consideration when investigating it as a DBS target. The differential results of anterior and posterior PPTg-DBS show the critical importance of intra-PPTg DBS location: Anterior PPTg electrodes caused severe freezing and worsened gait while some gait parameters improved with stimulation of posterior PPTg. The results suggest mechanisms of PPTg-DBS beyond the proposed activation of over-inhibited PPTg neurons, including aggravation of already dysfunctional inhibitory input by anterior PPTg-DBS and activation of ascending projections from posterior PPTg to the forebrain.

Une question fondamentale en neuroscience, ainsi que dans de nombreuses disciplines s’intéressant à la compréhension du comportement, telles que la psychologie, l’Economie, et la sociologie, concerne les processus décisionnels par lesquels les animaux et les humains sélectionnent des actions renforcées positivement ou négativement. Les processus décisionnels ainsi que leur base neuronale demeurent mal compris. D’autre part de nombreuses études ont révélé que les humains ainsi que les animaux prennent souvent des décisions sous-optimales. Notre principal objectif a été de comprendre la raison de ces comportements sous-optimaux. Par ailleurs, l’altération des processus sous-tendant la prise de décision, entraîne des pathologies. La compréhension des mécanismes décisionnels est essentielle au développement de stratégies de traitements plus efficaces. Dans cette étude nous avons proposé une nouvelle approche de l’étude des comportements décisionnels, basée sur l’hétérogénéité des préférences créées au cours de l’apprentissage du choix. Puis nous avons corrélé l’activité du putamen et du globus pallidus interne aux comportements préalablement décrits. Nos résultats montrent que bien que les primates apprennent à identifier la meilleure option et convergent vers une stratégie optimale dans un nombre important de sessions, ils n’arrivent pas en moyenne à optimiser leur comportement. Nous avons montré que ce comportement suboptimal des primates est caractérisé par la création de préférences irrationnelles par ces derniers pour des paramètres non pertinents de l’environnement. Nous avons finalement montré que bien qu’un faible nombre de neurones du putamen encode la valeur de l’action, leur contribution à l’activité de population est faible. L’activité du putamen reflète les futures performances des primates et prédit donc la formation des comportements irrationnels et rationnels. / A fundamental question in neuroscience, as well as in various fields such as economics, psychology and sociology, concerns the decision making processes by which animals and humans select actions based on reward and punishment. Both decision making processes and their neural basis are still poorly understood. Also, both human and animals often make suboptimal decisions in many tasks studied. Our first aim is to improve the understanding of why such sub-optimal decisions are made. Also, the alteration of decision making processes causes diseases, the understanding of whose mechanisms is essential in developing better treatment strategies. In this report, we propose a new approach which consists in extracting the neural substrates of choice behavior heterogeneity in between sessions. Our results show that although primates learn on average to identify the best option and converge to an optimal policy in a consequent number of sessions, they fail on average to optimize their behavior. We revealed that this suboptimal behavior was characterized by an unexpected high behavioral heterogeneity during the task that was due to the creation of irrelevant preferences by the monkeys. We finally show that although a few neurons of the putamen encode the action value, their contribution to the overall population activity is weak. Putamen activity rather reflects the futures performances and predicts the creation of rational and irrational behaviors.

Neural activity in dopaminergic areas such as the ventral tegmental area is influenced by timing processes, in particular by the temporal expectation of rewards during Pavlovian conditioning. Receipt of a reward at the expected time allows to compute reward-prediction errors which can drive learning in motor or cognitive structures. Reciprocally, dopamine plays an important role in the timing of external events. Several models of the dopaminergic system exist, but the substrate of temporal learning is rather unclear. In this article, we propose a neuro-computational model of the afferent network to the ventral tegmental area, including the lateral hypothalamus, the pedunculopontine nucleus, the amygdala, the ventromedial prefrontal cortex, the ventral basal ganglia (including the nucleus accumbens and the ventral pallidum), as well as the lateral habenula and the rostromedial tegmental nucleus. Based on a plausible connectivity and realistic learning rules, this neuro-computational model reproduces several experimental observations, such as the progressive cancelation of dopaminergic bursts at reward delivery, the appearance of bursts at the onset of reward-predicting cues or the influence of reward magnitude on activity in the amygdala and ventral tegmental area. While associative learning occurs primarily in the amygdala, learning of the temporal relationship between the cue and the associated reward is implemented as a dopamine-modulated coincidence detection mechanism in the nucleus accumbens.