A novel circuit driven by hypothalamic corticotropin-releasing hormone neurons mediates postoperative memory deficits

Perioperative neurocognitive disorders (PND) contribute substantially to morbidity and mortality; however, no therapeutic target has yet been identified. We hypothesized that the neural circuit underlying this surgical complication involves corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN). Using optogenetics, chemogenetics, electrophysiology, and behavioral tests, we demonstrate that surgery activates PVN ^CRH neurons. These neurons, via CRH receptor 1 (CRHR1), innervate glutamatergic (Glu) neurons in the hippocampal subiculum (Sub), ultimately leading to memory impairments. The PVN ^CRH receive projections from Glu neurons in the parabrachial nucleus (PBN), a brain region involved in processing peripheral sensory stimuli. Postoperative memory deficit is associated with activation of the PBN ^Glu-PVN ^CRH-Sub ^Glu circuit; chemogenetic inhibition of this circuitry rescues the memory deficit. Additionally, surgery-induced upregulation of circulating interleukin-1β (IL-1β) mediates activation of the PBN ^Glu-PVN ^CRH-Sub ^Glu circuit. This provides direct evidence linking peripheral inflammation to central cognitive dysfunction via a defined neural pathway. These findings advance our understanding of brain-body interactions in neurocognitive disorders and identify an anatomical target for potential intervention in PND.