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We hypothesized that neural projections from the medial prefrontal cortex (mPFC) to the amygdala contribute to PND pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using chemogenetic approaches, we selectively suppressed or excited the mPFC and its projections to the amygdala in a murine model exposed to sevoflurane. We assessed cognitive deficits, synaptic plasticity (AMPA receptor activity, long\u2010term potentiation [LTP]), mitochondrial stress, neuroinflammatory markers, and neuronal apoptosis in the amygdala. Additional interventions included pharmacological suppression of AMPA receptors, glutamate biosynthesis, and mitochondrial stress within the amygdala.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sevoflurane exposure activated the mPFC\u2010amygdala circuit. Chemogenetic suppression of the mPFC attenuated sevoflurane\u2010induced cognitive deficits, AMPA receptor hyperexcitation, mitochondrial dysfunction, neuroinflammation, and neuronal apoptosis in the amygdala. Retrograde inhibition of mPFC projections to the amygdala alleviated cognitive impairments, whereas retrograde excitation exacerbated them. Suppressing AMPA receptors, glutamate synthesis, or mitochondrial stress in the amygdala similarly reduced cognitive deficits and pathological alterations. Notably, mPFC suppression rescued sevoflurane\u2010induced LTP impairment in the amygdala.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings demonstrate that sevoflurane activates the mPFC\u2010amygdala circuit, driving PND\u2010associated cognitive deficits and neuropathological changes. Targeting this circuit or downstream mechanisms (AMPA signaling, mitochondrial stress) may mitigate sevoflurane\u2010induced PND. This study provides empirical evidence implicating specific neural circuitry in anesthetic\u2010related neurocognitive dysfunction.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70443","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T05:38:37Z","timestamp":1747373917000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Suppression of mPFC\u2010Amygdala Circuit Mitigates Sevoflurane\u2010Induced Cognitive Deficits in Aged Mice"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1859-7330","authenticated-orcid":false,"given":"Junhua","family":"Li","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Sun Yat\u2010sen Memorial Hospital Sun Yat\u2010sen University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat\u2010sen Memorial Hospital Sun Yat\u2010sen 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