Results from a new mouse study by researchers from the NYU Grossman School of Medicine and the University of Szeged demonstrate that restoring certain signals in a brain region that processes smells countered depression.

The findings are published in Neuron in an article titled, “Reinstating olfactory bulb-derived limbic gamma oscillations alleviates depression-like behavioral deficits in rodents.”

“Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker,” wrote the researchers. “Olfactory bulbectomy, an established model of depression that reduces limbic gamma oscillations, suffers from nonspecific 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.”

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,” is an important timing pattern for the encoding of complex information.

Depression 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 brain-wide gamma oscillations.

In the current study, the researchers stopped the function of the bulb and observed an increase in depression-like behaviors in mice. They 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.”

Removal of the bulb represents an older animal model for the study of major depression, but the process causes structural damage. The current research team designed a reversible method to avert damage, starting with a single, engineered strand of DNA encapsulated in a harmless virus, which when injected into neurons in the olfactory bulbs of rodents caused the cells to build certain protein receptors on their surfaces.

This allowed the researchers to inject the rodents with a drug, which spread system-wide, but only shut down the neurons in the bulb that had been engineered to have the designed drug-sensitive receptors. These tests revealed that chronic suppression of olfactory bulb signals, including gamma, not only induced depressive behaviors during the intervention, but for days afterward.

“Interfering with these endogenous rhythms can affect behaviors in rodent models of depression, suggesting that restoring gamma oscillations may alleviate depressive symptoms,” concluded the researchers.

“No one yet knows how the firing patterns of gamma waves are converted into emotions,” explained senior study author György Buzsáki, MD, PhD, the Biggs professor in the department of neuroscience and physiology at NYU Langone Health and a faculty member in its 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.”

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