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Patients with TLE often experience impaired consciousness. A recent awake mouse model study demonstrated decreased cortical cholinergic innervation during focal seizures with impaired consciousness, based on cortical slow wave activity and decreased behavioral responsiveness. But the underlying mechanisms for reduced cortical cholinergic activity are not fully understood. This study employs the same awake mouse model combined with electrophysiology recordings in key network nodes, cell-specific calcium imaging in the lateral septum, and neurotransmitter sensing in one of the major subcortical cholinergic systems, the nucleus basalis of Meynert (NBM). We demonstrate that decreased cortical cholinergic innervation during focal seizures comes from both direct inhibition and indirect de-excitation of the NBM, showing a parallel pathway NBM suppression mechanism from the LS directly and through the paratenial thalamic nucleus indirectly. This work contributes to a deeper understanding of the neural processes involved in impaired consciousness during focal seizures and may open the way to new treatments for this disorder.<\/jats:p>","DOI":"10.1101\/2025.09.17.676820","type":"posted-content","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T23:55:12Z","timestamp":1758153312000},"source":"Crossref","is-referenced-by-count":1,"title":["Lateral septal inhibition of nucleus basalis through direct and indirect pathways in focal limbic seizures"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1700-3203","authenticated-orcid":false,"given":"Jiayang","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lim-Anna","family":"Sieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Doan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengsan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Brodovskaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jadeep","family":"Kapur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica A.","family":"Cardin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hal","family":"Blumenfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025092019050785000_2025.09.17.676820v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2007.12.019"},{"issue":"1","key":"2025092019050785000_2025.09.17.676820v1.2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1155\/2011\/121243","article-title":"The effect of alterations in consciousness on quality of life (QoL) in epilepsy: searching for evidence","volume":"24","year":"2011","journal-title":"Behav Neurol"},{"key":"2025092019050785000_2025.09.17.676820v1.3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1998.tb01309.x"},{"key":"2025092019050785000_2025.09.17.676820v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2013.07.001"},{"key":"2025092019050785000_2025.09.17.676820v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70188-6"},{"key":"2025092019050785000_2025.09.17.676820v1.6","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awq316"},{"key":"2025092019050785000_2025.09.17.676820v1.7","doi-asserted-by":"crossref","first-page":"775781","DOI":"10.3389\/fneur.2021.775781","article-title":"Temporal Lobe Epilepsy and Psychiatric Comorbidity","volume":"12","year":"2021","journal-title":"Front Neurol"},{"key":"2025092019050785000_2025.09.17.676820v1.8","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000141086.91077.CD"},{"key":"2025092019050785000_2025.09.17.676820v1.9","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhh048"},{"key":"2025092019050785000_2025.09.17.676820v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/S1525-5050(02)00029-X"},{"key":"2025092019050785000_2025.09.17.676820v1.11","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16697"},{"key":"2025092019050785000_2025.09.17.676820v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.12.058"},{"issue":"1","key":"2025092019050785000_2025.09.17.676820v1.13","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.brs.2014.09.003","article-title":"Cortical network switching: possible role of the lateral septum and cholinergic arousal","volume":"8","year":"2015","journal-title":"Brain Stimul"},{"key":"2025092019050785000_2025.09.17.676820v1.14","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3846-09.2009"},{"key":"2025092019050785000_2025.09.17.676820v1.15","doi-asserted-by":"crossref","unstructured":"Sieu LA , Singla S , Liu JY , Zheng XY , Sharafeldin A , Chandrasekaran G , et al. 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