Effects of early-life neglect and cocaine use on PTSD-like behaviors

早期生活忽视和可卡因使用对 PTSD 样行为的影响

• 批准号: 10569007
• 负责人: James T. Porter
• 金额: $ 35.97万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-25 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569007
• 关键词: Address; Adolescence; Adolescent; Adult; Affect; African American; Amygdaloid structure; Animal Model; Behavior; Behavioral; Brain; Child Abuse; Child Abuse and Neglect; Clinical; Cocaine; Cocaine Abuse; Cocaine Dependence; Development; Disease; Exposure to; Extinction; FGF2 gene; Female; Freezing; Fright; Hippocampus; Impairment; Life; Measures; Mediating; Memory; Mental Depression; Messenger RNA; Minority Groups; Modeling; Molecular; Molecular Analysis; Neurons; Outcome; Phenotype; Population; Post-Traumatic Stress Disorders; Predisposition; Proteins; Rattus; Resources; Risk Factors; Severities; Shock; Slice; Specialized Center; Specificity; Stress; Substance Use Disorder; Substance abuse problem; Symptoms; Synapses; Time; Trauma; Viral Vector; child neglect; cocaine exposure; cocaine relapse; cocaine seeking; cocaine use; comorbidity; conditioned fear; conditioned place preference; conditioning; design; early life stress; experimental study; health disparity; knock-down; male; maternal separation; neglect; neuronal circuitry; novel; optogenetics; outcome disparities; trauma exposure; treatment planning

PROJECT SUMMARY The high degree of comorbidity between substance use disorder (SUD) and post-traumatic stress disorder (PTSD) in the US population suggests that similar underlying mechanisms contribute to both disorders such that having one disorder may predispose one to develop the other. A study of a mostly African-American urban civilian population found that their levels of cocaine use highly correlated with levels of childhood abuse and PTSD symptoms. This suggests that childhood abuse, cocaine addiction, and PTSD interact in minority populations and likely contribute to worse outcomes and health disparities. The vast majority of animal models examine cocaine use and PTSD separately. However, to be able to design better treatment plans for real-life clinical scenarios, we need to understand how these two disorders interact. In this project, we propose to combine animal models of child abuse and neglect with models of cocaine abuse and PTSD to examine to what degree one condition affects the other and to examine whether exposure to cocaine at different developmental stages increases the severity of PTSD-like phenotypes. Our central hypothesis is that developmental stress and cocaine abuse interact to increase the susceptibility to and worsen the severity of PTSD-like symptoms after trauma exposure in adulthood by altering overlapping neuronal circuits. Substance abuse often begins during adolescence, during which time the prefrontal circuits and hippocampal modulation of behavior is still being refined. Therefore, early life stress and adolescent cocaine exposure could alter hippocampal modulation of conditioned fear, potentially leading to increased susceptibility to more severe PTSD-like behaviors in adulthood. To begin to address these issues, in Aim 1, we will first evaluate whether early life neglect and adolescent cocaine use interact to increase susceptibility to and generalization of conditioned fear or impair fear extinction in a rat model. In Aim 2, we will evaluate whether fibroblast growth factor-2 mediates the effects of early life neglect and adolescent cocaine use on fear generalization and extinction. In Aim 3, we will evaluate how early life neglect and adolescent cocaine use interact to alter the excitability of the ventral hippocampus-to-infralimbic cortex portion of the fear circuit. Thus, we will examine the effects of developmental stress and cocaine use on PTSD- related behaviors from a behavioral, circuit, cellular, and molecular level. The Research Resources Core will provide essential support for this project, since the completion of this project's aims will require behavioral and molecular analysis.

项目概要 物质使用障碍（SUD）和创伤后应激障碍之间存在高度共病 (PTSD) in the US population suggests that similar underlying mechanisms contribute to both disorders such that 患有一种疾病可能会使一种疾病易患另一种疾病。对大多数非裔美国城市平民的研究 population found that their levels of cocaine use highly correlated with levels of childhood abuse and PTSD 症状。这表明儿童虐待、可卡因成瘾和创伤后应激障碍在少数群体中相互作用 并可能导致更糟糕的结果和健康差异。 The vast majority of animal models examine cocaine use and PTSD separately.然而，能够针对现实临床设计更好的治疗方案 情景中，我们需要了解这两种疾病如何相互作用。 In this project, we propose to combine 虐待和忽视儿童的动物模型与可卡因滥用和创伤后应激障碍模型，以检查到什么程度 一种情况会影响另一种情况，并检查是否在不同的发育阶段接触可卡因 increases the severity of PTSD-like phenotypes.我们的中心假设是发育压力和可卡因 虐待相互作用，增加创伤后 PTSD 样症状的易感性并使其严重程度恶化 通过改变重叠的神经元回路来暴露成年期。 Substance abuse often begins during 青春期，在此期间，前额叶回路和海马体的行为调节仍在进行中 精制。 Therefore, early life stress and adolescent cocaine exposure could alter hippocampal modulation of conditioned fear, potentially leading to increased susceptibility to more severe PTSD-like behaviors in adulthood. 为了开始解决这些问题，在目标 1 中，我们将首先评估早期生活忽视和青少年可卡因是否 use interact to increase susceptibility to and generalization of conditioned fear or impair fear extinction in a rat 模型。 In Aim 2, we will evaluate whether fibroblast growth factor-2 mediates the effects of early life neglect 以及青少年使用可卡因对恐惧泛化和消退的影响。在目标 3 中，我们将评估早期生活中的忽视 和青少年使用可卡因相互作用，改变腹侧海马到边缘下皮层的兴奋性 portion of the fear circuit.因此，我们将研究发育应激和可卡因使用对 PTSD 的影响。 从行为、回路、细胞和分子水平上的相关行为。 The Research Resources Core will 为该项目提供必要的支持，因为完成该项目的目标需要行为和 分子分析。