{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T06:28:00Z","timestamp":1787120880515,"version":"build-2736575974"},"reference-count":74,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sobeck-Zhang Foundation"},{"name":"NIH","award":["DA056804"],"award-info":[{"award-number":["DA056804"]}]},{"name":"NIH","award":["DA050908"],"award-info":[{"award-number":["DA050908"]}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>\n                    Insulin-like growth factor 1 (IGF1) signaling plays a critical role in brain function and declines significantly with aging. However, how these changes occur across different brain regions and cell types, and how they contribute to behavioral dysfunction, remains poorly understood. The prefrontal cortex (PFC), a key regulator of cognitive, emotional, and social behaviors, is particularly vulnerable to age-related changes. Here, we investigated age-associated changes in IGF1 and its receptor (IGF1R) in major neuronal populations of the PFC and examined their functional relevance. Using immunohistochemical analysis across young adult, middle-aged, and aged mice, we identified cell-type-dependent alterations in IGF1 and IGF1R expressions in the PFC of C57BL\/6 mice, characterized by a reduction of IGF1 in both excitatory (CaMKII\n                    <jats:sup>+<\/jats:sup>\n                    ) and inhibitory (GAD67\n                    <jats:sup>+<\/jats:sup>\n                    ) neurons, and a selective decrease of IGF1R in excitatory neurons. To determine the functional consequences of these changes, we employed an excitatory neuron-specific\n                    <jats:italic>Igf1r<\/jats:italic>\n                    conditional knockdown (cKD) model in the PFC of young adult mice. IGF1R cKD in excitatory neurons of young adult mice resulted in behavioral dysfunction across multiple domains, including increased anxiety-like behavior, reduced sociability, and impaired cognitive performance. Furthermore, chronic intra-PFC infusion of IGF1 alleviated age-associated behavioral impairments in aged mice, and these recovery effects depend on IGF1R in excitatory neurons. Together, these findings support a critical role for region- and cell type-specific IGF1 and IGF1R system in regulating behavioral function during aging and provide insight into mechanisms underlying age-associated behavioral declines.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2026.1858227","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T05:48:21Z","timestamp":1787118501000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell-type-dependent decline of IGF1 and IGF1R in the prefrontal cortex contributes to age-related behavioral changes"],"prefix":"10.3389","volume":"18","author":[{"given":"Shuwen","family":"Yue","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas","place":["Lawrence, KS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas","place":["Lawrence, KS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arushi","family":"Garg","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas","place":["Lawrence, KS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Sarovich","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas","place":["Lawrence, KS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas","place":["Lawrence, KS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendall","family":"Dickerson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas","place":["Lawrence, KS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas","place":["Lawrence, KS, United States"]},{"name":"Cofrin Logan Center for Addiction Research and Treatment, University of Kansas","place":["Lawrence, KS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.exger.2014.10.002","article-title":"Growth hormone, insulin-like growth factor-1 and the aging brain","volume":"68","author":"Ashpole","year":"2015","journal-title":"Exp. Gerontol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/S0070-2153(04)63006-7","article-title":"Life extension in the dwarf mouse","volume":"63","author":"Bartke","year":"2004","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1210\/er.2017-00073","article-title":"Insulin receptor isoforms in physiology and disease: an updated view","volume":"38","author":"Belfiore","year":"2017","journal-title":"Endocr. Rev."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"6726","DOI":"10.1523\/JNEUROSCI.0759-10.2010","article-title":"Interactive effects of stress and aging on structural plasticity in the prefrontal cortex","volume":"30","author":"Bloss","year":"2010","journal-title":"J. Neurosci."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.conb.2007.04.009","article-title":"Do thin spines learn to be mushroom spines that remember?","volume":"17","author":"Bourne","year":"2007","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/384033a0","article-title":"Dwarf mice and the ageing process","volume":"384","author":"Brown-Borg","year":"1996","journal-title":"Nature"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.1038\/nm1202-793","article-title":"Serum insulin-like growth factor I regulates brain amyloid-beta levels","volume":"8","author":"Carro","year":"2002","journal-title":"Nat. Med."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1016\/0896-6273(93)90173-o","article-title":"Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice","volume":"10","author":"Carson","year":"1993","journal-title":"Neuron"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.tics.2005.01.011","article-title":"Imaging the developing brain: what have we learned about cognitive development?","volume":"9","author":"Casey","year":"2005","journal-title":"Trends Cogn. Sci."