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.

项目摘要/摘要当前的应用是用于生物医学和行为连续性的管理补充 NIH研究项目赠款奖的首次接受者之间的研究。海马微电路是由兴奋性金字塔细胞组成，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，该神经元在局部发挥作用，可调节锥体细胞活性和同步性。在腹侧海马（VHIPP），微电路功能障碍与多种神经系统有关疾病，包括神经退行性疾病，神经发育疾病和精神病。先前的工作表明，VHIPP锥体细胞差异地调节了精神分裂症样行为取决于其下游目标。同样，独特的抑制性中间神经元类别（即白蛋白（PV） - 阳性和生长抑素（SST） - 阳性）也不同地调节了精神分裂症样行为。所以，当前建议的总体假设是PV-和SST阳性中间神经元差异化根据VHIPP锥体细胞的投影靶标，调节了VHIPP锥体细胞的功能。在K99阶段使用突触伙伴（EGRASP）和电子显微镜的奖励，增强的GFP重组为了证明PV-和SST阳性间神经元差异化支配VHIPP锥体细胞在其目标上（即NAC或MPFC）。具体而言，PV阳性中间神经元形成相似数量的突触在投射到NAC和MPFC的锥体细胞上。然而，SST阳性细胞形成明显较少在投射到MPFC的金字塔细胞上突触。此外，纤维光度法，体内电生理学和光遗传学用于测试PV-和 VHIPP中的SST阳性中间神经元。我们发现PV阳性中间神经元调节将投射到NAC或MPFC的锥体细胞，而SST阳性中间神经元仅调节 NAC投射锥体细胞的功能。这些发现与先前收集的行为数据一致证明SST阳性的中间神经元移植对与该行为的影响很小 VHIPP-MPFC途径。在奖励的R00阶段，我们已经开始检验以下假设。解剖学和功能会因慢性压力而改变，慢性压力是许多神经系统疾病的诱发因素，使用 Egrasp和纤维光度法。符合大脑计划的目标，结果将为您提供洞察力神经电路功能的基本原理，可能会导致治疗和预防的新策略毁灭性神经系统疾病。行政补充剂将确保取得进展为PI 接受乳腺癌治疗。