Hypothalamic PVH Tyrosine Hydroxylase‐Positive (Predominantly Dopaminergic) Neurons Mediate the Bidirectional Control of Neuropathic Pain and Comorbid Memory Impairments

ABSTRACT Background Neuropathic pain often co‐occurs with memory impairment, yet the underlying neural mechanisms remain unclear. Here, we identify tyrosine hydroxylase‐positive (TH + ) neurons in the paraventricular hypothalamic nucleus (PVH), the majority of which are dopaminergic, as a key node in the circuit mediating this comorbidity. Methods A neuropathic pain model was established in C57BL/6J mice through sciatic nerve chronic constriction injury (CCI). Mechanical and thermal hypersensitivity were assessed using Von Frey and cold plate tests, respectively. Memory function was evaluated using novel object recognition (NORT) and Y‐maze tests. Neural circuitry was traced using pseudorabies virus (PRV) retrograde tracing from the sciatic nerve. Neuronal activation was assessed by c‐Fos immunostaining and in vivo calcium imaging. The functional role of PVH tyrosine hydroxylase‐positive (PVH TH ) neurons was examined using chemogenetic inhibition and optogenetic activation combined with behavioral tests and in vivo electrophysiology. Results PRV tracing identified the PVH as a brain region receiving multi‐synaptic input from the sciatic nerve. CCI mice exhibited increased c‐fos expression and elevated calcium activity specifically within PVH TH neurons. Post hoc analysis confirmed that the majority of virally targeted TH + neurons were dopaminergic. Chemogenetic inhibition of these neurons alleviated both pain hypersensitivity and memory deficits induced by CCI. Conversely, optogenetic activation of these PVH TH neurons in naïve mice was sufficient to induce pain hypersensitivity and memory impairments. Conclusion Our results establish a critical role for PVH TH neurons (Predominantly Dopaminergic) in mediating pain–memory interactions and highlight their potential as a therapeutic target. Significance Statement This study addresses a major clinical problem by focusing on the comorbidity of chronic pain and memory impairment, a major unmet medical need. This research provides novel mechanistic insight by identifying a specific new cell type (PVH DA neurons) in a novel brain region (PVH) for this comorbidity, moving beyond traditional pain or memory centers. By utilizing state‐of‐the‐art techniques state‐of‐the‐art techniques (chemo‐/optogenetics, in vivo recording) to move beyond correlation and prove these neurons are both necessary and sufficient for the phenotypes. High therapeutic potential directly implies that targeting PVHDA neurons could lead to novel treatments that alleviate both pain and cognitive symptoms simultaneously, offering a superior approach to current single‐symptom therapies.