The Impact of Individual Vulnerability to Stress on Alcohol and Drug Seeking

个人对压力的脆弱性对酗酒和吸毒的影响

• 批准号: 10755029
• 负责人: Jose Colom Lapetina
• 金额: $ 3.57万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755029
• 关键词: Acute; Alcohols; Amygdaloid structure; Animals; Association Learning; Basic Science; Biological; Brain; Calcium; Cells; Characteristics; Code; Coupled; Cues; Data Analyses; Desire for food; Development; Diagnosis; Disease; Drug usage; Emotional; Event; Exhibits; Exposure to; Extinction; FOS gene; Fellowship; Female; Fright; Functional disorder; Genetic; Goals; Handedness; Heavy Drinking; Heterogeneity; Human; Image; Inbred Mouse; Individual; Learning; Left; Maintenance; Measures; Mediating; Memory; Mental disorders; Military Personnel; Modeling; Molecular; Mus; Negative Valence; Neurobiology; Neurons; Output; Performance; Persons; Pharmaceutical Preparations; Phase; Phenotype; Photons; Population; Positive Valence; Post-Traumatic Stress Disorders; Postdoctoral Fellow; Predisposition; Prevalence; Protocols documentation; Public Health; Research; Resistance; Risk; Rodent; Stress; Structure; Study models; Substance Use Disorder; Symptoms; Synapses; System; Techniques; Testing; Therapeutic; Tissue-Specific Gene Expression; Training; Trauma; Vulnerable Populations; Woman; Work; acute stress; alcohol use disorder; comorbidity; conditioning; deep sequencing; drug of abuse; experience; fear memory; immunoreactivity; improved; in vivo; in vivo calcium imaging; in vivo imaging; insight; male; member; memory recall; neural; neurophysiology; optogenetics; recruit; resilience; resilience factor; restraint; restraint stress; sex; stress disorder; stress resilience; stressor; transcriptomics; traumatic event

PROJECT SUMMARY Stress leads to the enhancement of memory in both humans and animals. This stress-enhanced memory has relevance to stress-related psychiatric disorders, such as posttraumatic stress disorder (PTSD), which is marked by heightened, perseverant memories of trauma. Interestingly, only approximately 10-20% of people develop the enduring symptoms of PTSD, despite nearly everyone experiencing at least one traumatic event in their lifetime. In addition, rates of PTSD are higher among women and military personnel. A protocol was developed by this group that results in differential susceptibility to stress enhancement of a remote (one month old) fear memory among male mice and a greater propensity for enhancement in females. Despite the clear importance of understanding the mechanisms supporting long-lasting, perseverant memory, the majority of basic memory research focuses on recent (~ 1 day old), not remote memory and does not incorporate a stress component. Additional research performed by the group with this protocol identified the basolateral amygdala (BLA) has a critical hub mediating stress-enhanced fear memory and the associated differential susceptibility. The primary goal of the current application is to delineate how stress engages and alters the function of the BLA to drive differential susceptibility to stress-enhanced fear memory. The work will place particular focus on sex as a biological variable and lateralized function of the BLA. Regarding the latter, the right hemisphere BLA is associated with negative valence, while the left is associated with positive valence. This is conserved from humans to rodents but is understudied in basic research. The central hypothesis of this proposal is that stress leads to lasting impacts on the BLA, resulting in differential susceptibility to remote stress-enhanced fear memory. The working hypothesis to be explored is that an intense acute stressor alters subsequent fear memory strength by influencing the recruitment of specific BLA cell populations to the memory trace. Work leading up to this proposal (F99 Aim 1A) details studies characterizing identity and laterality of neural ensembles supporting stress-induced memory enhancement. To examine how stress impacts experience coding to influence stress- enhanced fear memory (F99 Aim 1B), I will train in execution and data analysis of in vivo calcium imaging of the BLA. In transitioning to a postdoctoral fellowship, I will focus on research based on the high rate of co-morbidity between stress disorders and alcohol and substance sue disorders (K00). The research will incorporate neurophysiological and deep sequencing measures to further study how stress individually impacts function of the BLA and associated circuitry to influence alcohol or drug seeking. The proposed work will provide a much- needed, deep characterization of the impact of stress on the brain in the context of differential stress susceptibility. This information will then be used to guide cellular, molecular and circuit level mechanistic studies, with the goal of identifying therapeutic strategies.

项目摘要 压力会导致人类和动物的记忆增强。这种增强压力的记忆具有 与与压力相关的精神疾病有关，例如创伤后应激障碍（PTSD），该疾病被标记为 通过增强，持久的创伤记忆。有趣的是，只有大约10-20％的人发展 PTSD的持久症状，尽管几乎每个人都在他们的 寿命。此外，妇女和军事人员的PTSD率更高。制定了协议 由这个小组导致对遥控（一个月大的恐惧）压力增强的敏感性不同 雄性小鼠的记忆和女性增强的倾向更大。尽管很重要 了解支持持久，持久记忆的机制，大多数基本记忆 研究重点是最近（〜1天大），而不是远程记忆，并且不包含压力组成部分。 该小组对该方案进行的其他研究确定了基底外侧杏仁核（BLA）的 关键的枢纽介导压力增强的恐惧记忆和相关的差异敏感性。主要 当前应用的目标是描述压力参与和改变BLA的功能以驱动的功能 对压力增强的恐惧记忆的差异敏感性。这项工作将特别关注性作为一个 BLA的生物变量和侧向功能。关于后者，右半球是 与负价相关，而左价与正价有关。这是免于 人类对啮齿动物，但在基础研究中被研究了。该提议的核心假设是压力 导致对BLA的持久影响，从而导致对远程压力增强恐惧的敏感性不同 记忆。要探讨的工作假设是，强烈的急性压力源改变了随后的恐惧记忆 通过影响特定BLA细胞群体募集到记忆痕迹的强度。工作 该提案（F99 AIM 1A）详细介绍了表征支持神经合奏的身份和横向性的研究 压力引起的记忆增强。检查压力如何影响经验编码以影响压力的经验 - 增强的恐惧记忆（F99 AIM 1B），我将训练对体内钙成像的执行和数据分析 bla。在过渡到博士后奖学金时，我将基于高度疾病的高度研究专注于研究 在压力障碍与酒精和物质苏联疾病之间（k00）。该研究将纳入 神经生理和深度测序措施，以进一步研究压力如何单独影响 BLA和相关的电路影响酒精或毒品。拟议的工作将提供很多 - 需要的是，在差异压力的背景下，对压力对大脑的影响的深刻表征 敏感性。然后，此信息将用于指导细胞，分子和电路水平机械研究， 目的是确定治疗策略。