Activity-regulated cytoskeleton-associated protein mediates nucleus accumbens function via cell type-specific action”

活性调节的细胞骨架相关蛋白通过细胞类型特异性作用介导伏隔核功能–

• 批准号: 10042230
• 负责人: Rachel Penrod-Martin
• 金额: $ 41.11万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042230
• 关键词: Acute; Adult; Anxiety; Anxiety Disorders; Automobile Driving; Behavior; Behavioral; Behavioral Paradigm; Biochemical; Brain region; Brain-Derived Neurotrophic Factor; Cell physiology; Cells; Chronic stress; Clinical Research; Complex; Cytoskeleton; Data; Dendrites; Dopamine; Electrophysiology (science); Female; Fractionation; Future; Glutamate Receptor; Glutamates; Goals; Grant; Imaging Techniques; Knowledge; Mediating; Mediator of activation protein; Messenger RNA; Molecular; Mood Disorders; Moods; Motivation; Mus; Neurobiology; Neurons; Nucleus Accumbens; Outcome; Physiology; Population; Proteins; Regulation; Research; Rewards; Role; Sex Differences; Stress; Surface; Synapses; Synaptic plasticity; Techniques; Testing; Translations; Virus; Work; anxiety states; anxiety symptoms; anxiety-like behavior; base; behavioral response; cell behavior; cell type; experience; experimental study; fluorophore; glutamatergic signaling; improved; innovation; insight; knock-down; male; neurobiological mechanism; neuromechanism; novel; patch clamp; preclinical study; receptor; response; sex; single molecule; small hairpin RNA; synaptic function; treatment of anxiety disorders

Modified Project Summary/Abstract Section The Nucleus Accumbens (NAc) is a key brain region mediating mood-relevant behaviors but the cell types and molecules underlying this contribution are still being identified. Additionally, many NAc-relevant behaviors show sex differences, but we lack insight into the mechanisms mediating these differences. Studies on the molecular and cellular bases of sex differences in NAc function and behavior will fill a key knowledge gap by identifying novel targets and mechanisms. The long-term goal of this project is to determine the neurobiological mechanisms of activity-regulated cytoskeleton-associated protein (Arc) action in the adult NAc, focused on Arc’s role in mediating sex-specific cellular and behavioral NAc functions via cell type-specific action. The overall objective of this proposal is to determine the role and regulation of Arc in the NAc of male and female mice following NAc-related behavioral experiences (e.g. stress, motivation, novelty exposure). The central hypothesis is that Arc regulates NAc function and associated behaviors via cell type-specific synaptic action. The rationale for this project is that the identification of specific cell types mediating NAc-related behaviors, and Arc’s function in those cells, directs future hypotheses on the cellular and synaptic mechanisms of sex differences. The central hypothesis will be tested with two specific aims: 1) Establish the cell types inducing Arc following NAc-relevant behavioral experience and requiring Arc action to mediate behavioral responses; 2) Determine the subcellular localization of Arc and its role in synaptic plasticity in the NAc. In the first aim, key cell populations inducing Arc in response to NAc-relevant behavior experience will be identified using immunohistochemical techniques directed against Arc protein and genetically encoded, cell type-specific fluorophores. The cells requiring Arc action to mediate NAc-relevant behavior will be identified with in mice expressing genetically encoded cell type-specific cre, with cre-dependent shRNA virus delivery to the adult NAc. In the second aim, the subcellular localization of Arc will be assessed immediately following behavior experience using biochemical fractionation techniques. Additionally, Arc’s contribution to NAc synaptic function will be assessed using electrophysiological techniques to examine basal physiology and the ability to induce NAc-relevant, Arc-mediated forms of experimenter-induced synaptic plasticity (e.g. BDNF-induced LTP, DHPG induced-LTD). The research proposed in this application is innovative, as it is focused on examining a molecular mediator of NAc function, localizing roles for Arc in specific cell types within the NAc and connecting Arc action to cellular and behavioral sex differences. The proposed research is significant as it establishes a novel role for a single molecule (i.e. Arc) in specific cells of a single brain region (NAc) as mediator of sex differences in NAc function and behavior. The proposed experiments provide critical evidence for the relevance of Arc in NAc-mediated behavior, sex differences in NAc function and behavior, and critical information for future experiments to delineate the sex-specific regulation and function of Arc.

