TY - JOUR AU - Sierra, Rodrigo Ordoñez AU - Lizeth Katherine, Pedraza Correa AU - Barcsai, Lívia AU - Pejin, Andrea AU - Li, Qun AU - Kozák, Gábor AU - Takeuchi, Yuichi AU - Nagy, Anett Júlia AU - Lőrincz, László Magor AU - Devinsky, Orrin AU - Buzsáki, György AU - Berényi, Antal TI - Closed-loop brain stimulation augments fear extinction in male rats JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 14 PY - 2023 IS - 1 PG - 14 SN - 2041-1723 DO - 10.1038/s41467-023-39546-7 UR - https://m2.mtmt.hu/api/publication/34049040 ID - 34049040 AB - Dysregulated fear reactions can result from maladaptive processing of trauma-related memories. In post-traumatic stress disorder (PTSD) and other psychiatric disorders, dysfunctional extinction learning prevents discretization of trauma-related memory engrams and generalizes fear responses. Although PTSD may be viewed as a memory-based disorder, no approved treatments target pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. Here, we show that closed-loop, SWR triggered neuromodulation of the medial forebrain bundle (MFB) can enhance fear extinction consolidation in male rats. The modified fear memories became resistant to induced recall (i.e., ‘renewal’ and ‘reinstatement’) and did not reemerge spontaneously. These effects were mediated by D2 receptor signaling-induced synaptic remodeling in the basolateral amygdala. Our results demonstrate that SWR-triggered closed-loop stimulation of the MFB reward system enhances extinction of fearful memories and reducing fear expression across different contexts and preventing excessive and persistent fear responses. These findings highlight the potential of neuromodulation to augment extinction learning and provide a new avenue to develop treatments for anxiety disorders. LA - English DB - MTMT ER - TY - JOUR AU - Li, Qun AU - Takeuchi, Yuichi AU - Wang, Jiale AU - Gellért, Levente AU - Barcsai, Lívia AU - Lizeth Katherine, Pedraza Correa AU - Nagy, Anett Júlia AU - Kozák, Gábor AU - Nakai, Shinya AU - Kato, Shigeki AU - Kobayashi, Kazuto AU - Ohsawa, Masahiro AU - Horváth, Gyöngyi AU - Kékesi, Gabriella AU - Lőrincz, László Magor AU - Devinsky, Orrin AU - Buzsáki, György AU - Berényi, Antal TI - Reinstating olfactory bulb-derived limbic gamma oscillations alleviates depression-like behavioral deficits in rodents JF - NEURON J2 - NEURON VL - 111 PY - 2023 IS - 13 SP - 2065 EP - 2075 PG - 11 SN - 0896-6273 DO - 10.1016/j.neuron.2023.04.013 UR - https://m2.mtmt.hu/api/publication/33806908 ID - 33806908 N1 - Key resources table, experimental model and subject details: pp. e1-e5. LA - English DB - MTMT ER - TY - JOUR AU - Piszár, Ildikó AU - Lőrincz, László Magor TI - Differential Serotonergic Modulation of Synaptic Inputs to the Olfactory Cortex JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 3 PG - 11 SN - 1661-6596 DO - 10.3390/ijms24031950 UR - https://m2.mtmt.hu/api/publication/33789524 ID - 33789524 AB - Serotonin (5-hydroxytriptamine, 5-HT) is an important monoaminergic neuromodulator involved in a variety of physiological and pathological functions. It has been implicated in the regulation of sensory functions at various stages of multiple modalities, but its mechanisms and functions in the olfactory system have remained elusive. Combining electrophysiology, optogenetics and pharmacology, here we show that afferent (feed-forward) pathway-evoked synaptic responses are boosted, whereas feedback responses are suppressed by presynaptic 5-HT1B receptors in the anterior piriform cortex (aPC) in vitro. Blocking 5-HT1B receptors also reduces the suppressive effects of serotonergic photostimulation of baseline firing in vivo. We suggest that by regulating the relative weights of synaptic inputs to aPC, 5-HT finely tunes sensory inputs in the olfactory cortex. LA - English DB - MTMT ER - TY - JOUR AU - Atherton, Zoe AU - Nagy, Olivér AU - Barcsai, Lívia AU - Sere, Péter AU - Zsigri, Nikolett AU - Földi, Tamás AU - Gellért, Levente AU - Berényi, Antal AU - Crunelli, Vincenzo AU - Lőrincz, László Magor TI - Higher-order thalamic nuclei facilitate the generalization and maintenance of spike-and-wave discharges of absence seizures JF - NEUROBIOLOGY OF DISEASE J2 - NEUROBIOL DIS VL - 178 PY - 2023 PG - 13 SN - 0969-9961 DO - 10.1016/j.nbd.2023.106025 UR - https://m2.mtmt.hu/api/publication/33789523 ID - 33789523 N1 - Journal Article; Research Support, Non-U.S. Gov't AB - Spike-and-wave discharges (SWDs), generated by the cortico-thalamo-cortical (CTC) network, are pathological, large