Corticolimbic Circuits in Negative Affect

Project Summary/Abstract
The ability to seek out situations that elicit pleasure and avoid those that lead to aversion or discomfort is a
fundamental ability we all share, yet dysfunctional hedonic processing is prevalent in numerous psychiatric
illnesses including substance use disorders (SUDs), alcohol abuse, and depression. As such, it is critical to
understand the basic neural mechanisms underlying aversive affective states to ultimately apply treatment
strategies to restore normal hedonic processing and aid in the recovery of maladaptive behaviors in mental
illness. Here, we seek to understand the role of ‘top-down’ medial prefrontal cortex (mPFC) to nucleus
accumbens (NAc) processing of innate and conditioned negative affective processing, incorporating
electrophysiology, optogenetics, and a rat transcranial alternating current stimulation (tACS) method we
developed. We focus on one type of behavior (taste reactivity, TR), measured in innate (unconditioned) situations
and during conditioned taste aversion (CTA) and its extinction (restoration of positive affect). Notably, TR has
exceptional translational value since it is preserved across species with similar behaviors present in rats,
nonhuman primates and humans. Using electrophysiology, we will first determine how oscillatory, coordinated
rhythms in mPFC and NAc circuitry are linked to affective processing in real time in the naïve state, how this
signaling shifts when the sweet becomes devalued through CTA, and when it is restored in extinction. Since
human and animal studies indicate that strengthening the mPFC can reduce negative affect we will then
determine if strengthening these circuits using two distinct approaches can restore positive affect and associated
neural function. We will use optogenetics (channelrhodopsin) to determine if targeted optical strengthening of
infralimbic (IL)-NAc shell and/or prelimbic (PrL)-NAc core is sufficient to reduce negative affect and enhance
CTA extinction. We will also examine if our novel rat transcranial alternating current (tACS) system, a relatively
noninvasive approach with great translational value, can also modulate disrupted cortical oscillations in CTA,
strengthen overall mPFC-NAc circuit coherence, and determine if this approach can increase positive affect. In
both optogenetics and tACS studies, we will focus on 20 Hz (beta) frequency given its role in ‘top-down’ cognitive
control as well as 80 Hz (gamma) frequency given studies that implicate this signaling in reward processing.
Collectively, this multi-faceted approach will provide important insight into how mPFC-NAc systems modulate
normal hedonic processing, how these systems are disrupted as negative affective states emerge and provide
the foundation for the ultimate goal of developing methods to restore aberrant circuit function and hasten
recovery from negative emotional states.

Grant Number: 5R01DA052108-05
NIH Institute/Center: NIH
Principal Investigator: Regina Carelli