Science & Technology

Genetic changes associated with severe repetitive behavior in autism, schizophrenia, and drug addiction

The green fluorescence of the mouse brain highlights a cluster of striosome neurons (yellow arrow) that send distant connections (yellow arrow) to dopamine-producing cells (yellow arrowhead) in the midbrain. Striosome gene activation correlates with excessive repetitive behavior. Credit: Jill Crittenden

The Gravier Institute has identified genes associated with abnormal repetitive behavior commonly found in models of addiction and schizophrenia.

Extremely repetitive behaviors such as flapping, shaking, picking, and sniffing are common in many brain disorders such as autism, schizophrenia, Huntington’s disease, and drug addiction. These behaviors, called stereotyped behaviors, are also evident in animal models of drug addiction and autism.

In a new study published in European Journal of NeuroscienceResearchers at the McGovern Institute for Brain Research have identified genes that are activated in the brain before the onset of these severe repetitive behaviors.

“Our lab has discovered a small set of genes that are regulated in relation to the development of stereotyped behavior in animal models of drug addiction,” he said. MIT Professor at the Anne Gravier Institute, the lead author of the treatise. “I was surprised and interested in one of these genes being a schizophrenia susceptibility gene. This discovery was made to a variety of neurological and neuropsychiatric disorders, or to” typical “people under stress. It may help to understand the biological basis of repetitive stereotyped behavior, as seen. “

Shared molecular pathway

In a study led by research scientist Jill Critenden, scientists at the Gray Beer Institute are used to promote hyperactivity and stereotyped behavior in humans and laboratory animals, and to model the symptoms of schizophrenia. The mice were exposed to the exercise stimulant amphetamine.

They found that stimulant exposure, which promotes the longest repetitive behavior, leads to activation of genes regulated by neuregulin 1, a signaling molecule important for various cellular functions, including neuronal development and plasticity. Did. Mutations in the neuregulin 1 gene are risk factors for schizophrenia.

New discoveries highlight common molecular and circuit pathways of stereotyped behavior caused by substance abuse and brain damage, and influence why stimulant addiction is a risk factor for the development of schizophrenia.

“Experimental treatment with amphetamines has long been used in rodent and other animal studies to find better treatments for human schizophrenia. At the McGavan Brain Institute, MIT. He was a professor of brain science and cognitive science at. “Finding Neuregulin 1 was impressive — a potential hint to some of the underlying sharing mechanisms of these similarities.”

Drug exposure associated with repetitive behavior

Although many studies have measured changes in gene expression in animal models of drug addiction, this is the first study to assess changes in the entire genome that are particularly relevant to restricted repetitive behavior.

Stereotyped behavior is difficult to measure without labor-intensive direct observation because it consists of small movements and peculiar behaviors. In this study, the authors administered amphetamines (or saline controls) to mice and then measured how much they ran around with light beam blockade. Researchers have identified long periods of time during which the mice are not running (ie, may be engaged in restricted stereotyped behavior), videotaped the mice during these periods, and restricted repetition. We observed the severity of behaviors (such as sniffing and licking stereotyped behaviors).

They administered amphetamine once daily for 21 days to each mouse, and on average, mice showed little stereotyped behavior on the first day of drug exposure, but by day 7 of exposure all mice had long periods of time. Stereotyped behavior that gradually shortens in the next two weeks.

“I was surprised to see a decrease in stereotyped behavior after a week of treatment. In fact, I was planning my study with the expectation that repetitive behavior would be more intense, which is the result of stereotyped behavior. I realized that it was an opportunity to look at genetic changes that are specific to the high day, “said lead author Jill Critenden.

The authors compared changes in gene expression in the brains of mice treated with amphetamine for 1, 7, or 21 days. They are most likely to have genetic alterations associated with 7-day medications, especially those associated with stereotyped behavior, that underlie extreme repetitive behavior and can identify risk factor genes for such symptoms in the disease. I assumed.

Shared anatomical pathway

Previous studies by the Gray Beer Lab have shown that stereotyped behavior correlates directly with circumscribed gene activation of the striatum, a key forebrain region of habit formation. In animals with the strongest stereotypes, most of the striatum show no gene activation, but initial early gene induction remains high in clusters of cells called striosomes. Striosomes have recently been shown to strongly regulate cells that release dopamine, a neuromodulator that is severely destroyed in drug addiction and schizophrenia. Surprisingly, striosomes contain high levels of neuregulin 1.

“Our new data suggest that upregulation of neuregulin-responsive genes in animals with severe repetitive behavior reflects genetic alterations in striosome neurons that control dopamine release. “Crittenden explains. “Because dopamine can directly affect whether animals repeat behaviors or seek new behaviors, our study has shown the potential of the striosome circuit in controlling behavioral choices in health and neuropsychiatry. Emphasizes the role. “

Behavior and gene expression patterns

Striatal gene expression levels were measured by sequencing messenger RNA (mRNA) in dissected brain tissue. mRNA is read from an “active” gene and tells the protein synthesis mechanism how to make a protein that corresponds to the sequence of the gene. Proteins are the main components of cells, thereby controlling the function of each cell. The number of times a particular mRNA sequence is found reflects how often the gene was read when the cell material was collected.

To identify genes that were read into mRNA before stereotyped behavior was prolonged, researchers collected brain tissue 20 minutes after amphetamine injection, about 30 minutes before the peak of stereotyped behavior. They then identified genes with significantly different levels of corresponding mRNA in saline-treated and drug-treated mice.

A wide variety of genes showed moderate mRNA increases after initial amphetamine exposure. This induced mild hyperactivity and a variety of behaviors such as gait, snuff, and rearing of mice.

By day 7 of treatment, all mice had long been engaged in one particular repetitive behavior, such as sniffing the wall. Similarly, fewer genes were activated by day 7 compared to the first treatment day, but were strongly activated in all mice treated with amphetamine to induce stereotyped behavior.

By the 21st day of treatment, stereotyped behavior was as weak as gene upregulation. Compared to other treatments, fewer genes were strongly activated and more were suppressed. “Mice seemed to develop resistance to the drug, both in terms of behavioral and gene activation responses,” says Critenden.

“Finding behavioral patterns of gene regulation is a correlative task, and this first small study did not prove a’causal relationship’,” explains Graybiel. “But we hope that the surprising similarities between mRNA range and selectivity, and detected behavioral changes, will help further address the highly challenging goal of treating addiction. “

Reference: “Drug Induction” by Jill R. Critdenden, Teresa A. Gibson, Anne C. Smith, Hillary A. Bowden, Ferra Ildilim, Kyle B. Fischer, Michael Im, David E. Hausmann Changes in the Striatal Transcriptome Related to Sexual Repetitive Behavior, Anne M. Gray Beer, March 23, 2021 European Journal of Neuroscience..
DOI: 10.1111 / ejn.15116

This work was funded by the National Institute of Pediatric Health Development, the Sax Cabanau Foundation, the Broderick Foundation for Plant Cannabinoid Research at MIT, the James and Pat Poitras Research Foundation, the Simons Foundation, and the Stanley Psychiatric Research Center. It was. Broad Institute.

Genetic changes associated with severe repetitive behavior in autism, schizophrenia, and drug addiction Genetic changes associated with severe repetitive behavior in autism, schizophrenia, and drug addiction

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