Led by researchers from NYU Grossman School of Medicine and the University of Szeged in Hungary, a new study in mice and rats finds that restoring specific signals in the area of the brain that processes odors counteracts depression.
Publication in the journal nervous Online May 9, the results of the study are about 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 repeated periods (oscillations) of joint silence followed by joint activity. One such system, called gamma, repeats about 30 or more times per second, a timing pattern important for encoding complex information, possibly including emotions.
Although its causes are still not well understood, depression is reflected in gamma oscillation changes, according to previous studies, as an electrophysiological marker of disease in brain regions that control the sense of smell, which is also linked to emotions. These areas include the olfactory bulb adjacent to the nasal cavity, which is believed to be the source and “conductor” of gamma oscillations at the brain level.
To test this theory, the authors of the current study shut down bulb function using genetic and cellular signaling techniques, observed an associated increase in depression-like behaviors in the study rodents, then reversed these behaviors using a device that boosts cell-specific gamma signaling. brain at its natural pace.
says corresponding study author Antal Perini, MD, PhD, assistant professor in the department of neurology and physiology at NYU Langone Health. “This work demonstrates the power of gamma-boosting as a potential technique for counteracting depression and anxiety in situations where available medications are ineffective.”
Researchers say major depressive disorder is a common and serious mental illness that often resists drug treatment. The prevalence of the condition has increased dramatically since the start of the pandemic, with an estimated more than 53 million new cases.
Gamma waves are associated with emotions
Pathogenic changes in the timing and strength of gamma signals, potentially induced 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 emotion. However, the research team is not sure why. In one theory, depression originates, not within the olfactory bulb, but in changes in gamma patterns outgoing to other brain targets.
Removing the bulb is an older animal model for studying major depression, but the operation causes structural damage that may obscure researchers’ view of disease mechanisms. Thus, the current research team designed a reversible method to avoid damage, starting with a single engineered strand of DNA encapsulated in a harmless virus that, when injected into neurons in the olfactory bulbs of rodents, caused the cells to build up specific protein receptors on those cells. surfaces.
This allowed the researchers to inject the rodents with a drug, which spreads system-wide, but only shuts down neurons in the bulb that were engineered to have designer receptors that are sensitive to the drug. In this way investigators can selectively reverse and turn off communication between bulbar partner brain regions. These tests revealed that chronic inhibition of olfactory bulb signals, including gamma, not only induced depressive behaviors during the intervention, but for days afterwards.
To show the effect of losing gamma oscillation in the olfactory bulb, the team used several standard rodent tests of depression, including measures of anxiety, which is one of its main symptoms. The field recognizes that animal models of human psychological states will be limited, and so it uses a suite of tests to measure depressive behaviors that have proven useful over time.
Specifically, the tests looked at how long the animals would spend in the open (a measure of anxiety), whether they stopped swimming early when submerged (a measure of desperation), and whether they stopped drinking sugar water (they didn’t enjoy things as much). , and whether they refused to enter the maze (avoid stressful situations).
The researchers then used a custom-made device that records natural gamma oscillations from the olfactory bulb, and sends those accelerated signals to the rodents’ brains as a closed-loop electrical stimulation. The device was able to suppress or amplify gamma in healthy animals. Suppression of gamma oscillations in the olfactory lobe induced depression-like behaviors in humans. In addition, feeding an enlarged olfactory bulb signal into the brains of depressed mice restored normal gamma function in the limbic system, and reduced depressive behaviors by 40 percent (almost to normal).
“Nobody knows yet how patterns of gamma-wave firing are converted into emotion,” says study senior author Giorgi Bozaki, MD, PhD, Biggs Professor in the Department of Neuroscience and Physiology at NYU Langone Health and a faculty member in Neuroscience. . institute. “Going forward, we will work to better understand this link in the bulb, and in the areas it connects to, as behavior changes.”
Along with Berényi and 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. Perini is also the Principal Investigator in the Momentum Oscillatory Neural Networks Research Group, Department of Physiology at the University of Szeged in Hungary, together with senior study authors Qun Li and Yuichi Takeuchi, and authors Jiale Wang, Levente Gellért, Livia Barcsai and Lizeth Pedraza, Anett Nagy, Gábor Kozák, Gyöngyi Horváth, Gabriella Kékesi, Magor L? rincz. Study authors Shinya Nakai and Masahiro Osawa work with the Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, at Nagoya City University in Japan. Takeuchi is a faculty member in the Department of Physiology, Osaka City University College of Medicine and College of Pharmaceutical Sciences, Hokkaido University in Japan. Also study authors were Shigeki Kato and Kazuto Kobayashi Department of Molecular Genetics, Institute of Biomedical Sciences at Fukushima Medical University School of Medicine in Japan.