{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:51:37Z","timestamp":1785851497178,"version":"3.56.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004586","name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004586","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Depression is characterized by pathological lateral habenula (LHb) hyperactivity within the anti-reward circuitry. However, a unified framework explaining how exercise modulates this specific circuit remains to be established.Aims: To examine whether neurobiological evidence supports the Network-Mediated Habenular Attenuation (NMHA) Model, which proposes exercise as a systemic regulator of LHb pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A systematic synthesis was conducted following PRISMA guidelines and registered in PROSPERO. After a comprehensive search, 12 eligible studies met eligibility criteria. A quantitative synthesis was performed using a random-effects model, with Hedge\u2019s\n                      <jats:italic>g<\/jats:italic>\n                      used to estimate the magnitude of neuroplastic changes across the NMHA axes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Evidence suggests that exercise modulates LHb bursting via four convergent axes: (1) muscle-brain (peripheral-metabolic); (2) sensory-motor (monoaminergic); (3) cognitive-executive (top-down); and (4) hippocampal neurogenic (contextual). Quantitative synthesis revealed a robust global effect size (Hedges\u2019\n                      <jats:italic>g<\/jats:italic>\n                      =\u00a00.94; 95% CI [0.59, 1.29]). Heterogeneity was low (I\n                      <jats:sup>2<\/jats:sup>\n                      \u00a0=\u00a014.90%). Some axes exhibited large effect sizes, with the hippocampal-contextual axis showing the highest potency (Hedges\u2019\n                      <jats:italic>g<\/jats:italic>\n                      [1.95, 2.63]). These magnitudes provide a compensatory counter-signal to the pathological LHb burst firing observed in depressive states (Hedges\u2019\n                      <jats:italic>g<\/jats:italic>\n                      \u2248 1.00), providing mathematical support for the NMHA model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Exercise potentially acts as a circuit-breaker for anhedonia by modulating the anti-reward architecture. The observed variability in effect sizes (95% Prediction Interval: 0.21, 1.67) indicates that future studies may report effect sizes ranging from small to very large, reflecting the influence of different exercise protocols and depression models on circuit attenuation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The NMHA model positions exercise as a targeted neuromodulatory strategy. Future research should leverage high-field neuroimaging to translate these preclinical circuit-level findings into human clinical populations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpsyt.2026.1887822","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:25:06Z","timestamp":1785849906000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Exercise-induced attenuation of the lateral habenula: a multi-axial quantitative synthesis of circuit-level resilience in depression"],"prefix":"10.3389","volume":"17","author":[{"given":"Camila","family":"Ferreira-Vorkapic","sequence":"first","affiliation":[{"name":"Laboratory of Biosciences of Human Kinetics (LABIMH), PPGEnfBio\\Federal University of the State of Rio de Janeiro (UNIRIO)","place":["Rio de Janeiro, Brazil"]},{"name":"Graduate Program in Nursing and Biosciences, Federal University of the State of Rio de Janeiro - UNIRIO","place":["Rio de Janeiro, Brazil"]},{"name":"Unit Medical School, Tiradentes University - UNIT","place":["Aracaju, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego Moura","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Graduate Program in Nutritional Sciences (PPGCNUT), Federal University of Sergipe (UFS)","place":["Aracaju, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato Ramos","family":"Coelho","sequence":"additional","affiliation":[{"name":"Municipal Health Department of Contagem, Nomus Consulting, Brazilian Academic Consortium for Integrative Health (CABSIN), Laboratory of Biosciences of Human Kinetics (LABIMH), Federal University of the State of Rio de Janeiro (UNIRIO)","place":["Contagem, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika Anna","family":"Wiech","sequence":"additional","affiliation":[{"name":"Gdansk University of Physical Education and Sport, Faculty of Physical Culture, Department of Sport","place":["Gdansk, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Est\u00e9lio Henrique Martin","family":"Dantas","sequence":"additional","affiliation":[{"name":"Laboratory of Biosciences of Human Kinetics (LABIMH), PPGEnfBio\\Federal University of the State of Rio de Janeiro (UNIRIO)","place":["Rio de Janeiro, Brazil"]},{"name":"Graduate Program in Nursing and Biosciences, Federal University of the State of Rio de Janeiro - UNIRIO","place":["Rio de Janeiro, Brazil"]},{"name":"Graduate Program in Biosciences and Healh - PBS, Tiradentes University - UNIT","place":["Aracaju, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05860","article-title":"Lateral habenula as a source of negative reward signals in dopamine neurons","volume":"447","author":"Matsumoto","year":"2007","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature25752","article-title":"Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression","volume":"554","author":"Cui","year":"2018","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nature25509","article-title":"Ketamine blocks bursting in the lateral habenula to rapidly relieve depression","volume":"554","author":"Yang","year":"2018","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1016\/j.neuron.2009.02.001","article-title":"The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses","volume":"61","author":"Jhou","year":"2009","journal-title":"Neuron"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2866","article-title":"The habenula: from stress evasion to value-based decision-making","volume":"11","author":"Hikosaka","year":"2010","journal-title":"Nat Rev Neurosci"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.159.19.2349","article-title":"Effects of exercise training on older patients with major depression","volume":"159","author":"Blumenthal","year":"1999","journal-title":"Arch Internal Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.jpsychires.2016.02.023","article-title":"Exercise as a treatment for depression: A meta-analysis adjusting for publication bias","volume":"77","author":"Schuch","year":"2016","journal-title":"J Psychiatr Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1136\/bjsports-2022-106282","article-title":"Exercise as medicine for depressive symptoms? 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