{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T01:12:12Z","timestamp":1768525932837,"version":"3.49.0"},"posted":{"date-parts":[[2025,8,21]]},"group-title":"Neuroscience","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"crossref","award":["U01AA025932"],"award-info":[{"award-number":["U01AA025932"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"crossref","award":["R01AA027768"],"award-info":[{"award-number":["R01AA027768"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"crossref","award":["R01AA030293"],"award-info":[{"award-number":["R01AA030293"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Chronic alcohol use is a major modifiable risk factor for Alzheimer\u2019s disease (AD), yet the mechanisms by which it modulates AD pathophysiology remain unclear. Here, we examined circuit-level and pathological changes in two distinct AD mouse models, humanized A\u03b2 knock-in (hAPP-KI) (A\u03b2-driven) and PS19 (tau-driven), subjected to a chronic intermittent alcohol exposure paradigm. In hAPP-KI mice, alcohol increased A\u03b2 accumulation and excitatory transmission in the medial prefrontal cortex (mPFC) while reducing corticostriatal transmission and striatal cholinergic output. These alterations were accompanied by enhanced recruitment of microglia around A\u03b2 plaques. In contrast, alcohol-exposed PS19 mice displayed elevated mPFC-to-dorsomedial striatum (DMS) glutamatergic transmission and increased tau phosphorylation without significant changes in microglial activation or local mPFC excitatory drive. In wild-type mice, microglial depletion enhanced glutamatergic transmission onto cortical neurons, suggesting a homeostatic role for microglia in maintaining excitatory balance. Together, these findings reveal pathology-specific effects of alcohol on circuit dysfunction and propose microglia as an important modulator of alcohol-induced synaptic remodeling in the early stage of AD.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>Chronic alcohol exposure modulates glutamatergic transmission and neuroimmune responses in pathology-specific manners across A\u03b2- and tau-driven Alzheimer\u2019s disease mouse models.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>In hAPP-KI mice, alcohol increases mPFC excitatory input, A\u03b2 plaque burden, and microglial activation, while impairing corticostriatal transmission and striatal cholinergic signaling.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>In PS19 mice, alcohol enhances mPFC-to-striatum excitatory transmission and tau phosphorylation without altering local microglial activation or mPFC excitability.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Microglial depletion in wild-type mice recapitulates alcohol-induced glutamatergic changes in hAPP-KI mice, revealing a homeostatic role for microglia in regulating cortical excitatory balance.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.08.15.670607","type":"posted-content","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T19:45:12Z","timestamp":1755805512000},"source":"Crossref","is-referenced-by-count":0,"title":["Pathology-Specific Modulation of Corticostriatal Circuitry by Chronic Alcohol Consumption in Alzheimer\u2019s Disease Mouse Models"],"prefix":"10.64898","author":[{"given":"Yufei","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueyi","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruifeng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenbo","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Himanshu","family":"Gangal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuehua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025082500350470000_2025.08.15.670607v1.1","doi-asserted-by":"crossref","unstructured":"Adams JN , Maass A , Harrison TM , Baker SL , Jagust WJ (2019) Cortical tau deposition follows patterns of entorhinal functional connectivity in aging. Elife 8.","DOI":"10.7554\/eLife.49132"},{"key":"2025082500350470000_2025.08.15.670607v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13016"},{"key":"2025082500350470000_2025.08.15.670607v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2777-8"},{"key":"2025082500350470000_2025.08.15.670607v1.4","doi-asserted-by":"crossref","first-page":"631","DOI":"10.3233\/JAD-170841","article-title":"Disease Course Varies According to Age and Symptom Length in Alzheimer\u2019s Disease","volume":"64","year":"2018","journal-title":"J Alzheimers Dis"},{"key":"2025082500350470000_2025.08.15.670607v1.5","doi-asserted-by":"publisher","DOI":"10.3390\/MOLECULES25245789"},{"key":"2025082500350470000_2025.08.15.670607v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-0687-6"},{"key":"2025082500350470000_2025.08.15.670607v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0289-8"},{"key":"2025082500350470000_2025.08.15.670607v1.8","doi-asserted-by":"publisher","DOI":"10.1126\/science.1162844"},{"key":"2025082500350470000_2025.08.15.670607v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2016.05.016"},{"key":"2025082500350470000_2025.08.15.670607v1.10","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0333-5"},{"key":"2025082500350470000_2025.08.15.670607v1.11","doi-asserted-by":"crossref","unstructured":"Fisher RP , Matheny L , Ankeny S , Qin LY , Coleman L Jr, Vetreno RP (2025) Adolescent binge alcohol exposure accelerates Alzheimer\u2019s disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling. Front Aging Neurosci 17.","DOI":"10.3389\/fnagi.2025.1531628"},{"key":"2025082500350470000_2025.08.15.670607v1.12","unstructured":"Franklin KBJ , Paxinos G (2007) The mouse brain in stereotaxic coordinates, 3rd Edition."