{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T09:03:17Z","timestamp":1778922197944,"version":"3.51.4"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T00:00:00Z","timestamp":1686787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019111","name":"Perron Institute for Neurological and Translational Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019111","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020598","name":"Multiple Sclerosis Society of Western Australia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020598","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003521","name":"Department of Education, Australian Governement","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003521","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neural Circuits"],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Overreliance on habit is linked with disorders, such as drug addiction and obsessive-compulsive disorder, and there is increasing interest in the use of repetitive transcranial magnetic stimulation (rTMS) to alter neuronal activity in the relevant pathways and for therapeutic outcomes. In this study, we researched the brains of ephrin-A2A5<jats:sup>\u2212\/\u2212<\/jats:sup> mice, which previously showed perseverative behavior in progressive-ratio tasks, associated with low cellular activity in the nucleus accumbens. We investigated whether rTMS treatment had altered the activity of the dorsal striatum in a way that suggested altered hierarchical recruitment of brain regions from the ventral striatum to the dorsal striatum, which is linked to abnormal habit formation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Brain sections from a limited number of mice that underwent training and performance on a progressive ratio task with and without low-intensity rTMS (LI-rTMS) were taken from a previous study. We took advantage of the previous characterization of perseverative behavior to investigate the contribution of different neuronal subtypes and striatal regions within this limited sample. Striatal regions were stained for c-Fos as a correlate of neuronal activation for DARPP32 to identify medium spiny neurons (MSNs) and for GAD67 to identify GABA-ergic interneurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and discussion<\/jats:title><jats:p>Contrary to our hypothesis, we found that neuronal activity in ephrin-A2A5<jats:sup>\u2212\/\u2212<\/jats:sup> mice still reflected the typical organization of goal-directed behavior. There was a significant difference in the proportion of neuronal activity across the striatum between experimental groups and control but no significant effects identifying a specific regional change. However, there was a significant group by treatment interaction which suggests that MSN activity is altered in the dorsomedial striatum and a trend suggesting that rTMS increases ephrin-A2A5<jats:sup>\u2212\/\u2212<\/jats:sup> MSN activity in the DMS. Although preliminary and inconclusive, the analysis of this archival data suggests that investigating circuit-based changes in striatal regions may provide insight into chronic rTMS mechanisms that could be relevant to treating disorders associated with perseverative behavior.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fncir.2023.1179096","type":"journal-article","created":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T05:48:12Z","timestamp":1686808092000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Dorsal striatum c-Fos activity in perseverative ephrin-A2A5\u2212\/\u2212 mice and the cellular effect of low-intensity rTMS"],"prefix":"10.3389","volume":"17","author":[{"given":"Maitri","family":"Tomar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Rodger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Moretti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/S0091-3057(98)00112-9","article-title":"Effects of dopamine antagonists and accumbens dopamine depletions on time-constrained progressive-ratio performance","volume":"61","author":"Aberman","year":"1998","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B2","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/0006-8993(91)91403-N","article-title":"Immunohistochemical localization of DARPP-32 in striatal projection neurons and striatal interneurons: implications for the localization of D1-like dopamine receptors on different types of striatal neurons","volume":"568","author":"Anderson","year":"1991","journal-title":"Brain Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1007\/s00221-008-1356-2","article-title":"High- and low-frequency repetitive transcranial magnetic stimulation differentially activates c-Fos and zif268 protein expression in the rat brain","volume":"188","author":"Aydin-Abidin","year":"2008","journal-title":"Exp. Brain Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1002\/cne.902960402","article-title":"Expression ofC-fos-like protein as a marker for neuronal activity following noxious stimulation in the rat","volume":"296","author":"Bullitt","year":"1990","journal-title":"J. Comp. Neurol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.brs.2017.09.004","article-title":"Clinical and electrophysiological outcomes of deep TMS over the medial prefrontal and anterior cingulate cortices in OCD patients","volume":"11","author":"Carmi","year":"2018","journal-title":"Brain Stimul"},{"key":"B6","doi-asserted-by":"publisher","first-page":"5067","DOI":"10.1038\/s41467-019-13057-w","article-title":"Enhanced and unified anatomical labeling for a common mouse brain atlas","volume":"10","author":"Chon","year":"2019","journal-title":"Nat. Commun"},{"key":"B7","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1002\/dneu.20685","article-title":"Ephrin-A5 regulates the formation of the ascending midbrain dopaminergic pathways","volume":"69","author":"Cooper","year":"2009","journal-title":"Dev. Neurobiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1038\/nn1579","article-title":"Neural systems of reinforcement for drug addiction: From actions to habits to compulsion","volume":"8","author":"Everitt","year":"2005","journal-title":"Nat. Neurosci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1016\/S0896-6273(00)81060-0","article-title":"Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping","volume":"25","author":"Feldheim","year":"2000","journal-title":"Neuron"},{"key":"B10","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1176\/appi.ajp.2011.10071062","article-title":"Disruption in the balance between goal-directed behavior and habit learning in obsessive-compulsive disorder","volume":"168","author":"Gillan","year":"2011","journal-title":"Am. J. Psychiat."