Research Fellow National Institutes of Health; Penn State College of Medicine Bethesda, Maryland, United States
Disclosure(s):
Christina LaGamma: No financial relationships to disclose
Introduction Enkephalins are endogenous opioid peptides that signal through mu-opioid receptors to regulate reward function and are implicated in mood, movement, and substance use disorders. However, the precise mechanisms by which enkephalins exert their function is unknown. While previous research has investigated how opioids modulate dopaminergic (DA) neuron activity implicated in reward-related activities, few studies have investigated the neuronal populations providing opioid peptides to the ventral tegmental area (VTA) that may mediate behavior. Methods Here, we use viral-mediated anatomical tracing to identify sources of enkephalin to the VTA. To visualize these projections, Penk-Cre mice were injected unilaterally with AAVretrograde-CAG-Flex-tdTomato into the VTA and allowed a 3-week recovery period. Mice were euthanized, and brains were extracted for subsequent whole-brain imaging. We then examined fluorescence across the anteroposterior axis of the mouse brain and quantified positive enkephalin cells in all regions. Results We found that medial prefrontal cortex (mPFC), lateral hypothalamus (LH), and dorsal raphe nuclei (RN) are the main sources of enkephalin to the VTA. Furthermore, ongoing cell counts are being performed along the anteroposterior mouse brain axis to help elucidate the relative impact of key areas involved in VTA regulation. Conclusion These data suggest that enkephalins may exert their function on the VTA through distinct circuits. Additionally, given that predominant cell types in the PFC, LH, and dorsal raphe nuclei are glutamatergic, GABAergic, and serotonergic respectively, this suggests synchronization of diverse cell populations to coordinate behavior. These anatomical data will enable us to further functionally modulate VTA inputs via targeted viral knockout and local opioid receptor antagonist infusions, to determine how they impact VTA neuron activity and translation onto reward behaviors. Overall, this work will help advance our understanding of the neural mechanisms underlying neuropsychiatric conditions, specifically opioid use disorders, as well as elucidate potential functional targets for neurostimulation.
