CORTICOTROPIN RELEASING HORMONE SIGNALING AND NEWBORN NEURON CIRCUIT INTEGRATION

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DESCRIPTION (provided by applicant): Adult neurogenesis in the mammalian brain represents an extraordinary example of continued cellular and structural neuronal plasticity. Although the phenomenology of this process has been well established, the molecular and genetic mechanisms that guide newborn neuron synapse formation, synapse maintenance, and circuit integration are not well understood. Two brain areas that show continued neurogenesis include the subgranular layer of the hippocampal dentate gyrus, and the subventricular zone (SVZ) of the olfactory system. Interestingly, it has been found that multiple forms of neural activity affect the proliferation, survival, and synapse formation of newborn neurons. For example, exercise, learning, sensory stimulation, and treatments with antidepressants promote adult neurogenesis and circuit integration, whereas stress, sensory deprivation, and certain neuropathologies impair synaptogenesis and survival. These "activities" are relayed to newborn neurons via their repertoire of presynaptic inputs. However, the exact types, numbers, origins, and the nature of these inputs remain unknown. To elucidate the cell types that provide presynaptic inputs to newborn neurons, we have implemented a transsynaptic viral circuit tracing approach using engineered Rabies Virus (RV) and mouse genetics. We have identified a subpopulation of local Corticotropin-Releasing Hormone (CRH)-expressing neurons that provide selective and extensive inputs onto newborn granule cells. CRH has been found to influence a variety of neuromodulatory processes ranging from plasticity to neurotransmitter function. Moreover, CRH signaling has been implicated in a number of medical and psychological conditions, ranging from Alzheimer's disease to arousal, stress, anxiety, and depression. Interestingly, all of these states have been shown to influence adult neurogenesis. Thus, our discovery that CRH expressing neurons provide presynaptic inputs onto newborn granule cells represents a novel mechanism to promote synapse formation and circuit integration in the mammalian brain. To elucidate the functional role of CRH inputs onto newborn granule cells, we propose to test the following hypothesis: Presynaptic input from Corticotropin-Releasing Hormone expressing neurons promotes newborn granule cell circuit integration and synapse formation. Ultimately, we intend to understand the molecular and cellular mechanisms underlying synaptogenesis, circuit integration and neuronal survival in the adult brain. This knowledge will allow us to work towards novel therapeutic approaches for cell and circuit-based brain repair. PUBLIC HEALTH RELEVANCE: The mammalian brain continuously gives rise to newborn neurons throughout adult life, and these neurons integrate into preexisting circuits; however, the molecular and cellular mechanisms underlying this integration process are largely unknown. Towards uncovering these molecular programs, we have used viral transsynaptic tracing to reveal that local Corticotropin-Releasing Hormone (CRH)-expressing neurons provide selective and extensive input onto newborn neurons during periods of synaptogenesis and circuit integration. In the proposed research, we will investigate the detailed molecular, genetic, and electrophysiological mechanisms of how CRH-expressing inputs influence newborn neuron circuit integration in the adult brain with the expectation that our studies will provide valuable insight into conserved plasticity mechanisms by which the mammalian brain continually generates, sculpts, and maintains neural circuits.