Molecular and Neuroanatomical Processes of Opioid addiction

点击翻译按钮获取中文摘要

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.