Role of central amygdala dynorphin neurons in mediating chronic alcohol induced changes in acute stress responsivity

[Alcohol misuse likely disrupts normal stress responsivity by directly engaging stress systems. Altered threat responses are hallmarks of alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) which are often comorbid in U.S. active military and Veterans. Alcohol-altered threat responsivity may predispose Veterans to develop PTSD and partially explain this high comorbidity. In the last decade, AUD prevalence has grown faster in women and women already face higher risk of developing some stress/mood disorders. To develop targeted treatments for Veterans at-risk for or suffering from PTSD, particularly with comorbid AUD, it is pivotal to first understand the sex-specific brain mechanisms underlying alcohol-altered responses to threat.] The central amygdala (CeA) plays a key role in mediating stress- and alcohol-related behaviors and the peptide dynorphin (Dyn) within the CeA is likely involved in mediating these behaviors. Dyn-expressing CeA (CeADyn) neuronal activity is increased during male and female voluntary alcohol consumption. Further, stress/negative affect stimulates CeA Dyn expression, and behavioral responses to stressful threatening stimuli rely on the CeA. Thus, CeADyn neurons may be a key node in alcohol-stress interactions. In mice, when rapid, survival-promoting responses are required (e.g., during threat of predation), specific CeA neuronal subpopulations promote either freezing or fleeing. However, the role of CeADyn neurons in threat behavior is not fully known. CeADyn neurons overlap with multiple threat behavior-selecting populations so that the role of CeADyn neurons in threat responses is unclear. The CeA, and perhaps CeADyn neurons, is also involved in autonomic regulation during endocrine stress responses. There is evidence of autonomic dysfunction with both [stress/mood disorders (including PTSD)] and AUD such that stress resilience and coping measures are altered, like heart rate variability (HRV). The current studies aim to examine the role of CeADyn neuronal activity in mediating behavioral and physiological responses to [acute] threatening events. Two threat responsivity tasks, looming/sweeping disk (LSDT) and novelty suppressed feeding (NSFT) will be employed to address this research question and examine potential sex-related differences. It is hypothesized that chronic alcohol will engage CeADyn neurons in mediating sex- related differences in innate and chronic alcohol-(mal)adaptive threat responses. The role of CeADyn neurons in threat responses is unexplored and these studies aim to fill this void. Aim I will examine sex-dependent effects of CeADyn inhibition on innate behavioral and physiological threat responses and adaptive changes following chronic alcohol. Brain tissue will also be collected and undergo multiplex in situ analysis for Dyn and neuropeptide markers of known threat response-selecting subpopulations. Aim II will examine sex-dependent real-time activity of CeADyn-expressing neurons during distinct [acute] threat responses after chronic alcohol and pharmacological Dyn signaling antagonism. For both Aims, peripheral measures like HRV and corticosterone will be measured in parallel to investigate the actions on autonomic/endocrine threat responses and examine the possibility of these measures to serve as biomarkers of altered [baseline stress-responsivity] in Veterans. Multimodal evidence from in situ analysis of neuropeptide co-expression, real-time measurement of activity during different threat behaviors, and chemogenetic/pharmacological interrogation of the CeADyn system will provide a foundational overview of CeADyn function in [acute stress-chronic] alcohol interactions. Overall, this research will explore the impact of alcohol on threat responses [during acute exposure] to stressful stimuli to [provide a foundational understanding of this interaction that can be extended] to inform Veteran risk-reduction and treatment approaches for [stress/mood] disorders inclu Project Number: 1IK2BX006936-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Christina Lebonville | Institution: RALPH H JOHNSON VA MEDICAL CENTER, CHARLESTON, SC | Activity Code: IK2 | Study Section: Special Emphasis Panel[ZRD1 MHBA-U (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11189073