526 research outputs found

    Initiation of locomotion : optogenetic stimulation of midbrain nuclei

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    Initier la marche vient naturellement pour tout être vivant qui se déplace. Malgré cette apparente facilité, cet acte nécessite une interaction complexe entre différentes régions du cerveau et la moelle épinière. Une de ces régions a été découverte dans le mésencéphale et a été identifiée il y a maintenant 50 ans comme la région locomotrice mésencéphalique. En effet, la stimulation électrique de cette région engendre de manière systématique l’initiation de la locomotion dans de nombreuses espèces animales. Malgré tout, la localisation anatomique précise et l’identification des populations neuronales de cette région sont un sujet de débat encore aujourd’hui. Dans notre projet, nous avons utilisé les outils optogénetiques accessibles chez la souris afin de stimuler spécifiquement les populations glutamatergiques ou cholinergiques des deux noyaux qui constituent la région locomotrice mésencéphalique, le noyau cunéiforme (CnF) et le noyau pedonculopontin (PPN). Nous avons découvert que nous ne pouvions initier la marche en stimulant seulement les neurones glutamatergiques du noyau cunéiforme, indiquant ainsi que ces neurones constituent le corrélat anatomique de la région locomotrice mésencéphalique. Étant donné l’intérêt clinique de la stimulation profonde chez des patients parkinsoniens, épileptiques ou médullaires, il paraît d’autant plus urgent de définir la localisation et les fonctions précises des populations neuronales contribuant à cette région fonctionnelle.The act of initiating locomotion comes naturally to every living and moving the animal. Despite this apparent easiness, this act relies upon a complex neuronal interaction between brain regions and the spinal cord. One of those regions was found in the brainstem and has been identified 50 years ago as the mesencephalic locomotor region. Indeed, electrical stimulation of this region consistently leads to the initiation of locomotion in many species. However, the precise anatomical location and neuronal composition responsible for this effect on locomotion remained a matter of debate for years. Here, using neuronal specific optogenetic stimulation in mice, we stimulated either the glutamatergic or the cholinergic population in the two proposed nuclei that form the MLR (cuneiform and pedunculopontine nuclei, CnF and PPN). We simultaneously recorded kinematics and EMG activity and found that we could only reliably induce locomotion when stimulating the glutamatergic neurons of the CnF, therefore establishing those neurons as the correlates of the MLR. Considering that the MLR is being tested as a deep brain stimulation target for disease ranging from Parkinson to epilepsy and spinal cord injury, it seems even more urgent to ascertain precisely its anatomical location and physiological role

