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(Landmark Ed)"],"abstract":"<jats:p>Traumatic brain injury (TBI) remains a leading cause of chronic neurological impairment across the lifespan, with significant disparities in clinical recovery trajectories between pediatric and adult patients. Previous research has often been confined to a binary debate over the relative repair capacity of different age groups; however, this paradigm is insufficient for exploring the age-dependent molecular mechanisms of adaptation in depth. This review proposes a \u201cdivergent adaptation\u201d theoretical framework to systematically analyze age-dependent differences in the brain-derived neurotrophic factor (BDNF)\u2013miRNA network and its microenvironmental regulation\u2014including cerebrospinal fluid dynamics and the gut\u2013brain axis\u2014during TBI repair. In the pediatric brain, repair strategies primarily leverage developmental plasticity, characterized by elevated BDNF\/insulin-like growth factor-1 (IGF-1) expression and the active involvement of neurogenesis-promoting miRNAs such as miR-124, which facilitate neural circuit reorganization. However, this reparative process also entails risks, including aberrant circuit formation and vascular fragility. In contrast, the adult brain employs repair strategies focused on maintaining network stability: BDNF\/TrkB signaling shifts toward localized repair, while miR-129\u2013mediated inhibition of IGF-1 and epigenetic silencing mechanisms (e.g., BDNF promoter hypermethylation) constrain regenerative capacity and favor gliotic scar formation. Furthermore, cross-system mechanisms\u2014such as the unique cerebrospinal fluid dynamics in children and the \u201cdevelopmental window effect\u201d of the gut\u2013brain axis\u2014may contribute to distinct injury response patterns across ages. From a clinical translational perspective, we emphasize that intervention strategies must be precisely tailored according to age-specific mechanisms. For pediatric patients, potential approaches include exosome-mediated delivery of neurogenic miRNAs (e.g., miR-133b) and IGF-1 potentiation therapies. For adults, more suitable strategies may involve electroacupuncture-mediated modulation of the BDNF-miRNA axis or CRISPR\/dCas9-based reversal of epigenetic silencing. Additionally, natural compounds such as curcumin, which confer synergistic anti-inflammatory effects via the BDNF\/miRNA network, could represent a universal therapeutic strategy applicable across age groups. This field faces several limitations, however, including a scarcity of high-quality pediatric TBI data, a translational gap between animal models and clinical reality, and an incomplete understanding of cross-system mechanisms. Future studies should establish developmentally staged research systems and integrate multi-omics technologies to advance precision neuroregenerative strategies.<\/jats:p>","DOI":"10.31083\/fbl45754","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:35:31Z","timestamp":1788438931000},"source":"Crossref","is-referenced-by-count":0,"title":["From an Age-Stratified Perspective: Divergent Adaptive Mechanisms of the Traumatic Brain Injury Repair Network Between Pediatric and Adult Patients"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1023-1331","authenticated-orcid":true,"given":"Sixun","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Western Theater General Hospital, 610083 Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Western Theater General Hospital, 610083 Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Western Theater General