Adolescent Stress Alters Brain Genes, Affecting Adult Behavior

Summary: A new study reveals that excessive stress during adolescence can lead to long-lasting changes in gene expression in the brain, particularly those related to bioenergy functions.

This research indicates that such alterations may disrupt cell respiration and contribute to behavioral issues and psychiatric disorders in adulthood. Using a rat model, the study showed that stressed adolescent rats exhibited anxiety, reduced sociability, and cognitive impairments, linked to changes in genes controlling mitochondrial function in the prefrontal cortex.

These findings underscore the critical impact of adolescent stress on adult brain function and behavior.

Key Facts:

1. Stress in adolescence can cause lasting changes in brain gene expression, particularly affecting mitochondrial respiration, crucial for neuron function.
2. Behavioral assessments in rats exposed to adolescent stress showed marked impairments in anxiety, sociability, and cognition.
3. The study found specific gene alterations in the prefrontal cortex of stressed rats, associated with oxidative stress and mitochondrial function.

Source: FAPESP

Excessive stress during adolescence can cause alterations in the profile of genes expressed in the brain, especially those associated with bioenergy functions.

These alterations may affect cell respiration, resulting in behavioral problems and psychiatric disorders in adulthood, according to a study in rats conducted by researchers at the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP) in Brazil.

The results are reported in an article published in the journal Translational Psychiatry.

It is no secret that many changes occur in our bodies and behavior during adolescence when the brain undergoes structural and functional alterations shaped both by 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 in adulthood that correlate with psychiatric disorders,” said Thamyris Santos-Silva, first author of the article. At the time of the study, she was a PhD 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 a professor in FMRP-USP’s Department of Pharmacology.

“Susceptibility to adverse social and environmental factors, such as traumas, insults and abuse, increases during this period, and social experience can influence vulnerability and resilience to stress.”

The prefrontal cortex is a brain region that is extremely susceptible to stress during adolescence. When it matures, it is crucial to enhanced cognitive control of emotions normally observed in adulthood. In rats subjected to stress during adolescence, this region displayed 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 cell respiration, they are 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 response to stress.

The study, which was supported by FAPESP, began by analyzing behavioral responses to stress, such as anxiety, social interaction and cognition, in late-adolescent rats. The animals were exposed to a stress protocol for ten consecutive days that coincided with an intense period of brain plasticity. They were then submitted to specific tests to assess their behavior, and the results showed distinct impairment in every case. 

“We found that stressed animals in this life stage displayed a markedly poor behavioral profile, with anxiety, reduced sociability and impaired cognitive function,” Gomes said.

To discover whether these variations were reflected by gene expression, the researchers sent RNA samples to the Behavioral Genetics Laboratory of the Brain Mind Institute (BMI) at the Swiss Federal Institute of Technology in Lausanne (EPFL). The laboratory is led by Carmen Sandi, a professor of neuroscience. 

To investigate gene expression in the rats’ brains, the laboratory sequenced messenger RNA and analyzed the results using bioinformatics tools. This part of the study was funded under a joint institutional internationalization program run by USP and CAPES, the Ministry of Education’s Coordination for the Improvement of Higher Education Personnel (PrInt USP/CAPES). 

“The analysis showed alterations to the genes of the prefrontal cortex in the stressed animals. Among the ten most affected genes, several were associated with pathways linked to oxidative stress and mitochondrial function, a key cellular component of energy production for the brain,” Gomes said.

Consumption of oxygen by mitochondria in the brains of these animals was also found to be impaired by stress.

“We now have evidence of various kinds pointing to the importance of mitochondrial function in this behavioral profile,” Gomes said.

Next steps

Next steps for the researchers will include investigating whether this behavioral profile can serve as a basis for predicting an individual’s response to stress, and to what extent this actually does lead to the development of psychiatric disorders.

“Another route to advance the study would be to focus on genetic alterations, conducting tests to find out what happens when gene expression diminishes or improves. This could provide more evidence regarding the links between stress and the alterations in question, and even point to ways to combat them,” Gomes said.

About this stress, genetics, and behavior research news

Author: Heloisa Reinert
Source: FAPESP
Contact: Heloisa Reinert – FAPESP
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Transcriptomic analysis reveals mitochondrial pathways associated with distinct adolescent behavioral phenotypes and stress response” by Thamyris Santos-Silva et al. Translational Psychiatry

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Abstract

Transcriptomic analysis reveals mitochondrial pathways associated with distinct adolescent behavioral phenotypes and stress response

Adolescent individuals exhibit great variability in cortical dynamics and behavioral outcomes. The developing adolescent brain is highly sensitive to social experiences and environmental insults, influencing how personality traits emerge.

A distinct pattern of mitochondrial gene expression in the prefrontal cortex (PFC) during adolescence underscores the essential role of mitochondria in brain maturation and the development of mental illnesses.

Mitochondrial features in certain brain regions account for behavioral differences in adulthood. However, it remains unclear whether distinct adolescent behavioral phenotypes and the behavioral consequences of early adolescent stress exposure in rats are accompanied by changes in PFC mitochondria-related genes and mitochondria respiratory chain capacity.

We performed a behavioral characterization during late adolescence (postnatal day, PND 47–50), including naïve animals and a group exposed to stress from PND 31–40 (10 days of footshock and 3 restraint sessions) by z-normalized data from three behavioral domains: anxiety (light–dark box tests), sociability (social interaction test) and cognition (novel-object recognition test).

Employing principal component analysis, we identified three clusters: naïve with higher-behavioral z-score (HBZ), naïve with lower-behavioral z-score (LBZ), and stressed animals. Genome-wide transcriptional profiling unveiled differences in the expression of mitochondria-related genes in both naïve LBZ and stressed animals compared to naïve HBZ.

Genes encoding subunits of oxidative phosphorylation complexes were significantly down-regulated in both naïve LBZ and stressed animals and positively correlated with behavioral z-score of phenotypes. Our network topology analysis of mitochondria-associated genes found Ndufa10 and Cox6a1 genes as central identifiers for naïve LBZ and stressed animals, respectively.

Through high-resolution respirometry analysis, we found that both naïve LBZ and stressed animals exhibited a reduced prefrontal phosphorylation capacity and redox dysregulation.

Our findings identify an association between mitochondrial features and distinct adolescent behavioral phenotypes while also underscoring the detrimental functional consequences of adolescent stress on the PFC.