    Functional contribution of the mesencephalic locomotor region to locomotion

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    Parce qu'il est naturel et facile de marcher, il peut sembler que cet acte soit produit aussi facilement qu'il est accompli. Au contraire, la locomotion nécessite une interaction neurale complexe entre les neurones supraspinaux, spinaux et périphériques pour obtenir une locomotion fluide et adaptée à l'environnement. La région locomotrice mésencéphalique (MLR) est un centre locomoteur supraspinal situé dans le tronc cérébral qui a notamment pour rôle d'initier la locomotion et d'induire une transition entre les allures locomotrices. Cependant, bien que cette région ait initialement été identifiée comme le noyau cunéiforme (CnF), un groupe de neurones glutamatergiques, et le noyau pédonculopontin (PPN), un groupe de neurones glutamatergiques et cholinergiques, son corrélat anatomique est encore un sujet de débat. Et alors qu'il a été prouvé que, que ce soit lors d’une stimulation de la MLR ou pour augmenter la vitesse locomotrice, la plupart des quadrupèdes présentent un large éventail d'allures locomotrices allant de la marche, au trot, jusqu’au galop, la gamme exacte des allures locomotrices chez la souris est encore inconnue. Ici, en utilisant l'analyse cinématique, nous avons d'abord décidé d'identifier d’évaluer les allures locomotrices des souris C57BL / 6. Sur la base de la symétrie de la démarche et du couplage inter-membres, nous avons identifié et caractérisé 8 allures utilisées à travers un continuum de fréquences locomotrices allant de la marche au trot puis galopant avec différents sous-types d'allures allant du plus lent au plus rapide. Certaines allures sont apparues comme attractrices d’autres sont apparues comme transitionnelles. En utilisant une analyse graphique, nous avons également démontré que les transitions entre les allures n'étaient pas aléatoires mais entièrement prévisibles. Nous avons ensuite décidé d'analyser et de caractériser les contributions fonctionnelles des populations neuronales de CnF et PPN au contrôle locomoteur. En utilisant des souris transgéniques exprimant une opsine répondant à la lumière dans les neurones glutamatergiques (Glut) ou cholinergiques (CHAT), nous avons photostimulé (ou photo-inhibé) les neurones glutamatergiques du CnF ou du PPN ou les neurones cholinergiques du PPN. Nous avons découvert que les neurones glutamatergiques du CnF initient et modulent l’allure locomotrice et accélèrent le rythme, tandis que les neurones glutamatergiques et cholinergiques du PPN le ralentissent. En initiant, modulant et en accélérant la locomotion, notre étude identifie et caractérise des populations neuronales distinctes de la MLR. Définir et décrire en profondeur la MLR semble d’autant plus urgent qu’elle est devenue récemment une cible pour traiter les symptômes survenant après une lésion de la moelle épinière ou liés à la maladie de Parkinson.Because it is natural and easy to walk, it could seem that this act is produced as easily as it is accomplished. On the contrary, locomotion requires an intricate and complex neural interaction between the supraspinal, spinal and peripheric neurons to obtain a locomotion that is smooth and adapted to the environment. The Mesencephalic Locomotor Region (MLR) is a supraspinal brainstem locomotor center that has the particular role of initiating locomotion and inducing a transition between locomotor gaits. However, although this region was initially identified as the cuneiform nucleus (CnF), a cluster of glutamatergic neurons, and the pedunculopontine nucleus (PPN), a cluster of glutamatergic and cholinergic neurons, its anatomical correlate is still a matter of debate. And while it is proven that, either under MLR stimulation or in order to increase locomotor speed, most quadrupeds exhibit a wide range of locomotor gaits from walk, to trot, to gallop, the exact range of locomotor gaits in the mouse is still unknown. Here, using kinematic analysis we first decided to identify to assess locomotor gaits C57BL/6 mice. Based on the symmetry of the gait and the inter-limb coupling, we identified and characterized 8 gaits during locomotion displayed through a continuum of locomotor frequencies, ranging from walk to trot and then to gallop with various sub-types of gaits at the slowest and highest speeds that appeared as attractors or transitional gaits. Using graph analysis, we also demonstrated that transitions between gaits were not random but entirely predictable. Then we decided to analyze and characterize the functional contributions of the CnF and PPN’s neuronal populations to locomotor control. Using transgenic mice expressing opsin in either glutamatergic (Glut) or cholinergic (CHAT) neurons, we photostimulated (or photoinhibited) glutamatergic neurons of the CnF or PPN or cholinergic neurons of the PPN. We discovered that glutamatergic CnF neurons initiate and modulate the locomotor pattern, and accelerate the rhythm, while glutamatergic and cholinergic PPN neurons decelerate it. By initiating, modulating, and accelerating locomotion, our study identifies and characterizes distinct neuronal populations of the MLR. Describing and defining thoroughly the MLR seems all the more urgent since it has recently become a target for spinal cord injury and Parkinson’s disease treatment

    Targeting the pedunculopontine nucleus in Parkinson’s disease: Time to go back to the drawing board

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    Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147041/1/mds27540.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147041/2/mds27540_am.pd

    In vivo structural connectome of arousal and motor brainstem nuclei by 7 Tesla and 3 Tesla MRI

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    Brainstem nuclei are key participants in the generation and maintenance of arousal, which is a basic function that modulates wakefulness/sleep, autonomic responses, affect, attention, and consciousness. Their mechanism is based on diffuse pathways ascending from the brainstem to the thalamus, hypothalamus, basal forebrain and cortex. Several arousal brainstem nuclei also participate in motor functions that allow humans to respond and interact with the surrounding through a multipathway motor network. Yet, little is known about the structural connectivity of arousal and motor brainstem nuclei in living humans. This is due to the lack of appropriate tools able to accurately visualize brainstem nuclei in conventional imaging. Using a recently developed in vivo probabilistic brainstem nuclei atlas and 7 Tesla diffusion-weighted images (DWI), we built the structural connectome of 18 arousal and motor brainstem nuclei in living humans (n = 19). Furthermore, to investigate the translatability of our findings to standard clinical MRI, we acquired 3 Tesla DWI on the same subjects, and measured the association of the connectome across scanners. For both arousal and motor circuits, our results showed high connectivity within brainstem nuclei, and with expected subcortical and cortical structures based on animal studies. The association between 3 Tesla and 7 Tesla connectivity values was good, especially within the brainstem. The resulting structural connectome might be used as a baseline to better understand arousal and motor functions in health and disease in humans

