Led by researchers from NYU Grossman School of Medicine and Hungary’s University of Szeged, a new study in mice and rats found that restoring certain signals in a brain region that processes smells countered depression.

Published online May 9 in the journal Neuron, the study results revolve around nerve cells, also called neurons, which “fire”—emit electrical signals—to transmit information. Researchers in recent years discovered that effective communication between brain regions requires groups of neurons to synchronize their activity patterns in oscillations of joint silence followed by joint activity. One such rhythm, called gamma, repeats 30 times or more in a second and is an important timing pattern for the encoding of complex information, potentially including emotions.

Although the causes of depression remain poorly understood, it is reflected in gamma oscillation changes, according to past studies, as an electrophysiological marker of the disease in brain regions that manage the sense of smell, which have also been tied to emotions. These regions include the olfactory bulb adjacent to the nasal cavity, which is thought to be a source and conductor of gamma oscillations throughout the brain.

To test this theory, the current study authors shut down the function of the olfactory bulb in study rodents using genetic and cell signaling techniques, observed a related increase of depression-like behaviors in the subjects, and then reversed these behaviors using a device that boosted gamma signals of the brain at their natural pace.

“Our experiments revealed a mechanistic link between deficient gamma activity and behavioral decline in mice and rat models of depression, with the signal changes in the olfactory and connected limbic systems similar to those seen in depressed patients,” said corresponding study author Antal Berényi, MD, PhD, adjunct assistant professor in the Department of Neuroscience and Physiology at NYU Langone Health. “This work demonstrates the power of gamma enhancement as a potential approach for countering depression and anxiety in cases where available medications are not effective.”

Major depressive disorder is a common, severe psychiatric illness often resistant to drug therapy, the researchers say. The prevalence of the condition has dramatically increased since the start of the pandemic, with more than 53 million new cases estimated.

Gamma Waves Linked to Emotions

Disease-causing changes in the timing and strength of gamma signals, potentially caused by infections, trauma, or drugs, from the olfactory bulb to other brain regions of the limbic system, such as the piriform cortex and hippocampus, may alter emotions. However, the research team is not sure why. In one theory, depression arises not within the olfactory bulb but in changes to its outgoing gamma patterns to other brain targets.

Removal of the bulb represents an older animal model for the study of major depression, but the process causes structural damage that may cloud researchers’ view of disease mechanisms. To avoid this damage, the current research team designed a reversible method, starting with a single engineered strand of DNA encapsulated in a harmless virus. When injected into neurons in the olfactory bulbs of rodents, the DNA caused the cells to build certain protein receptors on their surfaces.

This let the researchers inject the rodents with a drug that spread system-wide but only shut down the neurons in the bulb that had been engineered to have the designed drug-sensitive receptors. This way the investigators could selectively and reversibly switch off the communication between the bulb partner brain regions. These tests revealed that chronic suppression of olfactory bulb signals, including gamma, not only induced depressive behaviors during the intervention, but for days afterward.

To show the effect of the loss of gamma oscillation in the olfactory bulb, the team used several standard rodent tests of depression, including measures of the anxiety that is one of its main symptoms. The field recognizes that animal models of human psychiatric conditions will be limited, and so uses a battery of tests to measure depressed behaviors that have proven useful over time.

Specifically, the tests looked at how long animals would spend in an open space, a measure of anxiety; whether they stopped swimming earlier when submerged, a measure of despair; whether they stopped drinking sugar water, a sign of taking less pleasure in things; and whether they refused to enter a maze, a sign they were avoiding stressful situations.

The researchers next used a custom-made device that recorded the natural gamma oscillations from the olfactory bulb, and sent those paced signals back into the rodents’ brains as closed-loop electrical stimulation. The device was able to suppress gamma in healthy animals or amplify it. Suppression of gamma oscillations in the olfactory lobe induced behaviors resembling depression in humans. In addition, feeding an amplified olfactory bulb signal back into the brains of depressed rats restored normal gamma function in the limbic system, and reduced the depressive behaviors by 40 percent, almost back to normal.

“No one yet knows how the firing patterns of gamma waves are converted into emotions,” said senior study author György Buzsáki, MD, PhD, the Biggs Professor of Neuroscience in the Department of Neuroscience and Physiology and a faculty member of the Neuroscience Institute. “Moving forward, we will be working to better understand this link in the bulb, and in the regions it connects to, as behavior changes.”

Along with Dr. Berényi and Dr. Buzsáki, the study was led by Orrin Devinsky, MD, professor in the Department of Neurology at NYU Langone and director of the Comprehensive Epilepsy Center. Dr. Berényi is also principal investigator of the Momentum Oscillatory Neuronal Networks Research Group in the Department of Physiology at the University of Szeged in Hungary, along with first study authors Qun Li and Yuichi Takeuchi, and authors Jiale Wang, Levente Gellért, Livia Barcsai, Lizeth Pedraza, Anett Nagy, Gábor Kozák, Gyöngyi Horváth, Gabriella Kékesi, and Magor Lőrincz. Study authors Shinya Nakai and Masahiro Ohsawa are with the Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, at Nagoya City University in Japan. Takeuchi is also a member of the faculty in the Department of Physiology, Osaka City University Graduate School of Medicine, and the Faculty of Pharmaceutical Sciences, Hokkaido University, Japan. Additional study authors were Shigeki Kato and Kazuto Kobayashi, members of the Department of Molecular Genetics, Institute of Biomedical Sciences, at Fukushima Medical University School of Medicine in Japan.

Funding for the study was provided through grants from the Hungarian Academy of Sciences Momentum II program; the National Research, Development and Innovation Office of Hungary; the Ministry of Innovation and Technology of Hungary; the Ministry of Human Capacities, Hungary; the Hungarian Scientific Research Fund; the Hungarian Brain Research Program; the European Union Horizon 2020 Research and Innovation Program; the Japan Society for the Promotion of Science; the Japan Ministry of Education, Culture, Sports, Science and Technology; and the Japan Agency for Medical Research and Development. Additional support came from the Kanae Foundation for the Promotion of Medical Science, the Life Science Foundation of Japan, the Takeda Science Foundation, the Japanese Neural Network Society, and the János Bolyai Fellowship.

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