Final Report Summary - NIMO (Neural and Immune Orchestrators of Forebrain Wiring)
Brain functioning relies on complex circuits that begin to be established in the embryo by developmental programs which coordinate the assembly of millions of neurons. Such programs can be modulated by environmental signals, as illustrated by the fact that prenatal inflammation is a major risk factor for schizophrenia and autism. Understanding how embryonic programs and external signals control cerebral 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. Our NImO project took advantage of mouse genetics to explore the role of several populations of cells in the development of the neocortex, which is essential for sensory perception, motor responses and cognition. First, we examined the roles of corridor neurons and Cajal-Retzius cells, which act as guidepost for sensory input to the neocortex. Second, we assessed the functions of microglia, immune cells that reside in the brain from the earliest steps of embryogenesis and mediate inflammatory signals. We found that corridor neurons and Cajal-Retzius cells are essential for respectively delineating the sizes of functional areas and the wiring of upper cortical circuits. In parallel, we showed that microglia control the development of dopaminergic inputs and inhibitory circuits of the neocortex, thereby regulating the flow of information in this major brain structure, with physiological and behavioral consequences. Importantly, our work also revealed that microglia respond even prenatally to a variety of external signals including the microbiome, revealing that this cell population constitutes an interface between environmental factors and the in utero assembly of brain circuits. Taken together, our project highlighted the importance of deciphering transient interactions to understand brain wiring in normal and pathological conditions and showed the importance of immune cells in the process, lying at the crossroads of developing circuits, inflammation and the microbiota. It revealed the importance to examine brain wiring in the context of a body and its environment, even at prenatal stages, with major implications for our understanding of the functional emergence of circuits and the etiology of neurodevelopment disorders.