Year: 2025
Type: article
Abstract: ABSTRACT Aversion to opioid withdrawal is a significant barrier to achieving lasting opioid abstinence. The central amygdala (CeA), a key brain region for pain, threat-detection, autonomic engagement, and valence assignment, is active during opioid withdrawal. However, the role of molecularly distinct CeA neural populations in withdrawal remains underexplored. Here, we investigated the activity dynamics, brain-wide connectivity, and functional contribution of Protein Kinase C-delta (PKCδ)-expressing neurons in the CeA lateral capsule (CeLC PKCδ ) during fentanyl withdrawal in mice. Mapping activity-dependent gene expression in CeLC PKCδ neurons revealed a highly withdrawal-active subregion in the anterior half of the CeA. Fiber photometry calcium imaging showed that opioid-naïve CeLC PKCδ neurons respond to salient noxious and startling stimuli. In fentanyl-dependent mice, naloxone-precipitated withdrawal increased spontaneous neural activity and enhanced responses to noxious stimuli. Chronic inhibition of CeLC PKCδ neurons throughout fentanyl exposure, via viral overexpression of the potassium channel Kir2.1, attenuated withdrawal signs in fentanyl-dependent mice. Lastly, we identified putative opioid-sensitive inputs to CeLC PKCδ neurons using rabies-mediated monosynaptic circuit tracing and color-switching tracers to map mu-opioid receptor-expressing inputs to the CeLC. Collectively, these findings suggest that the hyperactivity of CeLC PKCδ neurons underlies the somatic signs of fentanyl withdrawal, offering new insights into the amygdala cell-types and circuits involved in opioid dependence.
Source: Neuropsychopharmacology
Authors: Lisa M. Wooldridge, Jacqueline W. K. Wu, Adrienne Y. Jo, Morgan Zinn, Angela M. Lee, Malaika Mahmood, Savanna A. Cohen, Nora M. McCall, Corinna S. Oswell, Sophie A. Rogers, Gregory Corder
Institution: University of Pennsylvania
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,290
Awards: Harnessing cortical neuromodulation to disrupt pain perception, Circuitry dynamics underlying opioid-dependence: Integrating structural, functional, and transcriptomic mechanisms, Mapping opioid-dependence state transitions across structural, functional, and transcriptomic topologies, Educating Physician Scientists in Psychiatry (EPSP): Firing up the next generation of translational and clinical neuroscientists, Impact of fentanyl dependence on a parabrachio-amygdalar opioid circuit
OpenAlex ID: W4417503095