Targeting parvalbumin interneurons to mediate genetic risk for excessive drinking

Project Summary/Abstract
Impulsivity has been identified as both a risk factor for and consequence of an Alcohol Use Disorder. To identify
novel interventions to reduce alcohol use disorder development in at-risk populations, it is critical to clearly
define how neural circuits that underlie impulsivity are altered by familial risk. Thus, the overarching goal of this
work is to identify the neural circuit mechanisms underlying impulsivity, and how they are altered by genetic
risk for excessive drinking. The dorsomedial prefrontal cortex (dmPFC) is a brain region that controls impulsive
decision-making. Our lab has observed that dmPFC ensembles are required for strategy updates during delay
discounting (DD), a task which models impulsive choice, but the distinct roles of specific cell types within
dmPFC remain undetermined. This proposal will dive deeper into the contributions of specific cell-types and
provide conceptual training in translational behavioral models, PFC microcircuitry, computational techniques,
and technical training in high-density electrophysiology. Parvalbumin inhibitory interneurons (PV) are one of the
most abundant interneuron subtypes in dmPFC and are capable of precisely regulating dmPFC activity. In
particular, dmPFCPV-mediated gamma (ɣ) oscillations are known to be important for strategy updating and
flexible behavior. Alcohol-preferring (P) rats are a well-validated preclinical model of behavioral genetic risk for
excessive alcohol drinking. P rats drink much more alcohol than non-genetic risk progenitor strain controls
(Wistars) and exhibit similar behavioral phenotypes due to familial risk that match clinical findings (i.e.,
increased impulsive choice). Preliminary data from our lab indicates that markers of PV function (PV protein
and perineuronal net expression) are innately altered in P rats as compared to Wistars in dmPFC. This
proposal will test the hypothesis that genetic risk for excessive drinking is associated with reduced
dmPFCPV interneuron ɣ oscillatory activity, which results in deficits in strategy updating and increased
impulsive choice. Aim 1 of this proposal will combine high-density in vivo electrophysiology and optotagging
techniques to characterize 1) whether dmPFCPV interneuron-mediated ɣ oscillations facilitate strategy updating
during DD and 2) whether dmPFCPV activity is disrupted in P rats. Aim 2 of this proposal will determine
whether restoring dmPFC inhibitory tone via optogenetically inducing dmPFCPV ɣ oscillations is sufficient to
reduce impulsive choice in P rats. Performing these experiments in conjunction with my professional
development activities will enhance my conceptual training in the alcohol field and will provide the
computational neuroscience skills critical for my research and necessary to transition to independence.
Further, these results are expected to increase our understanding of the neurobiological and behavioral
changes that underlie genetic risk for alcohol misuse and assist in the development of novel approaches to
treat alcohol use disorder.

Grant Number: 1F32AA032416-01
NIH Institute/Center: NIH
Principal Investigator: Kathleen Bryant