{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T16:25:46Z","timestamp":1778775946224,"version":"3.51.4"},"reference-count":81,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T00:00:00Z","timestamp":1687132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Neuronal morphological characterization and behavioral phenotyping in mouse models help dissecting neural mechanisms of brain disorders. Olfactory dysfunctions and other cognitive problems were widely reported in asymptomatic carriers and symptomatic patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This led us to generate the knockout mouse model for Angiotensin Converting Enzyme-2 (ACE2) receptor, one of the molecular factors mediating SARS-CoV-2 entry to the central nervous system, using CRISPR-Cas9 based genome editing tools. ACE2 receptors and Transmembrane Serine Protease-2 (TMPRSS2) are widely expressed in the supporting (sustentacular) cells of human and rodent olfactory epithelium, however, not in the olfactory sensory neurons (OSNs). Hence, acute inflammation induced changes due to viral infection in the olfactory epithelium may explain transient changes in olfactory detectabilities. As ACE2 receptors are expressed in different olfactory centers and higher brain areas, we studied the morphological changes in the olfactory epithelium (OE) and olfactory bulb (OB) of ACE2 KO mice in comparison with wild type animals. Our results showed reduced thickness of OSN layer in the OE, and a decrease in cross-sectional area of glomeruli in the OB. Aberrations in the olfactory circuits were revealed by lowered immunoreactivity toward microtubule associated protein 2 (MAP2) in the glomerular layer of ACE2 KO mice. Further, to understand if these morphological alterations lead to compromised sensory and cognitive abilities, we performed an array of behavioral assays probing their olfactory subsystems\u2019 performances. ACE2 KO mice exhibited slower learning of odor discriminations at the threshold levels and novel odor identification impairments. Further, ACE2 KO mice failed to memorize the pheromonal locations while trained on a multimodal task implying the aberrations of neural circuits involved in higher cognitive functions. Our results thus provide the morphological basis for the sensory and cognitive disabilities caused by the deletion of ACE2 receptors and offer a potential experimental approach to study the neural circuit mechanisms of cognitive impairments observed in long COVID.<\/jats:p>","DOI":"10.3389\/fnins.2023.1180868","type":"journal-article","created":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T04:57:55Z","timestamp":1687150675000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Knockout of angiotensin converting enzyme-2 receptor leads to morphological aberrations in rodent olfactory centers and dysfunctions associated with sense of smell"],"prefix":"10.3389","volume":"17","author":[{"given":"Sarang","family":"Mahajan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepshikha","family":"Sen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anantu","family":"Sunil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priyadharshini","family":"Srikanth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shruti D.","family":"Marathe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karishma","family":"Shaw","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahesh","family":"Sahare","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjeev","family":"Galande","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nixon M.","family":"Abraham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.neuron.2010.01.009","article-title":"Synaptic inhibition in the olfactory bulb accelerates odor discrimination in mice","volume":"65","author":"Abraham","year":"2010","journal-title":"Neuron"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1016\/j.neuron.2004.11.017","article-title":"Maintaining accuracy at the expense of speed: stimulus similarity defines odor discrimination time in mice","volume":"44","author":"Abraham","year":"2004","journal-title":"Neuron"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e02109","DOI":"10.7554\/eLife.02109","article-title":"Long term functional plasticity of sensory inputs mediated by olfactory learning","volume":"3","author":"Abraham","year":"2014","journal-title":"Elife"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1007\/s11064-018-2679-4","article-title":"ACE2 in brain physiology and pathophysiology: evidence from transgenic animal models","volume":"44","author":"Alenina","year":"2019","journal-title":"Neurochem. Res."