Early life stress harms mental function and immune system in later years

October 24, 2004

Evidence continues to mount that prenatal and early experience can have profound long-term effects on the developing central nervous system and its regulation of basic physiology, psychology, and immune function. Several reports at this meeting demonstrate that this phenomenon is conserved across species-from the barn owl to rodents to humans-suggesting that these effects are mediated by fundamental mechanisms.

The new research was presented at the 34th Society for Neuroscience annual meeting in San Diego

Insight into one potential mechanism comes from studies showing how maternal care can induce alterations in gene methylation in offspring. Other new research is uncovering how stresses during pregnancy and early life can affect learning and memory, as well as immune function, much later in life, long after the stress has disappeared. Still other studies are unraveling the cellular basis for how early life stresses can lead to later cognitive impairment, the effects of using selective serotonin reuptake inhibitors such as Prozac during early development on the emotional behavior of adult mice, and how experience--hunting in the case of barn owls--can dramatically increase adult animals' adaptability to new stimuli. Together, these studies point to exciting new approaches for potentially lessening or preventing these long-term changes that can lead to disease or psychopathologies.

Stresses such as neglect and abuse during infancy may result in memory loss and impaired cognitive abilities that manifest later in life, a University of California , Irvine, study has found. The study, conducted in rats, clearly shows a late onset and slow progression of deficits in communication between brain cells in the hippocampus, a brain region involved in learning, storage, and recall of memories.

Kristen Brunson, a senior member of Tallie Z. Baram's group, and her colleagues, found that limiting the nesting material in cages where neonatal rats lived with their mothers led to emotional stress of both the mothers and their pups. All evidence of this stress disappeared by the time the pups reached adulthood. However, starting in middle age, these so-called "graduates" of early life stress began to forget the location of objects they had seen before. They also got worse at recognizing objects they had encountered on the previous day. These difficulties worsened as the rats grew older, much more rapidly than in rats that were raised for their first week of life under more nurturing conditions.

In collaboration with Gary Lynch, PhD, and Eniko Kramar, PhD, also of the University of California , Irvine, Brunson and Baram found that communication between brain cells, considered to be the cellular basis for learning and memory, was faulty in the middle-aged rats. Recordings of the electrical activity of brain cells appeared normal in young adult rats exposed to early life stress, but became very disturbed as they reached middle age.

"Now that concrete deficits in brain cell communication have been found in the early-life stressed, demented rats, it may be feasible to find the specific molecules involved and design medicines to prevent the deficits," Baram says.

In other work, researchers showed in rats that stress during the last third of pregnancy affects the ability of adult offspring to respond to challenges to their immune system. Heather Richardson, PhD, and her colleagues Soon Lee, PhD; Dong Seo, PhD, and Catherine Rivier, PhD, at the Salk Institute in La Jolla, Calif., found that the changes in the offsprings' response to immune challenges may be due in part to deficits in nitric oxide, a signaling system in the brain known to connect the immune and stress systems.

Twenty-nine pregnant rats were exposed daily to one of two stresses during the last third of their pregnancies; controls in this group were left alone. Adult female offspring were then given an intravenous injection of lipopolysaccharide, an immune challenger known to bring about stress and immune responses. The adult offspring were sacrificed at either zero, one, or two hours after lipopolysaccharide injection, and the researchers measured the expression of nitric oxide synthase, a gene critical for production of nitric oxide in the nervous system. About six animals were used in each of six groups.

Control animals showed a normal increase in nitric oxide synthase, while animals of mothers exposed to either of the two stressors during pregnancy failed to show this response.

"This finding shows that chronic stress experienced by mother rats during pregnancy may interfere with the normal development of the signaling system known to be important for communication between the stress and immune systems," says Richardson.

Serotonin reuptake inhibitors (SSRI) such as Prozac are increasingly being used to treat psychiatric conditions in children and pregnant women, yet little is known about their effects on the developing nervous system. New research by Mark Ansorge, PhD; Mingming Zhou, PhD; Alena Lira, BS; Rene Hen, PhD; and Jay Gingrich, PhD, at Columbia University describes the effects of SSRI use during early development on the emotional behaviors of adult mice. The work will be published in Science October 29.

