Mary L. Schneider

Growth and Development Following Prenatal Stress Exposure in Primates: An Examination of Ontogenetic Vulnerability

Previous studies have found that stressful events during pregnancy can influence the developing fetus, resulting in attentional and neuromotor problems. This prospective study examined whether periods of vulnerability exist for neurobehavioral impairments associated with prenatal stress, using a nonhuman primate model. Twenty-eight rhesus monkey infants were born to mothers in 3 groups: (1) early gestation stress involving mild psychological stress from gestational days 45-90, (2) mid-late gestation stress from days 90-145, and (3) undisturbed controls. Infants were separated from their mothers on days 4, 9, 15, and 22 (+/- 1) postpartum for growth and neurobehavioral assessments. Results indicated that infants from the early gestation stress condition weighed less than infants from mothers stressed during mid-late gestation. Moreover, whereas both groups scored lower than controls on measures of attention and neuromotor maturity, early gestation stress was associated with more pronounced and more pervasive motor impairments than mid-late gestation stress. These results suggest sensitivity to prenatal stress effects peaks during early gestation, tapering off during mid-late gestation. Clarifying the period of greatest vulnerability to prenatal stress moves toward elucidating the underlying mechanism for prenatal stress effects and may lead to more successful intervention and/or prevention.

The impact of prenatal stress, fetal alcohol exposure, or both on development: perspectives from a primate model

The question of whether psychosocial stress during pregnancy (alone or in combination with fetal alcohol exposure) has negative consequences for offspring has not been clearly established in human studies. In this article, we present an overview of three prospective longitudinal studies. Using rhesus monkeys as subjects, a noise or hormone stressor, alone or in combination with moderate level alcohol solution, was presented daily during different stages of pregnancy. Prenatal stress resulted in lighter birth weights in two of three studies, and males from the alcohol plus noise stress condition had reduced birth weights. There were no significant effects of any of the prenatal treatments on gestation duration. Both prenatal stress and moderate fetal alcohol exposure reduced attention span and neuromotor capabilities of offspring during the first month of life, while early gestation prenatal stress, during the period of neuronal migration, emerged as a period of enhanced vulnerability for these effects. Under conditions of challenge, prenatally stressed monkeys showed more disturbance behaviors and reduced locomotion and exploration as well as altered hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. Fetal alcohol exposed monkeys also showed increased HPA axis activity in response to stressful conditions. Finally, altered patterns of alcohol consumption during adolescence were associated with prenatal stress.

Repeated social stress during pregnancy impairs neuromotor development of the primate infant

Neuromotor responses were assessed in 90 infant squirrel monkeys born from normal and stressed pregnancies. Repeated psychological disturbance during pregnancy, evoked by disruption of the pregnant females social relationships, significantly altered the performance of the young infant on a standardized battery of neuromotor tests. As compared with infants from undisturbed pregnancies, infants from chronically stressed pregnancies had poorer motor abilities, impaired balance reactions, and reduced postrotary nystagmus. They also had shorter attention spans and looking episodes during the administration of orientation items. In contrast, when only a single stressful period was imposed during midgestation, infants were not significantly different from control subjects. These findings indicate that sustained stress across pregnancy can have deleterious effects on fetal development, but a short period of stress, at least when restricted to midgestation, does not appear to adversely affect neuromotor responses of the young primate infant.

Neurobehavioral assessment in rhesus monkey neonates (Macaca mulatta) : developmental changes, behavioral stability, and early experience

This prospective study documented developmental changes, individual stability, and the effects of early experience on the neurobehavioral repertoire of nursery-reared rhesus monkey neonates (Macaca mulatta) tested repeatedly across the first month of life. Thirty-six infants were tested three times weekly on a substantially modified version of the Neonatal Behavioral Assessment Scale. The infants were reared under several conditions in which their exposure to animate and inanimate objects varied. Eleven infants were reared with only a cloth, 8 were reared with an upright cloth-covered surrogate, 7 were reared with an upright movable cloth-covered surrogate, and 10 were reared with an upright movable cloth-covered surrogate and regular exposure to peers and novel toys. Infants reared with a movable surrogate demonstrated superior motor maturation in comparison to those reared with only a cloth or cloth-covered surrogate. However, infants reared with a movable surrogate as well as exposure to peers and novel toys showed not only greater motor maturation than cloth-reared infants but also greater responsiveness on orientation items and lower ratings of fearfulness when compared to infants in the three other conditions. Furthermore, the data indicate that behavioral stability of individual differences can be demonstrated in individuals undergoing rapid developmental change regardless of rearing conditions.

The effect of mild stress during pregnancy on birthweight and neuromotor maturation in rhesus monkey infants (Macaca mulatta)

This prospective study investigated whether mild maternal stress during pregnancy could influence performance on a variety of developmental measures in rhesus monkey infants ( Macaca mulatta ). Twenty-four infants were tested during the first month of life for interactive, neuromotor, and temperamental characteristics and capabilities using instruments adapted directly from human neonatal assessments. Twelve infants were derived from mothers exposed during pregnancy to a mild stressor in the form of a daily 10-min removal from home cage and exposure to three unpredictable noise stimuli. Twelve infants were derived from mothers undisturbed during pregnancy. Prenatally stressed infants had lower birthweights, were delayed in self-feeding, were more distractible, and had lower scores on a Motor Maturity composite score when compared to offspring from undisturbed pregnancies. Close inspection of the Motor Maturity score revealed that low muscle tonus, poor coordination, and slow response speed characterized the prenatally stressed offspring.

