Potential found to counter depression by restoring key brain rhythm
Study proposes role for gamma oscillations in future treatment

Date:
May 9, 2023
Source:
NYU Langone Health / NYU Grossman School of Medicine
Summary:
A new study in mice and rats found that restoring certain signals
in a brain region that processes smells countered depression.


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

Publishing in the journal Neuron online May 9, the study results revolve
around nerve cells (neurons), which "fire" -- or 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 repetitive periods (oscillations) of joint silence followed by joint activity. One such
rhythm, called "gamma," repeats about 30 times or more in a second, and
is an important timing pattern for the encoding of complex information, potentially including emotions.

Although its causes remain poorly understood, 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.

To test this theory, the current study authors shut down the function of
the bulb using genetic and cell signaling techniques, observed a related increase of depression-like behaviors in study rodents, 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," says corresponding study
author Antal Bere'nyi, 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. Thus, 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 let the researchers 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. 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 fordays 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 (measures despair), whether they stopped drinking sugar water
(took less pleasure in things), and whether they refused to enter a maze (avoided 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 to normal).

"No one yet knows how the firing patterns of gamma waves are converted
into emotions," says senior study author Gyo"rgy Buzsa'ki, 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." Along with Bere'nyi and Buzsa'ki, the study was led by Orrin Devinsky, MD, professor in the in Department of Neurology at NYU Langone,
and director of its Comprehensive Epilepsy Center. Bere'nyi is also
principal investigator of the Momentum Oscillatory Neuronal Networks
Research Group, 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 Gelle'rt, Livia Barcsai, Lizeth Pedraza,
Anett Nagy, Ga'bor Koza'k, Gyo"ngyi Horva'th, Gabriella Ke'kesi and
Magor L?rincz. Study authors Shinya Nakai and Masahiro Ohsawa are with
the Department of Neuro-pharmacology, Graduate School of Pharmaceutical Sciences, at Nagoya City University in Japan. Takeuchi is also faculty
in the Department of Physiology, Osaka City University Graduate School
of Medicine and Faculty 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.

* RELATED_TOPICS
o Health_&_Medicine
# Nervous_System # Psychology_Research #
Mental_Health_Research # Diseases_and_Conditions
o Mind_&_Brain
# Neuroscience # Depression # Disorders_and_Syndromes
# Psychiatry
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========================================================================== Story Source: Materials provided by NYU_Langone_Health_/_NYU_Grossman_School_of_Medicine.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Qun Li, Yuichi Takeuchi, Jiale Wang, Levente Gelle'rt, Livia
Barcsai,
Lizeth K. Pedraza, Anett J. Nagy, Ga'bor Koza'k, Shinya Nakai,
Shigeki Kato, Kazuto Kobayashi, Masahiro Ohsawa, Gyo"ngyi Horva'th,
Gabriella Ke'kesi, Magor L. Lőrincz, Orrin Devinsky, Gyo"rgy
Buzsa'ki, Antal Bere'nyi. Reinstating olfactory bulb-derived limbic
gamma oscillations alleviates depression-like behavioral deficits
in rodents. Neuron, 2023; DOI: 10.1016/j.neuron.2023.04.013 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/05/230509122011.htm

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