Forebrain functioning relies on complex circuits that begin to be established in the embryo by intrinsic developmental programs. Such programs coordinate the assembly of millions of neurons via an integrated choreography of neuronal migration and axonal navigation, which remains largely to be explored. In addition, intrinsic programs can be modulated by maternal environment, as illustrated by the fact that prenatal inflammation is a major risk factor for schizophrenia and autism. Understanding how embryonic programs and maternal signals control forebrain wiring is essential not only to progress in our comprehension of cerebral morphogenesis but also to provide a framework for assessing the etiology of neuropsychiatric disorders.
We have shown that two cell populations, corridor neurons and more recently microglia, act by their specific positioning and properties as orchestrators of forebrain wiring. Migrating corridor neurons regulate the ordering of thalamocortical axons, a main input to the neocortex. Microglia, the resident brain macrophages that are activated by prenatal inflammation, specifically regulate the progression of cortical and dopaminergic axons and the positioning of migrating cortical interneurons. Our work not only reveals the complex interactions governing forebrain wiring, but also a remarkable interplay in the development of the neural and immune systems. We now aim at deciphering the roles of these neural and immune cells during embryonic wiring of the forebrain. By multi-disciplinary approaches in mice we will investigate: i) how corridor neurons govern the ordering of thalamic axons; ii) how microglia regulate axonal progression and neuronal migration; iii) how microglia depletion or prenatal activation impacts in the long-term on forebrain functions. This ambitious project will provide essential knowledge on the intrinsic and extrinsic mechanisms governing forebrain wiring during normal and pathological development.
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