Corticotropin-releasing hormone neurons control trigeminal neuralgia-induced anxiodepression via a hippocampus-to-prefrontal circuit.

Anxiety and depression are frequently observed in patients suffering from trigeminal neuralgia (TN), but neural circuits and mechanisms underlying this association are poorly understood. Here, we identified a dedicated neural circuit from the ventral hippocampus (vHPC) to the medial prefrontal cortex (mPFC) that mediates TN-related anxiodepression. We found that TN caused an increase in excitatory synaptic transmission from vHPCCaMK2A neurons to mPFC inhibitory neurons marked by the expression of corticotropin-releasing hormone (CRH). Activation of CRH+ neurons subsequently led to feed-forward inhibition of layer V pyramidal neurons in the mPFC via activation of the CRH receptor 1 (CRHR1). Inhibition of the vHPCCaMK2A-mPFCCRH circuit ameliorated TN-induced anxiodepression, whereas activating this pathway sufficiently produced anxiodepressive-like behaviors. Thus, our studies identified a neural pathway driving pain-related anxiodepression and a molecular target for treating pain-related psychiatric disorders.

Transcriptome Analysis of the Mouse Medial Prefrontal Cortex in a Chronic Constriction Injury Model.

The medial prefrontal cortex (mPFC) is critical for both the sensory and emotional/cognitive components of pain. However, the underlying mechanism remains largely unknown. Here, we examined changes in the transcriptomic profiles in the mPFC of mice with chronic pain using RNA sequencing (RNA-seq) technology. A mouse model of peripheral neuropathic pain was established via chronic constriction injury (CCI) of the sciatic nerve. CCI mice developed sustained mechanical allodynia and thermal hyperalgesia, as well as cognitive impairment four weeks after surgery. RNA-seq was conducted 4 weeks after CCI surgery. Compared with contral group, RNA-seq identified a total 309 and 222 differentially expressed genes (DEGs) in the ipsilateral and contralateral mPFC of CCI model mice, respectively. GO analysis indicated that the functions of these genes were mainly enriched in immune- and inflammation-related processes such as interferon-gamma production and cytokine secretion. KEGG analysis further showed the enrichment of genes involved in the neuroactive ligand-receptor interaction signaling pathway and Parkinson disease pathway that have been reported to be importantly involved in chronic neuralgia and cognitive dysfunction. Our study may provide insights into the possible mechanisms underlying neuropathic pain and pain-related comorbidities.