Led by researchers at New York University Grossman School of Medicine and the University of Szeged in Hungary, a new study in mice and rats found that restoring certain signals in a region of the brain that processes odors counteracts depression.
Posting in the newspaper Neuron online May 9, the study results revolve around nerve cells (neurons), which “fire” (or emit electrical signals) to transmit information. In recent years, researchers have discovered that effective communication between brain regions requires groups of neurons to synchronize their activity patterns in repetitive periods (oscillations) of joint silence followed by joint activity. One of those rhythms, called “gamma,” repeats itself some 30 times or more in a second and is an important timing pattern for encoding complex information, potentially including emotions.
Although its causes are not yet well understood, depression is reflected in changes in the gamma oscillation, according to previous studies, as an electrophysiological marker of disease in the regions of the brain that handle the sense of smell, which have also been linked to the emotions. These regions include the olfactory bulb adjacent to the nasal cavity, which is believed to be a source and “driver” of gamma oscillations throughout the brain.
To test this theory, the authors of the current study shut down the bulb’s function using genetic and cell signaling techniques, observed a related increase in depression-like behaviors in the study rodents, and then reversed these behaviors using a device that increased the gamma signals from the brain at their natural rate.
“Our experiments revealed a mechanistic link between deficient gamma activity and decreased behavior in mouse and rat models of depression, with signal changes in the connected and olfactory limbic systems similar to those seen in depressed patients,” says the corresponding author. of the study, 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 to counteract depression and anxiety in cases where available medications are not effective.”
Major depressive disorder is a common serious psychiatric illness that is often resistant to drug therapy, the researchers say. The prevalence of the condition has increased dramatically 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, possibly caused by infection, trauma, or drugs, from the olfactory bulb to other brain regions of the limbic system, such as the piriform cortex and hippocampus, can alter the emotions. However, the research team isn’t sure why. In one theory, depression arises, not within the olfactory bulb, but in changes in its outgoing gamma patterns to other brain targets.
Bulb removal represents an older animal model for the study of major depression, but the process causes structural damage that can cloud researchers’ view of disease mechanisms. So the current research team devised a reversible method to avoid the damage, starting with a single strand of engineered DNA encapsulated in a harmless virus, which when injected into neurons in the rodents’ olfactory bulbs made the cells build certain protein receptors on their cells. surfaces.
This allowed the researchers to inject the rodents with a drug, which spread throughout the system, but only shut down the neurons in the bulb that had been engineered to have the drug-sensitive receptors engineered. In this way, the researchers could selectively and reversibly disable communication between brain regions of the associated bulb. These tests revealed that chronic suppression of olfactory bulb signals, including gamma, induced depressive behaviors not only during the intervention, but also for days afterward.
To show the effect of loss of gamma oscillation on the olfactory bulb, the team used several standard tests of depression in rodents, including measures of anxiety, which is one of its main symptoms. The field recognizes that animal models of human psychiatric conditions will be limited, so it uses a battery of tests to measure depressive behaviors that have proven useful over time.
Specifically, the tests looked at how long the animals spent in open space (a measure of anxiety), whether they stopped swimming earlier when submerged (measures despair), whether they stopped drinking sugar water (they enjoyed things less), and whether they refused to enter a maze (avoided stressful situations).
Next, the researchers used a custom-made device that recorded the natural gamma oscillations of the olfactory bulb and sent those rhythm signals back to 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 depression-like behaviors in humans. Furthermore, feeding an amplified signal from the olfactory bulb back into the brains of depressed rats restored normal gamma function in the limbic system and reduced depressive behaviors by 40 percent (close to normal).
“No one yet knows how gamma wave activation patterns are converted into emotions,” says the study’s senior author, György Buzsáki, MD, PhD, Biggs Professor in the Department of Neuroscience and Physiology at NYU Langone Health and a member of the Faculty of Neuroscience. Institute. “Moving forward, we will work to better understand this link in the bulb, and in the regions it connects to, as behavior changes.”
Along with Berényi and Buzsáki, the study was led by Orrin Devinsky, MD, a professor in NYU Langone’s Department of Neurology and director of its Comprehensive Epilepsy Center. Berényi is also Principal Investigator of the Momentum Oscillatory Neural Networks Research Group, Department of Physiology, University of Szeged in Hungary, along with study first authors Qun Li and Yuichi Takeuchi, and study authors Jiale Wang, Levente Gellért, Livia Barcsai , Lizeth Pedraza, Anett Nagy, Gábor Kozák, Gyöngyi Horváth, Gabriella Kékesi and Magor L?rincz. Study authors Shinya Nakai and Masahiro Ohsawa work in the Department of Neuropharmacology at Nagoya City University Graduate School of Pharmaceutical Sciences in Japan. Takeuchi is also a professor in the Department of Physiology at Osaka City University School of Medicine and in the School of Pharmaceutical Sciences at Hokkaido University in Japan. Also co-authors of the study were Shigeki Kato and Kazuto Kobayashi Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine in Japan.
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