amplitude oscillations and the hallmark of absence seizures (ASs). SWDs begin in a cortical initiation network in both humans and animal models, including the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), where it is located in the primary somatosensory cortex (S1). The behavioral manifestation of an AS occurs when SWDs spread from the cortical initiation site to the whole brain, however, the mechanisms behind this rapid propagation remain unclear. Here we investigated these processes beyond the principal CTC network, in higher-order (HO) thalamic nuclei (lateral posterior (LP) and posterior (PO) nuclei) since their diffuse connectivity and known facilitation of intracortical communications make these nuclei key candidates to support SWD generation and maintenance. In freely moving GAERS, multi-site LFP in LP, PO and multiple cortical regions revealed a novel feature of SWDs: during SWDs there are short periods (named SWD-breaks) when cortical regions far from S1, such the primary visual cortex (V1), become transiently unsynchronized from the ongoing EEG rhythm. Inactivation of HO nuclei with local muscimol injections or optogenetic perturbation of HO nuclei activity increased the occurrence of SWD-breaks and the former intervention also increased the SWD propagation-time from S1. The neural underpinnings of these findings were explored further by silicon probe recordings from single units of PO which uncovered two previously unknown groups of excitatory neurons based on their burst firing dynamics at SWD onset. Moreover, a switch from tonic to burst firing at SWD onset was shown to be an important feature since it was much less prominent for non-generalized events, i.e. SWDs that remained local to S1. Additionally, one group of neurons showed a reverse of this switch during SWD-breaks, demonstrating the importance of this firing pattern throughout the SWD. In summary, these results support the view that multiple HO thalamic nuclei are utilized at SWD onset and contribute to cortical synchrony throughout the paroxysmal discharge. LA - English DB - MTMT ER - TY - JOUR AU - Crunelli, Vincenzo AU - David, Francois AU - Morais, Tatiana P AU - Lőrincz, László Magor TI - HCN channels and absence seizures JF - NEUROBIOLOGY OF DISEASE J2 - NEUROBIOL DIS VL - 181 PY - 2023 PG - 13 SN - 0969-9961 DO - 10.1016/j.nbd.2023.106107 UR - https://m2.mtmt.hu/api/publication/33789490 ID - 33789490 AB - Hyperpolarization-activation cyclic nucleotide-gated (HCN) channels were for the first time implicated in absence seizures (ASs) when an abnormal Ih (the current generated by these channels) was reported in neocortical layer 5 neurons of a mouse model. Genetic studies of large cohorts of children with Childhood Absence Epilepsy (where ASs are the only clinical symptom) have identified only 3 variants in HCN1 (one of the genes that code for the 4 HCN channel isoforms, HCN1-4), with one (R590Q) mutation leading to loss-of-function. Due to the multi-faceted effects that HCN channels exert on cellular excitability and neuronal network dynamics as well as their modulation by environmental factors, it has been difficult to identify the detailed mechanism by which different HCN isoforms modulate ASs. In this review, we systematically and critically analyze evidence from established AS models and normal non-epileptic animals with area- and time-selective ablation of HCN1, HCN2 and HCN4. Notably, whereas knockout of rat HCN1 and mouse HCN2 leads to the expression of ASs, the pharmacological block of all HCN channel isoforms abolishes genetically determined ASs. These seemingly contradictory results could be reconciled by taking into account the well-known opposite effects of Ih on cellular excitability and network function. Whereas existing evidence from mouse and rat AS models indicates that pan-HCN blockers may provide a novel approach for the treatment of human ASs, the development of HCN isoform-selective drugs would greatly contribute to current research on the role for these channels in ASs generation and maintenance as well as offer new potential clinical applications. LA - English DB - MTMT ER - TY - JOUR AU - Piszár, Ildikó AU - Lőrincz, László Magor TI - Differential Serotonergic Modulation of Principal Neurons and Interneurons in the Anterior Piriform Cortex JF - FRONTIERS IN NEUROANATOMY J2 - FRONT NEUROANAT VL - 16 PY - 2022 PG - 7 SN - 1662-5129 DO - 10.3389/fnana.2022.821695 UR - https://m2.mtmt.hu/api/publication/32820872 ID - 32820872 LA - English DB - MTMT ER - TY - JOUR AU - Földi, Tamás AU - Lőrincz, László Magor AU - Berényi, Antal TI - Temporally Targeted Interactions With Pathologic Oscillations as Therapeutical Targets in Epilepsy and Beyond JF - FRONTIERS IN NEURAL CIRCUITS J2 - FRONT NEURAL CIRCUIT VL - 15 PY - 2021 PG - 13 SN - 1662-5110 DO - 10.3389/fncir.2021.784085 UR - https://m2.mtmt.hu/api/publication/32551790 ID - 32551790 N1 - Funding Agency and Grant Number: Momentum program II of the Hungarian Academy of Sciences of the National Research, Development and Innovation Office, Hungary [EFOP-3.6.1-16-2016-00008, EFOP 3.6.6-VEKOP-16-2017-00009, KKP133871/KKP20]; Ministry of Human Capacities, Hungary [20391-3/2018/FEKUSTRAT]; EUEuropean Commission [739593-HCEMM]; Hungarian Scientific Research FundOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [NN125601, FK123831]; Hungarian Brain Research Program [KTIA_NAP_13-2-2014-0014]; New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund [UNKP-20-5]; Janos Bolyai FellowshipHungarian Academy of Sciences Funding text: This work was supported by the Momentum program II of the Hungarian Academy of Sciences, EFOP-3.6.1-16-2016-00008, EFOP 3.6.6-VEKOP-16-2017-00009, and KKP133871/KKP20 grants of the National Research, Development and Innovation Office, Hungary, the 20391-3/2018/FEKUSTRAT of the Ministry of Human Capacities, Hungary, and the EU Horizon 2020 Research and Innovation Program (No. 739593-HCEMM), Hungarian Scientific Research Fund (Grants NN125601 and FK123831 to ML), the Hungarian Brain Research Program (grant KTIA_NAP_13-2-2014-0014 to ML). UNKP-20-5 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund to ML. ML was a grantee of the Janos Bolyai Fellowship. LA - English DB - MTMT ER - TY - JOUR AU - Sere, Péter AU - Nikolett, Zsigri AU - Raffai, Tímea AU - Furdan, Szabina AU - Győri, Fanni AU - Vincenzo, Crunelli AU - Lőrincz, László Magor TI - Activity of the Lateral Hypothalamus during Genetically Determined Absence Seizures JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 22 PY - 2021 IS - 17 PG - 8 SN - 1661-6596 DO - 10.3390/ijms22179466 UR - https://m2.mtmt.hu/api/publication/32167983 ID - 32167983 LA - English DB - MTMT ER - TY - JOUR AU - Iacone, Yasmine AU - Morais, Tatiana P. AU - David, Francois AU - Delicata, Francis AU - Sandle, Joanna AU - Raffai, Tímea AU - Parri, Harri Rheinallt AU - Weisser, Johan Juhl AU - Bundgaard, Christoffer AU - Klewe, Ib Vestergaard AU - Tamás, Gábor AU - Thomsen, Morten Skott AU - Crunelli, Vincenzo AU - Lőrincz, László Magor TI - Systemic administration of ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel inhibitor, blocks spontaneous absence seizures JF - EPILEPSIA J2 - EPILEPSIA VL - 62 PY - 2021 IS - 7 SP - 1729 EP - 1743 PG - 15 SN - 0013-9580 DO - 10.1111/epi.16926 UR - https://m2.mtmt.hu/api/publication/32037613 ID - 32037613 N1 - Funding Agency and Grant Number: Wellcome TrustWellcome TrustEuropean Commission [91882]; Orszagos Tudomanyos Kutatasi AlapprogramokOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [FK123831, NN125601]; Hungarian Brain Research Program [KTIA_NAP_13-2-2014-0014]; Ministry of Human Capacities, Hungary [20391-3/2018/FEKUSTRAT]; Marie Sklodowska-Curie Actions [H2020-MSCA-ITN-2016-722053]; Ester Floridia Neuroscience Research Foundation; Janos Bolyai FellowshipHungarian Academy of Sciences Funding text: Wellcome Trust, Grant/Award Number: 91882; Orszagos Tudomanyos Kutatasi Alapprogramok, Grant/Award Number: FK123831 and NN125601; Hungarian Brain Research Program, Grant/Award Number: KTIA_NAP_13-2-2014-0014; Ministry of Human Capacities, Hungary, Grant/Award Number: 20391-3/2018/FEKUSTRAT; Marie Sklodowska-Curie Actions, Grant/Award Number: H2020-MSCA-ITN-2016-722053; Ester Floridia Neuroscience Research Foundation; Magor L. Lorincz is a grantte of the Janos Bolyai Fellowship AB - Objective Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to be involved in the generation of absence seizures (ASs), and there is evidence that cortical and thalamic HCN channel dysfunctions may have a proabsence role. Many HCN channel blockers are available, but their role in ASs has been investigated only by localized brain injection or in in vitro model systems due to their limited brain availability. Here, we investigated the effect on ASs of orally administered ivabradine (an HCN channel blocker approved for the treatment of heart failure in humans) following injection of the P-glycoprotein inhibitor elacridar, which is known to increase penetration into the brain of