Hospital, 610083 Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Western Theater General Hospital, 610083 Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4311-7105","authenticated-orcid":true,"given":"Yuan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Western Theater General Hospital, 610083 Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0193-1881","authenticated-orcid":true,"given":"Haifeng","family":"Shu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Western Theater General Hospital, 610083 Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Ogonah MGT, Botchway S, Yu R, Schofield PW, Fazel S. An umbrella review of health outcomes following traumatic brain injury. Nature. Mental Health. 2025; 3: 83\u201391.","DOI":"10.1038\/s44220-024-00356-5"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Chen Z, Wang P, Cheng H, Wang N, Wu M, Wang Z, et al. Adolescent traumatic brain injury leads to incremental neural impairment in middle-aged mice: role of persistent oxidative stress and neuroinflammation. Frontiers in Neuroscience. 2023; 17: 1292014.","DOI":"10.3389\/fnins.2023.1292014"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Holland SK, Vannest J, Mecoli M, Jacola LM, Tillema JM, Karunanayaka PR, et al. Functional MRI of language lateralization during development in children. International Journal of Audiology. 2007; 46: 533\u2013551.","DOI":"10.1080\/14992020701448994"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Rapin I. Acquired aphasia in children. Journal of Child Neurology. 1995; 10: 267\u2013270.","DOI":"10.1177\/088307389501000401"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Tillema JM, Byars AW, Jacola LM, Schapiro MB, Schmithorst VJ, Szaflarski JP, et al. Cortical reorganization of language functioning following perinatal left MCA stroke. Brain and Language. 2008; 105: 99\u2013111.","DOI":"10.1016\/j.bandl.2007.07.127"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Orman G, Kralik SF, Meoded A, Desai N, Risen S, Huisman TAGM. MRI Findings in Pediatric Abusive Head Trauma: A Review. Journal of Neuroimaging: Official Journal of the American Society of Neuroimaging. 2020; 30: 15\u201327.","DOI":"10.1111\/jon.12670"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Jeong D, Beno S, Drake JM, Freire G. Clinical characteristics of upper cervical spine injuries in children: a retrospective case series. Journal of Neurosurgery. Pediatrics. 2024; 33: 452-460.","DOI":"10.3171\/2023.12.peds23197"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Oh T, Han KJ, Ambati VS, Yue JK, Burke JF, Lu AY, et al. Pediatric Cervical Spine Trauma: Injury Patterns, Diagnosis, and Treatment. Pediatric Neurosurgery. 2024; 59: 210\u2013228.","DOI":"10.1159\/000541483"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Wang Y, Liang J, Xu B, Yang J, Wu Z, Cheng L. TrkB\/BDNF signaling pathway and its small molecular agonists in CNS injury. Life Sciences. 2024; 336: 122282.","DOI":"10.1016\/j.lfs.2023.122282"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Hubbard SR, Till JH. Protein tyrosine kinase structure and function. Annual Review of Biochemistry. 2000; 69: 373\u2013398.","DOI":"10.1146\/annurev.biochem.69.1.373"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Crowder RJ, Freeman RS. Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 1998; 18: 2933\u20132943.","DOI":"10.1523\/JNEUROSCI.18-08-02933.1998"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Wang Q, Wang X, Shang Z, Zhao L. Mechanism and prospects of mitochondrial transplantation for spinal cord injury treatment. Stem Cell Research & Therapy. 