SfN18: Does stress during early development have long-term consequences for the brain?

Written by Martha Powell, Future Science Group

Research presented at SfN Neuroscience 2018 (3–7 November, San Diego, CA, USA) has investigated excessive stress during early childhood or fetal development and the long-term consequences this can have on the brain – from affecting an individual’s adulthood response to stress to increasing the likelihood of brain disorders.
The latest findings uncover more about the mechanisms by which stress disrupts brain development in addition to suggesting new strategies to combat the effects of stress, such as inhibiting stress hormone production or ‘resetting’ immune cell populations.

Targeting microglia has positive effects in mouse model of autism

It has been reported that the microglia could be mediating the increased risk of autism spectrum disorder (ASD) linked with maternal infection during pregnancy. Animal research presented at SfN Neuroscience [1] has assessed the role of microglia in ASD-like symptoms following maternal infection, revealing that they could be a therapeutic target.

The team discovered that mice exposed to inflammation in the womb displayed more repetitive behavior and social impairment than those not exposed. In addition, microglia in inflammation-exposed mice had more synapses in the medial prefrontal cortex, a region implicated in ASD. However, these behaviors and the elevated synapse levels were both eliminated when the mice were given a drug that renewed the microglial cell population.

Senior author, Tsuneya Ikezu (Boston University, MA, USA), commented: “These results suggest that overactivation of the maternal immune system alters the function of microglia throughout life, leading to more growth factor production, increased synapses and development of ASD-like behaviors, which were corrected by the drug treatment for the renewal of microglia.”

Maternal stress could influence fetal brain development via microbiome changes

Stress before or during pregnancy can alter the maternal microbiome, likely affecting fetal nutrition and brain development, according to new human and animal research released at SfN Neuroscience 2018 [2].

Scientists studied mice subjected to early stress during pregnancy, discovering increased pro-inflammatory bacteria in the maternal microbiome in addition to decreased fatty and amino acids, which are important for fetal development. The researchers also tested the microbiomes of pregnant women who experienced stress and trauma during childhood, noting that women who experienced more adverse events had altered gut bacteria, more inflammatory proteins and a heightened response to stress during pregnancy.

Understanding these microbiome differences may help identify biomarkers and treat stress-mediated effects on the fetus. Lead author, Eldin Jašarevic (University of Maryland, MD, USA), concluded: “Taken together, our translational approach demonstrates that the maternal gut microbiome is sensitive to psychological stress experience.”

Early-life stress increases stress sensitivity – changes in chromatin structure implicated

Childhood stress has been suggested to increase sensitivity to stress during adulthood; however, the biological basis has previously been unknown.

At SfN Neuroscience 2018, researchers presented new findings suggesting that early-life stress may cause lasting changes in chromatin structure, increasing vulnerability to stress in later life [3]. The team studied young mice separated from their mothers for several hours a day, observing that the RNA profiles of stressed and unstressed mice had differences in gene expression in a key brain reward region. Moreover, they discovered lasting changes to histone proteins in stressed pups.

Lead author, Catherine Pena (Icahn School of Medicine, NY, USA), explained: “A majority of the chromatin changes we found indicated that early-life stress makes DNA more open and accessible, suggesting that later input such as stress may have a greater effect on RNA transcription than usual. This indicates that early-life stress may prime the brain to be more susceptible to future stress via changes in chromatin structure.”

Mother’s presence in infant stress changes disruptions to brain

The presence or absence of a caregiver changes how early-life stress affects the brain, with social and emotional disruptions seen only in a mother’s presence, according to animal research presented at SfN Neuroscience 2018 [4].

To explore the impacts of early stress from a caregiver, researchers used a rat model of early-life abuse where mothers are given insufficient materials for nest-building, leading to negative behaviors towards their pups. Pups exposed to this were observed to have increased corticosterone, impaired social behavior and structural differences in the hippocampus and amygdala.

To further pinpoint the role of caregivers, pups were injected with corticosterone and then put in a cage with an awake mother, anesthetized mother or a plastic tube. All pups demonstrated hippocampal deficits but disruption if the amygdala and social behaviors only occurred when the mother was present (awake or not).

Study author, Regina Sullivan (New York University, NY, USA), commented: “Results from our study indicate that harmful effects of early-life stress are influenced by a mother’s presence. Elevated stress hormones negatively impacted hippocampal development regardless of maternal presence; however, amygdala development was only disrupted if stress hormone increases occurred while with the mother.”

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[1] Ikezu S, Van Enoo AA, Yeh H et al. Depletion and repopulation of microglia ameliorates maternal inflammation-induced neurobehavioral abnormalities and neuritogenic phenotype of microglia. Program and Abstracts of SfN Neuroscience 2018. San Diego, CA, USA, 3–7 November 2018 (Abstract 7936).

[2] Jasarevic E, Hantsoo L, Howard C et al. The pregnancy gut microbiome as a translational biomarker of maternal adversity and offspring immune programming. Program and Abstracts of SfN Neuroscience 2018. San Diego, CA, USA, 3–7 November 2018 (Abstract 15574).

[3] Pena CJ, Loh YHE, Farrelly L et al. Transcriptional priming by enduring chromatin modifications after early life stress. Program and Abstracts of SfN Neuroscience 2018. San Diego, CA, USA, 3–7 November 2018 (Abstract 5217).

[4] Raineki C, Opendak M, Sarro EC et al. Deconstructing infant trauma and pathology: infant hippocampus targeted by stress but stress paired with mother targets amygdala. Program and Abstracts of SfN Neuroscience 2018. San Diego, CA, USA, 3–7 November 2018 (Abstract 12036).