drug substrates for this efflux transporter. The action of ivabradine was also tested following in vivo microinjection into the cortical initiation network (CIN) of the somatosensory cortex and in the thalamic ventrobasal nucleus (VB) as well as on cortical and thalamocortical neurons in brain slices. Methods We used electroencephalographic recordings in freely moving Genetic Absence Epilepsy Rats From Strasbourg (GAERSs) to assess the action of oral administration of ivabradine, with and without elacridar, on ASs. Ivabradine was also microinjected into the CIN and VB of GAERSs in vivo and applied to Wistar CIN and GAERS VB slices while recording patch-clamped cortical Layer 5/6 and thalamocortical neurons, respectively. Results Oral administration of ivabradine markedly and dose-dependently reduced ASs. Ivabradine injection into CIN abolished ASs and elicited small-amplitude 4-7-Hz waves (without spikes), whereas in the VB it was less potent. Moreover, ivabradine applied to GAERS VB and Wistar CIN slices selectively decreased HCN channel-dependent properties of cortical Layer 5/6 pyramidal and thalamocortical neurons, respectively. Significance These results provide the first demonstration of the antiabsence action of a systemically administered HCN channel blocker, indicating the potential of this class of drugs as a novel therapeutic avenue for ASs. LA - English DB - MTMT ER - TY - JOUR AU - Gazea, Mary AU - Furdan, Szabina AU - Sere, Péter AU - Oesch, Lukas AU - Molnár, Benedek AU - Giovanni, Giuseppe Di AU - Fenno, Lief E. AU - Ramakrishnan, Charu AU - Mattis, Joanna AU - Deisseroth, Karl AU - Dymecki, Susan M. AU - Adamantidis, Antoine R. AU - Lőrincz, László Magor TI - Reciprocal lateral hypothalamic and raphé GABAergic projections promote wakefulness JF - JOURNAL OF NEUROSCIENCE J2 - J NEUROSCI VL - 41 PY - 2021 IS - 22 SP - 4840 EP - 4849 PG - 10 SN - 0270-6474 DO - 10.1523/JNEUROSCI.2850-20.2021 UR - https://m2.mtmt.hu/api/publication/31987689 ID - 31987689 N1 - Centre for Experimental Neurology, Department of Neurology, Inselspital, University Hospital Bern, University of Bern, Bern, 3010, Switzerland Department of Biomedical Research, Inselspital University Hospital Bern, University of Bern, Bern, 3010, Switzerland Department of Physiology, Anatomy, and Neuroscience, University of Szeged, Szeged, 6726, Hungary Department of Physiology, University of Szeged, Szeged, 6720, Hungary Neurosci ence Division, School of Bioscience, Cardiff University, Cardiff, CF10 3AX, United Kingdom Department of Physiology and Biochemistry, University of Malta, MSD 2080, Malta Departments of Psychiatry and Behavioral Sciences and Bioengineering, Stanford University, Stanford, CA 94305, United States CNC Program, Stanford University, Stanford, CA 94305, United States Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, United States Department of Genetics, Harvard Medical School, Boston, MA 02115, United States Concentris research management GmbH, Fürstenfeldbruck, D-82256, Germany Cited By :3 Export Date: 13 May 2022 CODEN: JNRSD Correspondence Address: Adamantidis, A.R.; Centre for Experimental Neurology, Switzerland; email: antoine.adamantidis@dbmr.unibe.ch. Correspondence Address: Lőrincz, M.L.; Department of Physiology, Hungary; email: mlorincz@gmail.com Funding details: National Institutes of Health, NIH, R01 DA034022 Funding details: European Research Council, ERC, 725850 Funding details: Deutsche Forschungsgemeinschaft, DFG, GA 2410/1-1, RGY0076/2012 Funding details: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF, 31003A_156156 Funding details: Hungarian Scientific Research Fund, OTKA, FK123831, KTIA_NAP_13-2-2014-0014, NN125601 Funding details: Ministry of Culture, Sports and Tourism, MCST, N. R&I 2013-01 EPILEFREE Funding text 1: This work was supported by Hungarian Scientific Research Fund Grants NN125601 and FK123831 to M.L.L., Hungarian Brain Research Program Grant KTIA_NAP_13-2-2014-0014 to M.L.L., National Institutes of Health R01 DA034022 to S.M. D., German Research Foundation GA 2410/1-1 to M.G., Human Frontier Science Program RGY0076/2012 to A.R.A., Swiss National Science Foundation Grant 31003A_156156 to A.R.A., and European Research Council Grant 725850 to A.R.A., MCST grant N. R&I 2013-01 EPILEFREE to G.D.G and Sz.F. M.L.L. is a grantee of the János Bolyai Fellowship. This work is dedicated to the loving memory of our friend and colleague István Ábrahám. pM.G., S.F., A.R.A., and M.L.L. contributed equally to this work. LA - English DB - MTMT ER -