2024; 15: 457.","DOI":"10.1186\/s13287-024-04077-5"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Lakshmipathy D, Rangarajan S, Barreau A, Lu J, Kleinberg G, Lucke-Wold B. Genetic Contributions to Recovery following Brain Trauma: A Narrative Review. Frontiers in Bioscience (Landmark Edition). 2024; 29: 103.","DOI":"10.31083\/j.fbl2903103"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Chen X, Chen A, Wei J, Huang Y, Deng J, Chen P, et al. Dexmedetomidine alleviates cognitive impairment by promoting hippocampal neurogenesis via BDNF\/TrkB\/CREB signaling pathway in hypoxic-ischemic neonatal rats. CNS Neuroscience & Therapeutics. 2024; 30: e14486.","DOI":"10.1111\/cns.14486"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Park H, Poo MM. Neurotrophin regulation of neural circuit development and function. Nature Reviews. Neuroscience. 2013; 14: 7-23.","DOI":"10.1038\/nrn3379"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Dietz RM, Orfila JE, Rodgers KM, Patsos OP, Deng G, Chalmers N, et al. Juvenile cerebral ischemia reveals age-dependent BDNF-TrkB signaling changes: Novel mechanism of recovery and therapeutic intervention. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2018; 38: 2223-2235.","DOI":"10.1177\/0271678x18766421"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Ohba S, Ikeda T, Ikegaya Y, Nishiyama N, Matsuki N, Yamada MK. BDNF locally potentiates GABAergic presynaptic machineries: target-selective circuit inhibition. Cerebral Cortex (New York, N.Y.: 1991). 2005; 15: 291\u2013298.","DOI":"10.1093\/cercor\/bhh130"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Wrigley S, Arafa D, Tropea D. Insulin-Like Growth Factor 1: At the Crossroads of Brain Development and Aging. Frontiers in Cellular Neuroscience. 2017; 11: 14.","DOI":"10.3389\/fncel.2017.00014"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Anderson SR, Vetter ML. Developmental roles of microglia: A window into mechanisms of disease. Developmental Dynamics: an Official Publication of the American Association of Anatomists. 2019; 248: 98\u2013117.","DOI":"10.1002\/dvdy.1"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Rusin D, Vahl Becirovic L, Lyszczarz G, Krueger M, Benmamar-Badel A, Vad Mathiesen C, et al. Microglia-Derived Insulin-like Growth Factor 1 Is Critical for Neurodevelopment. Cells. 2024; 13: 184.","DOI":"10.3390\/cells13020184"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Yue S, Wang Y, Wang ZJ. Insulin-like growth factor 1 regulates excitatory synaptic transmission in pyramidal neurons from adult prefrontal cortex. Neuropharmacology. 2022; 217: 109204.","DOI":"10.1016\/j.neuropharm.2022.109204"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Riikonen R. Insulin-Like Growth Factors in the Pathogenesis of Neurological Diseases in Children. International Journal of Molecular Sciences. 2017; 18: 2056.","DOI":"10.3390\/ijms18102056"},{"key":"ref23","unstructured":"Madathil SK, Saatman KE. IGF-1\/IGF-R Signaling in Traumatic Brain Injury: Impact on Cell Survival, Neurogenesis, and Behavioral Outcome. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. CRC Press\/Taylor & Francis: Boca Raton (FL). 2015."},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Apel PJ, Ma J, Callahan M, Northam CN, Alton TB, Sonntag WE, et al. Effect of locally delivered IGF-1 on nerve regeneration during aging: an experimental study in rats. Muscle & Nerve. 2010; 41: 335\u2013341.","DOI":"10.1002\/mus.21485"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Kim YK, Jo D, Arjunan A, Ryu Y, Lim YH, Choi SY, et al. Identification of IGF-1 Effects on White Adipose Tissue and Hippocampus in Alzheimer\u2019s Disease Mice via Transcriptomic and Cellular Analysis. International Journal of Molecular Sciences. 