Study offers insight into molecular biology of the brain in patients with bipolar disorder

In an in-depth study of one of the largest postmortem brain samples ever, scientists from the Lieber Institute for Brain Development, in collaboration with researchers from the Johns Hopkins School of Medicine and the Bloomberg School of Public Health , identified significant differences in gene expression in two specific brain regions of hundreds of patients with bipolar disorder.

The findings, published today in Natural neuroscience, represent the first time that researchers have been able to apply the discipline and tools of genetic research to brain samples from hundreds of patients with bipolar disorder (BD), a chronic, often debilitating, almost always incurable behavioral syndrome. The findings suggest that bipolar disorder may stem from chemical and structural changes in brain cells that affect how they communicate with each other.

This is the first deep dive into the molecular biology of the brain in people who have died from bipolar disorder; the study of real genes, not urine, blood or skin samples. If we can understand the mechanisms behind BD, if we can figure out what’s wrong with the brain, then we can start developing new targeted treatments for what has long been a mysterious disease. »


Dr. Thomas Hyde of the Lieber Institute and co-author of the article

Bipolar disorder is a severe mental illness characterized by extreme mood swings, with bouts of mania alternating with bouts of depression. It usually appears in people in their 20s and 30s and stays with them for life. It affects approximately 2.8% of the adult US population, or about 7 million people, at a terrible cost, with patients facing higher suicide rates, poorer quality of life and lower productivity than that of the general population. Some estimates put the annual cost of bipolar disease in the United States at $219.1 billion, or $88,443 per person per year. Treatment usually involves psychotherapy and medication and sometimes electroconvulsive therapy. While medications can be helpful in treating bipolar disorder, many patients find that they have bothersome side effects, and for some patients the medications don’t work at all. To develop more effective ways to treat this disease, it is important to understand the biology behind it.

Because the brain is a complex organ with many distinct anatomical and functional regions – and varied gene expression patterns – the scientists limited their study to two key regions of the limbic system, which plays a vital role in regulating behavior, emotions and memory. The regions were the amygdala and the subgenal anterior cingulate cortex (sACC), evidence of which strongly suggests underlying mood regulation and the pathophysiology of bipolar disorder.

Using advanced laboratory techniques, researchers measured levels of messenger RNA, an index of activated and expressed genes, in brain samples from the largest group of patients and normal controls ever assembled for the study. bipolar disorder (511 brain samples from 295 individual donors). ).

The abundance of tissue samples allowed the researchers to observe much more significant differentially expressed genes than had been detected in previous studies. In fact, they observed nearly eight times as many differentially expressed genetic characteristics in sACC compared to amygdala, suggesting that sACC may play a particularly important role – both in the regulation of mood in general and in comics in particular.

The researchers compared genes from control brains with those from individuals with bipolar disorder and found abnormalities in two gene families: one containing synapse-related genes and the second related to immune and inflammatory function. The synapse is the site where nerve cells communicate with each other, while immune and inflammatory genes are also involved in synapse function in the brain. Taken together, these findings suggest that bipolar disorder is caused by chemical and structural changes at the synapse, altering communication between brain cells. This miscommunication manifests as severe mood swings between depression and mania.

The authors of the article highlighted the importance of solving the mysteries of bipolar disorder through advances such as those achieved through basic research.

“This is a road map, not a treasure map,” said Daniel R. Weinberger, MD, chief executive and director of the Lieber Institute and co-author of the study. “We have a much better understanding of where to go as we dig to make new discoveries and develop new treatments.”

“There is finally a study using modern technology and our current understanding of genetics to find out how the brain is doing,” Dr Hyde added. “We know that BD tends to run in families, and there is strong evidence that there are inherited genetic abnormalities that put an individual at risk for bipolar disorder. Unlike conditions such as sickle cell disease, bipolar disorder does not result from a single genetic disease, rather most patients have inherited a group of variants spread over a number of genes.

Dr. Hyde noted that a major clinical study conducted by the National Institutes of Health, known as the Psychiatric Genetics Consortium, involving tens of thousands of people with bipolar disorder as well as normal control subjects, identified 31 variations of the genome that increase the risk. of illness. The current study from the Lieber Institute continues this progress at the genetic level in hundreds of brains.

“By examining messenger RNA in the brains of people with bipolar disorder, we were able to identify several genes that have alterations in the amount of messenger RNA they produce,” Dr. Hyde said. “By identifying these individual genes, we can begin to define the molecular changes that cause highly erratic moods. Ultimately, these findings promise new treatments targeting the abnormal chemical makeup in the brains of people with bipolar disorder.”

“Bipolar disorder, also known as manic-depressive disorder, is a very damaging and paradoxical condition, Dr. Weinberger said. “It can make people very productive so they can run countries and businesses, but it can also throw them into the meat grinder of dysfunction and depression. Patients with BD can live on two hours of sleep by night, saving the world with their abundance of energy, then become so self-destructive that they spend their family’s fortune in a week and lose all their friends as they spiral down. Bipolar disorder also has shared genetic links with other psychiatric disorders, such as schizophrenia, and is implicated in the overuse of drugs and alcohol.”

Dr Weinberger added: “Because society values ​​manic productivity, BD is often not viewed as the terrible disease that it is. But it can be a tragic affliction.”

Source:

Lieber Institute for Brain Development

Journal reference:

10.1038/s41593-022-01024-6

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