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Stress the international journal on the biology of stress.

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Prenatal stress alters early neurobehavior, stress reactivity and learning in non-human primates: a brief review.

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Schneider, M L

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2001

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183-193

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Stress The International Journal on the Biology of Stress

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Prenatal Stress Alters Early Neurobehavior, Stress Reactivity and Learning in Non-human Primates: A Brief Review Mary L. Schneider, Colleen F. Moore, Andrew D. Roberts & Onofre Dejesus To cite this article: Mary L. Schneider, Colleen F. Moore, Andrew D. Roberts & Onofre Dejesus (2001) Prenatal Stress Alters Early Neurobehavior, Stress Reactivity and Learning in Nonhuman Primates: A Brief Review, Stress, 4:3, 183-193, DOI: 10.3109/10253890109035017 To link to this article: http://dx.doi.org/10.3109/10253890109035017

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Prenatal Stress Alters Early Neurobehavior, Stress Reactivity and Learning in Non-human Primates: A Brief Review MARY L. SCHNEIDERasbqc*,COLLEEN F. MOORE', ANDREW D. ROBERTSd.eand ONOFRE DEJESUSe aDepartment of Kinesiology, 2175 Medical Science Center; 1300 University Avenue, Madison, WI 53706-1532, USA; bDepartment of Psychology, 422 Bmgden Hall, 1202 W Johnson St, Madison, W153706, USA; 'Harlow Centerfor Biological Psychology, 22 N Charter Street, Madison, WI 5371, USA; dDepartmentof Psychiatry, Wisconsin Psychiatric Institute and Clinics, 6001 Research Park Blvd., Madison WI 53719, USA; eDepurtmentof Medical Physics, 1530 Medical Science Center; 1300 University Avenue, Madison, WI 53706, USA (Received 3 March 2001; Revised 30 May 2001; In finalform 8 June 2001)

In this paper we review three prospective longitudinal studies from our laboratory examining the effects of prenatal stress on early neurobehavior, stress reactivity and learning performance in rhesus monkeys. Either a noise stressor or ACTH treatment was administered to pregnant monkeys during specific periods of pregnancy and offspring were examined repeatedly across development. In all three studies, the prenatally stressed monkeys showed reduced attention and impaired neuromotor functioning during the first month of life compared to controls from undisturbed pregnancies. When the monkeys were separated from their mothers or peers at 6-8 months of age, prenatally stressed monkeys exhibited more disturbance behavior and showed hypothalamic-pituitary-adrenal axis dysregulation. During adolescence, they exhibited impairments in learning, compared to controls. Keywords: Fetal alcohol exposure; Human studies; Macaca rnulatta; Noise stress; Cortisol; Birth weight; Positron emission tomography; Dopamine

INTRODUCTION

While we are experiencing a proliferation of research on the well-established association between stress and vulnerability to a number of diseases (Cohen and Williamson, 1991), whether stress to the pregnant mother adversely affects her future offspring's developmental outcome is a question that needs

The idea that stress during pregnancy can result in behavioral and physiological consequences to the offspring are age-old ideas, yet the notion has only recently begun to accumulate empirical support.

*Corresponding author. Address: Department of Kinesiology, 2175 Medical Science Center, 1300 University Avenue, Madison, WI 53706-1532, USA. Tel: +1-608-265-5118. Fax: +1-608-262-4020. E-mail: [email protected] 183


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further researching. The primate studies reviewed in this paper were conducted in order to compare offspring from pregnancies in which mothers experienced either mild chronic stressors or hormone treatments with offspring from undisturbed pregnancies. At the outset, we think that it is important to the raise the following question: What evidence is needed in order to conclude that stress to the pregnant mother can cause negative effects on offspring? We refer to Paarlberg et aZ. (1995) who discussed evidence from a number of sources linking psychological stress during pregnancy to adverse pregnancy outcomes. There is a relatively large body of correlational research on humans, including both retrospective and prospective studies, supporting a link between prenatal stress and adverse pregnancy outcomes. We summarize these studies in a subsequent section. There are, however, a number of methodological problems that limit conclusions from human research. Therefore, we believe it is important to investigate this phenomenon in experimental animal studies. In other words, before conclusions can be drawn with enough certainty to yield preventative recommendations, effects similar to those found in human studies need to be demonstrated in carefully controlled laboratory studies where the experimenter systematically manipulates prenatal stress. This is not possible with human studies. Although most of the animal work on prenatal stress has been conducted with rodents, it is also important to conduct studies with non-human primates, subjects that are more closely related to humans. In fact, when a similar pattern of findings associated with prenatal stress emerges across mammalian species, including non-human primates, extending the conclusions to humans becomes more compelling. Without studies of non-human primates, the leap in applying the results to humans seems too great. Another line of evidence required to conclude that prenatal stress causes adverse outcomes in human offspring involves establishing a plausible biological mechanism through which prenatal stress can exert its influence. We return to this issue later, when we review potential biological processes and how such