2024; 25: 2567.","DOI":"10.3390\/ijms25052567"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Deak F, Sonntag WE. Aging, synaptic dysfunction, and insulin-like growth factor (IGF)-1. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2012; 67: 611\u2013625.","DOI":"10.1093\/gerona\/gls118"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Chigogora S, Zaninotto P, Kivimaki M, Steptoe A, Batty GD. Insulin-like growth factor 1 and risk of depression in older people: the English Longitudinal Study of Ageing. Translational Psychiatry. 2016; 6: e898.","DOI":"10.1038\/tp.2016.167"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Saber H, Himali JJ, Beiser AS, Shoamanesh A, Pikula A, Roubenoff R, et al. Serum Insulin-Like Growth Factor 1 and the Risk of Ischemic Stroke: The Framingham Study. Stroke. 2017; 48: 1760\u20131765.","DOI":"10.1161\/STROKEAHA.116.016563"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Ma C, Wang Y, Wilson KM, Mucci LA, Stampfer MJ, Pollak M, et al. Circulating Insulin-Like Growth Factor 1-Related Biomarkers and Risk of Lethal Prostate Cancer. JNCI Cancer Spectrum. 2022; 6: pkab091.","DOI":"10.1093\/jncics\/pkab091"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Schir\u00f2 G, Iacono S, Ragonese P, Aridon P, Salemi G, Balistreri CR. A Brief Overview on BDNF-Trk Pathway in the Nervous System: A Potential Biomarker or Possible Target in Treatment of Multiple Sclerosis? Frontiers in Neurology. 2022; 13: 917527.","DOI":"10.3389\/fneur.2022.917527"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Feng L, Li B, Xi Y, Cai M, Tian Z. Aerobic exercise and resistance exercise alleviate skeletal muscle atrophy through IGF-1\/IGF-1R-PI3K\/Akt pathway in mice with myocardial infarction. American Journal of Physiology. Cell Physiology. 2022; 322: C164\u2013C176.","DOI":"10.1152\/ajpcell.00344.2021"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Spencer FSE, Elsworthy RJ, Breen L, Bishop JRB, Lucas SJE, Aldred S. Brain derived neurotrophic factor and secreted amyloid precursor protein-\u03b1 response to moderate and high intensity exercise. Physiological Reports. 2025; 13: e70366.","DOI":"10.14814\/phy2.70366"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Lesniak A, Pozna\u0144ski P, Religa P, Nawrocka A, Bujalska-Zadrozny M, Sacharczuk M. Loss of Brain-Derived Neurotrophic Factor (BDNF) Resulting From Congenital- Or Mild Traumatic Brain Injury-Induced Blood-Brain Barrier Disruption Correlates With Depressive-Like Behaviour. Neuroscience. 2021; 458: 1\u201310.","DOI":"10.1016\/j.neuroscience.2021.01.013"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Hong Y, Zhao T, Li XJ, Li S. Mutant Huntingtin Impairs BDNF Release from Astrocytes by Disrupting Conversion of Rab3a-GTP into Rab3a-GDP. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2016; 36: 8790\u20138801.","DOI":"10.1523\/JNEUROSCI.0168-16.2016"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Salem L, Saleh N, D\u00e9sam\u00e9ricq G, Youssov K, Dolbeau G, Cleret L, et al. Insulin-Like Growth Factor-1 but Not Insulin Predicts Cognitive Decline in Huntington\u2019s Disease. PloS One. 2016; 11: e0162890.","DOI":"10.1371\/journal.pone.0162890"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Zhang D, Yuan Y, Zhu J, Zhu D, Li C, Cui W, et al. Insulin-like growth factor 1 promotes neurological functional recovery after spinal cord injury through inhibition of autophagy via the PI3K\/Akt\/mTOR signaling pathway. Experimental and Therapeutic Medicine. 