The stress excessive during adolescence can cause alterations in the profile of genes expressed in the brain, especially those associated with bioenergetic functions. These alterations can affect cellular respiration, causing behavioral problems and psychiatric disorders in adulthood, according to a rat study conducted by researchers from the Ribeirão Preto Faculty of Medicine at the University of São Paulo (FMRP-USP) in Brazil.
The results of research were published in the journal Translational Psychiatry.
Adolescents with high stress thresholds: here are the repercussions in adulthood
It is no secret that many changes occur in our bodies and behavior during adolescence, when the brain undergoes structural and functional alterations shaped by both neurobiological and social factors.
“Like the human brain, the brain of an adolescent rat is highly plastic. This plasticity is seen at the molecular level and in terms of behavior. Changes in the expression profiles of specific genes in different brain regions lead to alterations in brain cell connectivity, which spread systemically and can produce persistent alterations into adulthood that correlate with psychiatric disorders,” said Thamyris Santos -Silva, first author of the article. At the time of the study, he was a Ph.D. candidate in pharmacology at FMRP-USP.
“Adolescence is a critical period for brain plasticity, which is significantly influenced by social experience,” added Felipe Villela Gomes, last author of the article and professor in the Department of Pharmacology of FMRP-USP. “Susceptibility to adverse social and environmental factors, such as trauma, insults, and abuse, increases during this period, and social experience may influence vulnerability and resilience to stress.”
The prefrontal cortex is a region of the brain that is extremely susceptible to stress during adolescence. As it matures, it is critical for improving cognitive control of emotions normally seen in adulthood. In rats subjected to stress during adolescence, this region showed lower levels of expression of genes that play a key role in mitochondrial respiration.
Mitochondria are organelles found in most cells of both humans and rats, as well as many other living organisms. Through cellular respiration, they constitute the main source of chemical energy for the functioning of neurons, one of the main types of brain cells. They therefore help regulate social behavior, including the stress response.
The study began by analyzing behavioral responses to stress, such as anxiety, social interaction and cognition, in rats in late adolescence. The animals were exposed to an attrition protocol for ten consecutive days which coincided with an intense period of brain plasticity. They were then subjected to specific tests to evaluate their behavior and the results showed a clear deficit in each case.
“We found that animals stressed at this stage of life showed a markedly poor behavioral profile, with anxiety, reduced sociability and impaired cognitive functions,” Gomes said.
To find out whether these variations were reflected in gene expression, the researchers sent RNA samples to the Behavioral Genetics Laboratory of the Brain Mind Institute (BMI) at the Federal Institute of Technology in Lausanne (EPFL). The laboratory is led by Carmen Sandi, Professor of Neuroscience.
To study gene expression in rat brains, the lab sequenced messenger RNA and analyzed the results using bioinformatics tools.
“The analysis showed alterations in prefrontal cortex genes in stressed animals. Among the ten most affected genes, many were associated with pathways linked to oxidative stress and mitochondrial function, a key cellular component for producing energy for the brain,” Gomes said.
Oxygen consumption by the mitochondria in the brains of these animals was also impaired by stress. “We now have a variety of evidence pointing to the importance of mitochondrial function in this behavioral profile,” Gomes said.
Next steps for researchers will include studying whether this behavioral profile can serve as a basis for predicting an individual's response to overstimulation and to what extent this actually leads to the development of psychiatric disorders.
“Another path to advance the study would be to focus on genetic alterations, conducting tests to find out what happens when gene expression decreases or improves. This could provide further evidence regarding the links between stress and the alterations in question, and even indicate ways in which to combat them,” Gomes said.
A surprising thing happened when researchers began to explore whether stress early in life exacerbates the effects of childhood TBI on health and behavior later in life. In one animal study, stress changed the level of activation of many more genes in the brain than those changed by a blow to the head.
It is already known that head injuries are common in young children, especially due to falls, and may be linked to mood disorders and social difficulties that emerge later in life. Negative childhood experiences are also very common and can increase the risk of disease, mental illness, and substance abuse in adulthood.
“But we don't know how these two things might interact,” said study senior author Kathryn Lenz, an associate professor of psychology at The Ohio State University.
“We wanted to understand whether experiencing traumatic brain injury in the context of stressful circumstances early in life could modulate the response to brain injury. And using an animal model allows us to really get into the mechanisms by which these two things might be impacting brain development as it is occurring.”
This first series of experiments in rats suggests that the potential for stress in early life to lead to lifelong health consequences may not be fully appreciated, Lenz said.
“We found that many, many, many more genes were differentially expressed as a result of manipulating stress in early life compared to manipulating traumatic brain injury,” Lenz said. “Stress is truly powerful and we should not underestimate the impact of stress in early life on brain development. I think it tends to be ignored, but it's an incredibly important public health topic.
The research poster was presented on November 12, 2023 at Neuroscience 2023, the annual meeting of the Society for Neuroscience.
The researchers temporarily separated newborn rats from their mothers every day for 14 days to induce stress that mimicked the effects of adverse childhood experiences, which include a variety of potentially traumatic events.
On day 15, a time when the rats were evolutionarily equivalent to a young child, the stressed and non-stressed rats were given a concussion-like head injury under anesthesia or no head injury. Three conditions – stress only, head trauma only, and stress combined with head trauma – were compared with uninjured, non-stressed rats.
First author Michaela Breach, a graduate student in Lenz's lab, examined gene expression changes in the hippocampus region of the animals' brains later in the juvenile period using single-nucleus RNA sequencing.
Stress alone and combined with traumatic brain injury (TBI) have produced some noteworthy results. Both conditions activated pathways in excitatory and inhibitory neurons associated with plasticity, which is the brain's ability to adapt to all types of changes, primarily to promote flexibility, but sometimes, when changes are maladaptive, resulting in negative outcomes .
“This may suggest that the brain is opening up to a new period of vulnerability or is actively changing during this time period in which it may program subsequent deficits,” Breach said.
Both conditions also had an effect on signaling related to oxytocin, a hormone linked to maternal behavior and social bonding. Stress alone and combined with head trauma activated this oxytocin pathway, but brain injury alone inhibited it.
“Both stress and TBI are linked to abnormal social behaviors, but we're seeing these different effects with oxytocin signaling,” Breach said. “This shows that the effect of stress could modulate how TBI is changing the brain as the combined treatment was different from TBI alone. Oxytocin is involved in the stress response and repair, so this could mean it could be an interesting modulator to pursue in the future.”
In behavioral tests conducted on rats aged into adulthood, only animals that experienced stress early in life were inclined to enter large spaces more frequently, a place that typically makes rodents feel vulnerable to predators.
“Overall, this suggests that they may take more risks later in life, which is consistent with human data showing that stress early in life can increase the risk of certain conditions such as ADHD, which can be characterized from risky behavior or substance use disorders,” Breccia said.
Behavioral data indicating the harmful effects of stress in early life provide further evidence of the need to address negative childhood experiences, Lenz said.
“Things like social support and enrichment can buffer the effects of stress early in life, as has been shown in animal models and people,” he said. “I don't think it can be emphasized enough how damaging early childhood stressors can be if they're not addressed.”
This work was supported by the Chronic Brain Injury Institute at Ohio State, the Brain Injury Association of America, and the National Science Foundation Graduate Research Fellowship.
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