Environmental enrichment highlights mitochondrial inner membrane function as a therapeutic target for sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a prevalent and significant neurological complication that arises following sepsis, for which there is currently no effective treatment. Environmental enrichment (EE) has been shown to exert a neuroprotective effect through various mechanisms, including the promotion of neurogenesis, enhancement of neuroplasticity, and the inhibition of inflammatory processes. However, the precise mechanisms underlying these effects remain poorly understood. Utilizing RNA sequencing data, our research demonstrated that energy metabolism facilitated by the mitochondrial inner membrane is crucial for the neuroprotective effects associated with EE. LPS exposure resulted in cognitive deficits, particularly characterized by diminished working memory. Mechanistically, LPS treatment in mice was associated with disrupted function of the mitochondrial inner membrane and altered mitochondrial energy metabolism within the hippocampus. Importantly, the administration of SS-31 was found to maintain mitochondrial integrity, enhance the functionality of the mitochondrial inner membrane, and ultimately mitigate both synaptic and cognitive deficits. Our research indicates that focusing on impaired mitochondrial inner membrane function could serve as a potentially effective preventive or therapeutic approach for SAE.