BNST PKCdelta Roles in Affective Behavior

BNST PKCdelta 在情感行为中的作用

• 批准号: 10321213
• 负责人: Kellie M Williford
• 金额: $ 3.18万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-11-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321213
• 关键词: Abstinence; Affect; Affective; American; Amygdaloid structure; Anxiety; Area; Award; Beds; Behavior; Behavioral Assay; Biological Assay; Brain; Budgets; Businesses; Calcium; Cell Nucleus; Cell physiology; Cells; Characteristics; Chronic stress; Clinical; Corticotropin-Releasing Hormone; Custom; D Cells; Data; Devices; Drug Exposure; Drug usage; Exposure to; Extinction (Psychology); Fellowship; Fiber; Foundations; Goals; Gold; Imaging Techniques; Institution; Intervention; Lead; Learning; Light; Maps; Measures; Mediating; Mental Depression; Mental disorders; Mentors; Microscopy; Modeling; Molecular; Neurons; Neuropeptides; Pharmaceutical Preparations; Phase; Phosphotransferases; Photometry; Play; Population; Post-Traumatic Stress Disorders; Postdoctoral Fellow; Proteins; Public Health; Publishing; Rabies; Relapse; Reporter; Research; Research Personnel; Research Project Grants; Resolution; Rodent; Rodent Model; Role; Self Administration; Signal Transduction; Societies; Stress; Substance Use Disorder; Substance abuse problem; System; Techniques; Therapeutic; Time; Treatment outcome; Work; addiction; anxiety-like behavior; approach avoidance behavior; base; biological adaptation to stress; career; cell type; conflict resolution; coping; cost; design; drug relapse; drug standard; experience; experimental study; improved; in vivo; innovation; insight; knock-down; new therapeutic target; optogenetics; prevent; protein kinase C-delta; recruit; restraint stress; skills; small hairpin RNA; substance use treatment; therapeutic target

Chronic stress exposure is implicated in several psychological disorders such as PTSD, anxiety, depression, and addiction, and stressful experiences are one of the most common causes of drug relapse. The Bed Nucleus of the Stria Terminals (BNST) is known to mediate many stress responses and anxiety-like behaviors that contribute to the cycle of relapse characteristic of substance use disorders. In the BNST, cells expressing corticotropin-releasing factor (BNSTCRF) play a role in increasing anxiety-like behaviors, and inhibition of CRF signaling in the BNST can prevent stress-induced reinstatement of drug seeking in rodent models. However, clinical efforts to target the CRF system as a treatment for substance use disorders have proved largely unsuccessful, highlighting the need for innovative therapeutic targets. BNST cells expressing Protein Kinase C- delta (BNSTPKCd) are an equally abundant but largely distinct population from the BNSTCRF cells. We have found that expression of this kinase is also dynamically regulated by stress, but the role of PKCd and BNSTPKCd cells in stress responses and anxiety-like behaviors remains understudied. Specific Aim 1 details the progress the applicant, Kellie Williford, has made toward characterizing the function of BNSTPKCd cells in stress- and anxiety-like behavior using a combination of in vivo optogenetics and fiber photometry approaches. The F99 phase of this proposal (Specific Aim 2) will expand upon these findings by investigating the function of BNSTPKCd cells through circuit-based connectivity. Here, rabies-mediated tracing will be used to determine the brain-wide afferents of the BNSTPKCd population. Additionally, shRNA-mediated knockdown will be used to investigate the functional significance of PKCd expression within cells in the BNST in mediating anxiety-like behavior. The K00 phase of this proposal (Specific Aim 3) will help prepare the applicant for a successful academic research career investigating the contributions of stress to drug relapse in substance use disorders. This postdoctoral phase will provide Ms Williford with experience in addiction-based experimental techniques and sharpen critical managerial and mentoring skills to thrive as an independent investigator. In doing so, this proposal will help provide insight into potential new therapeutic targets that can be manipulated to prevent maladaptive stress responses. In the long term, it will also equip the candidate to extend this work to stress- induced relapse of drug seeking and improve treatment outcomes for those struggling with substance use disorders.

慢性压力暴露与几种心理障碍有关，如创伤后应激障碍、焦虑、抑郁， 吸毒成瘾和精神压力是导致毒瘾复发的最常见原因之一。床上 纹状体终末核（BNST）是介导应激反应和焦虑样行为的重要神经元 导致药物使用障碍的复发周期。在BNST中，表达 促肾上腺皮质激素释放因子（BNSTCRF）可增加焦虑样行为，抑制CRF BNST中的信号传导可以防止啮齿动物模型中应激诱导的药物寻求的恢复。然而，在这方面， 将CRF系统作为物质使用障碍的治疗靶点的临床努力已经在很大程度上被证明 这一结果并不成功，这凸显了对创新治疗靶点的需求。表达蛋白激酶C-的BNST细胞 δ（BNSTPKCd）是与BNSTCRF细胞同样丰富但很大程度上不同的群体。我们有 发现这种激酶的表达也受到应激的动态调节，但PKCd和 BNSTPKCd细胞在应激反应和焦虑样行为中的作用仍有待研究。具体目标1详细信息 申请人Kellie Williford在表征BNSTPKCd细胞的功能方面取得的进展， 使用体内光遗传学和光纤光度法的组合来测量压力和焦虑样行为。 本提案的F99阶段（具体目标2）将通过调查功能来扩展这些发现 BNSTPKCd电池通过基于电路的连接。在这里，狂犬病介导的追踪将用于确定 BNSTPKCd群体的全脑传入。此外，shRNA介导的敲低将用于 研究PKCd在BNST细胞内表达在介导焦虑样 行为本建议书的K 00阶段（具体目标3）将帮助申请人为成功申请 学术研究生涯调查压力对物质使用障碍中药物复发的贡献。 这个博士后阶段将为威利福德女士提供基于成瘾的实验技术方面的经验 并提高关键的管理和指导技能，以作为独立调查员茁壮成长。在这样做时， 该提案将有助于深入了解潜在的新治疗靶点， 适应不良的应激反应从长远来看，这也将使候选人能够将这项工作扩展到强调- * 防止吸毒者复吸，并改善与药物使用作斗争者的治疗结果 紊乱