{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:58:38Z","timestamp":1792803518110,"version":"4.5.0"},"reference-count":40,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Military Operational Medicine Research Program at the United States Army Medical Research and Development Command","id":[{"id":"https:\/\/ror.org\/03cd02q50","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Traumatic brain injury (TBI) remains a significant public health concern, particularly among military personnel and contact sport athletes who are frequently exposed to repeated blast overpressure waves and mild concussive impacts, respectively. While moderate and severe TBIs have been extensively studied, the long-term neuroendocrine consequences of mild, repetitive brain trauma are poorly understood. In this study, we investigated the temporal dynamics of hypothalamic\u2013pituitary\u2013adrenal (HPA) axis dysregulation following repeated mild concussive head impacts and blast exposures using two clinically relevant rodent models. Male Sprague-Dawley rats were subjected to repeated mild concussive impacts using a modified weight drop model or repeated blast exposures using an advanced blast simulator. Plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone were measured on days 1 and 30 post-injuries. Our findings revealed that repeated blast exposures induced elevation of plasma ACTH and corticosterone on days 1 and 30 post-blasts. After the repeated mild concussive impacts, increased plasma levels of corticosterone were observed on days 1 and 30, but ACTH levels were increased only on day 30. This study is among the first to directly compare neuroendocrine outcomes of repeated mild concussive impacts and blast exposures within a unified experimental framework. Our findings demonstrate distinct temporal trajectories of HPA axis dysregulation depending on injury type and highlight plasma levels of ACTH and corticosterone as potential biomarkers of subclinical brain trauma. These insights may inform early diagnostic approaches and therapeutic strategies aimed at mitigating long-term stress-related complications following mild traumatic brain injuries.<\/jats:p>","DOI":"10.3390\/brainsci15080847","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T09:56:42Z","timestamp":1754647002000},"page":"847","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Differential Neuroendocrine Responses and Dysregulation of the Hypothalamic\u2013Pituitary\u2013Adrenal Axis Following Repeated Mild Concussive Impacts and Blast Exposures in a Rat Model"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5760-9437","authenticated-orcid":false,"given":"Rex Jeya Rajkumar","family":"Samdavid Thanapaul","sequence":"first","affiliation":[{"name":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9916-247X","authenticated-orcid":false,"given":"Jishnu K. S.","family":"Krishnan","sequence":"additional","affiliation":[{"name":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4739-648X","authenticated-orcid":false,"given":"Manoj Y.","family":"Govindarajulu","sequence":"additional","affiliation":[{"name":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chetan Y.","family":"Pundkar","sequence":"additional","affiliation":[{"name":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5733-1760","authenticated-orcid":false,"given":"Gaurav","family":"Phuyal","sequence":"additional","affiliation":[{"name":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph B.","family":"Long","sequence":"additional","affiliation":[{"name":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peethambaran","family":"Arun","sequence":"additional","affiliation":[{"name":"Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3235","DOI":"10.1089\/neu.2021.0062","article-title":"Epidemiology of chronic effects of traumatic brain injury","volume":"38","author":"Pugh","year":"2021","journal-title":"J. Neurotrauma"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/S1474-4422(17)30371-X","article-title":"Traumatic brain injury: Integrated approaches to improving prevention, clinical care, and research","volume":"16","author":"Maas","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_3","first-page":"1473","article-title":"Hypothalamo-pituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: A systematic review","volume":"318","author":"Schneider","year":"2017","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1002\/jnr.24604","article-title":"Neuroendocrine function and associated mental health outcomes following mild traumatic brain injury in OEF-deployed service members","volume":"98","author":"Ciarlone","year":"2020","journal-title":"J. Neurosci. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1001\/jamaneurol.2023.2907","article-title":"Neuropathologic and clinical findings in young contact sport athletes exposed to repetitive head impacts","volume":"80","author":"McKee","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.3171\/2013.7.JNS121822","article-title":"Role of subconcussion in repetitive mild traumatic brain injury","volume":"119","author":"Bailes","year":"2013","journal-title":"J. Neurosurg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1001\/jama.2017.8334","article-title":"Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football","volume":"318","author":"Mez","year":"2017","journal-title":"JAMA"},{"key":"ref_8","first-page":"134ra60","article-title":"Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model","volume":"4","author":"Goldstein","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/jcbfm.2009.203","article-title":"Traumatic brain injury: An overview of pathobiology with emphasis on military populations","volume":"30","author":"Cernak","year":"2010","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nrn1683","article-title":"Stress and the brain: From adaptation to disease","volume":"6","author":"Holsboer","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_11","first-page":"245","article-title":"Chronic neuropathological and behavioral changes in a repetitive mild TBI model","volume":"84","author":"Mouzon","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1007\/s13760-025-02755-6","article-title":"Endocrine dysfunction post-traumatic brain injury: Challenges and therapeutic approaches","volume":"125","author":"Soltani","year":"2025","journal-title":"Acta Neurol. Belg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/s40141-024-00468-0","article-title":"Post-Traumatic Hypopituitarism","volume":"12","author":"Blocher","year":"2024","journal-title":"Curr. Phys. Med. Rehabil. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1177\/0269215518785945","article-title":"Comparing disability between traumatic brain injury and spinal cord injury using the 12-item WHODAS 2.0 and the WHO minimal generic data set covering functioning and health","volume":"32","author":"Tenovuo","year":"2018","journal-title":"Clin. Rehabil."