The brain’s immune cells, microglia, must coordinate with developing neurons to build a properly functioning cortex, but the molecular signals that orchestrate this conversation remain unknown. This matters because when that coordination fails, the brain can end up with the wrong numbers or types of cells, a problem linked to autism, epilepsy, and schizophrenia. Researchers already know that many different genetic mutations can lead to these disorders, yet they often produce similar circuit-level deficits—suggesting a common developmental pathway gone wrong. This project aims to identify that pathway by tracking how microglia develop in the mouse cortex, pinpointing a critical window when they are sensitive to neuronal activity, and then uncovering the molecular signals microglia use to sense and respond to changes in excitatory neurons. If successful, the work will reveal fundamental mechanisms of brain assembly during development. It will also test whether altered neuronal activity in early life—caused by diverse genetic mutations—consistently disrupts microglial development, offering a unifying explanation for shared features across neurodevelopmental disorders. This is primarily fundamental science; a deeper understanding of how cell types coordinate their growth could eventually point toward new therapeutic targets, but no immediate clinical application is expected.
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Brain building is a complex process that requires the right type of cells in the right numbers and at the right time. The brain has evolved a modular system where individual cell types can develop and evolve on their own. While this gives full autonomy as to how these cells grow, certain coordination is required to ensure that the correct numbers of cells are present at the right time. The lack of or the dysregulation of this coordination can lead to an altered cellular balance that can ultimately impact normal cortical circuit functions as seen in neurodevelopmental disorders such as autism spectrum disorder, epilepsy and schizophrenia. The molecular mechanisms as to how this coordination occurs during development remains unknown. In this proposed research, I aim to study how this coordination is established during development and how it goes awry in neurodevelopmental disorders. I will determine how two cell types originating from different lineages, namely the excitatory neurons and the brain's resident immune cell, microglia, communicate and regulate their developmental progressions and functions in health and in disorders. More specifically, the first aim of my proposal focuses on elucidating the developmental trajectory of microglia in the mouse cerebral cortex under physiological conditions and the identification of a critical period during development in which microglia are susceptible to changes in pyramidal cell activity. Next, I will identify the molecular mechanisms in which microglia sense and react to changes in the excitatory neurons, leading them to tune their development and survival accordingly. In my last aim, I will focus on the changes in microglia development in models of neurodevelopmental disorders that typically exhibit altered neuronal activity and connectivity during early postnatal development. In this aim, I will study the impact of genetic mutations linked to neurodevelopmental disorders specifically in excitatory cells, on microglia development. Here, I hope to uncouple the impact of these changes arising due to the neuronal dysfunction from the altered microglia development. I will use state-of-the art techniques such as single-cell RNA sequencing and genetic manipulations to uncover the genetic basis of this communication. Biological insights obtained from this research will provide a better understanding as to how brains are built during development. In addition, this proposed research will provide potential mechanisms for the common deficits seen in neurodevelopmental disorders, despite the plethora of genetic mutations associated with it. These common impairments may arise from the altered neuronal activity and connectivity during a sensitive period of development that can have a lasting impact on microglia development. The fellowship will allow me to establish an independent research group to address these key questions in the field of developmental neurobiology and ultimately a better understanding of the pathophysiology of neurodevelopmental disorders.
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