{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:51:06Z","timestamp":1790142666413,"version":"4.0.1"},"reference-count":70,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T00:00:00Z","timestamp":1626220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FAU Brain Institute","award":["Jupiter Life Sciences Initiative"],"award-info":[{"award-number":["Jupiter Life Sciences Initiative"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hyperlipidemia and hypertension are modifiable risk factors for cognitive decline. About 25% of adults over age 65 use both antihypertensives (AHTs) and statins to treat these conditions. Recent research in humans suggests that their combined use may delay or prevent dementia onset. However, it is not clear whether and how combination treatment may benefit brain function. To begin to address this question, we examined effects of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and Captopril, an angiotensin-converting enzyme inhibitor (ACEI), administration on memory function, anxiety-like behavior, adult hippocampal neurogenesis and angiogenesis in adult and middle-aged male C57Bl\/6J mice. In adult mice (3-months-old) combination (combo) treatment, as well as administration of each compound individually, for six weeks, accelerated memory extinction in contextual fear conditioning. However, pattern separation in the touchscreen-based location discrimination test, a behavior linked to adult hippocampal neurogenesis, was unchanged. In addition, dentate gyrus (DG) neurogenesis and vascularization were unaffected. In middle-aged mice (10-months-old) combo treatment had no effect on spatial memory in the Morris water maze, but did reduce anxiety in the open field test. A potential underlying mechanism may be the modest increase in new hippocampal neurons (~20%) in the combo as compared to the control group. DG vascularization was not altered. Overall, our findings suggest that statin and anti-hypertensive treatment may serve as a potential pharmacotherapeutic approach for anxiety, in particular for post-traumatic stress disorder (PTSD) patients who have impairments in extinction of aversive memories.<\/jats:p>","DOI":"10.3390\/cells10071778","type":"journal-article","created":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T10:13:42Z","timestamp":1626257622000},"page":"1778","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Effects of Combined Anti-Hypertensive and Statin Treatment on Memory, Fear Extinction, Adult Neurogenesis, and Angiogenesis in Adult and Middle-Aged Mice"],"prefix":"10.3390","volume":"10","author":[{"given":"Seungwoo","family":"Yoo","sequence":"first","affiliation":[{"name":"Stiles-Nicholson Brain Institute and Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Stremlau","sequence":"additional","affiliation":[{"name":"National Institute on Aging (NIA), Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Pinto","sequence":"additional","affiliation":[{"name":"Stiles-Nicholson Brain Institute and Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1407-3441","authenticated-orcid":false,"given":"Hyewon","family":"Woo","sequence":"additional","affiliation":[{"name":"Stiles-Nicholson Brain Institute and Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Curtis","sequence":"additional","affiliation":[{"name":"Stiles-Nicholson Brain Institute and Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5727-434X","authenticated-orcid":false,"given":"Henriette","family":"van Praag","sequence":"additional","affiliation":[{"name":"Stiles-Nicholson Brain Institute and Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL 33458, USA"},{"name":"National Institute on Aging (NIA), Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.tics.2012.04.005","article-title":"Memory aging and brain maintenance","volume":"16","author":"Nyberg","year":"2012","journal-title":"Trends Cogn. Sci."},{"key":"ref_2","first-page":"1179546819839411","article-title":"Physical Exercise for Individuals with Hypertension: It Is Time to Emphasize its Benefits on the Brain and Cognition","volume":"13","author":"Cabral","year":"2019","journal-title":"Clin. Med. Insights Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1007\/s11906-015-0593-6","article-title":"Exercise, the Brain, and Hypertension","volume":"17","author":"Fu","year":"2015","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_4","first-page":"237","article-title":"Lifestyle Modifications to Prevent and Control Hypertension","volume":"10","author":"Samadian","year":"2016","journal-title":"Iran. J. Kidney Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s13668-019-0271-4","article-title":"Diet and Inflammation in Cognitive Ageing and Alzheimer\u2019s Disease","volume":"8","author":"McGrattan","year":"2019","journal-title":"Curr. Nutr. Rep."