This project, if successful, has the prospect of fundamentally revolutionizing our understanding of the mechanisms that regulate prenatal development of the cerebral cortex. We have discovered a novel mechanism for regulating cell production that may profoundly alter our basic understanding of mechanisms that regulate neocortical development and our appreciation for how maternal immune activation may alter cortical development and lead to psychiatric disorders. Regulation of precursor cell proliferation is central for ensuring that cell production does not exceed the requirements of the developing cerebral cortex. Unrestrained cell production during prenatal brain development would have profoundly negative consequences for brain organization and function. However, mechanisms that restrain cell proliferation are poorly understood. Microglial cells colonize the cerebral cortx during prenatal development. But, despite recent progress elucidating the functions of microglia in the developing CNS and a wealth of knowledge on microglial function in the mature brain, the functional roles of microglia during prenatal cortical development are not well understood. This project simultaneously addresses gaps in our knowledge on mechanisms that regulate the number of precursor cells and the functional role of microglia in the developing cerebral cortex. Our preliminary data show that 1) microglia colonize the neurogenic proliferative zones of the prenatal rat cerebral cortex; 2) microglia phagocytose neocortical precursor cells, particularly during late stages of cortical neurogenesis; 3) maternal immune activation (MIA) in pregnant rats activates microglia in the fetal cerebral cortex; and 4) increased microglia activation is associated with a significant decrease in the number of neural precursor cells in the neocortex. Our preliminary data lead to the testable hypotheses that microglia regulate the number of neural precursor cells in the cerebral cortex through phagocytosis, and that MIA will decrease the number of neural precursor cells and alter the number of neurons and glia in the cerebral cortex. This project will test our central hypothesis, Microglia regulate the number of neural precursor cells in the developing cerebral cortex.
Specific Aim 1 will quantify changes in fetal microglial activation state and precursor cell number after inducing MIA, treating with Dox, or eliminating microglia from the cortex, and quantify the number of neurons and glia in the mature cerebral cortex of animals in each group.
Specific Aim 2 will test the effect of M-CSF expression on microglial colonization of the neural proliferative zones in the developing cortex, and test the effect of exogenous microglia and cytokines on the expression of 'find me' signals by neural precursor cells.
Specific Aim 3 will test the capacity of pharmacological agents to attenuate the detrimental impact of MIA on the developing neocortex.
The human cerebral cortex is populated by approximately 60 billion cells. Mechanisms that stimulate and amplify cell production during development of the human cerebral cortex have been identified, but our understanding of the mechanisms that curtail cell production remains limited. This project aims to establish the role of central nervous system immune cells, microglia, in regulating the growth of the cerebral cortex under normal and pathological conditions.
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