Tracing the Biology of Experience

Adversity in childhood may cause health problems and disease at the other end of life, says a team of researchers embarking on a cradle-to-grave study of how early experiences embed themselves in biology.

“The challenge is not to document more correlations between early adversity and bad outcomes,” said Jack Shonkoff, who spoke at an April 15 colloquium on the childhood roots of adult disease at Children’s Hospital Boston. “The challenge is to identify causal mechanisms. The roots of hypertension, diabetes, and heart disease may be laid down early in life through the influence of toxic stress on gene expression. These early processes suggest that we rethink the focus and timing of policies in health promotion and disease prevention.”

The symposium showcased a new multidisciplinary effort to explore how early childhood experiences sculpt the neuronal structure and gene expression patterns of the brain in ways that persist throughout life. The collaborative project is being conducted under the auspices of the Center on the Developing Child at Harvard University, which is directed by Shonkoff, the Julius B. Richmond FAMRI professor of child health and development at HSPH and the Graduate School of Education. At the symposium, researchers from Children’s, HMS, and HSPH reviewed the foundation of evidence to date, ranging from the molecular to the epidemiological.

Studies in people and animals support the idea of sensitive periods in brain development. These sensitive periods, when the brain is more plastic and malleable, are thought to be the times when variations in parental care and other factors can permanently alter the offspring’s subsequent responses to life and its stresses.

Abandoned children raised in Romanian orphanages, for example, showed borderline mental retardation at age 4 and a half compared with children reared in their own families, according to a recent study led by Charles Nelson in the Dec. 21 Science. But orphans randomly assigned to high-quality foster care showed significant gains in cognitive function, better language skills, and fewer attachment problems, especially if placed by age 15 to 24 months. Unfortunately, the timing of the intervention had no impact on some measures of mental health recovery, especially attention deficit hyperactivity disorder.

The earlier, the better, for the foster care effect, Nelson and his colleagues concluded in their paper on cognitive recovery in socially deprived young children in the Bucharest Early Intervention Project. “A child’s brain is vastly underpowered if a child lives in an institution,” said Nelson, HMS professor of pediatrics and neuroscience at Children’s. The research team developed the foster care program as part of their study.

Likewise, Nelson said, cross-fostering young animals with “super mom” monkeys remediated many of the dramatic behavioral changes, if the intervention happened early enough, according to data from a study of similar early-life deprivation in rhesus monkeys by Oregon researchers. The changes in young monkeys varied by age of separation from their mothers. Animals separated at one week, before the youngsters formed attachments to their caregivers, developed autistic-like solitary behavior. Animals separated at four weeks showed obsessively clinging behavior. Behavior differences in both groups correlated with gene expression changes in the amygdala, as well as shorter dendrites and fewer synaptic contacts with other neurons in a section of the prefrontal cortex.

“There are critical or sensitive periods when the brain is especially receptive to being molded by the environment,” said Takao Hensch. “For the first time, the field is at a point where we can manipulate critical periods by understanding the biology.”

Back in the 1960s, HMS researchers Torsten Wiesel and David Hubel conducted the classic studies showing permanent rewiring of the brain based on sensory input. In kittens with a patch over one eye, it only took a few weeks for the axons serving the deprived eye to shrink, while the neurons to the open eye expanded. At a certain point, the primary visual cortex became hard-wired for only one eye; vision in the second eye was lost for good. Later in life, an eye patch did not jeopardize binocular vision.

Hensch and his colleagues are tracking down the molecular mechanisms and timing of these critical periods. In mice, they found that onset of plasticity or sensitivity to monocular deprivation coincides with the development of a type of neuron that expresses the inhibitory neurotransmitter GABA. Counter to intuition, “our research shows inhibition in the cortex allows brain plasticity to occur,” Hensch said. “We can trigger plasticity, an important step in the long series of studies, by enhancing GABA with benzodiazepines.” In the visual system of mice, the mechanism can be traced to a single type of GABA receptor, alpha-1, he said.

An Italian group took the research one step further by reactivating the plasticity in the brains of adult rats with a protease enzyme that dissolves the extracellular structures ensheathing large GABAergic neurons. “These enzymes may allow the whole process of anatomical rewiring to occur again,” Hensch said. “It strongly confirms the idea that molecules in the adult brain are preventing too much plasticity from happening.” Hensch and his colleagues have identified a factor that builds the mature GABA cell wrapping, findings now in press in the journal Cell.

“There is a time in life when the environment can powerfully sculpt brain maps,” said Hensch, HMS professor of neurology at Children’s and Harvard Faculty of Arts and Sciences professor of molecular and cellular biology. “Each of us has a unique set of maps to best represent the world, shaped in response to the unique sensory inputs bombarding our brains in infancy and childhood.” Autism and schizophrenia could be disorders of mistimed plasticity, perhaps by shifting the balance of developing inhibitory and excitatory signals in the brain, Hensch said.

In the collaboration, Hensch will be looking for stress-induced epigenetic changes in the brains of animal models. He and his colleagues will be investigating telomere length and other possible biomarker correlates of both early adversity and disease risk to compare to the Romanian cohort of children identified by Nelson and to an adult cohort studied by Laura Kubzansky, HSPH associate professor of society, human development, and health.

So far, the effect of chronic stress on physical health has been most extensively studied as the effect of anger, anxiety, or depression and on risk of coronary heart disease among adults, said Kubzansky, who teaches a class on stress and health at HSPH. Her own work has found higher levels of stress in adults who reported high levels of distress at age 7, suggesting that these early experiences can persist into adulthood with potential serious health consequences later in life.

“What’s new is that we’re trying to bring all this together in one coordinated effort, from cells to society, to understand the early roots of adult health and how social disparities become biologically embedded,” Kubzansky said.