Objective: The comorbidity of anxiety-like symptoms in neuropathic pain (NP) is a significant yet often overlooked health concern. Anxiety sufferers may have a lower tolerance for pain, but which is difficult to treat. Accumulating evidence suggests a strong link between astrocytes and the manifestation of NP with concurrent anxiety-like behaviors. And the anterior cingulate cortex (ACC) has emerged as a key player in pain modulation and related emotional processing. However, the complex mechanisms that astrocytes in ACC influence anxiety behavior in mouse models of NP remain largely unexplored.

Methods: Utilizing the traditional spared nerve injury (SNI) surgical model, we employed chemogenetic approaches, immunofluorescence, and western blot to investigate the functional significance and interactive dynamics between ACC astrocytes and excitatory neurons.

Results: Our results revealed that SNI surgery induces NP and delayed anxiety-like behaviors, accompanied by increased astrocyte activity in the ACC. Chemogenetic manipulation demonstrated that inhibiting astrocytes alleviates anxiety symptoms, while activating them exacerbates anxiety-like behaviors, affecting local excitatory neurons and synapse density. Direct manipulation of ACC excitatory neurons also significantly impacted anxiety-like behaviors.

Conclusions: Our results highlight the pivotal role of ACC astrocytes in modulating anxiety-like behavior, suggesting a novel therapeutic strategy for anxiety associated with NP by targeting astrocyte function.