mechanisms could alter an individual’s developmental trajectory through changes in brain development. We base our evidence of biological underpinnings on the rodent literature, as well as on our own non-human primates studies. Before we expand on these themes, one additional point to underscore is that, as developmentalists, we view prenatal stress as one risk factor, interacting in a complex multi-directional process with other factors to influence outcomes. In other words, we support a probabilistic multi-causality approach to development, in which prenatal stress is associated with a variety of developmental outcomes, given variability in other biological, psychological, and environmental factors which could positively or negatively affect outcome (Boyce et aZ., 1998; Cicchetti and Rogosch, 1996; Rutter and Sroufe, 2000; Sameroff, 2000). Simply stated, it is highly unlikely that prenatal stress affects all individuals in an identical manner.

HUMAN STUDIES OF PRENATAL STRESS In this section, we briefly review human studies examining effects of prenatal stress, by providing examples of the types of studies conducted in humans and illustrating some of the methodological issues. We divide the studies into two types: retrospective and prospective. Retrospective research compares individuals with different prenatal backgrounds, such as war victims or refugees, with individuals who did not experience adverse prenatal conditions. Other retrospective studies compare the prenatal conditions of children with psychiatric diagnoses to the prenatal conditions of those without such diagnoses. A retrospective study in Finland associated paternal death during pregnancy with an increased risk of schizophrenia and criminality. The comparison group consisted of children whose fathers died during their first year of life (Huttunen and Niskanen, 1978). Another study (Meijer, 1985) linked the stress of the Six-Day War in Israel in 1967 to social withdrawal, slow speech, and delayed development of self-care skills in children born from mothers pregnant during that war compared


PRENATAL STRESS IN PRIMATES

to children born one year later. Other retrospective studies have examined the prenatal condition of children diagnosed with attention deficit hyperactivity disorder (ADHD) and undifferentiated attention deficit disorder (UADD) and compared their mothers’ pregnancy records to those of typically developing children (McIntosh et al., 1995). The authors found that self-reported stress during pregnancy was one of four significant predictors of diagnoses. The other three included medical risk variables, smoking during pregnancy, and gestation length. In the human research using prospective designs, prenatal stress is assessed prior to birth. Most prospective studies of prenatal stress have focused on the association of stress during pregnancy with obstetric problems, such as premature delivery or low birth weight for gestation age (Dunkel-Schetter and Lobel, 1998; Lou et al., 1994; Wadhwa et al., 1993). Obstetric problems and low birth weight are, in turn, related to developmental outcome (Rose and Feldman, 2000). The general conclusion from such studies is that there is a relationship between prenatal stress and low birth weight and shorter gestation duration. However, this relationship may be mediated by other health risks (see Lobel, 1994; Paarlberg et al., 1995; Wadhwa, 1998, for reviews). There are, unfortunately, few prospective studies that have followed the offspring of prenatally stressed mothers. One such prospective study (Oyemade et al., 1994) examined the behavioral outcome of neonates of 477 predominantly African American women using the Brazelton neonatal assessment scale (Brazelton, 1984). Maternal measures of social support, anxiety, and quality of relationship with partner were examined to assess the mother’s level of stress experienced during pregnancy. An association was found between maternal stress level and the neonate’s ability to attend to stimuli and habituate to stimuli. Subsequent studies are needed to determine whether long-term behavioral effects are associated with the reported stress-induced neonatal early cognitive and attentional alterations. In a recent report from an ongoing prospective prenatal stress study, Huizink (2000) examined 230 Dutch women during pregnancy and examined their

