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：
9806339
负责人：
Jennifer Donegan
金额：
$ 10.86万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9806339
关键词：
Alzheimer&apos s Disease Anatomy Animals Area Attenuated Award BRAIN initiative Behavior Behavioral Binding Proteins Brain Diseases Brain region Cells Chronic Chronic stress Cognition Complex Development Plans Disease ES Cell Line Educational workshop Electrophysiology (science)Emotions Ensure Equilibrium Fiber Functional disorder Funding Goals Halorhodopsins Hippocampus (Brain)Institution Interneurons Label Laboratories Lead LoxP-flanked allele Maps Medial Mediating Mental disorders Mentors Metabolic Modeling Mus Neurobehavioral Manifestations Neurodegenerative Disorders Neurodevelopmental Disorder Neurons Neuropeptides Neurophysiology - biologic function Nucleus Accumbens Parkinson Disease Parvalbumins Pathway interactions Pattern Photometry Physiology Population Predisposing Factor Prefrontal Cortex Prevention Prevention strategy Process Pyramidal Cells Regulation Reporter Research Research Personnel Rhodopsin Risk Factors Rodent Model Schizophrenia Scientist Somatostatin Stress Structure Substance abuse problem Symptoms Synapses Synaptic Cleft Techniques Testing Time Training Transplantation Viral Vector Virus Vocational Guidance Work career development effective therapy experimental study extracellular hippocampal pyramidal neuron improved in vivo information processing insight meetings nervous system disorder neural circuit neurobiological mechanism neuronal circuitry novel strategies optogenetics psychological stressor reconstitution response skills stressor symposium treatment strategy

项目摘要

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 hypothesis of the current proposal is that PV- and SST-positive interneurons differentially regulate the function of ventral hippocampus pyramidal cells depending on their projection target. In the first aim, mammalian reconstitution across synaptic partners (mGRASP) will be used to test the hypothesis that PV- and SST-positive interneurons differentially innervate vHipp pyramidal cells depending on their target (i.e. the NAc or mPFC). In the second aim, fiber photometry, in vivo electrophysiology, and optogenetics will be used to test the functional regulation of NAc vs mPFC projecting vHipp neurons by PV- and SST-positive interneurons. Aim 3 will determine if microcircuit anatomy and function are altered by chronic stress, a predisposing factor for many neurological disorders. 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. My long-term goal is to become an independent scientist that studies the neurobiological mechanisms underlying psychiatric disorders so that new and more effective treatments can be developed. The research plan described above will be supplemented by a career development plan that will allow me to gain the skills necessary to achieve this goal. Specifically, I have assembled a team of mentors from both in and outside of my institution to provide scientific training and career guidance. Further, I will attend local and national conferences, workshops, and meetings to enhance my training and ensure that I gain the skills requisite of an independent investigator. Together, this award will provide me with scientific training and career development opportunities, and importantly it will allow me to establish my own, independent line of research, which will focus on the effect of chronic stress on vHipp microcircuits.

海马微电路由兴奋性锥体细胞组成，可整合信息并神经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) 中，微电路功能障碍与各种神经系统疾病，包括神经退行性疾病、神经发育障碍和精神疾病。先前的工作表明 vHipp 锥体细胞差异调节类似精神分裂症的行为取决于其下游目标。同样，独特的抑制类别中间神经元（即小白蛋白（PV）阳性和生长抑素（SST）阳性）也有不同的调节类似精神分裂症的行为。因此，当前提案的假设是 PV 和 SST 为正值中间神经元根据其差异调节腹侧海马锥体细胞的功能投影目标。在第一个目标中，哺乳动物跨突触伙伴的重建（mGRASP）将用于检验 PV 和 SST 阳性中间神经元差异支配 vHipp 锥体细胞的假设取决于他们的目标（即 NAc 或 mPFC）。第二个目标是纤维光度测定、体内电生理学、光遗传学将用于测试 PV-NAc 与 mPFC 投射 vHipp 神经元的功能调节和 SST 阳性中间神经元。目标 3 将确定微电路解剖结构和功能是否因慢性病而改变压力，是许多神经系统疾病的诱发因素。根据 BRAIN Initiative 的目标，结果将深入了解神经回路功能的基本原理，并可能带来新的策略治疗和预防破坏性神经系统疾病。我的长期目标是成为一名研究神经生物学机制的独立科学家潜在的精神疾病，以便开发新的、更有效的治疗方法。研究计划上述描述将辅以职业发展计划，使我能够获得技能实现这一目标所必需的。具体来说，我组建了一支由来自国内外的导师组成的团队机构提供科学的培训和职业指导。此外，我将参加地方和全国会议，研讨会和会议，以加强我的培训并确保我获得独立工作所需的技能研究者。总之，这个奖项将为我提供科学培训和职业发展机会，重要的是，它将使我能够建立自己的独立研究路线，重点关注效果 vHipp 微电路的慢性压力。