Développement et assemblage des circuits corticaux / Developmental assembly of cortical circuits

Séminaire FSER organisé par Gordon Fishell (NYU Neuroscience Institute) du 9 au 14 mars 2015

Participants

Alain Chédotal, Rosa Cossart, Sophie Deneve, Gordon Fishell, Sonia Garel, Anirvan Ghosh, Martyn Goulding, Kenneth Harris, Adam Kepecs, Attila Losonczy, Oscar Marin, Thomas Mrsic-Flogel, Franck Polleux, Nathalie Rochefort, Botond Roska, Bernardo Rudy, Scanziani Massimo

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Résumé

Les recherches des dix dernières années ont vu l’émergence d’un nombre considérable de données relatives à l’origine et la spécification des différents constituants cellulaires du cortex cérébral. Nous commençons à pouvoir déchiffrer le schéma de connectivité des circuits corticaux grâce à des outils tels que la physiologie classique, l’optogénétique et les méthodes virales de traçage. La question qui demeure, et qui motive notre effort collectif, est de comprendre d’une part la logique selon laquelle le néocortex construit des représentations complexes, et d’autre part sa capacité à agir en fonction des schémas résultants. Ce séminaire a réuni différents experts (17 participants dont 4 chercheurs juniors, couvrant différents domaines de recherche : neurobiologie du développement, génétique, physiologie, neurosciences des systèmes, neurosciences computationnelles, modélisation et biotechnologie) ayant jusqu’à présent très peu interagi, analysant le développement et la physiologie des circuits neuronaux, travaillant sur cette question à différents niveaux.

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Work over the past decade has seen a wealth of information coming to light concerning the origin and specification of the cell types that populate the cerebral cortex. In addition, knowledge of the connectivity of mature cortical circuits is being deciphered through the use of traditional physiology, optogenetics and viral tracing methods. A gap in this understanding has been a concerted effort to understand the logic by which the neocortex acquires it areal-specific wiring. While the answer to this conundrum almost certainly involves a combination of developmental genetic programs modulated by the competing actions of ascending sensory inputs and recurrent cortical activity, the precise contribution of each is unclear. The purpose of this meeting will be to bring together distinct groups working on this problem (17 scientists including 4 junior participants, working in Developmental Neurobiology, Genetics, Physiology, Systems Neuroscience, Computational Neuroscience, Modeling and Biotechnology) who to date have had limited interactions, developmental neurobiologists focusing on the specification of specific cell types with system oriented physiologists who are examining circuits as a holistic level. By the intense interaction that this form will provide, we hope to define a set of specific experiments that will drive the field to the next level.

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Compte-rendu

Sessions for this conference were divided into three groups:

1. Development
2. Circuit analysis
3. Computational approaches.

Over the first two days each of the participants presented short conceptual talks that presented their findings in the contexts of their underlying theories. Each talk was accompanied by short discussions initiated through “replay” comprised of a short 5 minute summary of the most salient points presented, given by another of the attendees. Specific talks were:

Gord Fishell (replay Oscar Marin)- The integration of interneurons into pallial and subpallial networks: the instruction set for circuit assembly. In this talk, a theoretical hypothesis concerning how interneurons were specified and integrated into brain circuits was presented. Central to this hypothesis was the ultimate function of specific interneurons relied on an early genetic program specified at birth, coupled with positional information that was imprinted on specific cells post-migration during the period during which their connectivity was established.

Martyn Goulding (replay Franck Polleux)- Inhibitory circuit analysis in mice: Dr. Goulding analyzed the function of interneurons in spinal cord circuits and discussed how insights into the spinal cord compare with those in the higher CNS. Using specific genetic silencing of genetically identified interneuron subtypes, the impact on locomotion was noted and this was translated into models of how spinal cord circuitry functions in real time.

Oscar Marin (replay Gord Fishell)- Molecular regulation of cortical interneuron diversity and plasticity: Data concerning the role of the ER81 Ets domain containing transcription factor was presented that demonstrated this gene was activity regulated and imparted the intrinsic functional character to Basket cells that regulated them to delayed Fast spiking phenotype, which is characteristic of those basket cells within superficial layers of the cortex. This character related to the induction of specific K+ channels that bestowed this character. In the absence of ER81 in these interneurons mice became susceptible to epilepsy.

