Project Summary/Abstract
Opioid use disorder is becoming more pervasive as the opioid epidemic continues. Opioids are heavily
prescribed and are highly effective for treating acute pain, but not chronic pain, resulting in a large risk factor
for abuse. The ability to predict specific individual susceptibility to opioid use disorder is limited, partially due to
the complex comorbidity with other mental and physical illnesses. This requires a more extensive
characterization that emphasizes innate individual differences in emotionality, pain sensitivity, and motivated
behaviors. Recent work from the Barker lab has characterized these differences by using a stress model in
rodents to give rise to these individual differences. These differences have been characterized through a
behavioral battery targeting negative valence, pain, and opioid preference. Mice have different susceptibility
profiles based on previous stressful experiences and mu-opioid receptors (MOR) within the lateral habenula
(LHb) are candidates for this maladaptive plasticity. The proposed aims target these potential molecular
pathways by using transcriptomics and testing the necessity of key anatomical structures using chemogenetic
manipulation. Aim 1 will assess how MOR expression within the LHb changes in response to stress and
across sexes. Beginning with behavioral testing, behavior profiles will be assessed, and MOR expression will
be quantified using qRT-PCR and in situ hybridization. Dimension reduction analysis will be applied to these
data sets to consolidate these parameters into opioid susceptibility profiles. Aim 2, will assess the necessity of
the LHb in stress-mediated changes in opioid susceptibility. The LHb will be chemogenetically modulated via
inhibitory DREADDs during foot shock and then characterization of opioid susceptibility will be performed
through behavioral testing. The completion of these aims will establish potential molecular and anatomical
targets for novel therapeutics as well as aid in the characterization of a translatable model of individualized
opioid susceptibility.
The proposed fellowship will provide the PI/trainee with a strong foundation for a career as an
independent neuroscientist while providing a training environment in line with the goals of diversity in the NIH.
The training incorporates ample professional development opportunities and strong faculty-student
mentorships and collaborations. This will provide strong technical training in the domains of experimental
design, behavior, molecular techniques, neuroanatomy, and statistics. Overall, this fellowship has significant
potential to elucidate translatable phenotypes imperative to the treatment and prevention of opioid use disorder
and provide the necessary training to become a valuable member of the addiction neuroscience community.