This study was undertaken to locate and characterise the neurons in the central nervous system that project to the kidney. In particular, the aim was to illustrate and characterise the neural link between regions in the hypothalamus known to influence renal function and fluid balance, and nerves known to innervate the kidney.

One feature of the brain is that different parts of it respond to different stimuli. This means not all brain regions or neurons within those regions are active at a given moment. This feature of the brain gives it the ability to encode and store a wide range of stimuli that are then used to make predictions about a changing external environment. Activation of non-overlapping neural populations is fundamental to the ability to encode a wide range of stimuli to represent a changing environment. To examine the limits of this idea we used genetic tools to label active cell populations following a neutral stimulus presentation or a learned negative association with the same stimulus. The study examined the degree of similarity between these active populations by comparing key features of the active neurons including gene expression and monosynaptic inputs. Another feature of the brain is its ability to store information. In a neural population recently activated by a salient stimulus, molecular processes occur that result in the formation and maintenance of a memory. Collectively these processes are referred to as plasticity, and act on short and long time scales to strengthen the connections between active neurons and weaken the connections between inactive ones. Plasticity processes are not only necessary for the formation and storage of memories but also for wiring up the nervous system during development. A molecule called ZIP has been shown to erase memories months after formation and specifically affects plasticity on longer time scales. However, the effects of ZIP on the developing brain are not well understood and difficult to study using ZIP’s typical delivery method of injection into the brain. To facilitate a developmental study of ZIP’s effects, we made a genetic tool that can specify where and when ZIP is delivered to the brain. Results of the study indicated that males were particularly vulnerable to ZIP during early development while females were unaffected. Together these results provide insight into the limits of information coding potential at the anatomical level and reveal a fundamental difference in plasticity processes in males and females. / 10000-01-01

Le but de ce travail est l'étude de la connectivité anatomique et fonctionnelle desréseaux neuronaux et le développement des nouveaux outils à cet effet. Car le dernieraspect est une préoccupation majeure de la neuroscience actuelle, nous avonsdeveloppé d'abord un nouveau traceur virale permettant la reconstruction neuronale.Nous avons ensuite appliqué cet et d'autres techniques pour sonder les défauts deconnectivité neuronale dans le syndrome de l'X fragile.Dans la première partie, nous avons discuté les avantages et inconvénients d'unetechnique émergente en utilisant un nouveau type de vecteur viral qui permet uneunique application pour l’étude du cerveau.Dans la deuxième partie, nous avons développé, au départ de ce vecteur viral, unenouvelle variante de faciliter le traçage et reconstruction des caractéristiquesmorphologiques de neurones. Nous avons montré la force de cette varianteantérograde du virus de la rage recombinant glycoprotéine supprimé pour lareconstruction de calcul de toutes les caractéristiques morphologiques clés deneurones: les dendrites, épines, les axones longs envergure dans tous les terminaux ducerveau et les boutons.Dans la troisième partie, nous avons examiné les modifications dans la connectivitédes structures cérébrales dans le syndrome du X fragile (FXS). FXS est le retardmental héréditaire la plus fréquente et la forme génétique la plus fréquente del'autisme, ce qui conduit à l'apprentissage et de la mémoire des déficits, lescomportements répétitifs, des convulsions et une hypersensibilité à des stimulisensoriels (visuels). Une des hypothèses éminents dans le domaine de l'autismesuppose une phénotype de hyper-connectivité locale mais de hypo-connectivité pourles connexions longue portée. Pour tester cette hypothèse dans un modèle de sourisFXS nous avons utilisé l'imagerie par résonance magnétique, pour balayer la totalitédu cerveau et de mesurer la connectivité anatomique et fonctionnel. Cela nous apermis d'identifier des altérations de connectivité dans plusieurs domains. Après nous8avons utilisé des traceurs viraux pour explorer un de ceux domains plus detaillé. Enutilisant le virus de la rage rétrograde à quantifier le nombre de neurones projetantvers ces zones, nous avons confirmé une connectivité d'entrée modifié pour le cortexvisuel primaire, ce qui pourrait contribuer au traitement visuel altéré de l'information.Nous avons découvert une connectivité réduite à longue portée globale anatomique etfonctionnelle entre plusieurs régions du cerveau, l'identification FXS comme unepathologie de la connectivité neuronale, ce qui pourrait expliquer les difficultés deplusieurs stratégies de sauvetage visant des cibles moléculaires sont actuellementconfrontés. / The goal of this work was the investigation of the anatomical and functionalconnectivity of neuronal networks and the development of novel tools for thispurpose. Since the latter aspect is a major focus of current neuroscience, we firstsought a novel viral tracer enabling sparse neuronal reconstruction and neuronclassification. We then applied this and other techniques to probe neuronalconnectivity defects in Fragile X Syndrome.In the first part we discussed the merits and drawbacks of a emergingtechnique using a new type of viral vector that allows in a unique manner mapping ofthe input of a given brain area.In the second part we developed, departing from this viral vector, a newvariant to facilitate the tracing and reconstructing of morphologic features of neurons.We showed the strength of this anterograde variant of the recombinant glycoproteindeletedrabies virus for computational reconstruction of all key morphologicalfeatures of neurons: dendrites, spines, long-ranging axons throughout the brain andbouton terminals.In the third part we examined alterations in the wiring of brain structures inthe Fragile X Syndrome (FXS). FXS is the most common inherited mental retardationand most frequent genetic form of autism, leading to learning and memory deficits,repetitive behavior, seizures and hypersensitivity to sensory (e.g. visual) stimuli. Oneof the eminent hypotheses in the autism field assumes a local hyper- connectivityphenotype but hypo-connectivity for long-ranging connections. To test this hypothesisin a FXS mouse model we used magnetic resonance imaging, to scan the entire brainand measure the anatomical and functional connectivity. This allowed us to identifyconnectivity alterations in several areas that we further explored using viral tracers.Using retrograde rabies virus to count the number of neurons projecting to such areaswe confirmed an altered input connectivity to the primary visual cortex, which couldcontribute to the altered visual information processing. We discovered an overallreduced anatomical and functional long-range connectivity between several brainareas, identifying FXS as pathology of neuronal connectivity, which might explain thedifficulties several rescue strategies aiming at molecular targets are currently facing.

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.

No description available.