Interneurons differentially regulate discrete pathways from ventral hippocampus

项目总结/摘要 目前的申请是生物医学和行为学连续性的行政补充 美国国立卫生研究院研究项目资助奖的第一次获得者之间的研究。海马微电路是 由兴奋性锥体细胞组成，这些细胞整合信息并支配下游大脑区域， 和抑制性中间神经元，其局部地起调节锥体细胞活性和同步性的作用。在 腹侧海马（vHipp），微电路功能障碍已与各种神经系统 在一些实施方案中，所述病症包括神经退行性疾病、神经发育病症和精神疾病。 以前的工作已经证明vHipp锥体细胞差异调节精神分裂症样行为 取决于它们的下游目标类似地，抑制性中间神经元的独特类别（即小清蛋白） （PV）阳性和生长抑素（SST）阳性）也不同地调节精神分裂症样行为。因此，我们认为， 目前提出的主要假设是PV和SST阳性中间神经元的差异， 根据其投射靶点调节vHipp锥体细胞的功能。在K99阶段， 为了获得更好的结果，使用了增强型GFP跨突触伴侣重组（eGRASP）和电子显微镜 为了证明PV和SST阳性中间神经元依赖于VHipp锥体细胞而不同地支配vHipp锥体细胞， 目标（即NAc或mPFC）。具体来说，PV阳性中间神经元形成的突触数量 投射到NAc和mPFC的锥体细胞上。然而，SST阳性细胞形成的数量明显较少， 投射到mPFC的锥体细胞上的突触。此外，纤维光度测定、体内电生理学和 光遗传学用于测试PV-和PV-对NAc与mPFC投射锥体细胞的功能调节。 vHipp中的SST阳性中间神经元。我们发现PV阳性的中间神经元调节着 投射到NAc或mPFC的锥体细胞，而SST阳性中间神经元仅调节 投射NAC的锥体细胞的功能。这些发现与之前收集的行为数据一致 这表明SST阳性中间神经元移植对与神经元相关的行为几乎没有影响。 vHipp-mPFC通路。在R 00阶段的奖励，我们已经开始测试的假设，微电路 解剖和功能被慢性压力改变，这是许多神经系统疾病的诱发因素， eGRASP和纤维光度法。根据BRAIN计划的目标，结果将提供以下方面的见解： 神经回路功能的基本原理，并可能导致新的战略，为治疗和预防 严重的神经系统疾病行政补充将确保作为PI取得进展 接受乳腺癌治疗

Project Summary/Abstract The current application is for an Administrative Supplement for Continuity of Biomedical and Behavioral Research Among First-Time Recipients of NIH Research Project Grant Awards. Hippocampal microcircuits are comprised of excitatory pyramidal cells, which integrate information and innervate downstream brain regions, and inhibitory interneurons, which function locally to regulate pyramidal cell activity and synchronicity. In the ventral hippocampus (vHipp), microcircuit dysfunction has been associated with a variety of neurological disorders, including neurodegenerative diseases, neurodevelopmental disorders, and psychiatric illnesses. Previous work has demonstrated that vHipp pyramidal cells differentially regulate schizophrenia-like behaviors depending on their downstream target. Similarly, unique classes of inhibitory interneurons (namely parvalbumin (PV)-positive and somatostatin (SST)-positive) also differently regulate schizophrenia-like behaviors. Therefore, the overarching hypothesis of the current proposal is that PV- and SST-positive interneurons differentially regulate the function of vHipp pyramidal cells depending on their projection target. During the K99 phase of the award, enhanced GFP recombination across synaptic partners (eGRASP) and electron microscopy were used to demonstrate that PV- and SST-positive interneurons differentially innervate vHipp pyramidal cells depending on their target (i.e. the NAc or mPFC). Specifically, PV-positive interneurons form a similar number of synapses on pyramidal cells that project to both the NAc and mPFC. SST-positive cells, however, form significantly fewer synapses on pyramidal cells that project to the mPFC. Further, fiber photometry, in vivo electrophysiology, and optogenetics were used to test the functional regulation of NAc vs mPFC projecting pyramidal cells by PV- and SST-positive interneurons in the vHipp. We found that PV-positive interneurons regulate the function of pyramidal cells that project to either the NAc or the mPFC while SST-positive interneurons only regulate the function of NAc-projecting pyramidal cells. These findings are in line with previously collected behavioral data demonstrating that SST-positive interneuron transplants have little impact on behaviors associated with the vHipp-mPFC pathway. During the R00 phase of the award, we have begun to test the hypothesis that microcircuit anatomy and function are altered by chronic stress, a predisposing factor for many neurological disorders, using eGRASP and fiber photometry. In line with the goals of the BRAIN Initiative, the results will provide insight into basic principles of neural circuit function and may lead to new strategies for the treatment and prevention of devastating neurological disorders. The Administrative Supplement will ensure that progress is made as the PI undergoes treatment for breast cancer.