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.jns.2012.08.028","article-title":"Evaluation of olfactory dysfunction in neurodegenerative diseases","volume":"323","author":"Barresi","year":"2012","journal-title":"J. Neurol. Sci."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1007\/s10495-022-01754-9","article-title":"COVID-19 causes neuronal degeneration and reduces neurogenesis in human hippocampus","volume":"27","author":"Bayat","year":"2022","journal-title":"Apoptosis"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1515\/intox-2017-0006","article-title":"Animal tests for anxiety-like and depression-like behavior in rats","volume":"10","author":"Belovicova","year":"2017","journal-title":"Interdiscip. Toxicol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"100575","DOI":"10.1016\/j.eclinm.2020.100575","article-title":"Quantitative assessment of olfactory dysfunction accurately detects asymptomatic COVID-19 carriers","volume":"28","author":"Bhattacharjee","year":"2020","journal-title":"EClinicalMedicine"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"2966","DOI":"10.1016\/j.celrep.2019.08.015","article-title":"Similarity and strength of glomerular odor representations define a neural metric of sniff-invariant discrimination time","volume":"28","author":"Bhattacharjee","year":"2019","journal-title":"Cell Rep."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"100081","DOI":"10.1016\/j.crneur.2023.100081","article-title":"Persistent olfactory learning deficits during and post-COVID-19 infection","volume":"4","author":"Bhowmik","year":"2023","journal-title":"Curr. Res. Neurobiol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1555","DOI":"10.1021\/acschemneuro.0c00210","article-title":"Expression of the SARS-CoV-2 entry proteins, ACE2 and TMPRSS2, in cells of the olfactory epithelium: identification of cell types and trends with age","volume":"11","author":"Bilinska","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1001\/jamapsychiatry.2021.0500","article-title":"How COVID-19 affects the brain","volume":"78","author":"Boldrini","year":"2021","journal-title":"JAMA Psychiat."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"eabc5801","DOI":"10.1126\/sciadv.abc5801","article-title":"Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia","volume":"6","author":"Brann","year":"2020","journal-title":"Sci. Adv."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/S0092-8674(00)80698-4","article-title":"The molecular architecture of odor and pheromone sensing in mammals","volume":"100","author":"Buck","year":"2000","journal-title":"Cells"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1021\/acschemneuro.0c00172","article-title":"SARS-CoV-2: olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection","volume":"11","author":"Butowt","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1126\/science.abd2985","article-title":"Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity","volume":"370","author":"Cantuti-Castelvetri","year":"2020","journal-title":"Science"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/nrg1619","article-title":"Gene targeting in mice: functional analysis of the mammalian genome for the twenty-first century","volume":"6","author":"Capecchi","year":"2005","journal-title":"Nat. Rev. Genet."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1001\/jamaophthalmol.2020.6339","article-title":"Presence of SARS-CoV-2 RNA in the cornea of Viremic patients with COVID-19","volume":"139","author":"Casagrande","year":"2021","journal-title":"JAMA Ophthalmol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.neuron.2020.06.032","article-title":"COVID-19 and the chemical senses: supporting players take center stage","volume":"107","author":"Cooper","year":"2020","journal-title":"Neuron"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1093\/chemse\/25.2.199","article-title":"Rewiring the olfactory bulb: changes in odor maps following recovery from nerve transection","volume":"25","author":"Costanzo","year":"2000","journal-title":"Chem. Senses"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1038\/nature00786","article-title":"Angiotensin-converting enzyme 2 is an essential regulator of heart function","volume":"417","author":"Crackower","year":"2002","journal-title":"Nature"},{"key":"ref22","first-page":"151","article-title":"Neurogenesis in the olfactory epithelium","volume":"2","author":"Crews","year":"1994","journal-title":"Perspect. Dev. Neurobiol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"eabf8396","DOI":"10.1126\/scitranslmed.abf8396","article-title":"COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters","volume":"13","author":"De Melo","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"E1","DOI":"10.1161\/01.res.87.5.e1","article-title":"A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9","volume":"87","author":"Donoghue","year":"2000","journal-title":"Circ. Res."