{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:46:27Z","timestamp":1785408387225,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,1]]},"group-title":"Neuroscience","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01MH105592"],"award-info":[{"award-number":["R01MH105592"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["F32MH135620"],"award-info":[{"award-number":["F32MH135620"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/04q36wn27","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The risk of developing psychiatric disorders, particularly stress-related disorders such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), is increased threefold in patients with epilepsy. While this increased risk may arise as a consequence of living with epilepsy, shared neurobiological mechanisms, particularly dysregulation of GABAergic signaling, may also contribute. To investigate this link, we investigated the function of GABAergic neurons co-expressing the neuropeptide cortistatin (CST), which has anticonvulsant effects and is implicated in both MDD and PTSD. Targeting CST+ neurons in the prelimbic cortex (PrL), a rodent brain region that is functionally and anatomically similar to the human dorsal anterior cingulate cortex (dACC), we found that ablating CST+ neurons disrupts context-dependent fear renewal, causes spontaneous convulsive seizures, dramatically increases susceptibility to chemically-induced seizures, and increases anxiety-like phenotypes following stressors. We further show that repeated chemogenetic inhibition of CST+ neurons increases the rate of seizure kindling in female mice, and that disruption of brain derived neurotrophic factor signaling in CST+ neurons phenocopies the effects of acute inhibition. These data support the hypothesis that epilepsy and stress-related psychiatric disorders potentially share common neurobiological mechanisms, and that loss of CST+ neuron function may be a critical feature underlying fear dysregulation and cortical hyperexcitability.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Loss of prelimbic CST+ neurons disrupts fear renewal, causes anxiety-like symptoms, and induces spontaneous seizures.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Inhibition of prelimbic CST+ by chemogenetics or BDNF inhibition by TrkB increases seizure susceptibility in females only.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>CST+ neurons represent a subset of primarily SST and PVALB expressing GABAergic neurons.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.28.702318","type":"posted-content","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T06:50:41Z","timestamp":1770015041000},"source":"Crossref","is-referenced-by-count":0,"title":["Cortistatin neurons in the prelimbic cortex regulate seizure susceptibility in female mice via BDNF\u2013TrkB signaling"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6777-5826","authenticated-orcid":false,"given":"Aaron J.","family":"Salisbury","sequence":"first","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"name":"Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4709-169X","authenticated-orcid":false,"given":"Lourdes","family":"Figueroa","sequence":"additional","affiliation":[{"name":"Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA"},{"name":"Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5237-0789","authenticated-orcid":false,"given":"Keri","family":"Martinowich","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"name":"Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA"},{"name":"Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"name":"Johns Hopkins Kavli Neuroscience Discovery Institute, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9292-8556","authenticated-orcid":false,"given":"Michael S.","family":"Totty","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026020511114392000_2026.01.28.702318v1.1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14310"},{"key":"2026020511114392000_2026.01.28.702318v1.2","doi-asserted-by":"publisher","DOI":"10.1111\/cns.12259"},{"key":"2026020511114392000_2026.01.28.702318v1.3","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-09-03221.2000"},{"key":"2026020511114392000_2026.01.28.702318v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(98)00609-X"},{"key":"2026020511114392000_2026.01.28.702318v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2019.106474"},{"key":"2026020511114392000_2026.01.28.702318v1.6","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0378-09.2009"},{"key":"2026020511114392000_2026.01.28.702318v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107501"},{"key":"2026020511114392000_2026.01.28.702318v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12632"},{"key":"2026020511114392000_2026.01.28.702318v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.06.002"},{"key":"2026020511114392000_2026.01.28.702318v1.10","doi-asserted-by":"publisher","DOI":"10.1097\/PSY.0000000000000463"},{"key":"2026020511114392000_2026.01.28.702318v1.11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2005.51204.x"},{"key":"2026020511114392000_2026.01.28.702318v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.07.004"},{"key":"2026020511114392000_2026.01.28.702318v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0552-7"},{"key":"2026020511114392000_2026.01.28.702318v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/381242a0"},{"key":"2026020511114392000_2026.01.28.702318v1.15","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-15-05868.1997"},{"key":"2026020511114392000_2026.01.28.702318v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.nlm.2012.02.003"},{"key":"2026020511114392000_2026.01.28.702318v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ynstr.2014.09.007"},{"key":"2026020511114392000_2026.01.28.702318v1.18","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2018.00387"},{"key":"2026020511114392000_2026.01.28.702318v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2017.05.024"},{"key":"2026020511114392000_2026.01.28.702318v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2016.188"},{"key":"2026020511114392000_2026.01.28.702318v1.21","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.6252"},{"key":"2026020511114392000_2026.01.28.702318v