Posts tagged social withdrawal

Findings Point to New Potential Drug Target—GABA Neurons—to Treat Patients with Depression and Other Mood Disorders

A new drug target to treat depression and other mood disorders may lie in a group of GABA neurons (gamma-aminobutyric acid –the neurotransmitters which inhibit other cells) shown to contribute to symptoms like social withdrawal and increased anxiety, Penn Medicine researchers report in a new study in the Journal of Neuroscience.

Experts know that people suffering from depression and other mood disorders often react to rejection or bullying by withdrawing themselves socially more than the average person who takes it in strides, yet the biological processes behind these responses have remained unclear.

Now, a preclinical study, from the labs of Olivier Berton, PhD, an assistant professor in the department of Psychiatry, with Collin Challis of the Neuroscience Graduate Group, and Sheryl Beck, PhD, a professor in the department of Anesthesiology at Children’s Hospital of Philadelphia, found that bullying and other social stresses triggered symptoms of depression in mice by activating GABA neurons, in a never-before-seen direct relationship between social stimuli and this neural circuitry.  Activation of those neurons, they found, directly inhibited levels of serotonin, long known to play a vital role in behavioral responses—without it, a depressed person is more likely to socially withdrawal.

 Conversely, when the researchers successfully put the brake on the GABA neurons, mice became more resilient to bullying and didn’t avoid once -perceived threats.

“This is the first time that GABA neuron activity—found deep in the brainstem—has been shown to play a key role in the cognitive processes associated with social approach or avoidance behavior in mammals,” said Dr. Berton. “The results help us to understand why current antidepressants may not work for everyone and how to make them work better—by targeting GABA neurons that put the brake on serotonin cells.”

Less serotonin elicits socially defensive responses such as avoidance or submission, where enhancement—the main goal of antidepressants—induces a positive shift in the perception of socio-affective stimuli, promoting affiliation and dominance. However, current antidepressants targeting serotonin, like SSRIs, are only effective in about 50 percent of patients. 

These new findings point to GABA neurons as a new, neural drug target that could help treat the other patients who don’t respond to today’s treatment.

For the study, “avoidant” mice were exposed to brief bouts of aggression from trained “bully” mice. By comparing gene expression in the brains of resilient and avoidant mice, Berton and colleagues discovered that bullying in avoidant mice puts GABA neurons in a state where they become more excitable and the mice exhibit signs of social defeat. Resilient mice, however, had no change in neuron levels and behavior.

To better understand the link between GABA and the development of stress resilience, Berton, Beck, and colleagues also devised an approach to directly manipulate levels: Lifting GABA inhibition of serotonin neurons reduced social and anxiety symptoms in mice exposed to bullies and also fully prevented neurobiological changes due to stress.

“Our paper provides a novel cellular understanding of how social defensiveness and social withdrawal develop in mice and gives us a stepping stone to better understand the basis of similar social symptoms in humans,” said Berton. “This has important implications for the understanding and treatment of mood disorders.”

(Source: uphs.upenn.edu)

Reduced production of myelin, a type of protective nerve fiber that is lost in diseases like multiple sclerosis, may also play a role in the development of mental illness, according to researchers at the Graduate School of Biomedical Sciences at Mount Sinai School of Medicine. The study is published in the journal Nature Neuroscience.

Myelin is an insulating material that wraps around the axon, the threadlike part of a nerve cell through which the cell sends impulses to other nerve cells. New myelin is produced by nerve cells called oligodendrocytes both during development and in adulthood to repair damage in the brain of people with diseases such as multiple sclerosis (MS).

A new study led by Patrizia Casaccia, MD, PhD, Professor of Neuroscience, Genetics and Genomics; and Neurology at Mount Sinai, determined that depriving mice of social contact reduced myelin production, demonstrating that the formation of new oligodendrocytes is affected by environmental changes. This research provides further support to earlier evidence of abnormal myelin in a wide range of psychiatric disorders, including autism, anxiety, schizophrenia and depression.

“We knew that a lack of social interaction early in life impacted myelination in young animals but were unsure if these changes would persist in adulthood,” said Dr. Casaccia, who is also Chief of the Center of Excellence for Myelin Repair at the Friedman Brain Institute at Mount Sinai School of Medicine. “Social isolation of adult mice causes behavioral and structural changes in neurons, but this is the first study to show that it causes myelin dysfunction as well.”

Dr. Casaccia’s team isolated adult mice to determine whether new myelin formation was compromised. After eight weeks, they found that the isolated mice showed signs of social withdrawal. Subsequent brain tissue analyses indicated that the socially isolated mice had lower-than-normal levels of myelin-forming oligodendrocytes in the prefrontal cortex, but not in other areas of the brain. The prefrontal cortex controls complex emotional and cognitive behavior.

The researchers also found changes in chromatin, the packing material for DNA. As a result, the DNA from the new oligodendrocytes was unavailable for gene expression.

After observing the reduction in myelin production in socially-isolated mice, Dr. Casaccia’s team then re-introduced these mice into a social group. After four weeks, the social withdrawal symptoms and the gene expression changes were reversed.

“Our study demonstrates that oligodendrocytes generate new myelin as a way to respond to environmental stimuli, and that myelin production is significantly reduced in social isolation,” said Dr. Casaccia. “Abnormalities occur in people with psychiatric conditions characterized by social withdrawal. Other disorders characterized by myelin loss, such as MS, often are associated with depression. Our research emphasizes the importance of maintaining a socially stimulating environment in these instances.”

At Mount Sinai, Dr. Casaccia’s laboratory is studying oligodendrocyte formation to identify therapeutic targets for myelin repair. They are screening newly-developed pharmacological compounds in brain cells from rodents and humans for their ability to form new myelin.

(Source: newswise.com)