Specificity and stability of cocaine ensembles

PROJECT SUMMARY AND ABSTRACT.
A key feature of cocaine use disorder is an increase in drug taking and seeking that develops over an
individual’s drug-use history. To this end, a large amount of work has been focused on understanding how
plasticity in reward-related brain regions strengthens circuits that drive motivation. However, in humans and
animal models, while chronic drug use increases drug seeking, it simultaneously reduces motivation for
alternative reinforcers such as sucrose. The goal of this proposal is to understand the neural mechanism by
which cocaine self-administration differentially alters the neural encoding drug and non-drug reinforcers.
The nucleus accumbens (NAc) is a key region that causally mediates reward encoding for both drug
and non-drug rewards. This region is comprised of medium spiny neurons (MSNs) that are largely segregated
into two non-overlapping populations based on their expressions of D1 and D2 type dopamine receptors. D1
MSNs, which specifically drive drug seeking, are activated at the population level by both drugs and sucrose
and undergo robust drug-induced plasticity following repeated cocaine use. Two questions guide our
research in this area: 1. Do cocaine and sucrose activate different populations of D1 MSNs? And 2.
Does repeated cocaine use differentially affect the ability of cocaine or sucrose to increase D1 MSN
activity in the NAc? Using cellular resolution imaging in awake and behaving animals with microendoscopes,
we will record single-cell neural activity in the same animals in response to sucrose and cocaine and determine
how cocaine self-administration alters the dynamics of each ensemble over time. We hypothesize that 1.
Cocaine and sucrose recruit non-overlapping neuronal populations, and 2. Cocaine self-administration
increases the ability of cocaine and decreases the ability of sucrose to increase D1 MSN activity.
The training plan includes a mentoring team led by Erin Calipari, PhD (sponsor) with collaborators Brad
Grueter, PhD, Thilo Womelsdorf, PhD, and Edward Nieh, PhD. This team will provide strong training in the use
of cellular resolution imaging in awake and behaving animals and computational analyses to understand the
relation of complex activity dynamics in the brain and in behavior. The training plan was specifically crafted to
build upon Dr. Bradley Barth’s strong foundation of computational modeling in peripheral tissues to bring his
training into the addiction field. Together this project will answer a fundamental question in the addiction field,
while also providing training to help Dr. Barth become an expert in the neural dysfunction that occurs as a
result of chronic drug use.

Grant Number: 1F32DA063284-01
NIH Institute/Center: NIH
Principal Investigator: Bradley Barth