The primary goal of this training proposal is to define the functional role and mechanisms of the mu opioid receptor (MOR) system in nucleus accumbens (NAc) medial shell. During my training period, I will be trained in novel genetic, in vivo imaging, and optogenetic approaches, as well as guided on a robust, specifically tailored career development plan designed to prepare me for eventual independence. The first research aim of this training proposal seeks to determine the functional role of MORs in NAc through constitutive and conditional knockout models and reversible pharmacological manipulations. Each of these models will be tested on multiple behavioral assays to determine whether MORs are necessary for generating motivated behaviors, or selectively recruited to enhance behaviors in highly motivated states (e.g., hunger). In a related, but separate set of experiments, Aim 1B uses cell type specific knockout and knockin models to further refine and identify the mechanisms through which MORs act to mediate motivated behaviors.
While Aim 1 identifies where and when MORs act, Aim 2A seeks to identify how MOR signaling alters neural activity in specific neuronal population ensembles of neurons with subsecond resolution. Finally, Aim 2B uses a temporally precise chimeric photosensitive mu opioid receptor and optogenetic methods to specifically and spatiotemporally activate MOR signaling pathways during discrete behaviors. This dual approach of observational in vivo imaging during MOR-dependent behaviors, coupled with experimenter controlled time-locked activation of MOR systems will provide important insights into the mechanisms of how MORs mediate motivated behaviors. The information gained from the studies outlined in this proposal may help provide insights into how endogenous opioid systems become highjacked during opioid addiction or other forms of drug abuse. A more refined analysis of this neuropeptide system will allow for more directed and targeted treatments for those suffering from addiction or mood/motivation disorders.
Since 2004, deaths from prescription opioid painkiller overdose have nearly doubled, and deaths from heroin overdose have increased nearly 6-fold (Abuse 2015). The rapid escalation of opioid substance abuse that contributes to the development of addiction is, in part, driven by activation of endogenous opioid systems in the brain. In particular, the mu opioid receptor system in nucleus accumbens has been consistently implicated in mediating the pleasurable and rewarding effects of natural and drug rewards (Koob and Volkow 2016; Richard et al. 2013). Therefore, the goal of this proposal is to refine and elucidate the functional and mechanistic substrates of this system in motivation and reward.
|Corder, Gregory; Castro, Daniel C; Bruchas, Michael R et al. (2018) Endogenous and Exogenous Opioids in Pain. Annu Rev Neurosci 41:453-473|