2021; 22: 1265.","DOI":"10.3892\/etm.2021.10700"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Obernosterer G, Leuschner PJF, Alenius M, Martinez J. Post-transcriptional regulation of microRNA expression. RNA (New York, N.Y.). 2006; 12: 1161\u20131167.","DOI":"10.1261\/rna.2322506"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Harrison EB, Hochfelder CG, Lamberty BG, Meays BM, Morsey BM, Kelso ML, et al. Traumatic brain injury increases levels of miR-21 in extracellular vesicles: implications for neuroinflammation. FEBS Open Bio. 2016; 6: 835\u2013846.","DOI":"10.1002\/2211-5463.12092"},{"key":"ref39","unstructured":"Lopez MS, Dempsey RJ, Vemuganti R. The microRNA miR-21 conditions the brain to protect against ischemic and traumatic injuries. Conditioning Medicine. 2017; 1: 35\u201346."},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Sandhir R, Gregory E, Berman NEJ. Differential response of miRNA-21 and its targets after traumatic brain injury in aging mice. Neurochemistry International. 2014; 78: 117\u2013121.","DOI":"10.1016\/j.neuint.2014.09.009"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Ritter A, Han J, Bianconi S, Henrich D, Marzi I, Leppik L, et al. The Ambivalent Role of miRNA-21 in Trauma and Acute Organ Injury. International Journal of Molecular Sciences. 2024; 25: 11282.","DOI":"10.3390\/ijms252011282"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Son G, Na Y, Kim Y, Son JH, Clemenson GD, Schafer ST, et al. miR-124 coordinates metabolic regulators acting at early stages of human neurogenesis. Communications Biology. 2024; 7: 1393.","DOI":"10.1038\/s42003-024-07089-2"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Wu P, He B, Li X, Zhang H. Roles of microRNA-124 in traumatic brain injury: a comprehensive review. Frontiers in Cellular Neuroscience. 2023; 17: 1298508.","DOI":"10.3389\/fncel.2023.1298508"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"Tapocik JD, Barbier E, Flanigan M, Solomon M, Pincus A, Pilling A, et al. microRNA-206 in rat medial prefrontal cortex regulates BDNF expression and alcohol drinking. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2014; 34: 4581\u20134588.","DOI":"10.1523\/JNEUROSCI.0445-14.2014"},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"Tian N, Cao Z, Zhang Y. MiR-206 decreases brain-derived neurotrophic factor levels in a transgenic mouse model of Alzheimer\u2019s disease. Neuroscience Bulletin. 2014; 30: 191\u2013197.","DOI":"10.1007\/s12264-013-1419-7"},{"key":"ref46","doi-asserted-by":"publisher","unstructured":"Zhao H, Li Y, Chen L, Shen C, Xiao Z, Xu R, et al. HucMSCs-Derived miR-206-Knockdown Exosomes Contribute to Neuroprotection in Subarachnoid Hemorrhage Induced Early Brain Injury by Targeting BDNF. Neuroscience. 2019; 417: 11\u201323.","DOI":"10.1016\/j.neuroscience.2019.07.051"},{"key":"ref47","doi-asserted-by":"publisher","unstructured":"Li SL, Li J, Zhou HS, Xiong LL. Research progress of IGF-1 and cerebral ischemia. Ibrain. 2021; 7: 57\u201367.","DOI":"10.1002\/j.2769-2795.2021.tb00066.x"},{"key":"ref48","doi-asserted-by":"publisher","unstructured":"Chen FS, Tong XY, Fang B, Wang D, Li XQ, Zhang ZL. The roles of microRNAs in spinal cord ischemia-reperfusion injury. Neural Regeneration Research. 2022; 17: 2593\u20132599.","DOI":"10.4103\/1673-5374.339471"},{"key":"ref49","doi-asserted-by":"publisher","unstructured":"Zheng YB, Jin X. Evidence for the Contribution of the miR-206\/BDNF Pathway in the Pathophysiology of Depression. The International Journal of Neuropsychopharmacology. 