This application for a Ruth L. Kirschstein NRSA for Individual Predoctoral Fellowship is submitted by Mary Jane Skelly, seeking funding for research training under the tutelage of Jeffrey L. Weiner, Ph.D., Professor in the Department of Physiology and Pharmacology at Wake Forest University School of Medicine. Dr. Weiner's lab is devoted to elucidating the relationship between anxiety and ethanol abuse disorders, and identifying the synaptic correlates of the maladaptive behaviors typical of these disorders. The experiments contained herein will extend this research by investigating, for the first time, the effects of chronic developmental stress in the form of adolescent social isolation on inhibitory adrenoreceptor (AR) signaling in the basolateral amygdala (BLA). We have shown that adolescent social isolation leads to increased expression of anxiety-like behaviors and ethanol self-administration, and occludes extinction of conditioned fear in adult male Long-Evans rats. Furthermore, evidence from our lab and many others implicates disrupted AR signaling in the etiology of these distinct but related behaviors, and we hypothesize that the BLA is an important neural locus where this disruption is expressed. Specifically, we propose that the balanced excitatory and inhibitory effects of norepinephrine acting on BLA ARs is altered by social isolation, resulting in increased BLA excitatory output, which in turn potentiates anxiety and ethanol drinking. Briefly, Aim 1 will investigate the effects of social isolation on signaling at BA inhibitory inputs (both local feed-back interneurons and feed-forward lateral paracapsular cells (LPCs)), and determine whether AR facilitation of GABAergic signaling at these inputs is altered following social isolation. Local inhibitory interneuron activity is known to be decreased by fear conditioning and increased following extinction~ as our data suggest that social isolation prevents extinction learning, we hypothesize that disrupted GABAergic signaling at local and LPC synapses may be to blame. Thus, this aim will also investigate whether BLA inhibitory synapses are differentially altered by fear conditioning and extinction training following social isolation, relative to group housed controls, and whether altered AR inhibition contributes to any observed differences. Importantly, Aim 2 will use osmotic minipumps to determine whether enhancing AR-mediated LPC GABAergic signaling, alone or while concomitantly blocking the excitatory effects of BLA ARs, reverses the stress-related behaviors symptomatic of social isolation. The proposed experiments stand to significantly advance our understanding of these commonly comorbid disorders, and could possibly point to new pharmacological targets for treating the symptoms of anxiety disorders, alcoholism, and PTSD.
Chronic early life stress increases risk of anxiety, post-traumatic stress disorder, and alcohol abuse in adulthood, but the mechanisms underlying these comorbidities are not fully understood. The proposed studies, if funded, will examine for the first time whether developmental stress disrupts the balanced effects of GABAergic and noradrenergic signaling in the basolateral amygdala, and investigate whether restoring this balance by pharmacologically manipulating adrenoreceptor signaling reverses the symptoms of chronic stress. The results of these studies could provide important insight into novel pharmacological treatments for anxiety and alcohol use disorders.
|Skelly, Mary J; Weiner, Jeff L (2014) Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use. Brain Behav 4:468-83|