修改项目摘要/摘要部分 伏隔核（NAc）是介导情绪相关行为的关键大脑区域，但这种贡献背后的细胞类型和分子仍在确定中。此外，许多NAC相关的行为表现出性别差异，但我们缺乏对介导这些差异的机制的了解。对NAc功能和行为性别差异的分子和细胞基础的研究将通过确定新的靶点和机制填补一个关键的知识空白。该项目的长期目标是确定成人NAc中活性调节的细胞因子相关蛋白（Arc）作用的神经生物学机制，重点关注Arc通过细胞类型特异性作用介导性别特异性细胞和行为NAc功能的作用。本提案的总体目标是确定Arc在雄性和雌性小鼠NAc中的作用和调节，这些小鼠经历了NAc相关的行为经历（例如压力、动机、新奇性暴露）。中心假设是Arc通过细胞类型特异性突触作用调节NAc功能和相关行为。该项目的基本原理是，鉴定介导NAC相关行为的特定细胞类型，以及Arc在这些细胞中的功能，指导未来关于性别差异的细胞和突触机制的假设。将以两个特定目标来测试中心假设：1）建立在NAC相关行为经验之后诱导Arc并且需要Arc作用来介导行为反应的细胞类型; 2）确定Arc的亚细胞定位及其在NAc中突触可塑性中的作用。在第一个目标中，将使用针对Arc蛋白和遗传编码的细胞类型特异性荧光团的免疫组织化学技术来鉴定响应于NAC相关行为经验而诱导Arc的关键细胞群体。需要Arc作用来介导NAc相关行为的细胞将在表达遗传编码的细胞类型特异性cre的小鼠中鉴定，其中cre依赖性shRNA病毒递送至成年NAc。在第二个目标中，Arc的亚细胞定位将在行为体验后立即使用生化分离技术进行评估。此外，将使用电生理学技术评估Arc对NAc突触功能的贡献，以检查基础生理学和诱导NAc相关的、Arc介导的实验者诱导的突触可塑性形式（例如BDNF诱导的LTP、DHPG诱导的LTD）的能力。本申请中提出的研究是创新的，因为它专注于检查NAc功能的分子介质，定位NAc内特定细胞类型中Arc的作用，并将Arc作用与细胞和行为性别差异联系起来。这项研究意义重大，因为它为单个脑区（NAc）的特定细胞中的单个分子（即Arc）确立了一种新的作用，作为NAc功能和行为性别差异的介导者。这些实验为Arc在NAc介导的行为中的相关性、NAc功能和行为的性别差异提供了重要证据，并为未来的实验提供了重要信息，以描述Arc的性别特异性调节和功能。

项目成果

Differential Roles of Oxytocin Receptors in the Prefrontal Cortex and Nucleus Accumbens on Cocaine Self-Administration and Reinstatement of Cued Cocaine Seeking in Male Rats.

• DOI: 10.1093/ijnp/pyad059
• 发表时间: 2023-12-18
• 期刊: The international journal of neuropsychopharmacology

Intolerance of uncertainty, anxiety sensitivity, and health anxiety during the COVID-19 pandemic: Exploring temporal relationships using cross-lag analysis.

• DOI: 10.1016/j.janxdis.2022.102660
• 发表时间: 2023-01
• 期刊: JOURNAL OF ANXIETY DISORDERS
• 影响因子: 10.3
• 作者: Bredemeier, Keith;Church, Leah D.;Bounoua, Nadia;Feler, Bridget;Spielberg, Jeffrey M.
• 通讯作者: Spielberg, Jeffrey M.