{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T02:52:52Z","timestamp":1789267972630,"version":"build-2803163510"},"reference-count":79,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Hong Kong"},{"name":"HKU Libraries"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>High-frequency stimulation (HFS) is a promising therapy for patients with depression. However, the mechanisms underlying the HFS-induced antidepressant-like effects on susceptibility and resilience to depressive-like behaviors remain obscure. Given that dopaminergic neurotransmission has been found to be disrupted in depression, we investigated the dopamine(DA)-dependent mechanism of the antidepressant-like effects of HFS of the prelimbic cortex (HFS PrL). We performed HFS PrL in a rat model of mild chronic unpredictable stress (CUS) together with 6-hydroxydopamine lesioning in the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA). Animals were assessed for anxiety, anhedonia, and behavioral despair. We also examined levels of corticosterone, hippocampal neurotransmitters, neuroplasticity-related proteins, and morphological changes in dopaminergic neurons. We found 54.3% of CUS animals exhibited decreased sucrose consumption and were designated as CUS-susceptible, while the others were designated CUS-resilient. HFS PrL in both the CUS-susceptible and CUS-resilient animals significantly increased hedonia, reduced anxiety, decreased forced swim immobility, enhanced hippocampal DA and serotonin levels, and reduced corticosterone levels when compared with the respective sham groups. The hedonic-like effects were abolished in both DRN- and VTA-lesioned groups, suggesting the effects of HFS PrL are DA-dependent. Interestingly, VTA-lesioned sham animals had increased anxiety and forced swim immobility, which was reversed by HFS PrL. The VTA-lesioned HFS PrL animals also had elevated DA levels, and reduced p-p38 MAPK and NF-\u03baB levels when compared to VTA-lesioned sham animals. These findings suggest that HFS PrL in stressed animals leads to profound antidepressant-like responses possibly through both DA-dependent and -independent mechanisms.<\/jats:p>","DOI":"10.3390\/cells12111449","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T03:20:06Z","timestamp":1684812006000},"page":"1449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Prelimbic Cortical Stimulation Induces Antidepressant-like Responses through Dopaminergic-Dependent and -Independent Mechanisms"],"prefix":"10.3390","volume":"12","author":[{"given":"Sharafuddin","family":"Khairuddin","sequence":"first","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4342-9849","authenticated-orcid":false,"given":"Wei Ling","family":"Lim","sequence":"additional","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"name":"Department of Biological Sciences, Sunway University, Bandar Sunway, Petaling Jaya 47500, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Aquili","sequence":"additional","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"name":"Discipline of Psychology, College of Health and Education, Murdoch University, Perth 6150, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1366-1284","authenticated-orcid":false,"given":"Ka Chun","family":"Tsui","sequence":"additional","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Chung-Kwan","family":"Tse","sequence":"additional","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shehani","family":"Jayalath","sequence":"additional","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, 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University, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan","family":"Blokland","sequence":"additional","affiliation":[{"name":"Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasin","family":"Temel","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands"},{"name":"Department of Neurosurgery, Maastricht University, 6229 HX Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6692-6285","authenticated-orcid":false,"given":"Lee Wei","family":"Lim","sequence":"additional","affiliation":[{"name":"Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"name":"Department of Biological Sciences, Sunway University, Bandar Sunway, Petaling Jaya 47500, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/nature07455","article-title":"The molecular neurobiology of depression","volume":"455","author":"Krishnan","year":"2008","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e535","DOI":"10.1038\/tp.2015.24","article-title":"Electrical stimulation alleviates depressive-like behaviors of rats: Investigation of brain targets and potential mechanisms","volume":"5","author":"Lim","year":"2015","journal-title":"Transl. 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