{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T09:15:50Z","timestamp":1774343750038,"version":"3.50.1"},"reference-count":51,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Neuropathic pain often co\u2010occurs with memory impairment, yet the underlying neural mechanisms remain unclear. Here, we identify tyrosine hydroxylase\u2010positive (TH\n                      <jats:sup>+<\/jats:sup>\n                      ) neurons in the paraventricular hypothalamic nucleus (PVH), the majority of which are dopaminergic, as a key node in the circuit mediating this comorbidity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\u2010maze tests. Neural circuitry was traced using pseudorabies virus (PRV) retrograde tracing from the sciatic nerve. Neuronal activation was assessed by c\u2010Fos immunostaining and in\u00a0vivo calcium imaging. The functional role of PVH tyrosine hydroxylase\u2010positive (PVH\n                      <jats:sup>TH<\/jats:sup>\n                      ) neurons was examined using chemogenetic inhibition and optogenetic activation combined with behavioral tests and in\u00a0vivo electrophysiology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      PRV tracing identified the PVH as a brain region receiving multi\u2010synaptic input from the sciatic nerve. CCI mice exhibited increased c\u2010fos expression and elevated calcium activity specifically within PVH\n                      <jats:sup>TH<\/jats:sup>\n                      neurons. Post hoc analysis confirmed that the majority of virally targeted TH\n                      <jats:sup>+<\/jats:sup>\n                      neurons were dopaminergic. Chemogenetic inhibition of these neurons alleviated both pain hypersensitivity and memory deficits induced by CCI. Conversely, optogenetic activation of these PVH\n                      <jats:sup>TH<\/jats:sup>\n                      neurons in na\u00efve mice was sufficient to induce pain hypersensitivity and memory impairments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our results establish a critical role for PVH\n                      <jats:sup>TH<\/jats:sup>\n                      neurons (Predominantly Dopaminergic) in mediating pain\u2013memory interactions and highlight their potential as a therapeutic target.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>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\u2010of\u2010the\u2010art techniques state\u2010of\u2010the\u2010art techniques (chemo\u2010\/optogenetics, in\u00a0vivo 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\u2010symptom therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejp.70233","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T21:37:08Z","timestamp":1773005828000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypothalamic PVH Tyrosine Hydroxylase\u2010Positive (Predominantly Dopaminergic) Neurons Mediate the Bidirectional Control of Neuropathic Pain and Comorbid Memory Impairments"],"prefix":"10.1002","volume":"30","author":[{"given":"Kangli","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Anesthesia and Pain Medicine Affiliated Hospital of Jiaxing University  Jiaxing 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