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Rackham School of Graduate Studies, University of Michigan","doi-asserted-by":"publisher","award":["Rackham Merit Fellowship"],"award-info":[{"award-number":["Rackham Merit Fellowship"]}],"id":[{"id":"10.13039\/100006801","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>General anesthetics work through a variety of molecular mechanisms while resulting in the common end point of sedation and loss of consciousness. Generally, the administration of common anesthetics induces reduction in synaptic excitation while promoting synaptic inhibition. Exogenous modulation of the anesthetics\u2019 synaptic effects can help determine the neuronal pathways involved in anesthesia. For example, both animal and human studies have shown that exogenously induced increases in acetylcholine in the brain can elicit wakeful-like behavior despite the continued presence of the anesthetic. However, the underlying mechanisms of anesthesia reversal at the cellular level have not been investigated. Here we apply a computational model of a network of excitatory and inhibitory neurons to simulate the network-wide effects of anesthesia, due to changes in synaptic inhibition and excitation, and their reversal by cholinergic activation through muscarinic receptors. We use a differential evolution algorithm to fit model parameters to match measures of spiking activity, neuronal connectivity, and network dynamics recorded in the visual cortex of rodents during anesthesia with desflurane <jats:italic>in vivo<\/jats:italic>. We find that facilitating muscarinic receptor effects of acetylcholine on top of anesthetic-induced synaptic changes predicts the reversal of anesthetic suppression of neurons\u2019 spiking activity, functional connectivity, as well as pairwise and population interactions. Thus, our model predicts a specific neuronal mechanism for the cholinergic reversal of anesthesia consistent with experimental behavioral observations.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009743","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T17:46:52Z","timestamp":1656006412000},"page":"e1009743","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Modeling cortical synaptic effects of anesthesia and their cholinergic reversal"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2455-6973","authenticated-orcid":true,"given":"Bolaji P.","family":"Eniwaye","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2586-8001","authenticated-orcid":true,"given":"Victoria","family":"Booth","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2241-1751","authenticated-orcid":true,"given":"Anthony G.","family":"Hudetz","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1722-986X","authenticated-orcid":true,"given":"Michal","family":"Zochowski","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,6,23]]},"reference":[{"key":"pcbi.1009743.ref001","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S0079-6123(05)50017-7","article-title":"General anesthesia and the neural correlates of consciousness","volume":"150","author":"MT Alkire","year":"2005","journal-title":"Prog Brain Res"},{"key":"pcbi.1009743.ref002","doi-asserted-by":"crossref","first-page":"2638","DOI":"10.1056\/NEJMra0808281","article-title":"Mechanisms of Disease General Anesthesia, Sleep, and Coma","volume":"363","author":"RS Schwartz","year":"2010","journal-title":"N Engl J Med"},{"key":"pcbi.1009743.ref003","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.tins.2018.01.003","article-title":"Neural Correlates of Unconsciousness in Large-Scale Brain Networks","volume":"41","author":"GA Mashour","year":"2018","journal-title":"Trends Neurosci"},{"key":"pcbi.1009743.ref004","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/nrn2372","article-title":"General anaesthesia: From molecular targets to neuronal pathways of sleep and arousal","volume":"9","author":"NP Franks","year":"2008","journal-title":"Nat Rev Neurosci"},{"key":"pcbi.1009743.ref005","doi-asserted-by":"crossref","DOI":"10.1088\/1361-6579\/aab4d0","article-title":"Emergence EEG pattern classification in sevoflurane anesthesia","volume":"39","author":"Z Liang","year":"2018","journal-title":"Physiol Meas"},{"key":"pcbi.1009743.ref006","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1097\/00000542-200309000-00024","article-title":"The Actions of Sevoflurane and Desflurane on the \u03b3-Aminobutyric Acid Receptor Type A: Effects of TM2 Mutations in the \u03b1 and \u03b2 Subunits","volume":"99","author":"K Nishikawa","year":"2003","journal-title":"Anesthesiology"},{"key":"pcbi.1009743.ref007","doi-asserted-by":"crossref","DOI":"10.1177\/1744806920903149","article-title":"Effects of sevoflurane and desflurane on the nociceptive responses of substantia gelatinosa neurons in the rat spinal cord dorsal horn: An in vivo patch-clamp analysis","volume":"16","author":"Y Inada","year":"2020","journal-title":"Mol Pain"},{"key":"pcbi.1009743.ref008","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1097\/00000539-200105000-00020","article-title":"Modulation of NMDA receptor function by ketamine and magnesium. 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