Ketamine reverses neural changes underlying depression-related behaviors in mice

Study sheds light on the neural mechanisms underlying remission of depression

April 11, 2019

Science Daily/NIH/National Institute of Mental Health

Researchers have identified ketamine-induced brain-related changes that are responsible for maintaining the remission of behaviors related to depression in mice -- findings that may help researchers develop interventions that promote lasting remission of depression in humans. The study, funded by the National Institute of Mental Health (NIMH), part of the National Institutes of Health, appears in the journal Science.

Major depression is one of the most common mental disorders in the United States, with approximately 17.3 million adults experienced a major depressive episode in 2017. However, many of the neural changes underlying the transitions between active depression, remission, and depression re-occurrence remain unknown. Ketamine, a fast-acting antidepressant which relieves depressive symptoms in hours instead of weeks or longer, provides an opportunity for researchers to investigate the short- and long-term biological changes underlying these transitions.

"Ketamine is a potentially transformative treatment for depression, but one of the major challenges associated with this drug is sustaining recovery after the initial treatment," said study author Conor Liston, M.D., Ph.D., of Weill Cornell Medicine, New York City.

To understand mechanisms underlying the transition from active depression to remission in humans, the researchers examined behaviors related to depression in mice. Researchers took high-resolution images of dendritic spines in the prefrontal cortex of mice before and after they experienced a stressor. Dendritic spines are protrusions in the part of neurons that receive communication input from other neurons. The researchers found that mice displaying behaviors related to depression had increased elimination of, and decreased formation of, dendritic spines in their prefrontal cortex compared with mice not exposed to a stressor. This finding replicates prior studies linking the emergence of behaviors related to depression in mice with dendritic spine loss.

In addition to the effects on dendritic spines, stress reduced the functional connectivity and simultaneous activity of neurons in the prefrontal cortex of mice. This reduction in connectivity and activity was associated with behaviors related to depression in response to stressors. Liston's group then found that ketamine treatment rapidly restored functional connectivity and ensemble activity of neurons and eliminated behaviors related to depression. Twenty-four hours after receiving a single dose of ketamine, mice exposed to stress showed a reversal of behaviors related to depression and an increase in dendritic spine formation when compared to stressed mice that had not received ketamine. These new dendritic spines were functional, creating working connections with other neurons.

The researchers found that while behavioral changes and changes in neural activity in mice happened quickly (three hours after ketamine treatment), dendritic spine formation happened more slowly (12-24 after hours after ketamine treatment). While further research is needed, the authors suggest these findings might indicate that dendritic spine regrowth may be a consequence of ketamine-induced rescue of prefrontal cortex circuit activity.

Although dendritic spines were not found to underly the fast-acting effects of ketamine on behaviors related to depression in mice, they were found to play an important role in maintaining the remission of those behaviors. Using a new technology developed by Haruo Kasai, Ph.D., and Haruhiko Bito, Ph.D., collaborators at the University of Tokyo, the researchers found that selectively deleting these newly formed dendritic spines led to the re-emergence of behaviors related to depression.

"Our results suggest that interventions aimed at enhancing synapse formation and prolonging their survival could be useful for maintaining the antidepressant effects of ketamine in the days and weeks after treatment," said Dr. Liston.

"Ketamine is the first new anti-depressant medication with a novel mechanism of action since the 1980s. Its ability to rapidly decrease suicidal thoughts is already a fundamental breakthrough," said Janine Simmons, M.D., Ph.D., chief of the NIMH Social and Affective Neuroscience Program. "Additional insights into ketamine's longer-term effects on brain circuits could guide future advances in the management of mood disorders."

https://www.sciencedaily.com/releases/2019/04/190411145105.htm

Psychedelic drugs promote neural plasticity in rats and flies

June 12, 2018

Science Daily/Cell Press

Psychedelic drugs may have mind-altering powers in the physical sense, too. A new study, published June 12 in the journal Cell Reports, found psychedelics, specifically DOI, DMT, and LSD, can change brain cells in rats and flies, making neurons more likely to branch out and connect with one another. The work supports the theory that psychedelics could help to fight depression, anxiety, addiction, and post-traumatic stress disorder.

"These are some of the most powerful compounds known to affect brain function, it's very obvious to me that we should understand how they work," says senior author David E. Olson, assistant professor in the Department of Chemistry and the Department of Biochemistry & Molecular Medicine at the University of California, Davis.

The idea that depression stems from imbalanced brain chemistry remains popular, but recent studies have revealed evidence that depression manifests as structural changes in brain circuits or atrophy in parts of the brain. This doesn't mean neurons die off during depression, but that neurites retract. Neurites are the sections -- either axons or dendrites -- of a neuron that project out to bridge the gap between two neurons at the synapse to facilitate communication.

"One of the hallmarks of depression is that the neurites in the prefrontal cortex -- a key brain region that regulates emotion, mood, and anxiety -- those neurites tend to shrivel up," says Olson. These brain changes also appear in cases of anxiety, addiction, and post-traumatic stress disorder.

In their paper, Olson and colleagues tested psychedelics from the amphetamine, tryptamine, and ergoline drug classes. In both test tube and animal experiments, the psychedelics showed functional and structural changes like those promoted by ketamine in cortical neurons. Psychedelics increased both the density of dendritic spines and the density of synapses. Some psychedelics tested, including LSD, proved to be more potent and efficacious than ketamine in promoting neurite growth.

The researchers did not do any human experiments, but experiments in both vertebrates and invertebrates showed psychedelics produced similar effects across species. This indicates the biological mechanisms that respond to psychedelics have remained the same across eons of evolution and that psychedelics will likely have the same brain growth (neural plasticity) effects in humans.

Olson and colleagues also set out to test how these psychedelics promoted neural plasticity, meaning they explored which biological pathways psychedelics activate that lead to neural growth. Ketamine's neural plasticity effects were previously shown to be dependent on a protein called brain-derived neurotrophic factor (BDNF). When the researchers blocked BDNF signaling, psychedelics lost their ability to promote neurite growth. BDNF binds to a receptor, called TrkB, that is part of a signaling pathway that includes mTOR, which is known to play a key role in the production of proteins necessary for the formation of new synapses. When the researchers experimented by inhibiting mTOR, it also completely blocked the psychedelics' ability to promote neurite growth. Olson thinks identifying the signaling pathways at play in psychedelic-induced brain changes will help future research identify compounds that could be developed into depression treatments.

"If we fully understand the signaling pathways that lead to neural plasticity, we might be able to target critical nodes along those pathways with drugs that are safer than ketamine or psychedelics," says Olson.

Although most psychedelics aren't considered to be addictive in the same way that cocaine is, they do produce hallucinations. Olson doesn't expect psychedelics to become prescription drugs for depression. "But a compound inspired by psychedelics very well could," he says.

https://www.sciencedaily.com/releases/2018/06/180612185207.htm