Environmental Influence on the Developing Brain

Before birth and early in life, the developing brain is acutely sensitive to its environment. A symposium at the Fifth Annual Aspen Brain Forum, hosted by the New York Academy of Sciences in New York City, explored how certain social and psychological aspects of environment influence biology and behavior.

Tracy L. Bale, of the University of Pennsylvania, noted that maternal stress during pregnancy is associated with increased risk of neurodevelopmental disorders like autism and schizophrenia in offspring, but questions of timing remain unresolved.

Animal research can give insights, she said; rodents perceive, process, and react to stress similarly to humans.

In the mouse, very early pregnancy—equivalent to the human first trimester—appears to be a sensitive period for gender-specific effects of maternal stress. Adult male, but not female offspring respond abnormally to stress, and are 10 percent smaller than normal. They pass these characteristics on to their own offspring, suggesting that prenatal stress has altered cells that will develop into sperm.

So early in gestation, maternal stress cannot directly affect the developing brain, Bale said, but it may act through the placenta.

She pointed out that in mice, some sex-linked genes in the placenta produce compounds that switch other genes off and on. “Because of them, the male and female placenta are poised to respond differently to a changing environment.”

Bale described experiments focused on O-linked-N-acetylglucosamine transferase (OGT), an enzyme that is twice as concentrated in normal female as male placenta. Among its functions, OGT helps construct proteins from DNA blueprints. Anything that alters OGT poses a broad threat to normal embryo development.

“We think of OGT as the biochemical canary in the placental coal mine,” she said.

Maternal stress reduces placental OGT in both sexes. Because the male normally has so much less, it may drop below a vulnerability threshold, she proposed.

To test the hypothesis, Bale’s team genetically engineered a mouse to produce no placental OGT in embryo. In adulthood, the males looked and acted very much like the offspring of mothers who had been stressed during pregnancy.

“Just by changing one gene in the placenta, you can dramatically reprogram how the brain is developing,” Bale said.

The prenatal environment should prepare an animal (or human) for its future world, she said. These experiments suggest how maternal stress might derail the process, leading to problems throughout life.

Parenting and Wiring

How early experiences shape a key brain circuit was the subject of a talk by Nim Tottenham, of Columbia University.

“The amygdala is important for learning emotional associations and maintaining vigilance, and strong connections to the prefrontal cortex (PFC) regulate its arousal. We’re interested in what the growth chart of this system looks like,” she said.

The relationship between the amygdala and the PFC is very different in children than in adolescents and adults “This switch interests us as we try to identify sensitive periods in development.”

Tottenham conjectured that because subcortical structures like the amygdala develop earlier than the PFC, to forge a connection the amygdala must “begin the conversation.”

Resting-state amygdala-PFC connectivity is absent in children, slowly developing after age 10, fMRI studies indicate. “This suggests that activations elicited by the environment are a prerequisite for establishing adult functional architecture between these regions,” she said.

Child-parent interactions may be instrumental in shaping the circuit during this period of plasticity, Tottenham said. In rodents, the mother’s presence quiets the amygdala in the first two weeks of life, and inhibits amygdala-based fear learning. When the mother is absent, “the infant acts like an adult.”

Studies in Tottenham’s lab suggested a similar process in young children. Amygdala reactivity declined when children were given pictures of their mothers while in the scanner, and the mother’s presence improved the child’s ability to control emotions like fear of strangers.

 “Daily phasic modulations of parental absence and presence may do important toning work for the system, keeping the system plastic longer and determining how it will function,” she said.

The lack of such fluctuations, as in institutionalized children, may result in atypical amygdala-PFC connections, heightened reactivity, and emotional dysregulation, Tottenham suggested. “These profiles may reflect adaptations that the brain makes in response to early environments.”

Disadvantaged Development

Martha J. Farah took a broader perspective, summarizing research on the impact of low socioeconomic status (SES) on the developing brain. “It’s not just about money: nutrition, environmental toxins, prenatal care, neighborhood factors” enter the equation, said Farah, of the University of Pennsylvania, and a Dana Alliance member. “Effects on child development are not a threshold phenomenon, ‘poor vs. non-poor.’ There’s a gradient.”

Numerous behavioral studies have found that SES effects cluster around particular neurocognitive systems, rather than general cognitive capacity: language, executive function, and declarative memory “bear the brunt,” she said.

Brain activity measures show more asymmetry in regions associated with language, in higher SES children. “There was more left hemisphere activation, the normal pattern for language specialization,” Farah said. One study found greater dorsolateral prefrontal cortex activation, corresponding to better executive processing.

In a study of learning and memory, children of lower SES showed less hippocampal activity than those of higher SES. “This is quite consistent with functional data,” Farah said.

Structural imaging told a similar tale. Five studies found a significant association between hippocampal volume and SES. An NIH study of normal brain development linked SES to cortical thickness in regions including the prefrontal cortex, inferior cingulate gyrus and inferior frontal gyrus, she said.

How might SES influence cognitive function? “There are many possible pathways; some directly affect the brain and body, others are more psychological,” Farah said.

Longitudinal data based on home visits found that cognitive stimulation promoted language development. “More surprisingly, measures of memory were responsive to parental nurturance” (e.g. attention, affection, and attitude toward discipline), she said.

Other studies link parental nurturance to hippocampal volume, and cognitive stimulation to temporal lobe differences. Much of this data “is highly consistent with the idea that the level of stress, which we know is higher in low SES homes, could be a mediating factor,” Farah said.

The Cost of Neglect
Charles A. Nelson, of Harvard University, discussed development under extreme conditions.

“Postnatal brain development is a heavily experience-dependent period of opportunity or vulnerability. When the brain expects but doesn’t receive input, it doesn’t know how to wire.”

Profound childhood neglect represents a situation in which “the brain is deprived of most expected experiences during sensitive periods,” he said, and institutionalization typically involves such neglect.

Nelson described findings from the ongoing Bucharest Early Intervention Project, a randomized controlled trial involving 136 children abandoned at birth to institutions in Romania. Half were placed in high quality foster homes when they were 6 to 31 months of age, and half remained in institutional care.

Follow-up testing to 12 years, found cognitive, and brain functional and structural differences between the two groups, and between both groups and never-institutionalized children. Age of foster care placement also made a difference.

Overall, “exposure to institutionalization early in life leads to reduction in electroencephalogram (EEG) power, gray and white matter, and connectivity. Foster care remediated some areas,” Nelson said.

EEG findings exemplified the importance of timing. Children placed in foster families before 24 months showed brain activity over the frontal lobe as robust as those who had never been institutionalized, while those placed later “looked like they never left the institution.”

Recently, the researchers analyzed stress response data. Pre-ejection period, a cardiac measure of sympathetic activation, was dramatically different in children who had and hadn’t been institutionalized. “Children placed in foster care showed some recovery, but it was incomplete,” Nelson said.

Cortisol, another stress marker, was more clearly sensitive to timing of family placement. “Those who were placed before 24 months looked just like the never-institutionalized kids,” Nelson said.

The majority of children not randomized to foster care had in fact left their institutions by age 8. That significant deficits endured support the conclusion that “effects are carried by where they lived in the first years of life,” explained Nelson.