Regulation of Hippocampal Neurogenesis and Behavior by Noggin

海马体(髋部)依赖的认知受到各种不同类型的环境刺激的调节， 但环境启动和/或调节行为的机制还没有完全理解。 成年近交系小鼠在依赖臀部的认知任务中表现出很大的变异性，而且有 髋关节内源性BMP信号水平与基线呈极显著负相关 认知表现。此外，暴露在锻炼或环境丰富的环境中会增加 BMP抑制剂noggin在髋关节中的作用，并在增强认知的同时减弱BMP信号 表现和神经再生增加。类似地，抗抑郁药可增加神经发生。 这些变化是由noggin表达的增加和一种 腹侧海马区BMP信号减少。脑室注射减少成年小鼠骨形态发生蛋白信号 在髋部输注、转基因过表达或病毒过表达noggin会产生许多效应 锻炼认知和情感行为以及神经发生。在臀部，noggin定位于 齿状颗粒神经元(GC)，膜去极化促进培养的GC释放noggin。 Sonic Hedgehog信号促进培养的GC释放更高水平的noggin。中断 纤毛(IFT88基因敲除)或纤毛转运抑制(Rab8a/b基因敲除)耗尽培养物中的noggin GC.总之，这些观察表明，BMP信号在调节两者中起着核心作用 神经发生和髋关节依赖行为，BMP信号受活性依赖性释放的调节 纤毛通过GC调节noggin表达和释放。这项提案将考验 假设： 1)齿状回GC释放noggin是环境刺激与细胞 海马神经源性生态位和海马区依赖行为的变化。 2)初级纤毛传递的环境信号与神经元活动协同调节 Noggin的表达和释放调控神经前体细胞的增殖。 3)DG电路的结构支持大体上平行的皮层和大脑之间的信息传输 皮质下系统通过成熟和未成熟神经元之间的相互作用。依赖于活动的发布 Noggin改变了这种功能连接，导致了海马体依赖行为的改变。

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.