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"9941","DOI":"10.1073\/pnas.1311685111","article-title":"Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett syndrome","volume":"111","author":"Castro","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/S0304-3940(02)00740-1","article-title":"Age-related upregulation of insulin-like growth factor receptor type I in rat cerebellum","volume":"330","author":"Chung","year":"2002","journal-title":"Neurosci. Lett."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1016\/j.cell.2009.11.014","article-title":"Reduced IGF-1 signaling delays age-associated proteotoxicity in mice","volume":"139","author":"Cohen","year":"2009","journal-title":"Cell"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"7020","DOI":"10.1523\/JNEUROSCI.2486-17.2018","article-title":"Persistent spiking activity underlies working memory","volume":"38","author":"Constantinidis","year":"2018","journal-title":"J. Neurosci."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1007\/s12017-015-8341-2","article-title":"NNZ-2566, a novel analog of (1-3) IGF-1, as a potential therapeutic agent for fragile X syndrome","volume":"17","author":"Deacon","year":"2015","journal-title":"NeuroMolecular Med."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"7507","DOI":"10.1523\/jneurosci.6410-09.2010","article-title":"Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment","volume":"30","author":"Dumitriu","year":"2010","journal-title":"J. Neurosci."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.neuroscience.2016.03.056","article-title":"The role of insulin-like growth factor 1 (IGF-1) in brain development, maturation and neuroplasticity","volume":"325","author":"Dyer","year":"2016","journal-title":"Neuroscience"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/s11357-019-00065-3","article-title":"Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice","volume":"41","author":"Farias Quipildor","year":"2019","journal-title":"Geroscience"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"13428","DOI":"10.1523\/JNEUROSCI.3662-08.2008","article-title":"Medial prefrontal cortex supports recollection, but not familiarity, in the rat","volume":"28","author":"Farovik","year":"2008","journal-title":"J. Neurosci."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.neuropharm.2017.12.001","article-title":"Insulin-mediated synaptic plasticity in the CNS: anatomical, functional and temporal contexts","volume":"136","author":"Ferrario","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"2360","DOI":"10.1523\/JNEUROSCI.3216-18.2021","article-title":"Insulin Bidirectionally alters NAc glutamatergic transmission: interactions between insulin receptor activation, endogenous opioids, and glutamate release","volume":"41","author":"Fetterly","year":"2021","journal-title":"J. Neurosci."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"e0244022","DOI":"10.1371\/journal.pone.0244022","article-title":"Distinct physical condition and social behavior phenotypes of CD157 and CD38 knockout mice during aging","volume":"15","author":"Gerasimenko","year":"2020","journal-title":"PLoS One"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"8174","DOI":"10.1073\/pnas.0402680101","article-title":"Dynamic mapping of human cortical development during childhood through early adulthood","volume":"101","author":"Gogtay","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1093\/geronb\/gbac110","article-title":"Aging is associated with multidirectional changes in social cognition: findings from an adult life-span sample ranging from 18 to 101 years","volume":"78","author":"Grainger","year":"2023","journal-title":"J. Gerontol. B Psychol. Sci. Soc. Sci."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"104929","DOI":"10.1016\/j.beproc.2023.104929","article-title":"Aging to 24 months increased C57BL\/6J mouse social sniffing and hippocampal Neto1 levels, and impaired female spatial learning","volume":"211","author":"Greene","year":"2023","journal-title":"Behav. Process."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1126\/science.1072994","article-title":"The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics","volume":"297","author":"Hardy","year":"2002","journal-title":"Science"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"e202201691","DOI":"10.26508\/lsa.202201691","article-title":"Brain IGF-I regulates LTP, spatial memory, and sexual dimorphic behavior","volume":"6","author":"Herrero-Labrador","year":"2023","journal-title":"Life Sci. Alliance"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/nature01298","article-title":"IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice","volume":"421","author":"Holzenberger","year":"2003","journal-title":"Nature"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"2027","DOI":"10.1523\/JNEUROSCI.16-06-02027.1996","article-title":"Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation","volume":"16","author":"Kuhn","year":"1996","journal-title":"J. Neurosci."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"365","DOI":"10.3389\/fnagi.2017.00365","article-title":"Insulin-like growth Factor-1 and Neuroinflammation","volume":"9","author":"Labandeira-Garcia","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/S0304-3835(03)00159-9","article-title":"The insulin-like growth factor system and cancer","volume":"195","author":"LeRoith","year":"2003","journal-title":"Cancer Lett."