Regulation of Hippocampal Neurogenesis and Behavior by Noggin

Noggin 对海马神经发生和行为的调节

• 批准号: 10655940
• 负责人: JOHN A KESSLER
• 金额: $ 58.53万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655940
• 关键词: Adult; Affective; Antidepressive Agents; Attenuated; Behavior; Behavioral; Brain; Brain region; Cilia; Coculture Techniques; Cognition; Cognitive; Complex; Cytoplasmic Granules; Environment; Enzyme-Linked Immunosorbent Assay; Exercise; Exposure to; Gene Expression; Generations; Goals; Hippocampus; Inbred Mouse; Infusion procedures; Knock-out; Link; Maps; Mediating; Membrane; Mus; Neurons; Newborn Infant; Performance; Plasma; Play; Proliferating; Property; Proteins; Rabies virus; Regulation; Role; Running; SHH gene; Signal Pathway; Signal Transduction; Stimulus; Structure; Surface; Synapses; System; Testing; Transgenic Organisms; Ventricular; Viral; Work; cognitive enhancement; cognitive function; cognitive performance; cognitive task; conditional knockout; dentate gyrus; designer receptors exclusively activated by designer drugs; environmental enrichment for laboratory animals; experience; in vivo; inhibitor; knock-down; nerve stem cell; neurogenesis; overexpression; plasmonics; response; sensor; smoothened signaling pathway; stem cells; targeted treatment

Hippocampus (HIP)-dependent cognition is regulated by a variety of different types of environmental stimuli, but the mechanisms by which the environment initiates and/or modulates behavior are not fully understood. Adult inbred mice display wide variability in performance on HIP-dependent cognitive tasks, and there is highly significant negative correlation between levels of endogenous BMP signaling in the HIP and baseline cognitive performance. Further, exposure to exercise or environmental enrichment increases expression of the BMP-inhibitor, noggin, in the HIP and attenuates BMP signaling concurrent with enhanced cognitive performance and increased neurogenesis. Similarly, antidepressants increase neurogenesis in association with behavioral changes, and these changes are mediated by an increase in noggin expression and a reduction in BMP signaling in the ventral hippocampus. Reducing BMP signaling in adult mice by ventricular infusion, transgenic overexpression, or viral overexpression of noggin in the HIP reproduces many effects of exercise on cognitive and affective behavior and on neurogenesis. In the HIP, noggin is localized within dentate granule neurons (GC),and membrane depolarization promotes noggin release from cultured GC. Sonic hedgehog signaling promotes even greater levels of release of noggin by cultured GC. Disruption of cilia (IFT88 knockout) or inhibition of transport to cilia (Rab8a/b knockdown) depletes noggin from cultured GC. In toto these observations suggest that BMP signaling plays a central role in regulating both neurogenesis and HIP-dependent behavior, that BMP signaling is regulated by activity-dependent release of noggin by GC, and that cilia regulate noggin expression and release by GC. This proposal will test the hypotheses that: 1) Release of noggin by dentate gyrus GC is a crucial link between environmental stimuli and both cellular changes in the hippocampal neurogenic niche, and hippocampus-dependent behavior. 2) Environmental signals transduced through primary cilia and neuronal activity cooperatively regulate expression and release of noggin to regulate neural progenitor proliferation. 3) The DG circuitry is structured to support the transfer of information between largely parallel cortical and subcortical systems via interactions between mature and immature neurons. Activity-dependent release of noggin alters this functional connectivity leading to changes in hippocampus-dependent behavior.

海马（HIP）依赖性认知受到多种不同类型的环境刺激的调节， 但是环境启动和/或调节行为的机制尚未完全理解。 成年近交小鼠在髋关节依赖性认知任务上表现出广泛的性能，并且有 臀部和基线中内源性BMP信号水平之间的高度显着负相关 认知表现。此外，暴露于运动或环境富集会增加 BMP抑制剂Noggin在髋关节中，并削弱BMP信号的同时发生的认知能力 性能和神经发生增加。同样，抗抑郁药增加了缔合的神经发生 随着行为的改变，这些变化是由Noggin表达和A的增加所介导的 腹侧海马中BMP信号的降低。通过心室减少成年小鼠的BMP信号传导 髋关节输注，转基因的过表达或Noggin的病毒过表达可再现 锻炼认知和情感行为以及神经发生。在臀部，Noggin位于 齿状颗粒神经元（GC）和膜去极化可促进培养的GC释放。 Sonic刺猬信号传导通过培养的GC促进了更大的Noggin释放水平。破坏 纤毛（IFT88淘汰赛）或抑制运输到纤毛的运输（Rab8a/b敲除）从培养的 GC。这些观察结果表明，BMP信号在调节这两种情况下起着核心作用 神经发生和髋关节依赖性行为，BMP信号传导受活动依赖性释放调节 GC的Noggin，纤毛调节Noggin的表达并通过GC释放。该建议将测试 假设： 1）通过齿状回GC释放Noggin是环境刺激与两个细胞之间的关键联系 海马神经源性生殖位和海马依赖性行为的变化。 2）通过原发性纤毛和神经元活动进行调节的环境信号 Noggin的表达和释放以调节神经祖细胞增殖。 3）DG电路的结构是支持在很大程度上平行皮质和 皮层系统通过成熟和未成熟神经元之间的相互作用。活动依赖性释放 Noggin改变了这种功能连接性，导致海马依赖性行为的变化。