Converging epidemiological studies indicate that a life-threatening event increases the incidence of post- traumatic stress disorder (PTSD), which carries a 30-50% comorbidity with substance use disorders (SUDs). Such comorbidity results in greater drug use and poorer treatment outcomes. The proposed research builds upon my recent publication, where I showed a remarkable overlap between the enduring neuroadaptations produced in nucleus accumbens core (NAcore) excitatory transmission after acute restraint stress and drug use. Recently, I paired a stressful event with a novel odor and found that the stress-conditioned odor alone induced cocaine seeking. In NAcore, ~95% of neurons are medium spiny neurons (MSNs) chemically coded as selectively expressing D1 or D2 dopamine receptors. Different studies showed that D1 activation generally promotes and D2 activation inhibits behaviors during drug seeking. At molecular level, I observed that activated matrix metalloproteases signal through ?3-integrins and are required for the transient synaptic plasticity (t-SP) characteristic of drug seeking elicited by cocaine cues. Here, I will examine the role of D1- and D2-MSN neuronal activity in response to stress-conditioned cues and determine if the changes in neuronal activity encode coping behavior or cocaine seeking. Furthermore, I will determine if changes in activity in D1- and D2-MSNs are integrin- mediated. To accomplish this, I will be trained in vivo single cell Ca2+ transients in real time. I will also use DREADDS technology for cell-type specific modulation and Cre-dependent shRNA for cell-specific target protein knockdown. In the K99 aims, I propose to determine if exposure to stress-conditioned cues elicit different patterns of activity during defensive burying (DB) (Aim 1). I will selectively inactivate D1- or D2-MSNs during restraint stress to evaluate the necessity of each cell type for encoding coping during DB (Aim 2A) and I will evaluate if the activity in either cell type is dependent upon ?3-integrin signaling using Cre-dependent shRNA knockdown (Aim 2B). MUSC provides an ideal research environment in which to attain this training and complete these aims, as it boasts one of the leading neuroscience departments for addiction research with multi-PI center grants. This training will enhance my qualifications for transitioning to an independent tenure-track faculty position at a major research institution, which is my ultimate goal. Moreover, Dr. Kalivas is a well-established mentor who has demonstrated abundant success in facilitating the transition of his postdoctoral trainees to faculty positions. Once I achieve a faculty appointment during the R00 period, I will determine if the changes in Ca2+ transient in D1- or D2-MSNs during stress-conditioned cues are similar to those observed during stress-induced cocaine seeking (Aim 3). I will examine the necessity of each cell type for encoding cocaine seeking (Aim 4A) and I will evaluate if the activity in either cell type is dependent upon ?3-integrin signaling (Aim 4B). These experiments have the potential to reveal novel neurobiological mechanisms of PTSD that induce the increased vulnerability to SUDs. Understanding this link will enhance our ability for rational drug design to treat comorbid PTSD and SUDs.
Important discoveries showed that a single traumatic event induces enduring cortico-striatal synaptic plasticity. The proposed experiments will provide insight into how stress disorders permanently alter brain structure and function, and how these changes increase vulnerability to drug use and relapse.
