{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T05:03:31Z","timestamp":1779944611856,"version":"3.53.1"},"reference-count":49,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003343","name":"Cambridge Trust","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003343","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Jameel Education Foundation Cambridge Scholarship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Adult hippocampal neurogenesis persists throughout the human lifespan, yet declines in Alzheimer\u2019s disease and major depression, associated in part with reduced brain-derived neurotrophic factor (BDNF) levels. For rodents, environmental enrichment, dichotomised primarily as physical activity and spatial complexity, robustly promotes adult hippocampal neurogenesis, but no framework has translated these findings to human environments. This review is the first to synthesise evidence across the full translational pathway, arguing that spatial complexity and physically active navigation in neighbourhoods and buildings constitute a humanised form of environmental enrichment. It proposes that standard indoor environments may represent a functionally impoverished condition for the human hippocampus, paralleling standard laboratory caging. An applied model is presented, mapping built environment features onto the neurobiological mechanisms regulating adult hippocampal neurogenesis, with BDNF as the central translatable biomarker linking environmental exposures to neurogenic outcomes. A methodological roadmap for future empirical validation is also outlined. This framework repositions the built environment as a modifiable determinant of adult hippocampal neurogenesis in humans, with implications for mitigating the risk of depression, cognitive impairment, and Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.3390\/ijms27114779","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T11:02:51Z","timestamp":1779793371000},"page":"4779","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Humanised Environmental Enrichment: Spatial Effects of Cities and Buildings on Adult Hippocampal Neurogenesis in Humans"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7754-6479","authenticated-orcid":false,"given":"Mohamed Hesham","family":"Khalil","sequence":"first","affiliation":[{"name":"Department of Architecture, University of Cambridge, Cambridge CB2 1PX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1038\/s41380-024-02815-y","article-title":"Hippocampal neurogenesis in adult primates: A systematic review","volume":"30","author":"Elliott","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","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":"ref_3","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.stem.2018.03.015","article-title":"Human hippocampal neurogenesis persists throughout aging","volume":"22","author":"Boldrini","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1523\/JNEUROSCI.0675-20.2020","article-title":"Evidences for adult hippocampal neurogenesis in humans","volume":"41","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/s41591-019-0375-9","article-title":"Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer\u2019s disease","volume":"25","author":"Cafini","year":"2019","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1016\/j.stem.2019.05.003","article-title":"Human hippocampal neurogenesis persists in aged adults and Alzheimer\u2019s disease patients","volume":"24","author":"Tobin","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1038\/s41586-026-10169-4","article-title":"Human hippocampal neurogenesis in adulthood, ageing and Alzheimer\u2019s disease","volume":"652","author":"Disouky","year":"2026","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/j.stem.2025.08.010","article-title":"Human adult hippocampal neurogenesis is shaped by neuropsychiatric disorders, demographics, and lifestyle-related factors","volume":"32","year":"2025","journal-title":"Cell Stem Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1038\/s41593-025-02027-9","article-title":"Cross-species analysis of adult hippocampal neurogenesis reveals human-specific gene expression but convergent biological processes","volume":"28","author":"Zhou","year":"2025","journal-title":"Nat. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1186\/s13287-024-03818-w","article-title":"Comprehensive characterization of the neurogenic and neuroprotective action of a novel TrkB agonist using mouse and human stem cell models of Alzheimer\u2019s disease","volume":"15","author":"Charou","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.1093\/cercor\/bhy096","article-title":"Hippocampal radial glial subtypes and their neurogenic potential in human fetuses and healthy and Alzheimer\u2019s disease adults","volume":"28","author":"Cipriani","year":"2018","journal-title":"Cereb. Cortex"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/nature25975","article-title":"Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults","volume":"555","author":"Sorrells","year":"2018","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.biopsych.2012.04.024","article-title":"Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression","volume":"72","author":"Boldrini","year":"2012","journal-title":"Biol. