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.

项目概要 海马体对于记忆和情感非常重要，是大脑的主要部位。 与各种神经和精神疾病相关的病理生理学。这个大脑的一个显着特征 该区域是其独特的成体神经发生能力，即不断产生新神经元的过程 来自齿状回 (DG) 中的放射状神经干细胞 (rNSC) 的整个生命周期。这些成年神经元（ABN） 经历突触可塑性增强的关键时期，在此期间它们对 海马体依赖性行为。成人海马神经发生（AHN）由神经元动态调节 电路活动。然而，一个长期存在的问题仍然是操纵神经回路是否可以诱导 足够的神经源性效应用于行为调节。最近，我们发现了一个关键的皮层下区域 下丘脑、乳头上核 (SuM)，激活后可有效促进 AHN。具体来说， SuM 神经元的模式化刺激促进 rNSC 的自我更新和神经源性增殖 ABN 的成熟，这共同有助于增加具有改进性能的 ABN 的产量。 重要的是，这些 SuM 增强的 ABN 的活性的化学遗传学操纵可以双向调节 记忆表现和先天焦虑。这些结果强调了 SuM- 的活动依赖性贡献 增强 ABN 的海马功能。有趣的是，SuM 神经元对环境高度敏感 新颖性（EN）并且是 EN 诱导的神经发生增强所必需的。基于这些发现，我们 提出以下目标，以破译 SuM 介导的 AHN 和活动调节的机制- SuM 增强的 ABN 对全脑网络动态的依赖贡献。目标 1 将确定 SuM 谷氨酸或 GABA 传输在介导 SuM 活性或环境新奇性诱导中的贡献 增强海马神经发生。目标 2 将确定 SuM 增强的功能特性 ABN 和 SuM 介导的神经发生增强的分子调节剂。目标 3 将决定 SuM 增强的 ABN 对局部海马回路和全脑网络的活动依赖性贡献 动力学。