Regulation and functional contribution of hypothalamic modified adult hippocampal neurogenesis

下丘脑修饰成人海马神经发生的调节和功能贡献

• 批准号: 10753956
• 负责人: Juan Song
• 金额: $ 75.79万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-06 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753956
• 关键词: Adult; Affective; Anatomy; Animals; Anxiety; Behavior; Behavioral; Brain; Brain region; Calcium; Cell Nucleus; Cells; Cognitive; Development; Electrophysiology (science); Emotions; Fiber; Functional Magnetic Resonance Imaging; Functional disorder; Glutamates; Hippocampus; Hypothalamic structure; Image; Knowledge; Life; Mediating; Memory; Mental disorders; Molecular; Nature; Neurons; Neurosciences; Pattern; Performance; Photometry; Play; Process; Production; Proliferating; Property; Proteomics; Radial; Regulation; Role; Site; Slice; Stimulus; Synaptic plasticity; Testing; adult neurogenesis; anxiety-like behavior; awake; critical period; dentate gyrus; gamma-Aminobutyric Acid; genetic manipulation; granule cell; improved; knock-down; memory retrieval; mouse model; nerve stem cell; nervous system disorder; neural circuit; neurogenesis; novel; novel therapeutic intervention; self-renewal; stem cells; transmission process

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.

项目总结