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"7332","DOI":"10.1073\/pnas.93.14.7332","article-title":"Localization of alpha type II calcium calmodulin-dependent protein kinase at glutamatergic but not gamma-aminobutyric acid (GABAergic) synapses in thalamus and cerebral cortex","volume":"93","author":"Liu","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e67267","DOI":"10.7554\/eLife.67267","article-title":"IGF-1 facilitates extinction of conditioned fear","volume":"10","author":"Maglio","year":"2021","journal-title":"eLife"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1111\/j.1471-4159.2006.03664.x","article-title":"Interaction between interferon gamma and insulin-like growth factor-1 in hippocampus impacts on the ability of rats to sustain long-term potentiation","volume":"96","author":"Maher","year":"2006","journal-title":"J. Neurochem."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2394","DOI":"10.1038\/s41467-018-04805-5","article-title":"Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice","volume":"9","author":"Mao","year":"2018","journal-title":"Nat. Commun."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1016\/S0306-4522(98)00143-2","article-title":"Insulin-like growth factor-1 ameliorates age-related behavioral deficits","volume":"87","author":"Markowska","year":"1998","journal-title":"Neuroscience"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"16807","DOI":"10.1073\/pnas.1113648108","article-title":"Inhibitory interneurons in a cortical column form hot zones of inhibition in layers 2 and 5A","volume":"108","author":"Meyer","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/j.neuron.2011.05.001","article-title":"Adult neurogenesis in the mammalian brain: significant answers and significant questions","volume":"70","author":"Ming","year":"2011","journal-title":"Neuron"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.neurobiolaging.2008.04.002","article-title":"Defects in IGF-1 receptor, insulin receptor and IRS-1\/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling","volume":"31","author":"Moloney","year":"2010","journal-title":"Neurobiol. Aging"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.bbr.2015.06.030","article-title":"Medial prefrontal cortex role in recognition memory in rodents","volume":"292","author":"Morici","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1038\/nrn3200","article-title":"The ageing cortical synapse: hallmarks and implications for cognitive decline","volume":"13","author":"Morrison","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.mcn.2011.07.008","article-title":"Reduced brain insulin-like growth factor I function during aging","volume":"49","author":"Muller","year":"2012","journal-title":"Mol. Cell. Neurosci."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1016\/j.exger.2006.06.061","article-title":"Stress resistance in long-lived mouse models","volume":"41","author":"Murakami","year":"2006","journal-title":"Exp. Gerontol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"308","DOI":"10.3389\/fncel.2019.00308","article-title":"Microglia express insulin-like growth factor-1 in the hippocampus of aged APP(swe)\/PS1(DeltaE9) transgenic mice","volume":"13","author":"Myhre","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"679801","DOI":"10.1155\/2012\/679801","article-title":"IGF1 as a potential treatment for Rett syndrome: safety assessment in six Rett patients","volume":"2012","author":"Pini","year":"2012","journal-title":"Autism Res. Treat."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1016\/j.bandc.2009.07.005","article-title":"Age-related differences in the involvement of the prefrontal cortex in attentional control","volume":"71","author":"Prakash","year":"2009","journal-title":"Brain Cogn."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"92","DOI":"10.3389\/fped.2014.00092","article-title":"GH dysfunction in engrailed-2 knockout mice, a model for autism spectrum disorders","volume":"2","author":"Provenzano","year":"2014","journal-title":"Front. Pediatr."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"1676","DOI":"10.1093\/cercor\/bhi044","article-title":"Regional brain changes in aging healthy adults: general trends, individual differences and modifiers","volume":"15","author":"Raz","year":"2005","journal-title":"Cereb. Cortex"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"247","DOI":"10.3233\/JAD-2005-8304","article-title":"Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine","volume":"8","author":"Rivera","year":"2005","journal-title":"J. Alzheimer's Dis"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"2222","DOI":"10.1093\/gerona\/glad219","article-title":"Reduced activity of glutamatergic neurons in the Prelimbic medial prefrontal cortex underlies the inherent aging-related physiological reduction in social dominance","volume":"78","author":"Shan","year":"2023","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1002\/npr2.12052","article-title":"Age-related behavioral changes from young to old age in male mice of a C57BL\/6J strain maintained under a genetic stability program","volume":"39","author":"Shoji","year":"2019","journal-title":"Neuropsychopharmacol. Rep."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/s13041-016-0191-9","article-title":"Age-related changes in behavior in C57BL\/6J mice from young adulthood to middle age","volume":"9","author":"Shoji","year":"2016","journal-title":"Mol. Brain"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"3245","DOI":"10.1073\/pnas.95.6.3245","article-title":"The absence of a major Ca2+ signaling pathway in GABAergic neurons of the hippocampus","volume":"95","author":"Sik","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/S0361-9230(99)00259-2","article-title":"Age and insulin-like growth factor-1 modulate N-methyl-D-aspartate receptor subtype expression in rats","volume":"51","author":"Sonntag","year":"2000","journal-title":"Brain Res. Bull."