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e958","DOI":"10.1038\/tp.2016.214","article-title":"The human BDNF gene: Peripheral gene expression and protein levels as biomarkers for psychiatric disorders","volume":"6","author":"Cattaneo","year":"2016","journal-title":"Transl. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10326","DOI":"10.1073\/pnas.1017099108","article-title":"Maturation time of new granule cells in the dentate gyrus of adult macaque monkeys exceeds six months","volume":"108","author":"Kohler","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/386493a0","article-title":"More hippocampal neurons in adult mice living in an enriched environment","volume":"386","author":"Kempermann","year":"1997","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/6368","article-title":"Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus","volume":"2","author":"Kempermann","year":"1999","journal-title":"Nat. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.neuroscience.2013.12.026","article-title":"Environmental enrichment induces neuroplastic changes in middle age female BalbC mice and increases the hippocampal levels of BDNF, p-Akt and p-MAPK1\/2","volume":"260","year":"2014","journal-title":"Neuroscience"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.3892\/mmr.2016.5470","article-title":"Increased protein expression levels of pCREB, BDNF and SDF-1\/CXCR4 in the hippocampus may be associated with enhanced neurogenesis induced by environmental enrichment","volume":"14","author":"Zhang","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4351","DOI":"10.1523\/JNEUROSCI.3239-15.2016","article-title":"Late-life environmental enrichment induces acetylation events and nuclear factor \u03baB-dependent regulations in the hippocampus of aged rats showing improved plasticity and learning","volume":"36","author":"Neidl","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"121","DOI":"10.3920\/CEP190036","article-title":"Continuous environmental enrichment and aerobic exercise improves spatial memory: Focus on rat hippocampal BDNF and NGF","volume":"16","author":"Santoso","year":"2020","journal-title":"Comp. Exerc. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Funabashi, D., Tsuchida, R., Matsui, T., Kita, I., and Nishijima, T. (2023). Enlarged housing space and increased spatial complexity enhance hippocampal neurogenesis but do not increase physical activity in mice. Front. Sports Act. Living, 5.","DOI":"10.3389\/fspor.2023.1203260"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.neuropharm.2018.03.042","article-title":"Lifelong environmental enrichment in the absence of exercise protects the brain from age-related cognitive decline","volume":"145","author":"Birch","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.neuroscience.2023.05.018","article-title":"Cell Proliferation and Cell Death Levels in the Dentate Gyrus Correlate with Home Range Size Among Adult Male Meadow Voles","volume":"523","author":"Sinks","year":"2023","journal-title":"Neuroscience"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.nlm.2018.02.014","article-title":"Topographical memory analyzed in mice using the Hamlet test, a novel complex maze","volume":"149","author":"Crouzier","year":"2018","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Fares, R.P., Belmeguenai, A., Sanchez, P.E., Kouchi, H.Y., Bodennec, J., Morales, A., Georges, B., Bonnet, C., Bouvard, S., and Sloviter, R.S. (2013). Standardized environmental enrichment supports enhanced brain plasticity in healthy rats and prevents cognitive impairment in epileptic rats. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053888"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Hutchinson, K.A., Mohammad, S., Garneau, L., McInnis, K., Aguer, C., and Adamo, K.B. (2019). Examination of the myokine response in pregnant and non-pregnant women following an acute bout of moderate-intensity walking. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01188"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1080\/23328940.2023.2176107","article-title":"Elevations in serum brain-derived neurotrophic factor following occupational heat stress are not influenced by age or common chronic disease","volume":"10","author":"Goulet","year":"2023","journal-title":"Temperature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e001629","DOI":"10.1136\/bmjsem-2023-001629","article-title":"Cognitive and biomarker responses in healthy older adults to a 18-hole golf round and different walking types: A randomised cross-over study","volume":"9","author":"Kettinen","year":"2023","journal-title":"BMJ Open Sport Exerc. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Li, Q., Zhang, L., Zhang, Z., Wang, Y., Zuo, C., and Bo, S. (2022). A shorter-bout of HIIT is more effective to promote serum BDNF and VEGF-A levels and improve cognitive function in healthy young men. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.898603"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7600\/jpfsm.11.1","article-title":"An 18-hole round of golf acutely elevates serum interleukin-6 and brain-derived neurotrophic factor concentration\u2014A pilot study","volume":"11","author":"Yasuoka","year":"2022","journal-title":"J. Phys. Fit. Sports Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Amerio, A., Brambilla, A., Morganti, A., Aguglia, A., Bianchi, D., Santi, F., Costantini, L., Odone, A., Costanza, A., and Signorelli, C. (2020). COVID-19 lockdown: Housing built environment\u2019s effects on mental health. