Project Summary / Abstract
Opioid Use Disorder (OUD) is a chronic, relapsing brain disease characterized by compulsive drug
seeking and use, engaging specific neurocircuits. One of the major projection systems implicated in regulating
behavior motivated by drugs of abuse including opioids is the basolateral amygdala (BLA) pathway to nucleus
accumbens (NAc). However, the BLA¿NAc projection mediates not only approach behavior, as required for
drug seeking, but also avoidance responses. This introduces the question as to the mechanisms by which a
single excitatory projection system mediates diametrically opposite behaviors. Our preliminary data revealed that
morphine (a rewarding opioid agonist) and naloxone (an aversive opioid antagonist) recruit two distinct groups
of neurons – neuronal ensembles or engrams – within the same (BLA) brain area. Moreover, selective activation
of morphine vs. naloxone reactive BLA axon terminals in the NAc induced opposing conditioned place preference
(CPP) and aversion (CPA) respectively. These preliminary data establish a role for two discrete drug-reactive
NAc-projecting BLA ensembles each differentially and selectively sensitive to activation by rewarding (morphine)
vs. aversive (naloxone) events which elicit the acquisition of approach vs. avoidance behavior. Based on these
results, we hypothesize that the expression of CPP and CPA are also mediated by similarly distinct BLA¿NAc
ensembles selectively sensitive to morphine vs. naloxone environmental context. In support of this hypothesis,
additional preliminary findings confirmed that the expression of morphine CPP and naloxone CPA are
accompanied by neuronal activation in both the BLA and NAc. The goal of this proposal is to confirm the function
of the morphine vs. naloxone context-reactive BLA¿NAc ensembles for the expression of CPP/CPA, and to
establish the brain-wide source of activation innervating these two distinct BLA¿NAc ensembles mediating
opposing behaviors. This K01 proposal will, therefore, test the central hypothesis that an environmental context
linked to morphine (Aim 1) vs. naloxone (Aim 2) recruits discrete NAc-projecting BLA ensembles, which are
activated by excitatory input (Aim 3) from brain areas that process information representing the respective
context, thereby engaging discrete BLA¿NAc ensembles to selectively regulate approach vs. avoidance
behavior. The training plan, under the primary mentorship of Dr. Friedbert Weiss at Scripps Research, provides
a comprehensive research and career development plan for acquiring the necessary experimental and
professional skills within a collaborative neuroscience environment. An experienced team of mentors and career
advisors will provide training critical for the candidate’s short- and long-term success, including: experiential and
didactic learning in study design, execution, and interpretation of behavioral models of drug seeking with a focus
on stimuli-responsive activated neurons. Finally, the professional development plan will equip the candidate to
lead a laboratory research program investigating the neurobiological control of drug seeking behavior by distinct
neuronal ensembles distributed across multiple brain areas comprising behaviorally relevant neurocircuits.