Franck Polleux (replay Martyn Goulding)- Molecular and cellular mechanisms regulating axon morphogenesis and presynaptic function in vivo. The phosphatase LKB2 was examined for its role in the distal branching and role in synaptogenesis in cortical projection cells. It was found that through a mechanism that remains uncertain, it functions to affect the motility of mitochondria, which in turn effects synaptic strength through specific Calcium signaling mechanisms mediated by the mitochondria.

Alain Chedotal (replay Anirvan Ghosh)- Development, function and evolution of commissural circuits: examined the function of different semaphorins in the formation of crossed commissures. It was found that a specific form is subject to alternative splicing that affects the formation of commissures and has relevance to human disease.

Sonia Garel (replay Nathalie Rochfort)- Neuronal and Immune orchestration of forebrain wiring: Examined the role of thalamic afferents that innervate the entorhinal cortex and plays a unique role in pioneering the thalamocortical pathway through a specific corridor. In addition, data concerning the role of microglia in the formation of cortical wiring was presented, suggesting a surprising interaction of the nervous and immune systems in wiring.

Rosa Cossart (replay Sonia Garel)- Spatial origin delineates GABAergic hub neurons in the developing neocortex: Examination of early so called “Hub cells” which had been previously demonstrated to play a role in the organization of the hippocampus, were examined for their contribution of the entorhinal cortex. From this a surprising principle demonstrating that early born GABAergic and glutamatergic cells had a privileged role in establishing the wiring of the specific regions of the pallium that they contribute to.

Anirvan Ghosh (replay Rosa Cossart)- What are we learning from the genetics of mental illness: Recent broad scale analysis of mutants occurring in humans was examined for their contribution to psychiatric disease. This data suggests how mutations in seemingly unrelated genes predispose individuals for risk for ASD, ADHD and schizophrenia. It promises to allow us to related disease to genes and hence to biological mechanism.

Massimo Scanziani (replay Attila Losonczy)- Cortical modulation of innate reflexes: Top down modulation is essential for allowing us to react to complex stimuli. Dr. Scanziani spoke of the role of descending modulation in the regulation of vestibule ocular reflexes. Specifically loss of vestibular response greatly diminishes our ability to respond to eye responses to movement.

Bernardo Rudy (replay Thomas Mrsic-Flogel)- Inhibitory and disinhibitory circuits in sensory processing: We have long recognized that we can increase our sensitivity to sensory input when engaged in a motor task, but the means by which this is achieved is unclear. Dr. Rudy demonstrated that a disinhibition circuit is able to mediate this phenomenon.

Thomas Mrsic-Flogel (replay Bernardo Rudy): The cellular basis of the perception of visual orientation within the cortex. It has long been recognized that cells within visual cortex respond to the orientation of light but the circuit basis of this phenomenon has remained elusive. Dr. Mrsic-Flogel explains how excitatory and inhibitory circuits cooperate to achieve such discrimination.

Attila Losonczy (replay Massimo Scanziani)- Developmental scaffolds of hippocampal network dynamics: Hippocampus is needed for the encoding of memory. Dr. Losonczy demonstrates how a combination of dynamics and developmental assembly establish the circuitry to achieve memory encoding.

Kenneth Harris (replay Botond Roska)- Neuronal diversity and the neocortical population code: In interpreting our environment we face a conflict between precision and need for sparse coding. Dr. Harris discusses a computational solution to the balance between these two competing drives to neural representation.

Sophie Deneve (replay Adam Kepecs)- Efficient coding in neural microcircuits: Brain function can utilize a bottom up (perceptive elements) or top down (Bayesian inference) to direct the solution of neural decoding. Under different circumstances one or the other predominates. In her talk, Dr. Deneve spoke on how to resolve this two conflicting modes of neural processing.

Botond Roska (replay Sophie Deneve)- Visual processing: from retina to cortex: The eye relays 17 distinct visual representations to the brain. How the brain uses this information to both recreate and act upon these representations is the fundamental challenge to understanding visual perception. Using cutting edge molecular and physiological methods, Dr. Roska tackles this problem.

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