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.01.050"},{"key":"2026020511114392000_2026.01.28.702318v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00341-5"},{"key":"2026020511114392000_2026.01.28.702318v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-019-0642-z"},{"key":"2026020511114392000_2026.01.28.702318v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4001835"},{"key":"2026020511114392000_2026.01.28.702318v1.26","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1972.00490080027002"},{"key":"2026020511114392000_2026.01.28.702318v1.27","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20052017"},{"key":"2026020511114392000_2026.01.28.702318v1.28","doi-asserted-by":"publisher","DOI":"10.1007\/s00221-009-1994-z"},{"key":"2026020511114392000_2026.01.28.702318v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03378-w"},{"key":"2026020511114392000_2026.01.28.702318v1.30","doi-asserted-by":"publisher","DOI":"10.1126\/science.1091031"},{"key":"2026020511114392000_2026.01.28.702318v1.31","doi-asserted-by":"publisher","DOI":"10.1007\/s00429-018-1783-1"},{"key":"2026020511114392000_2026.01.28.702318v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2011.01.060"},{"key":"2026020511114392000_2026.01.28.702318v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.09.024"},{"key":"2026020511114392000_2026.01.28.702318v1.34","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.21020162"},{"key":"2026020511114392000_2026.01.28.702318v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ynstr.2020.100238"},{"key":"2026020511114392000_2026.01.28.702318v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-024-02835-8"},{"key":"2026020511114392000_2026.01.28.702318v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(03)00471-8"},{"key":"2026020511114392000_2026.01.28.702318v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.09.039"},{"key":"2026020511114392000_2026.01.28.702318v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2014.184"},{"key":"2026020511114392000_2026.01.28.702318v1.40","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/675128"},{"key":"2026020511114392000_2026.01.28.702318v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3492"},{"key":"2026020511114392000_2026.01.28.702318v1.42","doi-asserted-by":"publisher","DOI":"10.1186\/1756-6606-4-11"},{"key":"2026020511114392000_2026.01.28.702318v1.43","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0310-19.2019"},{"key":"2026020511114392000_2026.01.28.702318v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-00787-0"},{"key":"2026020511114392000_2026.01.28.702318v1.45","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-04-01480.2002"},{"key":"2026020511114392000_2026.01.28.702318v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2007.04.032"},{"key":"2026020511114392000_2026.01.28.702318v1.47","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac073"},{"key":"2026020511114392000_2026.01.28.702318v1.48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0105-09.2009"},{"key":"2026020511114392000_2026.01.28.702318v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2019.07.024"},{"key":"2026020511114392000_2026.01.28.702318v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2024.109833"},{"key":"2026020511114392000_2026.01.28.702318v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2025.115300"},{"key":"2026020511114392000_2026.01.28.702318v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2021.135753"},{"key":"2026020511114392000_2026.01.28.702318v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.104974"},{"key":"2026020511114392000_2026.01.28.702318v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.07.003"},{"key":"2026020511114392000_2026.01.28.702318v1.55","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5117-14.2015"},{"key":"2026020511114392000_2026.01.28.702318v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2019.01.037"},{"key":"2026020511114392000_2026.01.28.702318v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2008.08.009"},{"key":"2026020511114392000_2026.01.28.702318v1.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2021.108083"},{"key":"2026020511114392000_2026.01.28.702318v1.59","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3548"},{"key":"2026020511114392000_2026.01.28.702318v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.03.020"},{"key":"2026020511114392000_2026.01.28.702318v1.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2004.03.026"},{"key":"2026020511114392000_2026.01.28.702318v1.62","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01463-4"},{"key":"2026020511114392000_2026.01.28.702318v1.63","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-66871-8"},{"key":"2026020511114392000_2026.01.28.702318v1.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2019.11.014"},{"key":"2026020511114392000_2026.01.28.702318v1.65","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-023-01790-2"},{"key":"2026020511114392000_2026.01.28.702318v1.66","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2022.102286"},{"key":"2026020511114392000_2026.01.28.702318v1.67","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-014-9560-1"},{"key":"2026020511114392000_2026.01.28.702318v1.68","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5159"},{"key":"2026020511114392000_2026.01.28.702318v1.69","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-17-07580.2002"},{"key":"2026020511114392000_2026.01.28.702318v1.70","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00841.2014"},{"key":"2026020511114392000_2026.01.28.702318v1.71","doi-asserted-by":"publisher","DOI":"10.1101\/2025.03.04.641498"},{"key":"2026020511114392000_2026.01.28.702318v1.72","doi-asserted-by":"publisher","DOI":"10.1186\/s42494-024-00159-2"},{"key":"2026020511114392000_2026.01.28.702318v1.73","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01404-9"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.01.28.702318","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T19:11:53Z","timestamp":1770318713000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.01.28.702318"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,1]]},"references-count":73,"URL":"https:\/\/doi.org\/10.64898\/2026.01.28.702318","relation":{},"subject":[],"published":{"date-parts":[[2026,2,1]]},"subtype":"preprint"}}