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

项目摘要 物质使用障碍与创伤后应激障碍的高度共病性 美国人群中的创伤后应激障碍（PTSD）表明，导致这两种疾病的潜在机制相似， 患有一种疾病可能会使一种疾病容易发展成另一种疾病。一项关于一个主要是非洲裔美国城市平民的研究 研究人员发现，他们的可卡因使用水平与儿童虐待和创伤后应激障碍的水平高度相关 症状这表明，童年虐待，可卡因成瘾和创伤后应激障碍在少数人群中相互作用 并可能导致更糟糕的结果和健康差异。绝大多数动物模型检查 可卡因使用和创伤后应激障碍然而，为了能够为现实生活中的临床设计更好的治疗计划， 我们需要了解这两种疾病如何相互作用。在本项目中，我们建议将联合收割机 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的模型，以检查在何种程度上 一种情况会影响另一种情况，并研究在不同发育阶段接触可卡因是否 增加PTSD样表型的严重程度。我们的核心假设是发展压力和可卡因 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，药物滥用通常始于 青春期，在此期间，前额叶回路和海马体对行为的调节仍在研究中。 完善.因此，早期生活压力和青少年可卡因暴露可能会改变海马调制， 条件性恐惧，可能导致成年后更严重的PTSD样行为的易感性增加。 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 使用交互作用增加大鼠对条件性恐惧的敏感性和泛化或削弱恐惧消退 模型在目标2中，我们将评估成纤维细胞生长因子-2是否介导了早期生活忽视的影响 和青少年可卡因使用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忽视 和青少年可卡因使用的相互作用，改变腹侧海马到边缘下皮层的兴奋性 恐惧回路的一部分因此，我们将研究发展压力和可卡因使用对PTSD的影响- 从行为、电路、细胞和分子水平来分析相关行为。研究资源核心将 为这个项目提供必要的支持，因为完成这个项目的目标将需要行为和 分子分析

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.