Project Summary
Recent years have witnessed an increasing prevalence of substance use disorders (SUDs) driven by the
availability of both prescription opioids and illicit synthetic drugs. Opioid users are at high risk for relapse and
overdose, with one study indicating that 71% of opioids users experience relapse within 1 month of abstinence.
The Centers for Disease Control and Prevention reported a 53.1% increase in national rates of overdoses
involving synthetic opioids in 2020 over the previous year. Although only a small subset of individuals who use
drugs develop a SUD, compulsive drug use is often associated with comorbid health problems and risk of
overdose, and current therapeutic approaches cannot address persistent drug craving or the risk of relapse.
Alterations to the prefrontal cortex (PFC) have been linked to addiction-associated behavior in both humans and
animal models. Furthermore, projections from the prelimbic region (PL) of the PFC to the nucleus accumbens
core (NAcC) and to the rostromedial tegmental nucleus (RMTg) have been found to respectively promote and
suppress drug-seeking. Although the PL consists of a heterogenous population of intermingled intratelencephalic
(IT) and pyramidal tract (PT) pyramidal neurons, the respective contributions of the IT and PT subpopulations to
aspects of addiction such as relapse remain unknown. We hypothesize that chronic heroin self-administration
leads to overactivation of IT ¿ NAcC and depression of PT ¿ RMTg, and dysregulation of these circuits drive
drug-seeking behavior in individual rats that exhibit a more severe addiction-like behavioral phenotype. Rats will
undergo an intermittent access (IntA) self-administration paradigm that produces individual variability in
addiction-like behaviors. Combinatorial viral approaches will be used to achieve selective expression of calcium
sensors or DREADDs in either IT or PT neurons in PL. The activity of PL pyramidal neurons will be observed
and manipulated using fiber photometry and chemogenetic techniques, respectively. We will first use fiber
photometry to characterize alterations to IT and PT neuronal activity in PL during heroin self-administration,
extinction, and cue-induced reinstatement in male and female rats exhibiting low- and high-risk addiction
phenotypes. We will then perform chemogenetic manipulations during a progressive ratio test and a cue-induced
reinstatement test to address the hypotheses that the IT ¿ NAcC circuit positively and bidirectionally regulates
drug-seeking behavior, while the PT ¿ RMTg circuit negatively and bidirectionally regulates drug-seeking
behavior. This research has the potential to elucidate the factors that predispose individuals to addiction and
confer vulnerability to relapse, which represents a major obstacle for those living with SUDs. Additionally, the
experiments described in this proposal will advance our understanding of the functional roles of PFC pyramidal
neuron subpopulations and their distinct downstream circuits. Thus, our findings will be a valuable contribution
both within the field of basic neurobiology and in the broader societal context of substance use disorders.
