Regulation and functional contribution of hypothalamic modified adult hippocampal neurogenesis

项目摘要 海马体对记忆和情感有相当重要的作用，它是 与各种神经和精神疾病有关的病理生理学。这个大脑的一个显著特征 该区域是成年神经发生的独特能力，是一个不断产生新神经元的过程 从放射状神经干细胞(RNSCs)在齿状回(DG)的整个生命周期。这些成年出生的神经元(ABN) 经历突触可塑性增强的关键时期，在此期间，它们对 依赖海马体的行为。成年海马区神经发生受神经动态调节 电路活动。然而，一个长期存在的问题是，操纵神经回路是否可以诱导 足够的神经源性效应来调节行为。最近，我们发现了大脑皮质下的一个关键区域 下丘脑，乳头上核(SUM)，激活后有效地促进AHN。具体来说， 模式刺激SUM神经元促进rNSCs的自我更新和神经源性增殖 ABN的成熟，这些共同有助于提高ABN的产量，并改善其性能。 重要的是，对这些总和增强的ABN活性的化学发生操纵是双向调节的 记忆力表现和天生的焦虑。这些结果突显了总和对经济活动的贡献。 增强了海马区的ABN功能。有趣的是，SUM神经元对环境高度敏感 新颖性(EN)和EN诱导的神经发生增强所必需的。基于这些发现，我们 提出以下旨在破译总和调节Ahn和活动的机制-- 总和增强的ABN对全脑网络动力学的依赖贡献。目标1将决定 总谷氨酸或GABA传递在调节总和活性或环境新颖性诱导中的作用 促进海马区神经发生。目标2将确定SUM增强的功能特性 ABN和潜在的SUM介导的促进神经发生的分子调节器。目标3将决定 SUM增强型ABN对局部海马环路和全脑网络的活动依赖性贡献 动力学。

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.