    The cellular diversity of the pedunculopontine nucleus: relevance to behavior in health and aspects of Parkinson's disease

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    The pedunculopontine nucleus (PPN) is a rostral brainstem structure that has extensive connections with basal ganglia nuclei and the thalamus. Through these the PPN contributes to neural circuits that effect cortical and hippocampal activity. The PPN also has descending connections to nuclei of the pontine and medullary reticular formations, deep cerebellar nuclei, and the spinal cord. Interest in the PPN has increased dramatically since it was first suggested to be a novel target for treating patients with Parkinson’s disease who are refractory to medication. However, application of frequency-specific electrical stimulation of the PPN has produced inconsistent results. A central reason for this is that the PPN is not a heterogeneous structure. In this article, we review current knowledge of the neurochemical identity and topographical distribution of neurons within the PPN of both humans and experimental animals, focusing on studies that used neuronally selective targeting strategies to ascertain how the neurochemical heterogeneity of the PPN relates to its diverse functions in relation to movement and cognitive processes. If the therapeutic potential of the PPN is to be realized, it is critical to understand the complex structure-function relationships that exist here

    From locomotor behavior to cerebellum evolution and development in squamate models

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    Locomotor behavior, the entire set of movements an individual utilizes to modify its spatial location in time, is a crucial attribute of an organism’s life. Though not responsible for movement initiation or rhythmic locomotor pattern generation, the cerebellum, an ancient and functionally conserved feature of the vertebrate brain, plays a key role in many aspects of motor performance. Variations in its morphology, relative size and cortical organization, likely resulting from divergent developmental programs, have been observed even in closely related vertebrate species, often reflecting a tight linkage between cerebellar organization and functional demands associated with ecologically relevant factors and distinct behavioral traits. Taking advantage of the extraordinary ecomorphological diversity of squamates (lizards and snakes) and adopting a multidisciplinary approach, this thesis explores the impact of locomotor behavior on squamate brain, particularly on different levels of cerebellar biological organization, and investigates cerebellar morphogenesis in two squamate species to gain insights on the developmental mechanisms potentially responsible for squamate cerebellar divergence. Along with significant variations in cerebellar morphology and relative size across squamates, this thesis first highlights a wide heterogeneity in Purkinje cell (PC) spatial layout as well as in gene expression pattern, all correlating with specific locomotor behaviors, unveiling unique relationships between a major evolutionary transition and organ specialization in vertebrates. At the developmental level, the thesis indicates that developmental features considered, so far, exclusive hallmarks of avian and mammalian cerebellogenesis characterize squamate cerebellar morphogenesis. Furthermore, the thesis suggests that variations in the spatiotemporal patterning of different cerebellar neurons could be, at least partially, at the base of the large phenotypic diversification of the squamate cerebellum. Finally, this thesis reveals that squamates provide an important framework to expand our knowledge on organ system-ecology relationships and central nervous system (CNS) development and evolution in vertebrates.Eliöiden toimintaan liittyy oleellisena osana niiden kyky liikkua, eli siirtyä paikasta toiseen erilaisten ruuminosien liikkeiden avulla. Pikkuaivot (cerebellum) ovat hyvin oleellinen osa selkärankaisten liikkeen säätelyä, ja niiden toiminta onkin säilynyt peruspiirteiltään samana selkärankaisten evoluution aikana. Vaikka pikkuaivojen rooliin ei kuulu liikkeen aloittaminen tai rytmisen liikkeen tahdin säätely, niillä on huomattava rooli muussa liikkeen säätelyssä. Tähän lukeutuvat esimerkiksi liikkeiden oppiminen ja korjaaminen. Pikkuaivoissa esiintyy hyvin paljon lajien välistä vaihtelua, mikä johtuu todennäköisesti yksilönkehityksen ja sen säätelyn eroavaisuuksista eri lajeilla. Eroja on havaittavissa niin pikkuaivojen morfologiassa, suhteellisessa koossa kuin myös niiden kuorikerroksen rakenteessa, usein jopa lähisukuisten lajien välillä. Nämä eroavaisuudet heijastelevatkin usein eläinten erilaisia toiminnallisia tarpeita, liittyen varsinkin käyttäytymispiirteisiin sekä muihin niiden ekologiaan linkittyviin tekijöihin. Suomumatelijoilla (liskoilla ja käärmeillä) on huomattava laaja kirjos erilaisia ekomorfologioita ja liikkumistapoja. Tämä väitöskirja keskittyykin selvittämään liikkumistapojen vaikutusta suomumatelijoiden aivoihin sekä yleisesti että erityisesti pikkuaivoja tarkastellen. Huomio keskittyy pikkuaivoissa sekä kokonaiskuvan muodostamiseen niiden rakenteesta että niiden yksilönkehitykseen. Yksilönkehityksen suhteen vertailussa ovat kaksi eri suomumatelijoiden edustajaa mahdollisten yksilönkehityksen muutosten mekanismien selvittämiseksi. Väitöskirjatyössä havaittiin suomumatelijoilla merkittävää pikkuaivojen morfologian ja suhteellisen koon lajienvälistä vaihtelua. Tämän lisäksi työn aikana havaittiin huomattavia eroja pikkuaivojen niin sanottujen Purkinjen solujen järjestäytymisessä sekä eri geenien luennassa erilaista liikkumistyyppiä edustavien lajien välillä. Purkinjen solujen järjestäytymisen ja geeniluennan havaittiin myös korreloivan erilaisten liikkumistyyppien kanssa, tuoden esiin mielenkiintoisen yhteyden evolutiivisten muutosten ja elinten erikoistumisen välillä. Samoin tulokset viittaavat siihen, että linnuille ja nisäkkäille ainutlaatuisiksi luultuja pikkuaivojen muodostumisen piirteitä löytyy myös suomumatelijoilta. Väitöskirjatyössä havaittiin lisäksi viitteitä suomumatelijoiden pikkuaivojen monimuotoisuuden taustalla olevista yksilönkehityksen muutoksista. Tulosten valossa on mahdollista, että pikkuaivojen neuronien kaavoituksen ajoituksen ja sijainnin muutokset voisivat ainakin osin olla syy suomumatelijoiden pikkuaivojen monimuotoisuuteen. Laajemmassa mielessä tulokset tuovat esiin myös suomumatelijoiden erittäin oleellisen roolin selkärankaisten evoluution tutkimuksessa kahdesta oleellisesta tulokulmasta: selkärankaisten keskushermoston yksilönkehityksen ja evoluution tutkimus sekä yleisemmällä tasolla elinsysteemien ja ekologian yhteyden selvittäminen