2024; 27: pyae039.","DOI":"10.1093\/ijnp\/pyae039"},{"key":"ref50","doi-asserted-by":"publisher","unstructured":"Li H, Tao R, Wang J, Xia L. Upregulation of miR-375 level ameliorates morphine analgesic tolerance in mouse dorsal root ganglia by inhibiting the JAK2\/STAT3 pathway. Journal of Pain Research. 2017; 10: 1279\u20131287.","DOI":"10.2147\/JPR.S125264"},{"key":"ref51","doi-asserted-by":"publisher","unstructured":"Zhu H, Xue C, Yao M, Wang H, Zhang P, Qian T, et al. miR-129 controls axonal regeneration via regulating insulin-like growth factor-1 in peripheral nerve injury. Cell Death & Disease. 2018; 9: 720.","DOI":"10.1038\/s41419-018-0760-1"},{"key":"ref52","doi-asserted-by":"publisher","unstructured":"Wang F, Wang L, Sui G, Yang C, Guo M, Xiong X, et al. Inhibition of miR-129 Improves Neuronal Pyroptosis and Cognitive Impairment Through IGF-1\/GSK3\u03b2 Signaling Pathway: An In Vitro and In Vivo Study. Journal of Molecular Neuroscience: MN. 2021; 71: 2299\u20132309.","DOI":"10.1007\/s12031-021-01794-x"},{"key":"ref53","doi-asserted-by":"publisher","unstructured":"Xie G, Chen H, He C, Hu S, Xiao X, Luo Q. The dysregulation of miRNAs in epilepsy and their regulatory role in inflammation and apoptosis. Functional & Integrative Genomics. 2023; 23: 287.","DOI":"10.1007\/s10142-023-01220-y"},{"key":"ref54","doi-asserted-by":"publisher","unstructured":"Gupta N, Jadhav S, Tan KL, Saw G, Mallilankaraman KB, Dheen ST. miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A. Frontiers in Cellular Neuroscience. 2020; 14: 132.","DOI":"10.3389\/fncel.2020.00132"},{"key":"ref55","doi-asserted-by":"publisher","unstructured":"Baby N, Alagappan N, Dheen ST, Sajikumar S. MicroRNA-134-5p inhibition rescues long-term plasticity and synaptic tagging\/capture in an A\u03b2(1-42)-induced model of Alzheimer\u2019s disease. Aging Cell. 2020; 19: e13046.","DOI":"10.1111\/acel.13046"},{"key":"ref56","doi-asserted-by":"publisher","unstructured":"Konovalova J, Gerasymchuk D, Arroyo SN, Kluske S, Mastroianni F, Pereyra AV, et al. Human-Specific Regulation of Neurotrophic Factors MANF and CDNF by microRNAs. International Journal of Molecular Sciences. 2021; 22: 9691.","DOI":"10.3390\/ijms22189691"},{"key":"ref57","doi-asserted-by":"publisher","unstructured":"Treble-Barna A, Heinsberg LW, Stec Z, Breazeale S, Davis TS, Kesbhat AA, et al. Brain-derived neurotrophic factor (BDNF) epigenomic modifications and brain-related phenotypes in humans: A systematic review. Neuroscience and Biobehavioral Reviews. 2023; 147: 105078.","DOI":"10.1016\/j.neubiorev.2023.105078"},{"key":"ref58","doi-asserted-by":"publisher","unstructured":"V\u00e1zquez-\u00c1gredos A, G\u00e1miz F, Gallo M. MicroRNA Regulation of the Environmental Impact on Adolescent Neurobehavioral Development: A Systematic Review. Frontiers in Cellular Neuroscience. 2022; 16: 956609.","DOI":"10.3389\/fncel.2022.956609"},{"key":"ref59","doi-asserted-by":"publisher","unstructured":"Hill CA, Vaddi S, Moffitt A, Kane AA, Marsh JL, Panchal J, et al. Intracranial volume and whole brain volume in infants with unicoronal craniosynostosis. The Cleft Palate-craniofacial Journal: Official Publication of the American Cleft Palate-Craniofacial Association. 2011; 48: 394\u2013398.","DOI":"10.1597\/10-051"},{"key":"ref60","doi-asserted-by":"publisher","unstructured":"Peterson MR, Cherukuri V, Paulson JN, Ssentongo P, Kulkarni AV, Warf BC, et al. Normal childhood brain growth and a universal sex and anthropomorphic relationship to cerebrospinal fluid. Journal of Neurosurgery. Pediatrics. 