Cell-type and projection-specific dissection of the bed nucleus of the stria terminalis in the mediation of social behavioral deficits induced by early life adversity

终纹床核的细胞类型和投影特异性解剖在调节早期生活逆境引起的社会行为缺陷中的作用

• 批准号: 10292283
• 负责人: Lindsay Renee Halladay
• 金额: $ 41.1万
• 依托单位: SANTA CLARA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2024-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292283
• 关键词: Address; Affective; Anterior; Anxiety; Basic Science; Behavior; Behavior Disorders; Behavioral; Behavioral Assay; Behavioral Model; Biological; Biomedical Research; Child; Child Abuse; Child Abuse and Neglect; Corticotropin-Releasing Hormone; Data; Disease; Dissection; Early-life trauma; Electrophysiology (science); Environment; Exhibits; Exposure to; FOS gene; Female; Functional disorder; Funding; Grant; Hyperactivity; Hypothalamic dysfunction; Hypothalamic structure; Image; Immunofluorescence Immunologic; Investigation; Knowledge; Label; Life; Measures; Mediating; Mediation; Mediator of activation protein; Mental disorders; Methods; Mission; Modeling; Motivation; Mus; National Institute of Mental Health; Neurons; Neurosecretory Systems; Pattern; Recording of previous events; Reporter; Research; Research Support; Rewards; Role; Social Anxiety Disorder; Social Behavior; Social Behavior Disorders; Social Interaction; Societies; Stimulus; Stress; Structure of terminal stria nuclei of preoptic region; Students; System; Testing; Training; Transgenic Organisms; Universities; Ventral Tegmental Area; Weaning; Work; abuse neglect; anxiety-like behavior; behavioral impairment; cell type; child neglect; childhood adversity; early life adversity; effective therapy; experience; experimental study; externalizing behavior; hypothalamic-pituitary-adrenal axis; in vivo; innovation; laboratory experience; maternal separation; neglect; neural circuit; neurodevelopment; neuromechanism; optogenetics; paraventricular nucleus; peer; relating to nervous system; response; reward circuitry; sex; social; social anxiety; social deficits; stem; therapeutic target; undergraduate student; vigilance

PROJECT SUMMARY Nearly one percent of children in the US experience childhood abuse or neglect, which can induce life-long behavioral deficits including social behavior disorders like social anxiety, attachment disorders, difficult peer relations, and externalizing behaviors. Investigations into the neural mechanisms mediating early life adversity- induced behavioral impairments have largely focused on dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and its release of the stress hormone corticotropin-releasing factor (CRF), which account for aspects of altered anxiety and responsiveness to stress induced by early life adversity. However, social interaction involves coordination between neural circuits promoting reward and circuits inhibiting anxiety, and thus neural substrates mediating early life adversity-induced social deficits likely extend beyond HPA axis dysfunction, but this has not been systematically investigated. Our proposed studies will address the extent to which early adversity-induced social deficits are driven by dysfunction in anxiety versus reward circuits, critical for effectively treating disorders spurred by childhood abuse and neglect. Our lab uses mouse maternal separation with early weaning (MSEW) to model early life adversity, which robustly reduces social interaction and increases anxiety- like behavior, recapitulating effects of childhood abuse and neglect. Our preliminary studies evidenced a central regulatory role for the anterior bed nucleus of the stria terminalis (aBNST) in MSEW-induced social deficits, so the critical next step is to explicate cell-type and projection-specific aBNST mechanisms governing MSEW- induced social deficits. First we will investigate the relationship between MSEW-induced social deficits and anxiety and reward mechanisms using a small battery of robust behavioral assays to determine whether social motivation and vigilance correlate with measures of social reward or anxiety-like behavior in MSEW and control mice. Next we will determine how CRF-expressing neurons in the aBNST, as well as aBNST projections to the paraventricular nucleus of the hypothalamus (PVN) or ventral tegmental area (VTA) contribute to anxiety- and reward-related mechanisms underlying MSEW-induced social deficits using a multiplexed approach that includes in vivo electrophysiology, combined retrograde labeling and immunofluorescence imaging, and projection-specific chemogenetic manipulation experiments. Notably, prior work in this field has mostly neglected female subjects, so we will include sex as a biological variable to enhance the rigor and translatability of our findings. Proposed studies will be conducted exclusively by undergraduate students in the PI's lab who are regularly trained on each method proposed here. Studies here are in line with the NIMH's mission to understand mental illness through basic research, will expose undergraduates to primary biomedical research, and will enhance the research environment at Santa Clara University.

项目摘要 在美国，近1％的儿童经历了童年时期的虐待或忽视，这可能会诱发终身 行为不足，包括社交行为障碍，例如社交焦虑，依恋障碍，困难的同伴 关系和外在行为。调查介导早期生命逆境的神经机制 - 诱导的行为障碍主要集中于下丘脑 - 垂体 - 肾上腺的失调 （HPA）轴及其释放应力激素皮质激素释放因子（CRF），该因子说明了方面 早期生命逆境引起的压力的改变改变和反应能力。但是，社会互动 涉及促进奖励和抑制焦虑的电路之间的神经回路之间的协调，从而 介导早期生命逆境引起的社会缺陷的底物可能超出HPA轴功能障碍，但 这尚未系统地研究。我们提出的研究将解决早期的程度 逆境引起的社会缺陷是由焦虑与奖励电路功能障碍驱动的，对有效的 治疗儿童虐待和忽视所激发的疾病。我们的实验室使用鼠标孕产妇分离 断奶（MSEW）建模早期生活逆境，这可以稳健地减少社交互动并增加焦虑 - 像行为一样，概括儿童虐待和忽视的影响。我们的初步研究证明了一个中心 MSEW诱导的社会缺陷中质末端（ABNST）前床核的调节作用，因此 关键的下一步是解释有关MSEW-的细胞类型和投影特定的ABNST机制 诱发的社会缺陷。首先，我们将研究MSEW引起的社会缺陷与 使用少量强大的行为分析来确定是否社交，焦虑和奖励机制 动机和警惕与MSEW和控制中的社会奖励或类似焦虑行为的度量相关 老鼠。接下来，我们将确定ABNST中表达CRF的神经元的表达方式，以及对 下丘脑（PVN）或腹侧对段区域（VTA）的旁脑核有助于焦虑和 MSEW诱导的与奖励相关的机制使用多重方法 包括体内电生理学，逆行标记和免疫荧光成像以及 投影特异性的化学发生操作实验。值得注意的是，该领域的先前工作主要忽略了 女性受试者，因此我们将把性作为一种生物变量，以增强我们的严格性和转换性 发现。拟议的研究将由PI实验室的本科生专门进行 根据此处提出的每种方法进行定期培训。这里的研究符合NIMH了解的使命 通过基础研究的精神疾病将使本科生暴露于初级生物医学研究中，并将 增强圣塔克拉拉大学的研究环境。