Alcohol use disorders represent a major public health problem, and to date, no comprehensive treatment or intervention is available. The Bed Nucleus of the Stria Terminalis (BNST) is involved in integrating cortical and subcortical inputs to orchestrate behavioral responses, and has been implicated in alcohol use and abuse, as well as stress related behaviors. The kappa opioid receptor (KOR) has been demonstrated in the BNST to alter neurotransmitter signaling , though its effect on glutamatergic transmission has yet to be elucidated. The goals of this project are to conduct a thorough investigation and characterization into the role of KORs on glutamatergic signaling in the BNST, and how this connection is altered by a model of alcohol dependence. To complete the first aim, I will use slice electrophysiology to evaluate the function, signaling, and locus of glutamatergic KORs in the BNST. To complete this second aim, I will use a combination of optogenetics, chronic-intermittent ethanol exposure, and slice electrophysiology to assess how KORs modulate pathways- specific inputs to the BNST both before and after ethanol exposure. Thus, this proposal will use a combination of innovative approaches to provide thorough and convergent evidence characterizing KOR modulation of glutamatergic transmission in the BNST.
The kappa opioid receptor (KOR)/dynorphin system modulates plasticity in the Bed Nucleus of the Stria Terminalis. Alcohol and stress related behaviors may further modulate this system. This work seeks to employ a mouse model to investigate the mechanism of KOR modulation and its role in a model of alcohol dependence. These studies will attempt to identify molecular changes in glutamatergic plasticity mediated by kappa opioid signaling, and how an alcohol-dependence like insult modulates this system.
|Crowley, Nicole A; Bloodgood, Daniel W; Hardaway, J Andrew et al. (2016) Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit. Cell Rep 14:2774-83|
|Kash, Thomas L; Pleil, Kristen E; Marcinkiewcz, Catherine A et al. (2015) Neuropeptide regulation of signaling and behavior in the BNST. Mol Cells 38:1-13|
|Pleil, Kristen E; Lowery-Gionta, Emily G; Crowley, Nicole A et al. (2015) Effects of chronic ethanol exposure on neuronal function in the prefrontal cortex and extended amygdala. Neuropharmacology 99:735-49|