Dorsomedial thalamic nucleus-medial prefrontal cortex inputs modulated spatial learning and memory in a mouse model of sepsis induced by cecal ligation puncture.

BACKGROUND: Sepsis-associated encephalopathy (SAE) often leads to cognitive impairment and even life-threatening conditions. Its pathophysiology is complex but remains unclear. We investigated the role of the mediodorsal thalamic nucleus-medial prefrontal cortex (MD-mPFC) pathway in alleviating cognitive dysfunction in a mouse model of cecal ligation puncture (CLP)-induced sepsis. METHODS: Neural projections from the MD to the mPFC were identified through retrograde tracing and viral expression. The MD-mPFC pathway was chemogenetically activated. Immunofluorescence staining was performed to determine the count of c-Fos-positive neurons in the mPFC cells. Cognitive functions of the mice were assessed using the Morris water maze, Barnes maze, novel object recognition, and open field tests. The expression of glutamate receptors and the downstream signaling molecules in the mPFC was determined through western blotting. RESULTS: MD-mPFC pathway activation alleviated cognitive dysfunction and anxiety-like behavior in the CLP-induced sepsis mouse model. The inhibition of glutamate receptors led to a decrease in the expression of c-Fos, a marker of neuronal activity, in the mPFC of the mice, indicating that glutamate receptors mediated the positive effects of the MD-mPFC pathway. Activation of the MD-mPFC pathway also led to increased levels of NMDAR, AMPAR, and downstream signaling molecules including CaMKIIa, p-CREB, and brain-derived neurotrophic factor in the mPFC. However, this increase was restrained by the inhibition of glutamate receptors using 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline(NBQX), an AMPAR inhibitor, or the NMDA receptor antagonist D-2-amino-5-phosphonopentanoate(D-AP5). CONCLUSION: The MD-mPFC pathway alleviated cognitive dysfunction in the mouse model of CLP-induced sepsis. Our findings highlight the role of glutamate receptors and the downstream signaling pathways as potential therapeutic targets for SAE-induced cognitive dysfunction and shed light on pathogenetic mechanism for SAE.