Suppression of mPFC-Amygdala Circuit Mitigates Sevoflurane-Induced Cognitive Deficits in Aged Mice

Abstract

Background

Perioperative neurocognitive disorders (PND) are common and costly complications in elderly surgical patients, yet the involvement of specific neural circuits in their etiology remains poorly understood. We hypothesized that neural projections from the medial prefrontal cortex (mPFC) to the amygdala contribute to PND pathogenesis.

Methods

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-term 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.

Results

Sevoflurane exposure activated the mPFC-amygdala circuit. Chemogenetic suppression of the mPFC attenuated sevoflurane-induced 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-induced LTP impairment in the amygdala.

Conclusions

These findings demonstrate that sevoflurane activates the mPFC-amygdala circuit, driving PND-associated cognitive deficits and neuropathological changes. Targeting this circuit or downstream mechanisms (AMPA signaling, mitochondrial stress) may mitigate sevoflurane-induced PND. This study provides empirical evidence implicating specific neural circuitry in anesthetic-related neurocognitive dysfunction.