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/nrneurol.2012.80","article-title":"Olfactory dysfunction in Parkinson disease","volume":"8","author":"Doty","year":"2012","journal-title":"Nat. Rev. Neurol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1038\/s41586-022-04569-5","article-title":"SARS-CoV-2 is associated with changes in brain structure in UK biobank","volume":"604","author":"Douaud","year":"2022","journal-title":"Nature"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"114969","DOI":"10.1016\/j.psychres.2022.114969","article-title":"Two-year follow-up of brain structural changes in patients who recovered from COVID-19: A prospective study","volume":"319","author":"Du","year":"2023","journal-title":"Psychiatry Res."},{"key":"ref28","doi-asserted-by":"publisher","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":"ref29","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1111\/j.1460-9568.2008.06346.x","article-title":"Olfactory deficits in mice overexpressing human wildtype alpha-synuclein","volume":"28","author":"Fleming","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"ref30","first-page":"101839","article-title":"SARS-CoV-2 receptors and entry genes are expressed in the human olfactory neuroepithelium and brain","author":"Fodoulian","year":"2020"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1007\/s12264-017-0170-x","article-title":"Olfactory dysfunction as an early biomarker in Parkinson\u2019s disease","volume":"33","author":"Fullard","year":"2017","journal-title":"Neurosci. Bull."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"4122","DOI":"10.1128\/JVI.02232-10","article-title":"Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response","volume":"85","author":"Glowacka","year":"2011","journal-title":"J. Virol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1002\/path.1570","article-title":"Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis","volume":"203","author":"Hamming","year":"2004","journal-title":"J. Pathol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"101044","DOI":"10.1016\/j.eclinm.2021.101044","article-title":"Cognitive deficits in people who have recovered from COVID-19","volume":"39","author":"Hampshire","year":"2021","journal-title":"EClinicalMedicine"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"15.7.1","DOI":"10.1002\/0471142905.hg1507s83","article-title":"Mouse genome editing using the CRISPR\/Cas system","volume":"83","author":"Harms","year":"2014","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cells"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1111\/cns.13569","article-title":"Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms","volume":"27","author":"Huang","year":"2021","journal-title":"CNS Neurosci. Ther."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1038\/s41591-021-01296-8","article-title":"SARS-CoV-2 infection of the oral cavity and saliva","volume":"27","author":"Huang","year":"2021","journal-title":"Nat. Med."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1007\/s00415-021-10655-x","article-title":"Long COVID: cognitive complaints (brain fog) and dysfunction of the cingulate cortex","volume":"269","author":"Hugon","year":"2022","journal-title":"J. Neurol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"bjac022","DOI":"10.1093\/chemse\/bjac022","article-title":"Loss of olfactory sensitivity is an early and reliable marker for COVID-19","volume":"47","author":"Iravani","year":"2022","journal-title":"Chem. Senses"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41580-021-00418-x","article-title":"Mechanisms of SARS-CoV-2 entry into cells","volume":"23","author":"Jackson","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"5165","DOI":"10.1038\/s41467-020-18880-0","article-title":"ACE2 mouse models: a toolbox for cardiovascular and pulmonary research","volume":"11","author":"Jia","year":"2020","journal-title":"Nat. Commun."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1093\/chemse\/bjg068","article-title":"Axon mis-targeting in the olfactory bulb during regeneration of olfactory neuroepithelium","volume":"28","author":"John","year":"2003","journal-title":"Chem. Senses"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"dmm039982","DOI":"10.1242\/dmm.039982","article-title":"CRISPR\/Cas9-mediated genome editing in nonhuman primates","volume":"12","author":"Kang","year":"2019","journal-title":"Dis. Model. Mech."