},{"key":"ref_6","first-page":"1097","article-title":"Diet and exercise in the management of hyperlipidemia","volume":"81","author":"Kelly","year":"2010","journal-title":"Am. Fam. Physician"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1002\/pds.3381","article-title":"Statins in the prevention of dementia and Alzheimer\u2019s disease: A meta-analysis of observational studies and an assessment of confounding","volume":"22","author":"Wong","year":"2012","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s40263-015-0230-6","article-title":"Antihypertensive Drugs, Prevention of Cognitive Decline and Dementia: A Systematic Review of Observational Studies, Randomized Controlled Trials and Meta-Analyses, with Discussion of Potential Mechanisms","volume":"29","author":"Rouch","year":"2015","journal-title":"CNS Drugs"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1097\/HJH.0b013e3283603f53","article-title":"Antihypertensive classes, cognitive decline and incidence of dementia","volume":"31","author":"Marpillat","year":"2013","journal-title":"J. Hypertens."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S1474-4422(08)70143-1","article-title":"Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): A double-blind, placebo controlled trial","volume":"7","author":"Peters","year":"2008","journal-title":"Lancet Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Barthold, D., Joyce, G., Brinton, R.D., Wharton, W., Kehoe, P., and Zissimopoulos, J. (2020). Association of combination statin and antihypertensive therapy with reduced Alzheimer\u2019s disease and related dementia risk. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0229541"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s13195-020-00589-3","article-title":"Beneficial association of angiotensin-converting enzyme inhibitors and statins on the occurrence of possible Alzheimer\u2019s disease after traumatic brain injury","volume":"12","author":"Li","year":"2020","journal-title":"Alzheimer Res. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e1435","DOI":"10.1212\/WNL.0000000000007174","article-title":"Effects of blood pressure and lipid lowering on cognition","volume":"92","author":"Bosch","year":"2019","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1484357","DOI":"10.1155\/2020\/1484357","article-title":"Effect of Combined Antihypertensive and Lipid-Lowering Therapies on Cognitive Function: A New Treatment Strategy?","volume":"2020","author":"Kuang","year":"2020","journal-title":"Cardiol. Res. Pract."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"813","DOI":"10.3171\/jns.2004.101.5.0813","article-title":"Atorvastatin reduction of intravascular thrombosis, increase in cerebral microvascular patency and integrity, and enhancement of spatial learning in rats subjected to traumatic brain injury","volume":"101","author":"Lu","year":"2004","journal-title":"J. Neurosurg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1089\/neu.2007.0288","article-title":"Statins Increase Neurogenesis in the Dentate Gyrus, Reduce Delayed Neuronal Death in the Hippocampal CA3 Region, and Improve Spatial Learning in Rat after Traumatic Brain Injury","volume":"24","author":"Lu","year":"2007","journal-title":"J. Neurotrauma"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.brainresbull.2019.01.018","article-title":"Atorvastatin prevents lipopolysaccharide-induced depressive-like behaviour in mice","volume":"146","author":"Taniguti","year":"2019","journal-title":"Brain Res. Bull."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2014.03.021","article-title":"The effect of simvastatin treatment on proliferation and differentiation of neural stem cells after traumatic brain injury","volume":"1602","author":"Xie","year":"2015","journal-title":"Brain Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1161\/STROKEAHA.107.490946","article-title":"Atorvastatin Promotes Presenilin-1 Expression and Notch1 Activity and Increases Neural Progenitor Cell Proliferation after Stroke","volume":"39","author":"Chen","year":"2008","journal-title":"Stroke"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2964","DOI":"10.1007\/s12035-018-1267-6","article-title":"Atorvastatin Rejuvenates Neural Stem Cells Injured by Oxygen\u2013Glucose Deprivation and Induces Neuronal Differentiation Through Activating the PI3K\/Akt and ERK Pathways","volume":"56","author":"Choi","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4864017","DOI":"10.1155\/2020\/4864017","article-title":"Rosuvastatin Improves Cognitive Function of Chronic Hypertensive Rats by Attenuating White Matter Lesions and Beta-Amyloid Deposits","volume":"2020","author":"Zheng","year":"2020","journal-title":"BioMed Res. Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"eaao0498","DOI":"10.1126\/scitranslmed.aao0498","article-title":"Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome","volume":"11","author":"Asiminas","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.bbr.2017.07.029","article-title":"Protective effect of atorvastatin on d-galactose-induced aging model in mice","volume":"334","author":"Kaviani","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1111\/epi.12686","article-title":"Protective effects of some statins on epileptogenesis and depressive-like behavior in WAG\/Rij rats, a genetic animal model of absence epilepsy","volume":"55","author":"Citraro","year":"2014","journal-title":"Epilepsia"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.stemcr.2013.11.002","article-title":"Simvastatin Promotes Adult Hippocampal Neurogenesis by Enhancing Wnt\/\u03b2-Catenin Signaling","volume":"2","author":"Robin","year":"2014","journal-title":"Stem Cell Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1177\/1533317519847042","article-title":"A Comparative Study on the Memory-Enhancing Actions of Oral Renin-Angiotensin System Altering Drugs in Scopolamine-Treated Mice","volume":"34","author":"Ababei","year":"2019","journal-title":"Am. J. Alzheimer Dis. Other Dement."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/0091-3057(89)90390-0","article-title":"The effects of ACE inhibitors captopril and SQ29,852 in rodent tests of cognition","volume":"33","author":"Costall","year":"1989","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7676512","DOI":"10.1155\/2016\/7676512","article-title":"Lipopolysaccharide-Induced Spatial Memory and Synaptic Plasticity Impairment Is Preventable by Captopril","volume":"2016","author":"Abareshi","year":"2016","journal-title":"Adv. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.lfs.2016.10.026","article-title":"The effects of captopril on lipopolysaccharide induced learning and memory impairments and the brain cytokine levels and oxidative damage in rats","volume":"167","author":"Abareshi","year":"2016","journal-title":"Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"16917","DOI":"10.3390\/ijms140816917","article-title":"ACE Inhibition with Captopril Retards the Development of Signs of Neurodegeneration in an Animal Model of Alzheimer\u2019s Disease","volume":"14","author":"Abdalla","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"917156","DOI":"10.1155\/2015\/917156","article-title":"Inhibition of ACE Retards Tau Hyperphosphorylation and Signs of Neuronal Degeneration in Aged Rats Subjected to Chronic Mild Stress","volume":"2015","author":"AbdAlla","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.biopsych.2020.02.005","article-title":"Angiotensin-Converting Enzyme Inhibitor Rapidly Ameliorates Depressive-Type Behaviors via Bradykinin-Dependent Activation of Mammalian Target of Rapamycin Complex 1","volume":"88","author":"Luo","year":"2020","journal-title":"Biol. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.1096\/fj.11-182873","article-title":"Perindopril, a centrally active angiotensin-converting enzyme inhibitor, prevents cognitive impairment in mouse models of Alzheimer\u2019s disease","volume":"25","author":"Dong","year":"2011","journal-title":"FASEB J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1089\/rej.2009.0944","article-title":"Protective Effects of Intranasal Losartan in the APP\/PS1 Transgenic Mouse Model of Alzheimer Disease","volume":"13","author":"Danielyan","year":"2010","journal-title":"Rejuvenation Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.nbd.2014.04.018","article-title":"Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer\u2019s disease model","volume":"68","author":"Ongali","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1748-717X-5-6","article-title":"Ramipril mitigates radiation-induced impairment of neurogenesis in the rat dentate gyrus","volume":"5","author":"Jenrow","year":"2010","journal-title":"Radiat. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s11060-010-0282-x","article-title":"Combined atorvastatin and ramipril mitigate radiation-induced impairment of dentate gyrus neurogenesis","volume":"101","author":"Jenrow","year":"2010","journal-title":"J. Neuro Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4275","DOI":"10.1038\/s41467-020-18046-y","article-title":"Steps towards standardized quantification of adult neurogenesis","volume":"11","author":"Zhao","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.euroneuro.2015.01.013","article-title":"The angiotensin converting enzyme inhibitor, captopril, prevents the hyperactivity and impulsivity of neurokinin-1 receptor gene \u2019knockout\u2019 mice: Sex differences and implications for the treatment of attention deficit hyperactivity disorder","volume":"25","author":"Porter","year":"2015","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1007\/s00702-010-0455-y","article-title":"Captopril potentiates the anticonvulsant activity of carbamazepine and lamotrigine in the mouse maximal electroshock seizure model","volume":"117","author":"Jakubus","year":"2010","journal-title":"J. Neural Transm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1054\/npep.2000.0845","article-title":"Comparative studies on the memory- enhancing actions of captopril and losartan in mice using inhibitory shock avoidance paradigm","volume":"35","author":"Raghavendra","year":"2001","journal-title":"Neuropeptides"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"135504","DOI":"10.1016\/j.neulet.2020.135504","article-title":"Effect of captopril, an angiotensin-converting enzyme inhibitor, on morphine analgesia and tolerance in rats, and elucidating the inflammation and endoplasmic reticulum stress pathway in this effect","volume":"741","author":"Taskiran","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_43","first-page":"681","article-title":"Place navigation impaired in rats with hippocampal lesions","volume":"297","author":"Morris","year":"1982","journal-title":"Nat. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/0166-4328(93)90091-4","article-title":"Emotional memory systems in the brain","volume":"58","author":"LeDoux","year":"1993","journal-title":"Behav. Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.yhbeh.2014.05.005","article-title":"The neurosteroid allopregnanolone impairs object memory and contextual fear memory in male C57BL\/6J mice","volume":"66","author":"Rabinowitz","year":"2014","journal-title":"Horm. Behav."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"40284","DOI":"10.1038\/srep40284","article-title":"Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation","volume":"7","author":"Benevento","year":"2017","journal-title":"Sci Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1073\/pnas.0911725107","article-title":"Running enhances spatial pattern separation in mice","volume":"107","author":"Creer","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1101\/lm.2001611","article-title":"Endurance factors improve hippocampal neurogenesis and spatial memory in mice","volume":"18","author":"Kobilo","year":"2011","journal-title":"Learn. Mem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"149","DOI":"10.7326\/0003-4819-137-3-200208060-00006","article-title":"Apolipoprotein E \u03f54 Allele, Elevated Midlife Total Cholesterol Level, and High Midlife Systolic Blood Pressure Are Independent Risk Factors for Late-Life Alzheimer Disease","volume":"137","author":"Kivipelto","year":"2002","journal-title":"Ann. Intern. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1007\/s11011-016-9803-4","article-title":"Atorvastatin ameliorates cognitive impairment, A\u03b21-42 production and Tau hyperphosphorylation in APP\/PS1 transgenic mice","volume":"31","author":"Zhou","year":"2016","journal-title":"Metab. Brain Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6163","DOI":"10.1007\/s12035-016-0134-6","article-title":"Atorvastatin Protects from A\u03b21\u201340-Induced Cell Damage and Depressive-Like Behavior via ProBDNF Cleavage","volume":"54","author":"Ludka","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s00401-019-02098-6","article-title":"ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer\u2019s disease","volume":"139","author":"Evans","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s13041-021-00758-x","article-title":"Simvastatin impairs hippocampal synaptic plasticity and cognitive function in mice","volume":"14","author":"Guo","year":"2021","journal-title":"Mol. Brain"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1007\/s00441-017-2735-4","article-title":"Review: Adult neurogenesis contributes to hippocampal plasticity","volume":"373","author":"Toda","year":"2018","journal-title":"Cell Tissue Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"881","DOI":"10.33549\/physiolres.933562","article-title":"The Effect of Hypertension on Adult Hippocampal Neurogenesis in Young Adult Spontaneously Hypertensive Rats and Dahl Rats","volume":"66","author":"Pistikova","year":"2017","journal-title":"Physiol. Res."