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"B521","DOI":"10.1093\/gerona\/54.12.B521","article-title":"Pleiotropic effects of growth hormone and insulin-like growth factor (IGF)-1 on biological aging: inferences from moderate caloric-restricted animals","volume":"54","author":"Sonntag","year":"1999","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.arr.2005.02.001","article-title":"Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging","volume":"4","author":"Sonntag","year":"2005","journal-title":"Ageing Res. Rev."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.ibror.2020.08.002","article-title":"Age-dependent changes in the medial prefrontal cortex and medial amygdala structure, and elevated plus-maze performance in the healthy male Wistar rats","volume":"9","author":"Sotoudeh","year":"2020","journal-title":"IBRO Rep."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1016\/j.cell.2013.05.002","article-title":"Dynamics of hippocampal neurogenesis in adult humans","volume":"153","author":"Spalding","year":"2013","journal-title":"Cell"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"63","DOI":"10.3233\/jad-2005-7107","article-title":"Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes?","volume":"7","author":"Steen","year":"2005","journal-title":"J. Alzheimer's Dis"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1016\/j.neurobiolaging.2004.07.010","article-title":"Local expression of GH and IGF-1 in the hippocampus of GH-deficient long-lived mice","volume":"26","author":"Sun","year":"","journal-title":"Neurobiol. Aging"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1210\/en.2004-1115","article-title":"Increased neurogenesis in dentate gyrus of long-lived Ames dwarf mice","volume":"146","author":"Sun","year":"","journal-title":"Endocrinology"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"2771","DOI":"10.1007\/s11357-022-00623-2","article-title":"Age-related decline in circulating IGF-1 associates with impaired neurovascular coupling responses in older adults","volume":"44","author":"Toth","year":"2022","journal-title":"Geroscience"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1111\/acel.12372","article-title":"IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging","volume":"14","author":"Toth","year":"2015","journal-title":"Aging Cell"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"e330","DOI":"10.1038\/tp.2013.102","article-title":"Loss of serum IGF-I input to the brain as an early biomarker of disease onset in Alzheimer mice","volume":"3","author":"Trueba-Saiz","year":"2013","journal-title":"Transl. Psychiatry"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1038\/nature10243","article-title":"Neuronal basis of age-related working memory decline","volume":"476","author":"Wang","year":"2011","journal-title":"Nature"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1016\/j.neuron.2012.12.032","article-title":"NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex","volume":"77","author":"Wang","year":"2013","journal-title":"Neuron"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"9541","DOI":"10.1038\/s41467-025-64585-7","article-title":"Prelimbic cortex to ventral tegmental area projection regulates early social isolation stress-potentiated heroin seeking in mice","volume":"16","author":"Wang","year":"2025","journal-title":"Nat. Commun."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"M648","DOI":"10.1093\/gerona\/58.7.M648","article-title":"Serum sex hormones, IGF-1, and IGFBP3 exert a sexually dimorphic effect on lean body mass in aging","volume":"58","author":"Waters","year":"2003","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref68","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.exger.2018.02.015","article-title":"Trajectories of plasma IGF-1, IGFBP-3, and their ratio in the Mayo Clinic study of aging","volume":"106","author":"Wennberg","year":"2018","journal-title":"Exp. Gerontol."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1037\/0033-2909.120.2.272","article-title":"An application of prefrontal cortex function theory to cognitive aging","volume":"120","author":"West","year":"1996","journal-title":"Psychol. Bull."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.1212\/WNL.0000000000000382","article-title":"Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy","volume":"82","author":"Westwood","year":"2014","journal-title":"Neurology"},{"key":"ref71","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.jphs.2025.01.002","article-title":"C57BL\/6J and C57BL\/6N mice show distinct aging-associated behavioral alterations","volume":"157","author":"Yamada","year":"2025","journal-title":"J. Pharmacol. Sci."},{"key":"ref72","doi-asserted-by":"publisher","first-page":"697621","DOI":"10.3389\/fnagi.2021.697621","article-title":"Functional aging in male C57BL\/6J mice across the life-span: a systematic behavioral analysis of motor, emotional, and memory function to define an aging phenotype","volume":"13","author":"Yanai","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"109204","DOI":"10.1016\/j.neuropharm.2022.109204","article-title":"Insulin-like growth factor 1 regulates excitatory synaptic transmission in pyramidal neurons from adult prefrontal cortex","volume":"217","author":"Yue","year":"2022","journal-title":"Neuropharmacology"},{"key":"ref74","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/B978-0-12-804281-6.00020-3","article-title":"Aging of the frontal lobe","volume":"163","author":"Zanto","year":"2019","journal-title":"Handb. Clin. Neurol."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2026.1858227\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T05:48:22Z","timestamp":1787118502000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2026.1858227\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":74,"alternative-id":["10.3389\/fnagi.2026.1858227"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2026.1858227","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]},"article-number":"1858227"}}