The mammalian neocortex is the center of higher sensory, motor and cognitive functions, and is composed of dozens of functionally and anatomically distinct areas. Each neocortical area contains a unique set of neuronal types distributed across six layers. Construction of this complex cellular organization begins with area-specific regulation of neurogenesis during embryonic development. Because of their area- specific pattern of projections, the thalamocortical axons (TCAs) are ideally positioned to influence the fundamental ground plan of the neocortex by regulating neural progenitor cells. In addition, recent studies have discovered that microglia, resident immune cells in the brain, modulate many aspects of cortical development including neurogenesis. However, how TCAs and microglia each regulate neurogenesis in the neocortex is poorly understood. In this grant proposal, we plan to fill these knowledge gaps by 1) developing genetic approaches to molecularly dissect the role of TCAs on neuron-committed neural progenitor cells in the future primary sensory cortex and 2) testing the novel hypothesis that TCAs promote the maturation of microglia via a TCA-derived neuropeptide and its receptor that is specifically expressed in immune cells in developing cortex. Because development of microglia is heavily influenced by maternal environment, our research will shed light on how intrinsic genetic programs and extrinsic environmental factors may converge on common mechanisms that control fundamental organization of the cortical architecture. This will lead to a better understanding of the pathogenesis of many neurological and psychiatric disorders that stem from aberrant regulation of embryonic neurogenesis.
The proposed research is relevant to public health because abnormal cortical development is involved in many neurological and psychiatric disorders. In particular, microglia are implicated in developmental and degenerative brain disorders, and determining how their maturation is potentially affected by the genetic program during embryogenesis will have an impact on understanding the causes and possible treatment of these disorders.
