Interneurons differentially regulate discrete pathways from ventral hippocampus

中间神经元差异调节腹侧海马的离散通路

基本信息

批准号：
10616351
负责人：
Jennifer Donegan
金额：
$ 7.76万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10616351
关键词：
Administrative Supplement Affect Alzheimer&apos s Disease Anatomy Animals Area Attenuated Award BRAIN initiative Behavior Behavioral Behavioral Research Binding Proteins Biomedical Research Brain Diseases Brain region Breast Cancer Treatment Cells Chronic Chronic stress Cognition Complex Data Disease ES Cell Line Electron Microscopy Electrophysiology (science)Emotions Ensure Equilibrium Fiber Functional disorder Funding Genetic Genetic Recombination Goals Halorhodopsins Hippocampus Intellectual functioning disability Interneurons Label Laboratories LoxP-flanked allele Maps Medial Mediating Mental disorders Metabolic Modeling Mus Neurobehavioral Manifestations Neurodegenerative Disorders Neurodevelopmental Disorder Neurons Neuropeptides Neurophysiology - biologic function Nucleus Accumbens Parkinson Disease Parvalbumins Pathway interactions Pattern Phase Photometry Physiology Population Predisposing Factor Prefrontal Cortex Prevention Prevention strategy Process Pyramidal Cells Regulation Reporter Research Project Grants Research Proposals Risk Factors Rodent Model Schizophrenia Somatostatin Stress Structure Substance abuse problem Symptoms Synapses Synaptic Cleft Techniques Testing Time Transplantation United States National Institutes of Health Viral Vector Virus Work autism spectrum disorder cold stress experimental study extracellular hippocampal pyramidal neuron improved in vivo information processing insight nervous system disorder neural circuit neuronal circuitry novel therapeutic intervention optogenetics postsynaptic presynaptic psychological stressor reconstitution response stressor treatment strategy

项目摘要

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.

项目概要/摘要当前的申请是生物医学和行为连续性的行政补充首次获得 NIH 研究项目资助奖的研究人员。海马微电路是由兴奋性锥体细胞组成，它整合信息并支配下游大脑区域，和抑制性中间神经元，其局部功能调节锥体细胞活动和同步性。在腹侧海马（vHipp）微电路功能障碍与多种神经系统疾病有关疾病，包括神经退行性疾病、神经发育障碍和精神疾病。先前的研究表明，vHipp 锥体细胞差异性地调节精神分裂症样行为取决于他们的下游目标。同样，独特类别的抑制性中间神经元（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。所以，当前提案的总体假设是 PV 和 SST 阳性中间神经元存在差异根据 vHipp 锥体细胞的投射目标调节其功能。在K99阶段奖，使用增强型 GFP 跨突触伙伴重组 (eGRASP) 和电子显微镜证明 PV 和 SST 阳性中间神经元差异性地支配 vHipp 锥体细胞，具体取决于他们的目标（即 NAc 或 mPFC）。具体来说，PV 阳性中间神经元形成相似数量的突触位于投射到 NAc 和 mPFC 的锥体细胞上。然而，SST 阳性细胞的形成明显较少锥体细胞上的突触投射到 mPFC。此外，光纤光度测定法、体内电生理学和光遗传学用于测试 PV 和 mPFC 投射锥体细胞对 NAc 与 mPFC 的功能调节 vHipp 中 SST 阳性中间神经元。我们发现 PV 阳性中间神经元调节锥体细胞投射到 NAc 或 mPFC，而 SST 阳性中间神经元仅调节 NAc 投射锥体细胞的功能。这些发现与之前收集的行为数据一致证明 SST 阳性中间神经元移植对与 vHipp-mPFC 通路。在颁奖的R00阶段，我们已经开始检验微电路的假设慢性压力会改变解剖结构和功能，慢性压力是许多神经系统疾病的诱发因素，使用 eGRASP 和光纤光度测定。根据 BRAIN Initiative 的目标，研究结果将提供以下方面的见解：神经回路功能的基本原理，并可能导致治疗和预防的新策略毁灭性的神经系统疾病。行政补充文件将确保作为 PI 取得进展接受乳腺癌治疗。