    Brain-Wide Analysis of the Supraspinal Connectome Reveals Anatomical Correlates to Functional Recovery After Spinal Injury

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    The supraspinal connectome is essential for normal behavior and homeostasis and consists of numerous sensory, motor, and autonomic projections from brain to spinal cord. Study of supraspinal control and its restoration after damage has focused mostly on a handful of major populations that carry motor commands, with only limited consideration of dozens more that provide autonomic or crucial motor modulation. Here, we assemble an experimental workflow to rapidly profile the entire supraspinal mesoconnectome in adult mice and disseminate the output in a web-based resource. Optimized viral labeling, 3D imaging, and registration to a mouse digital neuroanatomical atlas assigned tens of thousands of supraspinal neurons to 69 identified regions. We demonstrate the ability of this approach to clarify essential points of topographic mapping between spinal levels, measure population-specific sensitivity to spinal injury, and test the relationships between region-specific neuronal sparing and variability in functional recovery. This work will spur progress by broadening understanding of essential but understudied supraspinal populations

    Brainstem Circuits Controlling Action Diversification

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    Neuronal circuits that regulate movement are distributed throughout the nervous system. The brainstem is an important interface between upper motor centers involved in action planning and circuits in the spinal cord ultimately leading to execution of body movements. Here we focus on recent work using genetic and viral entry points to reveal the identity of functionally dedicated and frequently spatially intermingled brainstem populations essential for action diversification, a general principle conserved throughout evolution. Brainstem circuits with distinct organization and function control skilled forelimb behavior, orofacial movements, and locomotion. They convey regulatory parameters to motor output structures and collaborate in the construction of complex natural motor behaviors. Functionally tuned brainstem neurons for different actions serve as important integrators of synaptic inputs from upstream centers, including the basal ganglia and cortex, to regulate and modulate behavioral function in different contexts

