Project Details
Description
Project Summary
Opioid use disorder is a life-long burden for many individuals, imposing high personal, financial, and health costs.
Even after prolonged abstinence, many individuals in recovery will go on to relapse, including those that received
medication-assisted treatments. Repeated opioid exposure usurps normal reward circuit function by producing
long-lasting molecular changes that alter physiology and support continued drug use. These cellular adaptations
have been implicated in sustained relapse vulnerability, but we lack a clear understanding of what drives their
persistence. There is a further lack of information on the precise molecular adaptations underlying altered circuit
function, and in which specific circuits they act to promote relapse. Understanding this “who, what, when, and
where,” will be key to identifying new therapeutic targets. Here, we will answer these questions using a multi-
level approach that allows us to sequence, manipulate, and record from neurons in specific circuits in the context
of opioid self-administration and relapse.
Our preliminary data show that both genetically-distinct and genetically-identical neuron subtypes in the ventral
tegmental area (VTA) undergo differential molecular adaptations after fentanyl self-administration, which we
hypothesize arises from activity-dependent transcriptional changes in specific circuits. We further hypothesize
the transcriptional changes are sustained by methylation and demethylation at the gene promoters. We will first
record calcium activity in VTA neurons that project to either the nucleus accumbens (NAc) or amygdala (AMY)—
projections known to be important for drug intake and relapse, respectively. Then, in the same neurons from the
same animals, we will identify which gene networks are transcriptionally changed after self-administration and
persist until relapse testing. Next, we will identify the DNA methylation marks driving sustained differential
expression, with an emphasis on genes important for synaptic plasticity. Next, we will use CRISPR/dCas9 fusion
constructs to manipulate methylation states at our identified loci in specific circuits. This proposal will allow us to
define the specific VTA circuits that support opioid intake and relapse, which gene networks support activity of
these circuits, and how DNA methylation cements the transcriptional landscape to alter behavior. This award will
allow research into neural mechanisms of opioid use disorder with unprecedented resolution, and has the
potential to transform how we approach studying the genetics of substance use disorders. Together, this critical
information will help inform new treatment strategies to prevent relapse.
Status | Active |
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Effective start/end date | 7/1/23 → 5/31/25 |
Funding
- NATIONAL INSTITUTE ON DRUG ABUSE: $498,000.00
- NATIONAL INSTITUTE ON DRUG ABUSE: $498,000.00
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