The Effects of Prenatal Alcohol Exposure on Behavior: Rodent and Primate Studies

The use of alcohol by women during pregnancy is a continuing problem. In this review the behavioral effects of prenatal alcohol from animal models are described and related to studies of children and adults with FASD. Studies with monkeys and rodents show that prenatal alcohol exposure adversely affects neonatal orienting, attention and motor maturity, as well as activity level, executive function, response inhibition, and sensory processing later in life. The primate moderate dose behavioral findings fill an important gap between human correlational data and rodent mechanistic research. These animal findings are directly translatable to human findings. Moreover, primate studies that manipulated prenatal alcohol exposure and prenatal stress independently show that prenatal stress exacerbates prenatal alcohol-induced behavioral impairments, underscoring the need to consider stress-induced effects in fetal alcohol research. Studies in rodents and primates show long-term effects of prenatal and developmental alcohol exposure on dopamine system functioning, which could underpin the behavioral effects.

Prenatal stress alters brain biogenic amine levels in primates

In this study, we assessed behavioral responses to social separation at 8 months of age and cerebrospinal fluid (CSF) concentrations of biogenic amines and metabolites at 8 and 18 months of age in 12 rhesus monkeys derived from either stressed or undisturbed pregnancies. Compared to controls from undisturbed pregnancies, prenatal stress-derived monkeys had higher concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), and 3,4-dihydroxyphenylacetic acid in CSF than controls. Norepinephrine and MHPG response to stress were both correlated between 8 and 18 months of age. There were few group differences in behavior during social separation; however, several behavioral differences between groups were found when monkeys were reunited with cage mates. Prenatally stressed monkeys spent more time clinging to their surrogates and exploring (including eating and drinking), while controls showed more locomotion and social play with their cage mates. Collectively, our findings suggest that chronic unpredictable psychological stress during pregnancy has long-lasting effects on noradrenergic and dopaminergic activity and behavior in the offspring of gestationally stressed primate mothers.

Moderate Alcohol Consumption and Psychological Stress during Pregnancy Induce Attention and Neuromotor Impairments in Primate Infants

This study examined the effect of moderate alcohol and/or psychological stress during prenancy on off-spring growth and behavior in 33 rhesus monkey infants (Macaca mulatta). Infants were derived from 1 of 3 groups of female: (1) alcohol-consuming,0.6g/Kg, Daily throughou gestation (equivalet, to 1-2 drinks), beginning 5 day prior to breeding;(2) alcohol-consuming (as above) and exposed to mild psychological stress(removal from home cage and exposed to 3 random noise bursts); (3) sucrose-consuming, equivolemic, and equicaloric to the alcohol solution.Beginning on day 4 postpartum, intantrs underwent brief weekly separations from their mother for assessment of growth, behavior, and facial dimensions. Results indicated that moderate alcohol consumption throughout pregnancy was sufficient to affect attention and neuromotor functioning, even though the infants were normol in birthweight, gestational length, and facial dimensions, Moreover, alcohol-induced neuromotor impairments were exacerbated by maternal exposure to psychological stress, and males from the alcohol/stress condition had reduced birthweights. Finally, although all females consuming alcohol produced viable offspring, alcohol accompanie by stress during gestation resulted in 23% fetal losses (abortion and stillbirths).

Sensory Processing Disorder in a Primate Model: Evidence From a Longitudinal Study of Prenatal Alcohol and Prenatal Stress Effects

Disrupted sensory processing, characterized by over- or underresponsiveness to environmental stimuli, has been reported in children with a variety of developmental disabilities. This study examined the effects of prenatal stress and moderate-level prenatal alcohol exposure on tactile sensitivity and its relationship to striatal dopamine system function in thirty-eight 5- to 7-year-old rhesus monkeys. The monkeys were from four experimental conditions: (a) prenatal alcohol exposed, (b) prenatal stress, (c) prenatal alcohol exposed + prenatal stress, and (d) sucrose controls. Increased D(2) receptor binding in the striatum, evaluated using positron emission tomography neuroimaging, was related to increased withdrawal (aversion) responses to repetitive tactile stimuli and reduced habituation across trials. Moreover, prenatal stress significantly increased overall withdrawal responses to repetitive tactile stimulation compared to no prenatal stress.

High-affinity dopamine D2/D3 PET radioligands 18F-fallypride and 11C-FLB457: a comparison of kinetics in extrastriatal regions using a multiple-injection protocol.

18F-Fallypride and 11C-FLB457 are commonly used PET radioligands for imaging extrastriatal dopamine D2/D3 receptors, but differences in their in vivo kinetics may affect the sensitivity for measuring subtle changes in receptor binding. Focusing on regions of low binding, a direct comparison of the kinetics of 18F-fallypride and 11C-FLB457 was made using a MI protocol. Injection protocols were designed to estimate K1, k2, fNDkon, Bmax, and koff in the midbrain and cortical regions of the rhesus monkey. 11C-FLB457 cleared from the arterial plasma faster and yielded a ND space distribution volume (K1/k2) that is three times higher than 18F-fallypride, primarily due to a slower k2 (FAL:FLB; k2=0.54 min−1:0.18 min−1). The dissociation rate constant, koff, was slower for 11C-FLB457, resulting in a lower KDapp than 18F-fallypride (FAL:FLB; 0.39 nM:0.13 nM). Specific D2/D3 binding could be detected in the cerebellum for 11C-FLB457 but not 18F-fallypride. Both radioligands can be used to image extrastriatal D2/D3 receptors, with 11C-FLB457 providing greater sensitivity to subtle changes in low-receptor-density cortical regions and 18F-fallypride being more sensitive to endogenous dopamine displacement in medium-to-high-receptor-density regions. In the presence of specific D2/D3 binding in the cerebellum, reference region analysis methods will give a greater bias in BPND with 11C-FLB457 than with 18F-fallypride.