    The circuit and synaptic organization of the basal ganglia output : mechanistic insights on movement disorders and action control

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    Understanding the neural circuitry underlying movement is a neuroscientific challenge that promises to help refining currently available treatments for movement disorders. Key structures for movement and action control are the basal ganglia nuclei, whose complexity has only just started to be resolved. The constituent papers of this thesis analyzed different levels of basal ganglia circuit organization and function. In paper 1 we used a 6-hydroxydopamine (6-OHDA) lesion model of Parkinson’s Disease (PD) to study glutamatergic synapses in the substantia nigra reticulata (SNr). We found that NMDA receptors synaptic function in the SNr is altered in 6-OHDA lesioned mice. NMDA receptor blockade transiently rescued hypolocomotion in 6-OHDA lesioned mice. In paper 2 we used a mutated Leucin Rich Repeat Kinase 2 (LRRK2-G2019S) mouse model and studied midbrain adaptations in a middle age range that precedes the onset of neurodegeneration. LRRK2-G2019S mice had increased exploratory behavior compared to their wild-type littermate. In midbrain dopamine neurons glutamatergic neurotransmission was affected in a region-specific manner, but no change in firing was identified. In paper 3 we used the same model to investigate the firing and glutamatergic synapses of SNr neurons. We found no change in firing whereas glutamate release but not N-Methyl-D-Aspartate (NMDA) receptors was altered in SNr neurons. In paper 4 we analyzed the organization of synaptic inputs to the associative and sensorimotor SNr. We found that inputs from the direct pathway are homogeneously distributed across SNr subregions whereas inputs from the indirect pathway are biased to the sensorimotor SNr. In alcohol exposed mice, inputs from the sensorimotor striatum were selectively potentiated. In paper 5 we focused on the indirect pathway projections to the globus pallidus external segment and identified distinct mechanisms of presynaptic modulation by cannabinoid 1 (CB1) and GABAB receptors. In summary, we have investigated several basal ganglia circuits and their synaptic adaptations in disease models. We revealed key features of the SNr circuit organization and its adaptations in mouse models of PD. We found that distinct subpopulations of SNr neurons are part of the associative and sensorimotor loops, and that direct and direct pathway inputs are differentially integrated in these neurons. These findings are relevant to understanding how the SNr shapes the behavioral output of the basal ganglia circuits. In mouse models of PD and alcohol use disorder the synaptic inputs to the SNr are reorganized. These findings open novel views and research directions on the functional organization of the basal ganglia output

    Brainstem circuits involved in skilled forelimb movements

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    Movement is the main output of the nervous system as well as the fundamental form of interaction animals have with their environment. Due to its function and scope, movement has to be characterized by both stability and flexibility. Such apparently conflicting attributes are reflected in the complex organization of the motor system, composed of a vast network of widely distributed circuits interacting with each other to generate an appropriate motor output. Different neuronal structures, located throughout the brain, are responsible for producing a broad spectrum of actions, ranging from simple locomotion to complex goal directed movements such as reaching for food or playing a musical instrument. The brainstem is one of such structures, holding considerable importance in the generation of the motor output, but also largely unexplored, due to its less-than-accessible anatomic location, functional intricacies and the lack of appropriate techniques to investigate its complexity. Despite recent advances, a deeper understanding of the role of brainstem neuronal circuits in skilled movements is still missing. In this dissertation, we investigated the involvement of the lateral rostral medulla (LatRM) in the construction of skilled forelimb behaviors. The focus of my work was centered on elucidating the anatomical and functional relationships between LatRM and the caudal brainstem, and specifically on the interactions with the medullary reticular formation, considering both its ventral (MdV) and dorsal subdivisions (MdD). In summary, we reveal the existence of anatomically segregated subpopulations of neurons in the lower brainstem which encode different aspects of skilled forelimb movements. Moreover, we show that LatRM neurons are necessary for the correct execution of skilled motor programs and their activation produces complex coordinated actions. All this evidence suggests that LatRM may be a key orchestrator for skilled movements by functioning as integration center for upstream signals as well as coordinator by selecting the appropriate effectors in the lower medulla and the spinal cord
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