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children after birth. Pregnant mothers completed questionnaires three times during pregnancy, and researchers assessed state and trait anxiety, depression, locus of control, and pregnancy-related fears and worries. Infants were tested 3 and 8 months after birth on the Bayley Scales of Infant Development (Bayley, 1969). Results indicated that prenatal stress was negatively related to infant mental and motor development, after statistically adjusting for gestational age at birth, birth weight, and postnatal stress level of the mother. Whether these adverse effects on infant behavior will persist into childhood requires longitudinal follow-up. These retrospective and prospective research designs present different methodological issues and because of this yield results with different degrees of inferential strength. Because memory is reconstructive, retrospective self-report data can be unintentionally biased based on the knowledge of the child’s outcome. Prospective studies do not have the problem of memory bias, but all human studies have many potentially confounding variables, including the use of alcohol, tobacco, and socioeconomic status, each known to have negative influences on child outcome (Brooke, et al., 1989). For example, mothers of those children in utero during the Six-Day War might have altered their nutritional intake or been exposed to toxic substances or alterations in life-style as a result of the war. The issue of potential confounding variables is also at play in prospective studies; hence, it is important to note whether such variables are statistically controlled. Further, even prospectively measuring stress in people is subject to the uncertainties of any self-report measure, whereas manipulating stress in animal studies is more precise. For example, life event scales, which are used in most human studies as a measure of stress, also reflect personal psychological characteristics, such as anxiety and depression, rather than life events per se (Kasl and Rapp, 1991). Another issue related to life events questionnaires is that they do not adequately capture the most predictive measure of stress, which is chronic and daily stress (Herbert and Cohen, 1993) and do not adequately take into account the perceived controllability of stress situations. A final potential

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confound with many of the prenatal stress studies, both retrospective and prospective, is that postnatal environmental conditions, including maternal stress, can be related to prenatal conditions, rendering the results of these studies difficult to interpret. For example, divorce during pregnancy can lead to postnatal stress and reduced family economic resources as well. Thus, many of the human studies, while interesting and suggestive of directions for further research, need to be interpreted with an appropriate degree of caution.

ANIMAL STUDIES The findings from animal studies (predominantly rodent) provide compelling evidence that prenatal stress does affect offspring. In studies in which a variety of stressors have been used, administered across a variety of times during pregnancy (Koehl et al., 1997; McCormick et al., 1995; Peters, 1990; Takahashi and Kalin, 1991; Williams et al., 1995), results consistently indicate that prenatal stress during pregnancy has adverse effects on offspring. Among the most robust findings are that prenatally stressed male rats show reduced male-typical sexual behavior (see Ward and Reed, 1985, for a review) and females are partially masculinized (Kinsley and Bridges, 1988). Moreover, evidence converging from multiple studies demonstrates an association between prenatal stress and several correlates of emotionality, including decreased ambulation in the open field and increased defensive freezing. The theme across studies is that prenatal stress contributes to heightened behavioral responsivity to stressors in rodents (see Weinstock, 1997, for a review). Some rodent studies have shown that prenatal stress is associated with abnormal regulation of hypothalamic-pituitary-adrenal (HPA) axis function in offspring. This effect is seen under baseline conditions (Fride et al., 1986; Peters, 1982), but it is most striking after exposure to stressful events or situations (Fride et al., 1986; McCormick et al., 1995; Takahashi et al., 1992). However, the effects of prenatal stress can be altered, or even reversed, by post-natal stress (see

Meaney et al., 1996 for an overview of biological processes affected by early life stress in the rat). Recent work by Lehmann et al. (2000) shows that prenatal and postnatal stress can have different effects on different response systems in the rat.

Possible Underlying Mechanisms for the Effects of Prenatal Stress Stressful events stimulate the release of stress hormones-corticotrophin-releasing hormone (CRH), adrenocorticotrophic hormone (ACTH), and glucocorticoids-accompanied by the release of epinephrine and norepinephrine. Stress hormones could have adverse effects on fetal development through several routes. First, evidence suggests that stress hormones can decrease blood flow to the uterus, thereby reducing oxygen levels in the placenta (Meyers, 1975; Morishima et al., 1978). Other studies point to the effect of stress hormones on metabolic functions, resulting in insufficient maternal weight gain associated with infant low birth weight (Picone et al., 1982). The underlying mechanism for prenatal stressinduced HPA axis dysregulation is not fully known. Several lines of evidence, however, suggest that stress hormones, or other substances the mother produces as a result of stressful experiences, do cross the placenta, at least in small amounts during stress episodes and can influence fetal brain development. This hypothesis was supported by a study in which stressed dams were adrenalectomized to prevent stress-induced increases in glucocorticoid secretion (Barbazanges et al., 1996). The results showed no effects of prenatal stress in the rat offspring. Conversely, when dams were injected with CRH from day 14 to 21 of gestation, the rat pups showed effects similar to those observed in offspring from prenatally stressed pregnancies (Williams et al., 1995). Other studies have shown that elevated levels of glucocorticoids in the rodent dam cross the placenta, and postmortem examinations have shown alterations in the hippocampus of the developing offspring (Henry et al., 1994). In prenatally stressed rats, researchers have