2021; 28: 458\u2013468.","DOI":"10.3171\/2021.2.PEDS201006"},{"key":"ref61","doi-asserted-by":"publisher","unstructured":"Adelson PD, Srinivas R, Chang Y, Bell M, Kochanek PM. Cerebrovascular response in children following severe traumatic brain injury. Child\u2019s Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery. 2011; 27: 1465\u20131476.","DOI":"10.1007\/s00381-011-1476-z"},{"key":"ref62","doi-asserted-by":"publisher","unstructured":"Huang X, Wan M, Yang Q, Ding X, Zhou Z. The stromal cell-derived factor-1 \u03b1 (SDF-1\u03b1)\/cysteine-X-cysteine chemokine receptor 4 (CXCR4) axis: a possible prognostic indicator of acute ischemic stroke. The Journal of International Medical Research. 2019; 47: 1897\u20131907.","DOI":"10.1177\/0300060519827173"},{"key":"ref63","doi-asserted-by":"publisher","unstructured":"Wang Y, Deng Y, Zhou GQ. SDF-1alpha\/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model. 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Phytomedicine. 2024; 129: 155566.","DOI":"10.1016\/j.phymed.2024.155566"},{"key":"ref93","doi-asserted-by":"publisher","unstructured":"Yang Y, Rao C, Yin T, Wang S, Shi H, Yan X, et al. Application and underlying mechanism of acupuncture for the nerve repair after peripheral nerve injury: remodeling of nerve system. Frontiers in Cellular Neuroscience. 2023; 17: 1253438.","DOI":"10.3389\/fncel.2023.1253438"},{"key":"ref94","doi-asserted-by":"publisher","unstructured":"Stocker RA. Intensive Care in Traumatic Brain Injury Including Multi-Modal Monitoring and Neuroprotection. Medical Sciences (Basel, Switzerland). 2019; 7: 37.","DOI":"10.3390\/medsci7030037"},{"key":"ref95","doi-asserted-by":"publisher","unstructured":"Haefeli J, Ferguson AR, Bingham D, Orr A, Won SJ, Lam TI, et al. A data-driven approach for evaluating multi-modal therapy in traumatic brain injury. Scientific Reports. 2017; 7: 42474.","DOI":"10.1038\/srep42474"},{"key":"ref96","doi-asserted-by":"publisher","unstructured":"Juan SMA, Daglas M, Adlard PA. Tau Pathology, Metal Dyshomeostasis and Repetitive Mild Traumatic Brain Injury: An Unexplored Link Paving the Way for Neurodegeneration. Journal of Neurotrauma. 2022; 39: 902\u2013922.","DOI":"10.1089\/neu.2021.0241"},{"key":"ref97","doi-asserted-by":"publisher","unstructured":"Pedersen M\u00d8, Jensen R, Pedersen DS, Skjolding AD, Hempel C, Maretty L, et al. Metallothionein-I+II in neuroprotection. BioFactors (Oxford, England). 2009; 35: 315\u2013325.","DOI":"10.1002\/biof.44"},{"key":"ref98","doi-asserted-by":"publisher","unstructured":"Tang Y, Zhong R, Liang J, Liu S, Liu W, Liu T, et al. Neuroprotection of IGF-1 in neonatal hypoxic-ischemic brain injury through downregulation of FoXO3a-PUMA pathway. Frontiers in Cellular Neuroscience. 2025; 19: 1685800.","DOI":"10.3389\/fncel.2025.1685800"},{"key":"ref99","doi-asserted-by":"publisher","unstructured":"van Rooij E, Kauppinen S. Development of microRNA therapeutics is coming of age. EMBO Molecular Medicine. 2014; 6: 851\u2013864.","DOI":"10.15252\/emmm.201100899"},{"key":"ref100","doi-asserted-by":"publisher","unstructured":"Traber GM, Yu AM. RNAi-Based Therapeutics and Novel RNA Bioengineering Technologies. The Journal of Pharmacology and Experimental Therapeutics. 2023; 384: 133\u2013154.","DOI":"10.1124\/jpet.122.001234"},{"key":"ref101","doi-asserted-by":"publisher","unstructured":"Bintu L, Yong J, Antebi YE, McCue K, Kazuki Y, Uno N, et al. Dynamics of epigenetic regulation at the single-cell level. Science (New York, N.Y.). 2016; 351: 720\u2013724.","DOI":"10.1126\/science.aab2956"},{"key":"ref102","doi-asserted-by":"publisher","unstructured":"Ma H, Tu LC, Naseri A, Huisman M, Zhang S, Grunwald D, et al. 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