Interneurons differentially regulate discrete pathways from ventral hippocampus

项目摘要/摘要 目前的申请是关于生物医学和行为的连续性的行政补充 美国国立卫生研究院研究项目资助奖首次获得者的研究。海马区微电路是 由兴奋的锥体细胞组成，这些细胞整合信息并神经支配下游的大脑区域， 抑制性中间神经元在局部发挥作用，调节锥体细胞的活动和同步性。在 腹侧海马区(VHipp)微回路功能障碍与多种神经系统疾病相关 精神障碍，包括神经退行性疾病、神经发育障碍和精神疾病。 以前的工作已经证明vHipp锥体细胞对精神分裂症样行为有不同的调节作用 这取决于它们的下游目标。同样，独特类别的抑制性中间神经元(即小白蛋白 (PV)阳性和生长抑素(SST)阳性)对精神分裂症样行为的调节也不同。因此， 目前提出的主要假设是PV和SST阳性的中间神经元是不同的 VHipp锥体细胞的功能依赖于它们的投射靶点。在K99阶段的 奖，使用了突触伙伴间增强型GFP重组(EGRASP)和电子显微镜 证明PV和SST阳性中间神经元对vHipp锥体细胞的不同支配依赖于 在他们的目标(即NAC或mPFC)上。具体地说，PV阳性中间神经元形成类似数量的突触 在同时投射到NAC和mPFC的锥体细胞上。然而，SST阳性细胞形成的数量明显减少 锥体细胞上的突触投射到mPFC。此外，纤维光度法、活体电生理学和 用光遗传学方法检测PV-和mPFC对NAC和mPFC投射锥体细胞的功能调节 VHipp内SST阳性中间神经元。我们发现PV阳性的中间神经元调节 投射到NAC或mPFC的锥体细胞，而SST阳性的中间神经元仅调节 NAC-投射锥体细胞的功能。这些发现与之前收集的行为数据是一致的 证明SST阳性的神经元间移植对与 VHipp-mPFC通路。在颁奖的R00阶段，我们已经开始测试微电路的假设 慢性应激改变了人体的解剖和功能，而慢性应激是许多神经疾病的易感因素。 EGRASP和纤维光度法。与大脑倡议的目标一致，结果将提供对 神经回路功能的基本原理，并可能导致新的治疗和预防策略 毁灭性的神经紊乱。行政副刊将确保作为PI取得进展 正在接受乳腺癌的治疗。

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.