Abstract 4359122: Hypothalamic CRH Neurons Regulate Cardiac Function and Peripheral Immunity Following Myocardial Infarction

Abstract

Background: Myocardial infarction (MI) is a leading cause of mortality worldwide and is often followed by poor prognosis, with many patients progressing to ischemic heart failure. Beyond cardiovascular damage, acute MI is frequently accompanied by profound psychological disturbances, including elevated stress levels and increased susceptibility to depression. The immune system plays a central role in post-MI healing, and emerging evidence suggests that neuroimmune interactions may influence disease progression. Research Question: Previous studies suggest that distinct brain circuits mediate large-scale leukocyte redistribution and functional changes during acute stress. However, it remains unclear whether and how these brain circuits regulate peripheral immune responses following MI. Methods: We utilized the iDISCO-ClearMap pipeline to generate whole-brain activity maps in a murine model of MI at days 1, 3, 7, and 14 post-infarction, focusing on the spatial and temporal dynamics of cFOS–positive cells across brain regions. Neuronal activation will be validated using fiber photometry. To explore causal relationships, we conducted chemogenetic manipulations in CRH-Cre mice, including Cre-dependent expression of caspase3 and hM3D(Gq) viruses to either ablate or activate CRH neurons, respectively. Cardiac function was assessed via echocardiography, and flow cytometry was used to evaluate immune cell populations in the infarcted heart. Results: iDISCO-ClearMap analysis revealed robust activation of the central amygdala, locus coeruleus, rostral ventrolateral medulla, and CRH neurons within the paraventricular hypothalamus (PVH) following MI. CRH neuron ablation was associated with increased mortality and reduced cardiac performance. On day 3 after MI, mice with CRH neuron activation showed elevated serum corticosterone and a marked reduction in leukocyte and monocyte infiltration in the infarct zone. Targeted activation of PVH CRH neurons seems to improve survival and preserve cardiac function following MI, further validation is needed to confirm these effects. Conclusion: CRH neurons in the PVH appear to play a critical role in coordinating neuroimmune responses following MI. Their ablation was associated with worsened cardiac damage, suggesting that CRH-targeted therapies may represent a potential avenue for improving clinical outcomes in MI patients.