Serotonin is most commonly known for its role as a neurotransmitter that has an influence on mood, anxiety, aggression, sleep, appetite, and cognition. During early life, serotonin also aids in brain development, in such processes as division, differentiation, and migration of neurons and development of connections between neurons. Serotonin reuptake inhibitors work by blocking the serotonin transporter (5-HTT) and thus enhancing serotonin transmission.

The investigators used a strategy involving drug treatment in normal and genetically engineered mice to investigate whether early postnatal inhibition of 5-HTT function alters emotional behavior later in life. Mice with full, intermediate, and abolished 5-HTT gene expression were treated with either saline (control) or fluoxetine from postnatal day four to 21. The mice were tested as adults several weeks after fluoxetine exposure was stopped.

Further embargoed details on this research may be obtained from Jessica Lawrence-Hurt, AAAS Office of Public Programs, 202-326-7088, scipak@aaas.org.

In another report, Martha Farah, PhD, and her colleagues at the University of Pennsylvania found that the stress of living in inner city poverty affected learning and memory development in children.

Farah and her colleagues studied the effect of early childhood stress on the later cognitive abilities of 60 inner city middle schoolers. The children's home lives had been assessed at ages 4 and 8. To measure the degree to which children were protected from, or exposed to, stress at these ages, levels of parental warmth, acceptance, and responsivity, were tallied. The amount of cognitive stimulation received at home was also measured.

When the children were middle schoolers, they took two memory tests, in which they performed a simple task with line drawings of objects and photos of faces and were later asked to recognize which objects and faces they had seen previously. The social and emotional quality of earlier home life was the only factor that affected learning, as measured by these tests.

"The finding that only the social and emotional quality of these children's homes affected their learning ability in later childhood mirrors findings on early stress and memory development in animal research," Farah says. "Other factors often thought to influence children's cognitive development--cognitive stimulation, mother's IQ, or prenatal drug exposure-had no effect on memory."

Joseph Bergan, a graduate student in the laboratory of Eric Knudsen, PhD, and his colleagues at Stanford University investigated how experience shapes the functional properties of the central nervous system in barn owls. Barn owls have proven to be an excellent model for studying how experience brings about changes in the brain, as well as how these changes become more difficult with old age.

Barn owls must localize prey precisely in order to hunt successfully at night. Hunting relies on the accurate localization of both auditory and visual stimuli-processes that can be monitored in several brain areas. The investigators measured the alignment between auditory and visual space maps within these brain areas in 12 normal adult owls. The relationship of auditory and visual stimuli was then disrupted using glasses that shifted the visual world 17 degrees horizontally. While wearing prismatic glasses, some owls were allowed to hunt while others were fed dead mice. After 10 weeks, the alignment between auditory and visual maps was remeasured. The researchers found that the experience of hunting dramatically increased the adult owls' ability to adapt to novel audiovisual relationships.

"This work shows that the adult owl's auditory localization pathway is more plastic than previously thought," says Bergan. "But we also found that adult owls need much more specific sensory experience- hunting, for example-to bring about changes in neural function than do juvenile owls."

In other work, Michael Meaney of McGill University, Douglas Hospital Research Center, in Montreal, Canada, describes how variations in maternal care can result in sustained alterations in gene expression in offspring. Meaney will give a special lecture on "Environmental 'Programming' of Individual Differences in Defensive and Reproductive Behaviors through Maternal Effects on Chromatin Structure and Gene Expression," Tuesday, October 26, at 11:15 a.m.

In the rat, maternal effects on stress responses involve stable, postnatal alterations in chromatin structure such as DNA methylation. "Early experience can actually modify protein-DNA interactions that regulate gene expression," Meaney says. "The effects of mother-infant interaction on chromatin structure might define a basis for the development of stable individual differences in hormone function and behavior over the lifespan."

Society for Neuroscience

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