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4116","DOI":"10.3390\/ijerph120404116","article-title":"Functioning and disability analysis of patients with traumatic brain injury and spinal cord injury by using the world health organization disability assessment schedule 2.0","volume":"12","author":"Kuo","year":"2015","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1089\/neu.2019.6591","article-title":"Long-term effects of blast exposure: A functional study in rats using an advanced blast simulator","volume":"37","author":"Arun","year":"2020","journal-title":"J. Neurotrauma"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Marmarou, C.R., Prieto, R., Taya, K., Young, H.F., and Marmarou, A. (2009). Marmarou weight drop injury model. Animal Models of Acute Neurological Injuries, Humana Press.","DOI":"10.1007\/978-1-60327-185-1_34"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1089\/neu.2023.0367","article-title":"Repeated mild concussive events heighten the vulnerability of brain to blast exposure","volume":"41","author":"Arun","year":"2024","journal-title":"J. Neurotrauma"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1179069519872213","DOI":"10.1177\/1179069519872213","article-title":"Blast-related traumatic brain injury: Current concepts and research considerations","volume":"13","author":"Bryden","year":"2019","journal-title":"J. Exp. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.nec.2016.05.009","article-title":"Repetitive head impacts and chronic traumatic encephalopathy","volume":"27","author":"McKee","year":"2016","journal-title":"Neurosurg. Clin. N. Am."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ledreux, A., Pryhoda, M.K., Gorgens, K., Shelburne, K., Gilmore, A., Linseman, D.A., and Granholm, A.C. (2020). Assessment of long-term effects of sports-related concussions: Biological mechanisms and exosomal biomarkers. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00761"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1179069519892933","DOI":"10.1177\/1179069519892933","article-title":"Traumatic brain injury and posttraumatic stress disorder: Comorbid consequences of war","volume":"14","author":"Dieter","year":"2019","journal-title":"Neurosci. Insights"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hellewell, S.C., Granger, D.A., and Cernak, I. (2023). Blast-induced neurotrauma results in spatially distinct gray matter alteration alongside hormonal alteration: A preliminary investigation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076797"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.cjtee.2016.03.001","article-title":"Damage of vascular endothelial barrier induced by explosive blast and its clinical significance","volume":"19","author":"Wang","year":"2016","journal-title":"Chin. J. Traumatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.neuropharm.2018.09.023","article-title":"Blast-induced \u201cPTSD\u201d: Evidence from an animal model","volume":"145","author":"Sosa","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1089\/neu.2020.7398","article-title":"Progressive cognitive and post-traumatic stress disorder-related behavioral traits in rats exposed to repetitive low-level blast","volume":"38","author":"Perez","year":"2021","journal-title":"J. Neurotrauma"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Aravind, A., Ravula, A.R., Chandra, N., and Pfister, B.J. (2020). Behavioral deficits in animal models of blast traumatic brain injury. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.00990"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Tapp, Z.M., Godbout, J.P., and Kokiko-Cochran, O.N. (2019). A tilted axis: Maladaptive inflammation and HPA axis dysfunction contribute to consequences of TBI. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00345"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1210\/en.2018-00203","article-title":"Differential responses of the HPA axis to mild blast traumatic brain injury in male and female mice","volume":"159","author":"Russell","year":"2018","journal-title":"Endocrinology"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Fesharaki-Zadeh, A., and Datta, D. (2024). An overview of preclinical models of traumatic brain injury (TBI): Relevance to pathophysiological mechanisms. Front. Cell. Neurosci., 18.","DOI":"10.3389\/fncel.2024.1371213"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1002\/j.2040-4603.2016.tb00694.x","article-title":"Regulation of the hypothalamic-pituitary-adrenocortical stress response","volume":"6","author":"Herman","year":"2016","journal-title":"Compr. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.psyneuen.2016.02.027","article-title":"Sympathetic nervous system contributes to enhanced corticosterone levels following chronic stress","volume":"68","author":"Lowrance","year":"2016","journal-title":"Psychoneuroendocrinology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1080\/10253890.2018.1470238","article-title":"Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility","volume":"21","author":"Gjerstad","year":"2018","journal-title":"Stress"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.cjtee.2018.02.003","article-title":"Current understanding of neuroinflammation after traumatic brain injury and cell-based therapeutic opportunities","volume":"21","author":"Xiong","year":"2018","journal-title":"Chin. J. Traumatol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Elder, G.A., Gama Sosa, M.A., De Gasperi, R., Stone, J.R., Dickstein, D.L., Haghighi, F., and Ahlers, S.T. (2015). Vascular and inflammatory factors in the pathophysiology of blast-induced brain injury. Front. Neurol., 6.","DOI":"10.3389\/fneur.2015.00048"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.biopsych.2021.09.024","article-title":"Mental health consequences of traumatic brain injury","volume":"91","author":"Howlett","year":"2022","journal-title":"Biol. Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S460","DOI":"10.1016\/j.pmrj.2011.08.008","article-title":"Long-term consequences of repetitive brain trauma: Chronic traumatic encephalopathy","volume":"3","author":"Stern","year":"2011","journal-title":"PM&R"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"bnaa002","DOI":"10.1210\/endrev\/bnaa002","article-title":"Dynamics of ACTH and cortisol secretion and implications for disease","volume":"41","author":"Lightman","year":"2020","journal-title":"Endocr. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Veldhuis, J.D. (2008). Pulsatile hormone secretion: Mechanisms, significance and evaluation. Ultradian Rhythms from Molecules to Mind: A New Vision of Life, Springer.","DOI":"10.1007\/978-1-4020-8352-5_10"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1258\/000456303322326371","article-title":"Analytical and clinical aspects of adrenocorticotrophin determination","volume":"40","author":"Talbot","year":"2003","journal-title":"Ann. Clin. Biochem."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/8\/847\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:26:11Z","timestamp":1760034371000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/8\/847"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,8]]},"references-count":40,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["brainsci15080847"],"URL":"https:\/\/doi.org\/10.3390\/brainsci15080847","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,8]]}}}