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.