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
Not all sleep is equal when it comes to cleaning the brain
February 27, 2019
Science Daily/University of Rochester Medical Center
New research shows how the depth of sleep can impact our brain's ability to efficiently wash away waste and toxic proteins. Because sleep often becomes increasingly lighter and more disrupted as we become older, the study reinforces and potentially explains the links between aging, sleep deprivation, and heightened risk for Alzheimer's disease.
"Sleep is critical to the function of the brain's waste removal system and this study shows that the deeper the sleep the better," said Maiken Nedergaard, M.D., D.M.Sc., co-director of the Center for Translational Neuromedicine at the University of Rochester Medical Center (URMC) and lead author of the study. "These findings also add to the increasingly clear evidence that quality of sleep or sleep deprivation can predict the onset of Alzheimer's and dementia."
The study, which appears in the journal Science Advances, indicates that the slow and steady brain and cardiopulmonary activity associated with deep non-REM sleep are optimal for the function of the glymphatic system, the brain's unique process of removing waste. The findings may also explain why some forms of anesthesia can lead to cognitive impairment in older adults.
The previously unknown glymphatic system was first described by Nedergaard and her colleagues in 2012. Prior to that point, scientists did not fully understand how the brain, which maintains its own closed ecosystem, removed waste. The study revealed a system of plumbing which piggybacks on blood vessels and pumps cerebral spinal fluid (CSF) through brain tissue to wash away waste. A subsequent study showed that this system primarily works while we sleep.
Because the accumulation of toxic proteins such as beta amyloid and tau in the brain are associated with Alzheimer's disease, researchers have speculated that impairment of the glymphatic system due to disrupted sleep could be a driver of the disease. This squares with clinical observations which show an association between sleep deprivation and heightened risk for Alzheimer's.
In the current study, researchers conducted experiments with mice that were anesthetized with six different anesthetic regimens. While the animals were under anesthesia, the researchers tracked brain electrical activity, cardiovascular activity, and the cleansing flow of CSF through the brain. The team observed that a combination of the drugs ketamine and xylazine (K/X) most closely replicated the slow and steady electrical activity in the brain and slow heart rate associated with deep non-REM sleep. Furthermore, the electrical activity in the brains of mice administered K/X appeared to be optimal for function of the glymphatic system.
"The synchronized waves of neural activity during deep slow-wave sleep, specifically firing patterns that move from front of the brain to the back, coincide with what we know about the flow of CSF in the glymphatic system," said Lauren Hablitz, Ph.D., a postdoctoral associate in Nedergaard's lab and first author of the study. "It appears that the chemicals involved in the firing of neurons, namely ions, drive a process of osmosis which helps pull the fluid through brain tissue."
The study raises several important clinical questions. It further bolsters the link between sleep, aging, and Alzheimer's disease. It is known that as we age it becomes more difficult to consistently achieve deep non-REM sleep, and the study reinforces the importance of deep sleep to the proper function of the glymphatic system. The study also demonstrates that the glymphatic system can be manipulated by enhancing sleep, a finding that may point to potential clinical approaches, such as sleep therapy or other methods to boost the quality of sleep, for at-risk populations.
Furthermore, because several of the compounds used in the study were analogous to anesthetics used in clinical settings, the study also sheds light on the cognitive difficulties that older patients often experience after surgery and suggests classes of drugs that could be used to avoid this phenomenon. Mice in the study that were exposed to anesthetics that did not induce slow brain activity saw diminished glymphatic activity.
"Cognitive impairment after anesthesia and surgery is a major problem," said Tuomas Lilius, M.D., Ph.D., with the Center for Translational Neuromedicine at the University of Copenhagen in Denmark and co-author of the study. "A significant percentage of elderly patients that undergo surgery experience a postoperative period of delirium or have a new or worsened cognitive impairment at discharge."
https://www.sciencedaily.com/releases/2019/02/190227173111.htm