Reinstating olfactory bulb-derived limbic gamma oscillations alleviates depression-like behavioral deficits in rodents

Qun Li; Yuichi Takeuchi; Jiale Wang; Levente Gellért; Livia Barcsai; Lizeth K Pedraza; Anett J Nagy; Gábor Kozák; Shinya Nakai; Shigeki Kato; Kazuto Kobayashi; Masahiro Ohsawa; Gyöngyi Horváth; Gabriella Kékesi; Magor L Lőrincz; Orrin Devinsky; György Buzsáki; Antal Berényi

doi:10.1016/j.neuron.2023.04.013

Reinstating olfactory bulb-derived limbic gamma oscillations alleviates depression-like behavioral deficits in rodents

Neuron. 2023 Jul 5;111(13):2065-2075.e5. doi: 10.1016/j.neuron.2023.04.013. Epub 2023 May 9.

Authors

Qun Li¹, Yuichi Takeuchi², Jiale Wang³, Levente Gellért¹, Livia Barcsai⁴, Lizeth K Pedraza⁵, Anett J Nagy⁴, Gábor Kozák⁵, Shinya Nakai⁶, Shigeki Kato⁷, Kazuto Kobayashi⁷, Masahiro Ohsawa⁸, Gyöngyi Horváth⁹, Gabriella Kékesi⁹, Magor L Lőrincz¹⁰, Orrin Devinsky¹¹, György Buzsáki¹², Antal Berényi¹³

Affiliations

¹ MTA-SZTE "Momentum" Oscillatory Neuronal Networks Research Group, Department of Physiology, University of Szeged, Szeged 6720, Hungary; HCEMM-SZTE Magnetotherapeutics Research Group, University of Szeged, Szeged 6720, Hungary.
² MTA-SZTE "Momentum" Oscillatory Neuronal Networks Research Group, Department of Physiology, University of Szeged, Szeged 6720, Hungary; Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan; Department of Physiology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan; Department of Biopharmaceutical Sciences and Pharmacy, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
³ MTA-SZTE "Momentum" Oscillatory Neuronal Networks Research Group, Department of Physiology, University of Szeged, Szeged 6720, Hungary; Faculty of Agriculture, University of Szeged, Szeged 6720, Hungary.
⁴ MTA-SZTE "Momentum" Oscillatory Neuronal Networks Research Group, Department of Physiology, University of Szeged, Szeged 6720, Hungary; HCEMM-SZTE Magnetotherapeutics Research Group, University of Szeged, Szeged 6720, Hungary; Neunos Inc, Boston, MA 02108, USA.
⁵ MTA-SZTE "Momentum" Oscillatory Neuronal Networks Research Group, Department of Physiology, University of Szeged, Szeged 6720, Hungary.
⁶ Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
⁷ Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
⁸ MTA-SZTE "Momentum" Oscillatory Neuronal Networks Research Group, Department of Physiology, University of Szeged, Szeged 6720, Hungary; Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
⁹ Department of Physiology, University of Szeged, Szeged 6720, Hungary.
¹⁰ MTA-SZTE "Momentum" Oscillatory Neuronal Networks Research Group, Department of Physiology, University of Szeged, Szeged 6720, Hungary; Department of Physiology, Anatomy and Neuroscience, Faculty of Sciences University of Szeged, Szeged 6726, Hungary; Neuroscience Division, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
¹¹ Department of Neurology, NYU Langone Comprehensive Epilepsy Center, NYU Grossman School of Medicine, New York, NY 10016, USA.
¹² Neuroscience Institute, New York University, New York, NY 10016, USA.
¹³ MTA-SZTE "Momentum" Oscillatory Neuronal Networks Research Group, Department of Physiology, University of Szeged, Szeged 6720, Hungary; HCEMM-SZTE Magnetotherapeutics Research Group, University of Szeged, Szeged 6720, Hungary; Neunos Inc, Boston, MA 02108, USA; Neuroscience Institute, New York University, New York, NY 10016, USA. Electronic address: drberenyi@gmail.com.

Abstract

Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker. Olfactory bulbectomy, an established model of depression that reduces limbic gamma oscillations, suffers from non-specific effects of structural damage. Here, we show that transient functional suppression of olfactory bulb neurons or their piriform cortex efferents decreased gamma oscillation power in limbic areas and induced depression-like behaviors in rodents. Enhancing transmission of gamma oscillations from olfactory bulb to limbic structures by closed-loop electrical neuromodulation alleviated these behaviors. By contrast, silencing gamma transmission by anti-phase closed-loop stimulation strengthened depression-like behaviors in naive animals. These induced behaviors were neutralized by ketamine treatment that restored limbic gamma power. Taken together, our results reveal a causal link between limbic gamma oscillations and depression-like behaviors in rodents. Interfering with these endogenous rhythms can affect behaviors in rodent models of depression, suggesting that restoring gamma oscillations may alleviate depressive symptoms.

Keywords: OBx; closed loop; depression; electrical stimulation; gamma oscillation; miniSOG; olfactory bulb; optogenetics; rat.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Depression / therapy
Depressive Disorder, Major*
Neurons
Olfactory Bulb* / physiology
Rodentia