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17165973"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.jad.2023.05.004","article-title":"Housing conditions and changes in professional activity during lockdown and the risk of prevalent and incident depression: Findings from the CONSTANCES cohort","volume":"335","author":"Gouraud","year":"2023","journal-title":"J. Affect. Disord."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Khalil, M.H., and Steemers, K. (2025). Brain Booster Buildings: Modelling Stair Use as a Daily Booster of Brain-Derived Neurotrophic Factor. Buildings, 15.","DOI":"10.3390\/buildings15203730"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1037\/prj0000483","article-title":"Getting out of the house: The relationship of venturing into the community and neurocognition among adults with serious mental illness","volume":"45","author":"McCormick","year":"2022","journal-title":"Psychiatr. Rehabil. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"620.e9","DOI":"10.1016\/j.neurobiolaging.2011.02.013","article-title":"Spatial navigation training protects the hippocampus against age-related changes during early and late adulthood","volume":"33","author":"Schaefer","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.jalz.2016.06.2364","article-title":"Associations of neighborhood environment with brain imaging outcomes in the Australian Imaging, Biomarkers and Lifestyle cohort","volume":"13","author":"Cerin","year":"2017","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_38","first-page":"e12551","article-title":"Geospatial environmental complexity, spatial brain volume, and spatial behavior across the Alzheimer\u2019s disease spectrum","volume":"16","author":"Shin","year":"2024","journal-title":"Alzheimer\u2019s Dement. Diagn. Assess. Dis. Monit."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Khalil, M.H. (Front. Arch. Res., 2026). The Architectural Spatial Complexity Index (A-SCI): Assessment of Cognitive Enrichment for Hippocampal Neurogenesis, Front. Arch. Res., in press.","DOI":"10.1016\/j.foar.2025.12.016"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"38322","DOI":"10.1038\/s41598-025-22209-6","article-title":"Acute high-intensity interval training, but not reduced-exertion high-intensity interval training increase brain-derived neurotrophic factor in a block randomized controlled trial","volume":"15","author":"Evelis","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.psychres.2017.04.034","article-title":"Measuring BDNF in saliva using commercial ELISA: Results from a small pilot study","volume":"254","author":"Vrijen","year":"2017","journal-title":"Psychiatry Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1016\/S0028-3908(98)00141-5","article-title":"Transport of brain-derived neurotrophic factor across the blood\u2013brain barrier","volume":"37","author":"Pan","year":"1998","journal-title":"Neuropharmacology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/0169-328X(95)00250-V","article-title":"Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF","volume":"36","author":"Poduslo","year":"1996","journal-title":"Mol. Brain Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1038\/s41380-024-02504-w","article-title":"The impact of adult neurogenesis on affective functions: Of mice and men","volume":"29","author":"Alonso","year":"2024","journal-title":"Mol. Psychiatry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"102600","DOI":"10.1016\/j.stemcr.2025.102600","article-title":"Adult hippocampal neurogenesis: New avenues for treatment of brain disorders","volume":"20","author":"Chen","year":"2025","journal-title":"Stem Cell Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9655","DOI":"10.1038\/s41598-019-45976-5","article-title":"Associations between Serum and Plasma Brain-Derived Neurotrophic Factor and Influence of Storage Time and Centrifugation Strategy","volume":"9","author":"Gejl","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1113\/JP283582","article-title":"Fasting for 20 h Does Not Affect Exercise-Induced Increases in Circulating BDNF in Humans","volume":"601","author":"Gibbons","year":"2023","journal-title":"J. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Khalil, M.H., and Steemers, K. (2026). Vertical Architecture and Mental Health: Assessment of Depressive Symptoms Among Dwellers in Apartments and Multi-Storey Houses. Buildings, 16.","DOI":"10.3390\/buildings16101950"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Khalil, M.H. (2026). Comparative Analysis of Maze Complexity: Implications for Adult Hippocampal Neurogenesis. Front. Neurosci., 20.","DOI":"10.3389\/fnins.2026.1766823"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4779\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T04:23:45Z","timestamp":1779942225000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4779"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,26]]},"references-count":49,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27114779"],"URL":"https:\/\/doi.org\/10.3390\/ijms27114779","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,26]]}}}