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1152\/jn.00255.2022","article-title":"COVID-19 and olfactory dysfunction: a looming wave of dementia?","volume":"128","author":"Kay","year":"2022","journal-title":"J. Neurophysiol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"5932","DOI":"10.1016\/j.cell.2021.10.027","article-title":"Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb","volume":"184","author":"Khan","year":"2021","journal-title":"Cells"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"3625","DOI":"10.1007\/s00018-018-2815-y","article-title":"Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response","volume":"75","author":"Klempin","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1159\/000513040","article-title":"Evidence of SARS-CoV2 entry protein ACE2 in the human nose and olfactory bulb","volume":"209","author":"Klingenstein","year":"2020","journal-title":"Cells Tissues Organs"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41392-020-00460-9","article-title":"Not only ACE2-the quest for additional host cell mediators of SARS-CoV-2 infection: Neuropilin-1 (NRP1) as a novel SARS-CoV-2 host cell entry mediator implicated in COVID-19","volume":"6","author":"Kyrou","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"100347","DOI":"10.1016\/j.bbih.2021.100347","article-title":"Post-acute sequelae of COVID-19: evidence of mood & cognitive impairment","volume":"17","author":"Lamontagne","year":"2021","journal-title":"Brain Behav. Immun. Health"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1007\/s12105-020-01212-5","article-title":"ACE2 & TMPRSS2 expressions in Head & Neck Tissues: A systematic review","volume":"15","author":"Lechien","year":"2021","journal-title":"Head Neck Pathol."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"e51804","DOI":"10.3791\/51804","article-title":"Olfactory assays for mouse models of neurodegenerative disease","volume":"90","author":"Lehmkuhl","year":"2014","journal-title":"JoVE"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1186\/s12967-020-02670-9","article-title":"Parkinson\u2019s disease following COVID-19: causal link or chance occurrence?","volume":"18","author":"Li","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.3174\/ajnr.A7072","article-title":"Brain and lung imaging correlation in patients with COVID-19: could the severity of lung disease reflect the prevalence of acute abnormalities on neuroimaging? A global multicenter observational study","volume":"42","author":"Mahammedi","year":"2021","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"150002","DOI":"10.1038\/sdata.2015.2","article-title":"Human olfactory receptor responses to odorants","volume":"2","author":"Mainland","year":"2015","journal-title":"Sci. Data"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.euroneuro.2021.10.864","article-title":"The impact of the prolonged COVID-19 pandemic on stress resilience and mental health: a critical review across waves","volume":"55","author":"Manchia","year":"2022","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1007\/s11882-018-0796-4","article-title":"Olfactory dysfunction in neurodegenerative diseases","volume":"18","author":"Marin","year":"2018","journal-title":"Curr Allergy Asthma Rep"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"eaam7263","DOI":"10.1126\/science.aam7263","article-title":"Poor human olfaction is a 19th-century myth","volume":"356","author":"McGann","year":"2017","journal-title":"Science"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/s41593-020-00758-5","article-title":"Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19","volume":"24","author":"Meinhardt","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/S1474-4422(20)30442-7","article-title":"SARS-CoV-2 and the risk of Parkinson\u2019s disease: facts and fantasy","volume":"20","author":"Merello","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"602970","DOI":"10.3389\/fgeed.2020.602970","article-title":"Methodologies and challenges for CRISPR\/Cas9 mediated genome editing of the mammalian brain","volume":"2","author":"Nishizono","year":"2020","journal-title":"Front. Genome Ed."},{"key":"ref62","article-title":"Neurotropic SARS-CoV-2: causalities and realities","volume-title":"COVID-19 pandemic, mental health and neuroscience - new scenarios for understanding and treatment","author":"Pardasani","year":"2022"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"e21836","DOI":"10.1096\/fj.202100167R","article-title":"Multimodal learning of pheromone locations","volume":"35","author":"Pardasani","year":"2021","journal-title":"FASEB J."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"100299","DOI":"10.1016\/j.esxm.2020.100299","article-title":"The impact of COVID-19 on sexual health: A preliminary framework based on a qualitative study with clinical sexologists","volume":"9","author":"Pascoal","year":"2021","journal-title":"Sex. Med."