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：
10634672
负责人：
Jennifer Donegan
金额：
$ 24.9万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634672
关键词：
Affect 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 Genetic Goals Halorhodopsins Hippocampus Institution Intellectual functioning disability Interneurons Label Laboratories 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 autism spectrum disorder career development cold stress effective therapy experimental study extracellular hippocampal pyramidal neuron improved in vivo information processing insight meetings nervous system disorder neural circuit neurobiological mechanism neuron component neuronal circuitry novel strategies novel therapeutic intervention optogenetics postsynaptic presynaptic 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，该神经元在局部起作用锥体细胞活性和同步性。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，神经发育疾病和精神病。先前的工作表明，VHIPP锥体细胞对调节精神分裂症样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（即白蛋白（PV） - 阳性和生长抑素（SST）阳性）也对调节也有所不同精神分裂症样行为。因此，当前建议的假设是PV和SST阳性中神经元差异调节腹侧海马锥体细胞的功能投影目标。在第一个目的中，跨突触伙伴（MGRASP）的哺乳动物重构将用于检验PV-和SST阳性间神经元差异支配VHIPP锥体细胞的假设取决于其目标（即NAC或MPFC）。在第二个目标中，纤维光度法，体内电生理学，和光遗传学将用于测试PV-的NAC与MPFC投射VHIPP神经元的功能调节和SST阳性中间神经元。 AIM 3将确定微电路解剖结构和功能是否因慢性而改变压力是许多神经系统疾病的诱人因素。符合大脑计划的目标，结果将为神经电路功能的基本原理提供见解，并可能导致新的策略治疗和预防毁灭性神经系统疾病。我的长期目标是成为研究神经生物学机制的独立科学家潜在的精神疾病，以便可以开发出新的和更有效的治疗方法。研究计划上面描述的将由一项职业发展计划补充，这将使我能够获得技能实现这一目标所必需的。具体来说，我已经组建了一个来自我的内外的导师团队提供科学培训和职业指导的机构。此外，我将参加当地和民族会议，讲习班和会议，以增强我的培训，并确保我获得独立的技能研究者。该奖项将为我提供科学培训和职业发展机会，重要的是，这将使我能够建立自己的独立研究线，这将重点放在效果上 VHIPP微电路的慢性应激。