Life Stressors Trigger Neurological Disorders

When mothers are exposed to trauma, illness, alcohol or other drug abuse, these stressors may activate a single molecular trigger in brain cells that can go awry and activate conditions such as schizophrenia, post-traumatic stress disorder and some forms of autism.

Until now, it has been unclear how much these stressors have impacted the cells of a developing brain. Past studies have shown that when an expectant mother exposes herself to alcohol or drug abuse or she experiences some trauma or illness, her baby may later develop a psychiatric disorder, including some forms of autism or post-traumatic stress disorder, later in life. But the new findings, published online in Neuron, identifies a molecular mechanism in the prenatal brain that may help explain how cells go awry when exposed to certain environmental conditions.

Kazue Hasimoto-Torii, PhD, Principal Investigator of the Center for Neuroscience, Children’s National Health System, and a Scott-Gentle Foundation investigator, is lead author of the paper. Torii was previously at Yale, whose researchers were co-authors in the report. The research was funded primarily through National Institutes of Health grants.

Researchers found that mouse embryos exposed to alcohol, methyl-mercury, or maternal seizures activate a single gene, HSF1, also known as heat shock factor, in cerebral cortex. The HSF1 “plays a crucial role in the response of brain cells to prenatal environmental insults,” the researchers reported. “The gene protects and enables brain cells to survive prenatal assaults. Mice lacking the HSF1 gene showed structural brain abnormalities and were prone to seizures after birth following exposures to very low levels of toxins.”

Even in mice where the HSF1 gene was properly activated to combat environmental insults, the molecular mechanism alone may permanently change how brain cells respond, and may be a reason why someone may be more susceptible to neuropsychiatric disorders later in life.

Innovative work with stem cells also provided findings that supported the theory that stress induces vulnerable cells to malfunction, the researchers reported. For the study, researchers created stem cells from biopsies of people diagnosed with schizophrenia. Stem cells are capable of becoming many different tissue types, including neurons. In the study, genes from the stem cells of those with schizophrenia responded more dramatically when exposed to environmental insults than stem cells from non-schizophrenic individuals.

While it has been generally accepted that exposure to harmful environmental factors increase the susceptibility of the brain to neurological and psychiatric disorders, new types of environmental agents are continuingly added to the mix, requiring evolving studies, Hasimoto-Torii says.

Hashimoto-Torii notes that autism rates have increased substantially and “more people are having these exposures to environmental stressors,” she says. While there have been many studies that have identified singular stressors, such as alcohol, there have not been enough studies to focus on many different environmental factors and their impacts, such as heavy metals as well as alcohol and other toxic exposure, she adds.

Identifying many risk factors helped Hashimoto-Torii and other researchers identify the gene that may be linked to neurological problems. “Different stressors may have different stress responses,” she says. She examined risk factors specifically involving epilepsy, ADHD, autism and schizophrenia. Eventually, it may open the door “to provide therapy in the future to reduce the risk” and protect vulnerable cells.

Researchers search for earliest roots of psychiatric disorders

Newborns whose mothers were exposed during pregnancy to any one of a variety of environmental stressors — such as trauma, illness, and alcohol or drug abuse — become susceptible to various psychiatric disorders that frequently arise later in life. However, it has been unclear how these stressors affect the cells of the developing brain prenatally and give rise to conditions such as schizophrenia, post-traumatic stress disorder, and some forms of autism and bipolar disorders. 

Now, Yale University researchers have identified a single molecular mechanism in the developing brain that sheds light on how cells may go awry when exposed to a variety of different environmental insults. The findings, to be published in the May 7 issue of the journal Neuron, suggest that different types of stressors prenatally activate a single molecular trigger in brain cells that may make exposed individuals susceptible to late-onset neuropsychiatric disorders.

The researchers found that mouse embryos exposed to alcohol, methyl-mercury, or maternal seizures all activate in the developing brain cells a single gene — HSF1 or heat shock factor — which protects and enables some of the brain cells to survive prenatal insult. Mice lacking the HSF1 gene showed structural brain abnormalities and were prone to seizures after birth, even after exposure to very low levels of the toxins.

In addition, researchers created stem cells — which are capable of becoming many different tissue types, including neurons — from biopsies of individuals diagnosed with schizophrenia. Genes from these “schizophrenic” stem cells responded more dramatically when exposed to environmental insults than stem cells obtained from non-schizophrenic individuals. The findings provide support to the thesis that stress induces vulnerable cells to malfunction.

“It appears that different types of environmental stressors can trigger the same condition if they occur at the same period of prenatal development,” said Yale’s Pasko Rakic, senior author of the study. “Conversely, the same environmental stressor may cause different pathologies, if it occurs at different times during pregnancy.”

Since HSF1 activation can potentially serve as a permanent marker of the stressed/damaged cell, it opens the possibility of identifying these cells in adults in order to explore the pathogenesis of postnatal disorders and how to protect vulnerable cells.