Locus coeruleus-hippocampus noradrenergic activation alleviates sepsis-associated encephalopathy by promoting astrocytic AQP4-related autophagy via α2A-AR

Sepsis may impair the LC-HP-NA, increase astrocyte reactivity, and cause long-term neurocognitive dysfunction. Chemogenetic activation of the LC-HP-NA system in septic mice reverses these effects. The proposed cellular mechanism is as follows: activation of the LC-HP-NA system stimulates hippocampal astrocytic α 2 A-AR, which, through the cAMP-PKA signaling pathway, regulates AQP4-mediated, PPAR-γ/mTOR dependent autophagy. This process reduces astrocyte reactivity and confers long-term cognitive protection. • Sepsis disrupts the locus coeruleus-hippocampus noradrenergic system, causing cognitive deficits in mice. • Activating this noradrenergic pathway suppresses astrocyte reactivity and improves cognition in septic mice. • The neuroprotection depends on astrocytic α2A-adrenoceptors and is alleviated by AQP4 overexpression. • α2A-AR activation inhibits AQP4 via cAMP/PKA, thereby enhancing PPAR-γ/mTOR-dependent autophagy. • Autophagy induction through this pathway is sufficient to reduce astrocyte reactivity. • A novel LC-astrocyte noradrenergic axis is identified as a therapeutic target for septic encephalopathy. Sepsis-associated encephalopathy (SAE) is a frequent and devastating complication of sepsis, yet effective targeted therapies remain unavailable. The locus coeruleus-hippocampus noradrenergic (LC-HP-NA) system is critical for neurocognitive regulation; however, its role and mechanisms in SAE remain poorly understood. This study aims to confirm that LC-HP-NA activation alleviates sepsis-induced long-term neurocognitive impairment, and clarify the underlying mechanism, focusing on hippocampal astrocytic α 2 A-adrenoceptor (α 2 A-AR) and aquaporin-4 (AQP4)-related autophagy. Using chemogenetics to activate the LC-HP-NA, genetic manipulation (astrocytic α 2 A-AR knockdown and AQP4 overexpression), in vivo sepsis mouse models, and in vitro lipopolysaccharide (LPS)-stimulated primary astrocyte cultures. Techniques included microdialysis, western blotting, immunofluorescence, Transmission Electron Microscope and behavioral tests. Sepsis impaired the LC-HP-NA system and long-term neurocognition, with increased hippocampal astrocytic AQP4 expression and inhibited autophagy. LC-HP-NA activation elevated hippocampal noradrenaline release, promoted astrocytic autophagy, suppressed astrocyte reactivity, restored synaptic structures, and improved long-term cognitive function. Notably, knockdown of hippocampal astrocytic α 2 A-AR or overexpression of astrocytic AQP4 eliminated the neuroprotective effects of LC-HP-NA activation. Mechanistically, in LPS-stimulated astrocytes, α 2 A-AR activation reduced AQP4 expression, enhanced PPAR-γ/mTOR-dependent autophagy, and decreased astrocyte reactivity, mediated by the cyclic adenosine monophosphate (cAMP)/ protein kinase A (PKA) signaling pathway. LC-HP-NA activation alleviates SAE via astrocytic α 2 A-AR, promoting AQP4-dependent autophagy through the cAMP/PKA. This provides a therapeutic target for SAE.