Regulation and functional contribution of hypothalamic modified adult hippocampal neurogenesis

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Project Summary The hippocampus has considerable importance for memory and emotion, and it is a major site of pathophysiology associated with various neurological and psychiatric disorders. One striking feature of this brain region is its unique capacity for adult neurogenesis, a process by which new neurons are continuously generated from radial neural stem cells (rNSCs) throughout life in the dentate gyrus (DG). These adult-born neurons (ABNs) undergo a critical period of heightened synaptic plasticity, during which they make unique contribution to hippocampus-dependent behavior. Adult hippocampal neurogenesis (AHN) is dynamically regulated by neural circuit activity. However, a long-standing question remains on whether manipulating neural circuits can induce sufficient neurogenic effects for behavioral modulation. Recently, we identified a key subcortical region in the hypothalamus, supramammillary nucleus (SuM), which upon activation effectively promote AHN. Specifically, patterned stimulation of SuM neurons promotes self-renewal and neurogenic proliferation of rNSCs and maturation of ABNs, which collectively contributes to increased production of ABNs with improved properties. Importantly, chemogenetic manipulation of the activity of these SuM-enhanced ABNs bidirectionally modulates memory performance and innate anxiety. These results highlight activity-dependent contribution of SuM- enhanced ABNs in hippocampal function. Interestingly, SuM neurons are highly responsive to environmental novelty (EN) and are required for EN-induced enhancement of neurogenesis. Building upon these findings, we propose the following aims to decipher mechanisms underlying SuM-mediated modulation of AHN and activity- dependent contribution of SuM-enhanced ABNs to brain-wide network dynamics. Aim 1 will determine the contribution of SuM glutamate or GABA transmission in mediating SuM-activity or environmental-novelty induced enhancement of hippocampal neurogenesis. Aim 2 will determine the functional properties of SuM-enhanced ABNs and molecular regulators underlying SuM-mediated enhancement of neurogenesis. Aim 3 will determine activity-dependent contribution of SuM-enhanced ABNs to local hippocampal circuit and brain-wide network dynamics.