Regulation of Hippocampal Neurogenesis and Behavior by Noggin

海马（HIP）依赖性认知受各种不同类型的环境刺激调节， 但是环境启动和/或调节行为的机制还没有完全理解。 成年近交系小鼠在HIP依赖性认知任务上表现出广泛的变异性， HIP和基线中内源性BMP信号传导水平之间存在高度显著的负相关性 认知绩效此外，暴露于运动或环境丰富增加表达， BMP-抑制剂，头蛋白，在HIP和减弱BMP信号传导同时增强认知 性能和增加神经发生。类似地，抗抑郁药增加神经发生， 行为改变，这些变化是由noggin表达的增加和 腹侧海马中BMP信号的减少。通过心室肌抑制成年小鼠的BMP信号传导 头蛋白在HIP中的输注、转基因过表达或病毒过表达再现了许多作用， 锻炼对认知和情感行为以及神经发生的影响。在HIP中，头蛋白位于 齿状颗粒神经元（GC），和膜去极化促进头蛋白从培养的GC释放。 Sonic hedgehog信号传导促进培养的GC释放更高水平的头蛋白。破坏 纤毛（IFFT 88敲除）或抑制向纤毛的转运（Rab 8a/B敲除）从培养的 GC.总的来说，这些观察表明BMP信号在调节这两个过程中起着核心作用。 神经发生和HIP依赖性行为，BMP信号转导是由活性依赖性释放的 GC法测定Noggin表达，GC法测定纤毛对Noggin表达和释放的调节作用。这项提案将考验 假设： 1)齿状回GC释放noggin是环境刺激与细胞内 海马神经原生态位的变化和海马依赖性行为。 2)通过初级纤毛和神经元活动传递的环境信号协同调节 表达和释放头蛋白以调节神经祖细胞增殖。 3)DG电路的结构是支持信息在大部分平行的皮层和皮层之间的传递， 皮质下系统通过成熟和未成熟神经元之间的相互作用。活性依赖性释放 noggin改变了这种功能性连接，导致依赖于大脑皮层的行为发生变化。

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.