Posts tagged gene activity

Dysfunction in dopamine signaling profoundly changes the activity level of about 2,000 genes in the brain’s prefrontal cortex and may be an underlying cause of certain complex neuropsychiatric disorders, such as schizophrenia, according to UC Irvine scientists.

This epigenetic alteration of gene activity in brain cells that receive this neurotransmitter showed for the first time that dopamine deficiencies can affect a variety of behavioral and physiological functions regulated in the prefrontal cortex.

The study, led by Emiliana Borrelli, a UCI professor of microbiology & molecular genetics, appears online in the journal Molecular Psychiatry.

“Our work presents new leads to understanding neuropsychiatric disorders,” Borrelli said. “Genes previously linked to schizophrenia seem to be dependent on the controlled release of dopamine at specific locations in the brain. Interestingly, this study shows that altered dopamine levels can modify gene activity through epigenetic mechanisms despite the absence of genetic mutations of the DNA.”

Dopamine is a neurotransmitter that acts within certain brain circuitries to help manage functions ranging from movement to emotion. Changes in the dopaminergic system are correlated with cognitive, motor, hormonal and emotional impairment. Excesses in dopamine signaling, for example, have been identified as a trigger for neuropsychiatric disorder symptoms.

Borrelli and her team wanted to understand what would happen if dopamine signaling was hindered. To do this, they used mice that lacked dopamine receptors in midbrain neurons, which radically affected regulated dopamine synthesis and release.

The researchers discovered that this receptor mutation profoundly altered gene expression in neurons receiving dopamine at distal sites in the brain, specifically in the prefrontal cortex. Borrelli said they observed a remarkable decrease in expression levels of some 2,000 genes in this area, coupled with a widespread increase in modifications of basic DNA proteins called histones – particularly those associated with reduced gene activity.

Borrelli further noted that the dopamine receptor-induced reprogramming led to psychotic-like behaviors in the mutant mice and that prolonged treatment with a dopamine activator restored regular signaling, pointing to one possible therapeutic approach.

The researchers are continuing their work to gain more insights into the genes altered by this dysfunctional dopamine signaling.

(Source: news.uci.edu)

Finding of disrupted brain gene orchestration gives first direct evidence of circadian rhythm changes in depressed brains, opens door to better treatment

Every cell in our bodies runs on a 24-hour clock, tuned to the night-day, light-dark cycles that have ruled us since the dawn of humanity. The brain acts as timekeeper, keeping the cellular clock in sync with the outside world so that it can govern our appetites, sleep, moods and much more.

But new research shows that the clock may be broken in the brains of people with depression — even at the level of the gene activity inside their brain cells.

It’s the first direct evidence of altered circadian rhythms in the brain of people with depression, and shows that they operate out of sync with the usual ingrained daily cycle. The findings, in the Proceedings of the National Academy of Sciences, come from scientists from the University of Michigan Medical School and other institutions.

The discovery was made by sifting through massive amounts of data gleaned from donated brains of depressed and non-depressed people. With further research, the findings could lead to more precise diagnosis and treatment for a condition that affects more than 350 million people worldwide.

What’s more, the research also reveals a previously unknown daily rhythm to the activity of many genes across many areas of the brain – expanding the sense of how crucial our master clock is.

In a normal brain, the pattern of gene activity at a given time of the day is so distinctive that the authors could use it to accurately estimate the hour of death of the brain donor, suggesting that studying this “stopped clock” could conceivably be useful in forensics. By contrast, in severely depressed patients, the circadian clock was so disrupted that a patient’s “day” pattern of gene activity could look like a “night” pattern — and vice versa.

The work was funded in large part by the Pritzker Neuropsychiatric Disorders Research Fund, and involved researchers from the University of Michigan, University of California’s Irvine and Davis campuses, Weill Cornell Medical College, the Hudson Alpha Institute for Biotechnology, and Stanford University.

The team uses material from donated brains obtained shortly after death, along with extensive clinical information about the individual. Numerous regions of each brain are dissected by hand or even with lasers that can capture more specialized cell types, then analyzed to measure gene activity. The resulting flood of information is picked apart with advanced data-mining tools.

Lead author Jun Li, Ph.D., an assistant professor in the U-M Department of Human Genetics, describes how this approach allowed the team to accurately back-predict the hour of the day when each non-depressed individual died – literally plotting them out on a 24-hour clock by noting which genes were active at the time they died. They looked at 12,000 gene transcripts isolated from six regions of 55 brains from people who did not have depression.

This provided a detailed understanding of how gene activity varied throughout the day in the brain regions studied. But when the team tried to do the same in the brains of 34 depressed individuals, the gene activity was off by hours. The cells looked as if it were an entirely different time of day.