},{"key":"2025082500350470000_2025.08.15.670607v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39623-x"},{"key":"2025082500350470000_2025.08.15.670607v1.14","doi-asserted-by":"publisher","DOI":"10.1101\/2024.1109.1121.614247"},{"key":"2025082500350470000_2025.08.15.670607v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01459-0"},{"key":"2025082500350470000_2025.08.15.670607v1.16","doi-asserted-by":"crossref","first-page":"3775","DOI":"10.1016\/j.cell.2025.04.006","article-title":"Alzheimer\u2019s disease patient-derived high-molecular-weight tau impairs bursting in hippocampal neurons","volume":"188","year":"2025","journal-title":"Cell"},{"key":"2025082500350470000_2025.08.15.670607v1.17","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.2174\/1567205013666160603005035","article-title":"The Association Between Alcohol Use and the Progression of Alzheimer\u2019s Disease","volume":"13","year":"2016","journal-title":"Current Alzheimer Research"},{"key":"2025082500350470000_2025.08.15.670607v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02714-z"},{"key":"2025082500350470000_2025.08.15.670607v1.19","unstructured":"Huang Y , Xie X , Huang Z , Chen R , Gangal H , Wang X , Souza K , Hunter J , Wu X , Reddy DS , Chin J , Wang J (2025) Early-Stage Corticostriatal Circuit Hyperactivity Impairs Cholinergic Function and Cognitive Flexibility in an Alzheimer\u2019s Model. Under review following resubmission with Nature Neuroscience."},{"key":"2025082500350470000_2025.08.15.670607v1.20","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adn2446"},{"key":"2025082500350470000_2025.08.15.670607v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2967"},{"key":"2025082500350470000_2025.08.15.670607v1.22","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abh4284"},{"key":"2025082500350470000_2025.08.15.670607v1.23","doi-asserted-by":"crossref","unstructured":"Kang S , Lee J , Min PH , Choi DS (2025) Moderate ethanol exposure disrupts energy homesotasis between central and peripheral system in APP\/PS1 mice. Mol Brain 18.","DOI":"10.1186\/s13041-025-01192-z"},{"key":"2025082500350470000_2025.08.15.670607v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-021-00269-y"},{"key":"2025082500350470000_2025.08.15.670607v1.25","doi-asserted-by":"crossref","unstructured":"Lees B , Meredith LR , Kirkland AE , Bryant BE , Squeglia LM (2020) Effect of alcohol use on the adolescent brain and behavior. Pharmacology Biochemistry and Behavior 192.","DOI":"10.1016\/j.pbb.2020.172906"},{"key":"2025082500350470000_2025.08.15.670607v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-019-0332-9"},{"key":"2025082500350470000_2025.08.15.670607v1.27","doi-asserted-by":"crossref","unstructured":"Lv ZZ , Chen LX , Chen P , Peng HP , Rong Y , Hong W , Zhou Q , Li N , Li BX , Paolicelli RC , Zhan Y (2024) Clearance of D-amyloid and synapses by the optogenetic depolarization of microglia is complement selective. Neuron 112.","DOI":"10.1016\/j.neuron.2023.12.003"},{"key":"2025082500350470000_2025.08.15.670607v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.05.014"},{"key":"2025082500350470000_2025.08.15.670607v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0081-9"},{"key":"2025082500350470000_2025.08.15.670607v1.30","doi-asserted-by":"publisher","DOI":"10.1172\/JCI154969"},{"key":"2025082500350470000_2025.08.15.670607v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/J.NEURON.2016.03.006"},{"key":"2025082500350470000_2025.08.15.670607v1.32","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1038\/s41467-017-01150-x","article-title":"Earliest accumulation of beta-amyloid occurs within the default-mode network and concurrently affects brain connectivity","volume":"8","year":"2017","journal-title":"Nature Communications"},{"key":"2025082500350470000_2025.08.15.670607v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.07.025"},{"key":"2025082500350470000_2025.08.15.670607v1.34","first-page":"135","article-title":"The risks associated with alcohol use and alcoholism","volume":"34","year":"2011","journal-title":"Alcohol Res Health"},{"key":"2025082500350470000_2025.08.15.670607v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2019.05.022"},{"key":"2025082500350470000_2025.08.15.670607v1.36","doi-asserted-by":"crossref","unstructured":"Sabia S , Fayosse A , Dumurgier J , Dugravot A , Akbaraly T , Britton A , Kivim\u00e4ki M , Singh-Manoux A (2018) Alcohol consumption and risk of dementia: 23 year follow-up of Whitehall II cohort study. Bmj-Brit Med J 362.","DOI":"10.1136\/bmj.k2927"},{"key":"2025082500350470000_2025.08.15.670607v1.37","first-page":"a006189","article-title":"Neuropathological Alterations in Alzheimer Disease","volume":"1","year":"2011","journal-title":"Csh Perspect Med"},{"key":"2025082500350470000_2025.08.15.670607v1.38","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.alcohol.2022.08.003","article-title":"Precocious emergence of cognitive and synaptic dysfunction in 3xTg-AD mice exposed prenatally to ethanol","volume":"107","year":"2023","journal-title":"Alcohol"},{"key":"2025082500350470000_2025.08.15.670607v1.39","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0003-15.2015"},{"key":"2025082500350470000_2025.08.15.670607v1.40","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12512"},{"key":"2025082500350470000_2025.08.15.670607v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2020.112641"},{"key":"2025082500350470000_2025.08.15.670607v1.42","doi-asserted-by":"crossref","unstructured":"Xie XY , Lu JY , Ma TF , Cheng YF , Woodson K , Bonifacio J , Bego K , Wang XH , Wang J (2023) Linking input- and cell-type-specific synaptic plasticity to the reinforcement of alcohol-seeking behavior. Neuropharmacology 237.","DOI":"10.1016\/j.neuropharm.2023.109619"},{"key":"2025082500350470000_2025.08.15.670607v1.43","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-080317-061725"},{"key":"2025082500350470000_2025.08.15.670607v1.44","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay0198"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.08.15.670607","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:23:14Z","timestamp":1768468994000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.08.15.670607"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":44,"URL":"https:\/\/doi.org\/10.1101\/2025.08.15.670607","relation":{},"subject":[],"published":{"date-parts":[[2025,8,21]]},"subtype":"preprint"}}