found hypersensitivity of cholinergic neurons of the septum and hippocampus, areas with connections to the hypothalamus, and associated with HPA axis dysregulation (Day et al., 1998). Thus, stress-induced increases in maternal glucocorticoids provide one mechanism by which prenatal stress exerts its deleterious effects on offspring HPA axis regulation. In summary, experimental studies of rodents show that stress hormones, directly or indirectly, can have a negative effect on fetal development and are likely to adversely affect offspring behavior and stress responsivity. Of course, research on the effects of prenatal stress on the offspring of non-human primates has not been as extensive as the research on rodents. As we already noted, non-human primate research on this topic is an important link between the rodent research and the human epidemiological studies. Nevertheless, direct extrapolation from nonhuman primates to humans is not possible because among other differences, there are also differences among primate species in their reproductive endocrinology, including pregnancy related changes in stress hormones, such as CRH, ACTH, and the glucocorticoids (Smith et al., 1999).

WISCONSIN PRENATAL STRESS PRIMATE STUDIES In this section we give an overview of three prospective longitudinal studies from our laboratory on the effects of prenatal stress on rhesus monkey behavioral development. Details of the studies are presented elsewhere (Schneider, 1992a,b,c; Schneider et al., 1992; 1997; 1998; 1999).Table I shows the type and timing of stressor, other prenatal manipulations,

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and postnatal rearing condition. In addition to these three studies, we will briefly mention results of neuroimaging studies involving a sub-group of animals from another study (Schneider et al., 1997) that were prenatally exposed to both stress and maternal alcohol consumption. Based on a review of the literature, four major hypotheses were examined in our studies. First, we expected that prenatally stressed monkeys would show differences in pregnancy outcomes, such as birthweight or gestation duration, based on findings from rodent and human studies (Lobe1 et al., 1992; Paarlberg et al., 1995; Wadhwa, 1998). Second, we predicted that prenatally stressed monkeys would show more signs of stress reactivity than controls. This prediction was based on rodent work suggesting that prenatal stress contributes to heightened behavioral responsivity to stressors (see Weinstock, 1997, for a review). Third, we speculated that impairments in offspring neurobehavior, including attention and learning, might be found. Finally, we predicted similarities between prenatally stressed monkeys and monkeys from ACTH-treated pregnancies, given evidence from rodent studies suggesting that maternal endocrine activation is one of the mechanisms underlying prenatal stress effects (Maccari et al., 1995).

METHODS All subjects were rhesus monkeys (Mucaca mulafta). The mothers were members of a large breeding colony at the Harlow Primate Laboratory. All studies were approved in advance by the Institutional Animal Care Committee at the University of Wisconsin-Madison.

TABLE I Conditions for prenatal stresdfetal alcohol studies Study

Treatment employed

1 2

Noise stress Noise stress

3

ACTH

Timing of treatment (days) 90-145 50-90 90- 145 20- 134

Postnatal rearing

Reference

Nursery Mother

Schneider et al., 1992 a,b,c Schneider et al., 1999

Mother

Schneider et aL, 1992



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Once pregnancy was determined, they were randomly assigned to prenatal stress or control groups. In two of the studies, a noise stressor consisting of three random noise blasts during a lOmin removal from the home cage was employed during pregnancy. It was administered five times weekly (M-F) to mimic recurrent daily episodic stress. Control animals were undisturbed, except for normal animal husbandry. In our first study, we administered the noise stressor during mid-late gestation (days 90- 145 in a 165-day gestation period). We selected this time to reduce possible fetal loss by avoiding stress to the female during very early pregnancy or late pregnancy (Schneider, 1992a). In study 2, we administered the stressor during early gestation (days 45-90) or during mid-late gestation (days 90- 145) to compare effects across different phases of pregnancy (Schneider et al., 1999). Maternal plasma cortisol level was measured on day 135 after exposure to the noise stressor to determine whether the stressor elevated maternal stress hormones (Schneider et al., 1999). The stressor did result in significant elevated serum cortisol (baseline mean SE = 25.2 2.2 pgdl, post stress = 34.8 ? 2.4 pg dl). In study 3, pregnant rhesus monkeys were administered adrenocorticotrophic hormone (ACTH), a hormone normally secreted by the pituitary in response to stress, while controls were administered a saline solution. Results were compared with data from the noise stressor studies, in order to determine whether maternal endocrine activation could be a mechanism, at least in part, underlying prenatal stress effects (Schneider et al., 1992). In Study 1 we hand-reared the infants to prevent the possibility of confounding the prenatal stress condition with differential maternal treatment. To minimize possible negative social effects from handrearing, we added toys, climbing devices, and surrogates to the nursery cages, and socialized the infants in play groups in the nursery (see Schneider and Suomi, 1992, for details). In Studies 2 and 3 we reared the monkeys with their mothers to determine whether the effects would replicate under normal laboratory rearing conditions.