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Beheshti, F., Akbari, H.R., Baghcheghi, Y., Mansouritorghabeh, F., Sani, S.S.M., and Hosseini, M. (2021). Beneficial effects of angiotensin converting enzyme inhibition on scopolamine-induced learning and memory impairment in rats, the roles of brain-derived neurotrophic factor, nitric oxide and neuroinflammation. Clin. Exp. Hypertens., 1\u201311.","DOI":"10.1080\/10641963.2021.1901112"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1002\/hipo.20543","article-title":"Functional analysis of neurovascular adaptations to exercise in the dentate gyrus of young adult mice associated with cognitive gain","volume":"19","author":"Clark","year":"2009","journal-title":"Hippocampus"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"918280","DOI":"10.4061\/2011\/918280","article-title":"Comparison of Vascular Perturbations in an A\u03b2-Injected Animal Model and in AD Brain","volume":"2011","author":"Jantaratnotai","year":"2011","journal-title":"Int. J. Alzheimer Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1523\/JNEUROSCI.1010-19.2019","article-title":"Age-Dependent Remarkable Regenerative Potential of the Dentate Gyrus Provided by Intrinsic Stem Cells","volume":"40","author":"Licht","year":"2020","journal-title":"J. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"262","DOI":"10.14336\/AD.2017.0613","article-title":"CLARITY for High-resolution Imaging and Quantification of Vasculature in the Whole Mouse Brain","volume":"9","author":"Zhang","year":"2018","journal-title":"Aging Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.tics.2019.01.006","article-title":"Exercise and Hippocampal Memory Systems","volume":"23","author":"Voss","year":"2019","journal-title":"Trends Cogn. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.12688\/f1000research.19317.1","article-title":"Interactions between the hippocampus, prefrontal cortex, and amygdala support complex learning and memory","volume":"8","author":"Yavas","year":"2019","journal-title":"F1000 Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"8462","DOI":"10.1523\/JNEUROSCI.3624-13.2014","article-title":"Neuronal Ensembles in Amygdala, Hippocampus, and Prefrontal Cortex Track Differential Components of Contextual Fear","volume":"34","author":"Zelikowsky","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1016\/j.biopsych.2013.08.024","article-title":"Angiotensin Type 1 Receptor Inhibition Enhances the Extinction of Fear Memory","volume":"75","author":"Marvar","year":"2014","journal-title":"Biol. Psychiatry"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41398-020-01043-6","article-title":"Evaluation of an angiotensin Type 1 receptor blocker on the reconsolidation of fear memory","volume":"10","author":"Swiercz","year":"2020","journal-title":"Transl. Psychiatry"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.nlm.2015.11.012","article-title":"Angiotensin-(1-7)\/Mas axis modulates fear memory and extinction in mice","volume":"127","author":"Lazaroni","year":"2016","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/nn.2499","article-title":"Synaptic correlates of fear extinction in the amygdala","volume":"13","author":"Amano","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1126\/science.1186909","article-title":"Induction of Fear Extinction with Hippocampal-Infralimbic BDNF","volume":"328","author":"Peters","year":"2010","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1038\/sj.npp.1301642","article-title":"Disruption of AMPA Receptor Endocytosis Impairs the Extinction, but not Acquisition of Learned Fear","volume":"33","author":"Dalton","year":"2007","journal-title":"Neuropsychopharmacology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"658686","DOI":"10.3389\/fnbeh.2021.658686","article-title":"Genetic Depletion of BDNF Impairs Extinction Learning of a Spatial Appetitive Task in the Presence or Absence of the Acquisition Context","volume":"15","author":"Krenzek","year":"2021","journal-title":"Front. Behav. Neurosci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/7\/1778\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:30:24Z","timestamp":1760164224000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/7\/1778"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,14]]},"references-count":70,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["cells10071778"],"URL":"https:\/\/doi.org\/10.3390\/cells10071778","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,14]]}}}