{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T05:14:38Z","timestamp":1791868478753,"version":"4.3.4"},"reference-count":80,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T00:00:00Z","timestamp":1664755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Mental Health","award":["R01 MH100820"],"award-info":[{"award-number":["R01 MH100820"]}]},{"name":"National Institute of Mental Health","award":["MH127483"],"award-info":[{"award-number":["MH127483"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dopamine D4 receptor (D4R) mechanisms are implicated in psychiatric diseases characterized by cognitive deficits, including schizophrenia, ADHD, and autism. The cellular mechanisms are poorly understood, but impaired neuronal synchronization in cortical networks was proposed to contribute to these deficits. In animal experiments, D4R activation was shown to generate aberrant increased gamma oscillations and to reduce performance on cognitive tasks requiring functional prefrontal cortex (PFC) and hippocampus (HPC) networks. While fast oscillations in the gamma range are important for local synchronization within neuronal ensembles, long-range synchronization between distant structures is achieved by slow rhythms in the delta, theta, alpha ranges. The characteristics of slow oscillations vary between structures during cognitive tasks. HPC activity is dominated by theta rhythm, whereas PFC generates unique oscillations in the 2\u20134 Hz range. In order to investigate the role of D4R on slow rhythms, cortical activity was recorded in rats under urethane anesthesia in which slow oscillations can be elicited in a controlled manner without behavioral confounds, by electrical stimulation of the brainstem reticular formation. The local field potential segments during stimulations were extracted and subjected to fast Fourier transform to obtain power density spectra. The selective D4R agonist A-412997 (5 and 10 mg\/kg) and antagonists L-745870 (5 and 10 mg\/kg) were injected systemically and the peak power in the two frequency ranges were compared before and after the injection. We found that D4R compounds significantly changed the activity of both HPC and PFC, but the direction of the effect was opposite in the two structures. D4R agonist enhanced PFC slow rhythm (delta, 2\u20134 Hz) and suppressed HPC theta, whereas the antagonist had an opposite effect. Analogous changes of the two slow rhythms were also found in the thalamic nucleus reuniens, which has connections to both forebrain structures. Slow oscillations play a key role in interregional cortical coupling; delta and theta oscillations were shown in particular, to entrain neuronal firing and to modulate gamma activity in interconnected forebrain structures with a relative HPC theta dominance over PFC. Thus, the results of this study indicate that D4R activation may introduce an abnormal bias in the bidirectional PFC\u2013HPC coupling which can be reversed by D4R antagonists.<\/jats:p>","DOI":"10.3390\/ijms231911705","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T23:39:31Z","timestamp":1665272371000},"page":"11705","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Differential Effect of Dopamine D4 Receptor Activation on Low-Frequency Oscillations in the Prefrontal Cortex and Hippocampus May Bias the Bidirectional Prefrontal\u2013Hippocampal Coupling"],"prefix":"10.3390","volume":"23","author":[{"given":"Carolina Wilnerzon","family":"Th\u00f6rn","sequence":"first","affiliation":[{"name":"Department Psychiatry at BIDMC, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3353-5242","authenticated-orcid":false,"given":"Vasilios","family":"Kafetzopoulos","sequence":"additional","affiliation":[{"name":"Department Psychiatry at BIDMC, Harvard Medical School, Boston, MA 02215, USA"},{"name":"Department of Psychiatry, Medical School, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4371-3249","authenticated-orcid":false,"given":"Bernat","family":"Kocsis","sequence":"additional","affiliation":[{"name":"Department Psychiatry at BIDMC, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1176\/appi.ajp.2010.09091379","article-title":"Research domain criteria (RDoC): Toward a new classification framework for research on mental disorders","volume":"167","author":"Insel","year":"2010","journal-title":"Am. 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