Much work has been done examining the critical role of chronic early life stress (e.g. adolescent social isolation) on psychiatric disorders and addiction in adulthood. Our lab has developed a model of adolescent social isolation (aSI) which engenders robust increases in a wide range of behaviors that have been linked with increased vulnerability to alcohol addiction, including increases in anxiety-like behaviors and ethanol intake and preference. We have shown that aSI also results in a hyper-excitable basolateral amygdala (BLA), a brain region heavily implicated in anxiety and motivated behaviors. Investigation by other groups suggests that the BLA and nucleus accumbens (NAc) are critical components of a network that regulates reinforcement and reinstatement of drug seeking and drug taking. In fact, modulation of BLA-NAc synapses has recently been shown to bi-directionally regulate motivated behaviors. Moreover, we have shown that the NAc, following aSI, shows disruption in catecholamine signaling. Thus, this proposal, for the first time, will examine the BLA projection to the nucleus accumbens (NAc), in a model of chronic early life stress. Our central hypothesis is that chronic early life stress leads to increased excitability in the BLA-NAc circuit and that this adaptation contributes to the ?addiction vulnerable? phenotype engendered by this model.
In Aim 1, we will employ electrophysiological and optogenetic techniques to test the hypothesis that aSI strengthens BLA- NAc glutamatergic synaptic function and disrupts addiction-related plasticity.
In Aim 2, we will test the hypothesis that aSI disruption of BLA-NAc glutamatergic synapses contributes to the escalation in ethanol intake observed following this chronic early life stressor. We will use chemogenetics to manipulate this circuit, as well as an operant ethanol self-administration task. Collectively, these studies may shed new light on the specific neural circuits through which early life stress heightens risk of alcohol misuse in life and potentially identify novel targets for the development of more effective therapies for alcohol use disorder.
Our recent work suggest that increases in intrinsic excitability of glutamatergic projecting neurons within the basolateral amygdala (BLA) may contribute to the behavioral phenotype engendered by adolescent social isolation, which models elements of alcohol addiction vulnerability. Although the BLA plays an important role in modulating behaviors linked with the heightened risk of alcohol addiction, like increases in ethanol drinking and anxiety-like behaviors, the specific BLA efferents responsible for these effects are not fully understood. The overarching goal of the proposed studies is to use a multidisciplinary experimental approach to test the hypothesis that adaptive changes in the excitatory projection from the BLA to the nucleus accumbens contribute to the escalation in ethanol intake observed following adolescent social isolation. Collectively, these experiments will help to further our understanding of the specific brain circuits that contribute to an increased risk of alcoholism.