},{"key":"B11","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1126\/science.134.3483.943","article-title":"Progressive Ratio as a Measure of Reward Strength","volume":"134","author":"Hodos","year":"1961","journal-title":"Science."},{"key":"B12","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/S0028-3908(02)00069-2","article-title":"Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system","volume":"43","author":"Keck","year":"2002","journal-title":"Neuropharmacology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1093\/cercor\/bht322","article-title":"GAD67 deficiency in parvalbumin interneurons produces deficits in inhibitory transmission and network disinhibition in mouse prefrontal cortex","volume":"25","author":"Lazarus","year":"2015","journal-title":"Cereb. Cortex"},{"key":"B14","doi-asserted-by":"publisher","first-page":"4093","DOI":"10.1073\/pnas.1207531110","article-title":"Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues","volume":"110","author":"Liu","year":"2013","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"10780","DOI":"10.1523\/JNEUROSCI.0723-14.2014","article-title":"Low-intensity repetitive transcranial magnetic stimulation improves abnormal visual cortical circuit topography and upregulates BDNF in Mice","volume":"34","author":"Makowiecki","year":"2014","journal-title":"J. Neurosci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"113011","DOI":"10.1016\/j.bbr.2020.113011","article-title":"Concurrent LI-rTMS induces changes in c-Fos expression but not behavior during a progressive ratio task with adult ephrin-A2A5-\/- mice","volume":"400","author":"Moretti","year":"2021","journal-title":"Behav. Brain Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"137","DOI":"10.3389\/fnins.2020.00137","article-title":"rTMS-Induced Changes in Glutamatergic and Dopaminergic Systems: Relevance to Cocaine and Methamphetamine Use Disorders","volume":"14","author":"Moretti","year":"2020","journal-title":"Front. Neurosci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"20571","DOI":"10.1038\/s41598-022-24934-8","article-title":"Low intensity repetitive transcranial magnetic stimulation modulates brain - wide functional connectivity to promote anti - correlated c - Fos expression","volume":"12","author":"Moretti","year":"2022","journal-title":"Sci. Rep."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1016\/j.biopsych.2007.01.018","article-title":"Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial","volume":"62","author":"O'Reardon","year":"2007","journal-title":"Biol. Psychiatry"},{"key":"B20","volume-title":"Paxinos and Franklin's the Mouse Brain in Stereotaxic Coordinates","author":"Paxinos","year":"2012"},{"key":"B21","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1523\/ENEURO.0163-17.2018","article-title":"Online LI-rTMS during a Visual Learning Task : differential Impacts on Visual Circuit and Behavioural Plasticity in Adult Ephrin-A2A5 Mice","volume":"5","author":"Poh","year":"2018","journal-title":"eNeuro"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.1096\/fj.11-194878","article-title":"Transcranial pulsed magnetic field stimulation facilitates reorganization of abnormal neural circuits and corrects behavioral deficits without disrupting normal connectivity","volume":"26","author":"Rodger","year":"2012","journal-title":"FASEB J"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1111\/j.1460-9568.2012.08036.x","article-title":"Changes in nucleus accumbens and neostriatal c-Fos and DARPP-32 immunoreactivity during different stages of food-reinforced instrumental training","volume":"35","author":"Segovia","year":"2012","journal-title":"Eur. J. Neurosci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1016\/j.mcn.2004.03.009","article-title":"Disruption of EphA\/ephrin-A signaling in the nigrostriatal system reduces dopaminergic innervation and dissociates behavioral responses to amphetamine and cocaine","volume":"26","author":"Sieber","year":"2004","journal-title":"Mol. Cell. Neurosci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/35058515","article-title":"Multiple roles of eph receptors and ephrins in neural development","volume":"2","author":"Wilkinson","year":"2001","journal-title":"Nat. Rev. Neurosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1016\/j.neuroimage.2006.01.015","article-title":"User-guided 3D active contour segmentation of anatomical structures: Significantly improved efficiency and reliability","volume":"31","author":"Yushkevich","year":"2006","journal-title":"Neuroimage"}],"container-title":["Frontiers in Neural Circuits"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncir.2023.1179096\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T05:48:16Z","timestamp":1686808096000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncir.2023.1179096\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,15]]},"references-count":26,"alternative-id":["10.3389\/fncir.2023.1179096"],"URL":"https:\/\/doi.org\/10.3389\/fncir.2023.1179096","relation":{},"ISSN":["1662-5110"],"issn-type":[{"value":"1662-5110","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,15]]},"article-number":"1179096"}}