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"9713","DOI":"10.1523\/JNEUROSCI.21-24-09713.2001","article-title":"Structure and emergence of specific olfactory glomeruli in the mouse","volume":"21","author":"Potter","year":"2001","journal-title":"J. Neurosci."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1056\/NEJMc2011400","article-title":"Multiorgan and renal tropism of SARS-CoV-2","volume":"383","author":"Puelles","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"11727","DOI":"10.1073\/pnas.2003138117","article-title":"Cell entry mechanisms of SARS-CoV-2","volume":"117","author":"Shang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref68","doi-asserted-by":"publisher","first-page":"2493","DOI":"10.1038\/nprot.2014.171","article-title":"CRISPR\/Cas-mediated genome editing in the rat via direct injection of one-cell embryos","volume":"9","author":"Shao","year":"2014","journal-title":"Nat. Protoc."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"249","DOI":"10.31887\/DCNS.2019.21.3\/mrossner","article-title":"Assessing behavior and cognition in rodents, nonhuman primates, and humans: Where are the limits of translation?","volume":"21","author":"Stephan","year":"2022","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/s41531-020-00123-0","article-title":"COVID-19 and possible links with Parkinson\u2019s disease and parkinsonism: from bench to bedside","volume":"6","author":"Sulzer","year":"2020","journal-title":"NPJ Parkinsons Dis."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1038\/s41591-020-0868-6","article-title":"SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes","volume":"26","author":"Sungnak","year":"2020","journal-title":"Nat. Med."},{"key":"ref72","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1016\/j.neuron.2011.07.026","article-title":"A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex","volume":"71","author":"Taniguchi","year":"2011","journal-title":"Neuron"},{"key":"ref73","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.bbr.2006.04.025","article-title":"Olfactory discrimination deficits in mice lacking the dopamine transporter or the D2 dopamine receptor","volume":"172","author":"Tillerson","year":"2006","journal-title":"Behav. Brain Res."},{"key":"ref74","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.ejim.2020.04.037","article-title":"The pivotal link between ACE2 deficiency and SARS-CoV-2 infection","volume":"76","author":"Verdecchia","year":"2020","journal-title":"Eur. J. Intern. Med."},{"key":"ref75","doi-asserted-by":"publisher","first-page":"16024","DOI":"10.1038\/npjamd.2016.24","article-title":"Deficiency of angiotensin-converting enzyme 2 causes deterioration of cognitive function","volume":"2","author":"Wang","year":"2016","journal-title":"NPJ Aging Mech. Dis."},{"key":"ref76","doi-asserted-by":"publisher","first-page":"2512","DOI":"10.1001\/jama.2020.8391","article-title":"Olfactory dysfunction in COVID-19: diagnosis and management","volume":"323","author":"Whitcroft","year":"2020","journal-title":"JAMA"},{"key":"ref77","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.coviro.2021.02.006","article-title":"Coronavirus entry: how we arrived at SARS-CoV-2","volume":"47","author":"Whittaker","year":"2021","journal-title":"Curr. Opin. Virol."},{"key":"ref78","volume-title":"COVID-19 pandemic triggers 25% increase in prevalence of anxiety and depression worldwide","year":"2022"},{"key":"ref79","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1016\/j.cell.2013.08.022","article-title":"One-step generation of mice carrying reporter and conditional alleles by CRISPR\/Cas-mediated genome engineering","volume":"154","author":"Yang","year":"2013","journal-title":"Cells"},{"key":"ref80","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1002\/ijgo.13193","article-title":"Effect of the COVID-19 pandemic on female sexual behavior","volume":"150","author":"Yuksel","year":"2020","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref81","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.jtos.2020.06.007","article-title":"ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection","volume":"18","author":"Zhou","year":"2020","journal-title":"Ocul. Surf."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2023.1180868\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T04:58:00Z","timestamp":1687150680000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2023.1180868\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,19]]},"references-count":81,"alternative-id":["10.3389\/fnins.2023.1180868"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2023.1180868","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,19]]},"article-number":"1180868"}}