TRPV1 signaling as a sex-specific mechanism of contextual fear generalization

TRPV1 信号传导作为情境恐惧泛化的性别特异性机制

• 批准号: 10091528
• 负责人: REBECCA M SHANSKY
• 金额: $ 19.63万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091528
• 关键词: AMPA Receptors; Adult; Amygdaloid structure; Animals; Area; Auditory; Behavior; Behavioral; Binding; Biochemistry; Biology; Brain; CNR1 gene; Cations; Complex; Data; Development; Dorsal; Endocannabinoids; Endocytosis; Exhibits; Female; Freezing; Fright; Future; Hip region structure; Hippocampus (Brain); Infusion procedures; Investigation; Lead; Learning; Mediating; Mediator of activation protein; Memory; Microscopy; Modeling; Neurobiology; Neurons; Pathology; Patients; Pharmacology; Physiological; Play; Post-Traumatic Stress Disorders; Predisposition; Prevalence; Rattus; Resolution; Rodent; Rodent Model; Role; Sex Bias; Sex Differences; Signal Transduction; Stress; Structure; Synapses; Synaptic Membranes; Synaptic plasticity; Therapeutic; Trauma; United States; Vanilloid; Woman; Work; anandamide; behavioral pharmacology; biological adaptation to stress; clinically relevant; conditioned fear; conditioning; endogenous cannabinoid system; experience; experimental study; hippocampal subregions; insight; male; memory process; men; neuromechanism; new therapeutic target; novel; patient population; post-traumatic symptoms; pre-clinical; pre-clinical research; receptor; recruit; response; sex; therapeutic development; trafficking; vanilloid receptor subtype 1

Summary Women are twice as likely as men to develop Post-Traumatic Stress Disorder (PTSD) after a trauma, but the neurobiological basis for this discrepancy is poorly understood. One hallmark symptom of PTSD is a re- experiencing of the trauma in safe situations, a “generalization” phenomenon that can be studied using preclinical rodent models like Pavlovian fear conditioning. Because both women and female rodents exhibit a greater tendency to generalize fear in safe contexts, better insight into potential sex-dependent factors that disrupt aversive context processing could lead to the development of novel treatments for PTSD. Preliminary data from our lab points to a novel role for the endocannabinoid system in conferring a sex-specific susceptibility to contextual fear generalization. Specifically, we observe a TRPV1-mediated increase in contextual fear generalization in females, but not males. A deeper investigation into this provocative finding may open new avenues for therapeutic development for women with PTSD. But in order to identify key areas and mechanisms to target for manipulation, we must first conduct exploratory studies to help guide the direction of larger-scale interrogations. The work we propose here will first determine whether our behavioral effects are selectively mediated by either the dorsal or ventral hippocampus (Aim 1), and then examine potential sex differences in mechanisms of eCB- and fear conditioning-related synaptic plasticity (Aim 2). We will carry out these Aims using a combination of behavioral pharmacology, fluorescent microscopy, biochemistry, and high resolution neuronal structural analysis. Together, these experiments will identify potential mediators of our behavioral effects, opening up our model for more focused interrogation and providing insight into sex-specific mechanisms of fundamental learning and memory processes.

摘要 女性在创伤后患创伤后应激障碍(PTSD)的可能性是男性的两倍，但 这种差异的神经生物学基础还知之甚少。创伤后应激障碍的一个显著症状是 安全情境中的创伤体验--一种可以用来研究的“泛化”现象 临床前啮齿动物模型，如巴甫洛夫恐惧条件反射。因为雌性和雌性啮齿动物都表现出 更倾向于在安全的环境中概括恐惧，更好地洞察潜在的性别依赖因素 干扰厌恶情境处理可能导致创伤后应激障碍的新治疗方法的发展。初步 我们实验室的数据表明，内源性大麻素系统在赋予特定性别的 易受背景恐惧的影响。具体地说，我们观察到TRPV1介导的 情境性恐惧在女性中普遍存在，但在男性中不是。对这一挑衅性发现进行更深入的调查 可能会为患有创伤后应激障碍的女性开辟治疗发展的新途径。但为了确定关键领域 而机制要针对操纵，首先要进行探索性研究，以帮助指导 更大规模审讯的方向。我们在这里提出的工作首先将决定我们的行为 效应由背侧或腹侧海马区选择性地介导(目标1)，然后检查 与ECB和恐惧条件作用相关的突触可塑性机制的潜在性别差异(目标2)。我们 将利用行为药理学、荧光显微镜、 生物化学和高分辨率神经元结构分析。总而言之，这些实验将确定 我们的行为影响的潜在中介者，打开了我们的模型，以便更集中的审讯和 提供对基本学习和记忆过程的性别特有机制的洞察。

项目成果

CB1R blockade unmasks TRPV1-mediated contextual fear generalization in female, but not male rats.

• DOI: 10.1038/s41386-023-01650-z
• 发表时间: 2023-09
• 期刊: NEUROPSYCHOPHARMACOLOGY
• 影响因子: 7.6
• 作者: Huckleberry, Kylie A.;Calitri, Roberto;Li, Anna J.;Mejdell, Mackenna;Singh, Ashna;Bhutani, Vasvi;Laine, Mikaela A.;Nastase, Andrei S.;Morena, Maria;Hill, Matthew N.;Shansky, Rebecca M.
• 通讯作者: Shansky, Rebecca M.