Region-Specific Modifications Of Synaptic Proteins In Response To Early-Life Adversity In The Rat Brain

Drug addiction is a serious condition affecting approximately 19.7 million people in the United States alone (SAMHSA 2018). Exposure to stress and other adverse conditions has been shown to impact drug-taking behavior and making individuals more vulnerable to addiction. In those already suffering from addiction, abstaining from drug use often gives way to relapse after a stressful event (Lu, Shepard et al. 2003; Shaham, Erb et al. 2000). The experience of adversity during early-life can cause long-lasting changes in the brain, affecting development, behavior, learning and memory, and critical thinking processes, which may persist into adulthood (Aisa, Tordera et al. 2007; Anisman, Zaharia et al. 1998; Banihashemi, O\u27Neill et al. 2011; Card, Levitt et al. 2005; Hill, Kiss Von Soly et al. 2014; Huot, Plotsky et al. 2002; Kalinichev, Easterling et al. 2002; Kinkead and Gulemetova 2010; Kuhn and Schanberg 1998; Roceri, Hendriks et al. 2002; Romano-Lopez, Mendez-Diaz et al. 2015; Ryan, Musazzi et al. 2009). An overarching goal of our laboratory, and specifically the focus of this Dissertation, is to examine the neurological mechanisms that are altered by stress or adversity and promote increased vulnerability to addiction. The goal of this project was to evaluate neurochemical changes in the brain that are caused by early-life adversity, experienced in the form of neonatal maternal separation, and may promote an increased vulnerability to addiction. Our studies incorporated both molecular and behavioral methodologies, comprising the two specific aims of this Dissertation. Specific Aim 1 identifies changes in the expression of addiction-related synaptic proteins in adult male rats with a history of early-life adversity. These animals showed significant changes in the expression of several proteins in four distinct brain regions, as measured by Western blot. Specific Aim 2 utilizes the behavioral assays of conditioned-place preference to methamphetamine and light-dark box to assess motivation and anxiety and help elucidate the effects that early-life adversity has on behaviors that are related to drug use. A significant increase in anxiety-like behavior was seen in animals exposed to adversity in early-life, compared to those reared under normal conditions. However, no changes were seen in motivation or response to drug administration in animals that were exposed to adversity early in life. Together, the findings of both Aims of this Dissertation demonstrate that early-life adversity can lead to persistent modifications of protein expression in the brain and to altered behavior in adulthood. While we did not observe any changes in the response of our animals to drug application in this paradigm and at the doses tested, other investigators have shown changes in drug-taking behavior in rats exposed to the same neonatal maternal separation model of stress or early-life adversity. The results of the present work include enhanced anxiety-like behavior and modified expression of proteins involved in synaptic function and signaling, both of which may underlie or inform the mechanisms through which increased vulnerability to addiction is mediated in individuals exposed to stress or adversity in early-life. Thus, the goal of this Dissertation was to examine how neural and behavioral changes resulting from exposure to early-life adversity contribute to increased vulnerability to addiction