Hypoactivity of the prelimbic cortex projecting to the lateral entorhinal cortex contributes to neuropathic pain-induced object recognition memory impairment in mice.

Memory impairment is a common comorbidity of chronic pain that significantly compromises patients' quality of life, yet the underlying neuronal circuit mechanisms remain poorly understood. Here, we employed a spared nerve injury (SNI) mouse model of chronic neuropathic pain and evaluated short-term memory performance using a novel object recognition test (NORT). Mice exhibited mechanical allodynia and object recognition memory (ORM) deficits 21 days following SNI surgery. Functional Magnetic Resonance Imaging (fMRI) analyses revealed a reduction in functional connectivity between the prelimbic cortex (PrL) and the lateral entorhinal cortex (LEC) in SNI mice. Viral tracing confirmed a direct monosynaptic anatomical projection from the PrL to the LEC, originating primarily from PrL layer 5 neurons. c-Fos immunostaining and in vivo calcium fiber photometry further demonstrated that both the PrL and LEC neurons were activated in response to novel object recognition, whereas these neuronal responses were significantly attenuated in SNI mice. Importantly, selective chemogenetic and optogenetic activation of the PrL-LEC pathway improved memory impairment in SNI mice without affecting pain sensitivity or locomotor activity. Chemogenetic inhibition of this pathway impaired ORM performance in normal mice. Our findings underscore the important role of PrL-LEC pathway hypoactivity in mediating short-term memory deficits associated with chronic pain and suggest this circuit as a promising therapeutic target for pain-related cognitive dysfunction.