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.

项目概要 美国近百分之一的儿童在童年时期经历过虐待或忽视，这可能导致终身 行为缺陷，包括社交行为障碍，如社交焦虑、依恋障碍、难以相处的同伴 关系和外化行为。研究介导早期生活逆境的神经机制 诱发的行为障碍主要集中在下丘脑-垂体-肾上腺的失调 (HPA) 轴及其释放的应激激素促肾上腺皮质激素释放因子 (CRF)，其中包括以下方面 改变焦虑和对早期生活逆境引起的压力的反应。然而，社交互动 涉及促进奖励的神经回路和抑制焦虑的神经回路之间的协调，因此神经 调节早期生活逆境引起的社会缺陷的底物可能超出 HPA 轴功能障碍的范围，但是 这尚未得到系统的调查。我们提出的研究将解决早期的程度 逆境引起的社交缺陷是由焦虑与奖励回路的功能障碍引起的，这对于有效地进行社交活动至关重要 治疗因儿童期虐待和忽视而引起的疾病。我们的实验室使用小鼠母体分离技术进行早期分离 断奶（MSEW）来模拟早期生活的逆境，这大大减少了社交互动并增加了焦虑- 像行为一样，概括童年虐待和忽视的影响。我们的初步研究证明了一个核心 终纹前床核 (aBNST) 在 MSEW 引起的社交缺陷中的调节作用，因此 下一步关键是阐明控制 MSEW 的细胞类型和投射特异性 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 焦虑和奖励机制使用一小部分强大的行为分析来确定社交是否有效 动机和警惕性与 MSEW 和控制中的社会奖励或焦虑样行为的测量相关 老鼠。接下来我们将确定 aBNST 中表达 CRF 的神经元以及 aBNST 对 下丘脑室旁核 (PVN) 或腹侧被盖区 (VTA) 会导致焦虑和 使用多重方法研究 MSEW 引起的社会缺陷背后的奖励相关机制 包括体内电生理学、组合逆行标记和免疫荧光成像，以及 投影特异性化学遗传学操作实验。值得注意的是，该领域的先前工作大多忽略了 女性受试者，因此我们将性别作为一个生物学变量，以增强我们的研究的严谨性和可译性 发现。拟议的研究将由 PI 实验室的本科生专门进行，他们是 定期接受此处提出的每种方法的培训。这里的研究符合 NIMH 的使命，即了解 通过基础研究来治疗精神疾病，将使本科生接触初级生物医学研究，并将 改善圣克拉拉大学的研究环境。