“There really was a moment of discovery,” says Li, who led the analysis of the massive amount of data generated by the rest of the team and is a research assistant professor in U-M’s Department of Computational Medicine at Bioinformatics. “It was when we realized that many of the genes that show 24-hour cycles  in the normal individuals were well-known circadian rhythm genes – and when we saw that the people with depression were not synchronized to the usual solar day in terms of this gene activity. It’s as if they were living in a different time zone than the one they died in.”

Huda Akil, Ph.D., the co-director of the U-M Molecular & Behavioral Neuroscience Institute and co-director of the U-M site of the Pritzker Neuropsychiatric Disorders Research Consortium, notes that the findings go beyond previous research on circadian rhythms, using animals or human skin cells, which were more easily accessible than human brain tissues.

“Hundreds of new genes that are very sensitive to circadian rhythms emerged from this research — not just the primary clock genes that have been studied in animals or cell cultures, but other genes whose activity rises and falls throughout the day,” she says. “We were truly able to watch the daily rhythm play out in a symphony of biological activity, by studying where the clock had stopped at the time of death. And then, in depressed people, we could see how this was disrupted.”

Now, she adds, scientists must use this information to help find new ways to predict depression, fine-tune treatment for each depressed patient, and even find new medications or other types of treatment to develop and test. One possibility, she notes, could be to identify biomarkers for depression – telltale molecules that can be detected in blood, skin or hair.

And, the challenge of determining why the circadian clock is altered in depression still remains. “We can only glimpse the possibility that the disruption seen in depression may have more than one cause. We need to learn more about whether something in the nature of the clock itself is affected, because if you could fix the clock you might be able to help people get better,” Akil notes.

The team continues to mine their data for new findings, and to probe additional brains as they are donated and dissected. The high quality of the brains, and the data gathered about how their donors lived and died, is essential to the project, Akil says. Even the pH level of the tissue, which can be affected by the dying process and the time between death and freezing tissue for research, can affect the results. The team also will have access to blood and hair samples from new donors.

(Source: uofmhealth.org)

Abuse during childhood is different.

A study of adult civilians with PTSD (post-traumatic stress disorder) has shown that individuals with a history of childhood abuse have distinct, profound changes in gene activity patterns, compared to adults with PTSD but without a history of child abuse.

A team of researchers from Atlanta and Munich probed blood samples from 169 participants in the Grady Trauma Project, a study of more than 5000 Atlanta residents with high levels of exposure to violence, physical and sexual abuse and with high risk for civilian PTSD.

The results were published Monday, April 29 in Proceedings of the National Academy of Sciences, Early Edition.

“These are some of the most robust findings to date showing that different biological pathways may describe different subtypes of a psychiatric disorder, which appear similar at the level of symptoms but may be very different at the level of underlying biology,” says Kerry Ressler, MD, PhD, professor of psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center.

“As these pathways become better understood, we expect that distinctly different biological treatments would be implicated for therapy and recovery from PTSD based on the presence or absence of past child abuse.”

Ressler, a Howard Hughes Medical Institute Investigator, is co-director of the Grady Trauma Project, along with co-author Bekh Bradley, PhD, assistant professor of psychiatry and behavioral sciences at Emory and director of the Trauma Recovery Program at the Atlanta Veterans Affairs Medical Center.

The first author of the paper is Divya Mehta, PhD, a postdoctoral fellow in Munich. The senior author is Elisabeth Binder, MD, PhD, associate professor of psychiatry and behavioral sciences at Emory and group leader at the Max-Planck Institute of Psychiatry in Munich, Germany.

Mehta and her colleagues examined changes in the patterns of which genes were turned on and off in blood cells from patients. They also looked at patterns of methylation, a DNA modification on top of the four letters of the genetic code that causes genes to be ‘silenced’ or made inactive.

Study participants were divided into three groups: people who experienced trauma without developing PTSD, people with PTSD who were exposed to child abuse, and people with PTSD who were not exposed to child abuse.

The researchers were surprised to find that although hundreds of genes had significant changes in activity in the PTSD with and without child abuse groups, there was very little overlap in patterns between these groups. The two groups shared similar symptoms of PTSD, which include intrusive thoughts such as nightmares and flashbacks, avoidance of trauma reminders, and symptoms of hyperarousal and hypervigilance.

The PTSD with child abuse group displayed more changes in genes linked with development of the nervous system and regulation of the immune system, while the PTSD minus child abuse group displayed more changes in genes linked with apoptosis (cell death) and growth rate regulation. In addition, changes in methylation were more frequent in the PTSD with child abuse group. The authors believe that these biological pathways may lead to different mechanisms of PTSD symptom formation within the brain.

The Max Planck/Emory scientists were probing gene activity in blood cells, rather than brain tissue. Similar results have been obtained by researchers studying the influence of child abuse on the brains of people who had committed suicide.

“Traumatic events that happen in childhood are embedded in the cells for a long time,” Binder says. “Not only the disease itself, but the individual’s life experience is important in the biology of PTSD, and this should be to be reflected in the way we treat these disorders.”

(Source: news.emory.edu)