*

*

RESULTS Measures of Birth Weight and Gestation Duration Birth weight effects were found in the two noise stressor studies, but not in the third study in which ACTH was administered. The mean birth weight of the prenatally stressed offspring was significantly lower than controls in Study 1 (Schneider et al., 1992). In Study 2, the early prenatal stress monkeys had lower birth weights than controls (Schneider et al., 1999). Moreover, all birth weights were within two standard deviations of what is considered “normal” for rhesus monkeys. Therefore, none of our subjects would be categorized as having clinically classified low birth weight comparable to the clinical condition in human infants. No effects of prenatal stress on gestation duration were detected in any of our prenatal stress studies.

Neonatal Behavioral Testing To determine whether prenatal stress affected infant developmental outcome, we tested the infants throughout the neonatal period, using a test adapted directly from the Neonatal Behavioral Assessment Scale used to test human newborns (Brazelton, 1984; Schneider and Suomi, 1992). Strikingly similar results were found across all three studies. Specifically, a behavioral profile was found in the prenatally stressed monkeys, which included shortened attention span and reduced neuromotor capabilities. Moreover, in Study 2, early gestation stress, compared to mid-late gestation stress, was found to be a period of enhanced vulnerability to the development of reduced neuromotor functioning. Study 3, in which rhesus mothers were treated with ACTH injections during pregnancy, yielded infants who not only were delayed motorically, but also were significantly more irritable and difficult to console. This last study suggests that one mechanism for the infant neurobehavioral impairments includes, at least to some degree, maternal activation of the hypothaiamo-pituitary-adrenalaxis. Understanding brain changes occurring during early gestation can shed light on the mechanisms


behind our findings. Based on the elegant work of Rakic (1995) on fetal brain development in rhesus monkeys, we note that our early stress period in Study 2 covers the period of neuronal migration, days 40 to approximately 70- 100 in the rhesus monkey. Neuronal migration is one period during which the mammalian brain is highly sensitive to disturbances, such as toxins, viruses, and genetic mutations (Galaburda et al., 1989).


Offspring Response to Stressors When the monkeys were juveniles, adolescents, and adults, we examined them under stressful situations, such as social separation, new group formation, or placement in an unfamiliar environment (Schneider, 1992c; Clarke and Schneider, 1993; 1997; Clarke et al., 1994; Schneider and Moore, 2000). Under such challenging conditions, prenatally stressed monkeys showed an increase in disturbance behavior, more clinging to cage-mates, abnormal behaviors such as stereotypies and decreased exploration, locomotion, and play behavior, as compared to controls (Schneider, 1992c; Clarke and Schneider, 1993; 1997; Schneider and Moore, 2000). We also measured ACTH and cortisol responses during social separation in Studies 1 and 2. While there were no differences at baseline (normal housing conditions), we did find that the increase from baseline was significantly larger for the prenatally stressed monkeys from Study 1 and for the early-gestation stressed monkeys from Study 2 (Schneider and Moore, 2000).

Learning During Adolescence When the monkeys from Study 2 were 3234 months old, we tested them using a cognitive task, non-matching-to-sample, requiring the monkeys to learn the rule that the non-matching object conceals the reward. The non-matching rule requires not just working memory, but also demands shifting attention from the familiar to the unfamiliar object, functions dependent on limbic structures, basal ganglia, prefrontal and frontal cortex (Mishkin et aZ.,

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1984; Schneider et al., 2001; Wise et al., 1996). The principal findings of this study were: (1) monkeys from mothers exposed to stress during early gestation, compared to mid-late gestation stressed offspring and controls, required more trials in acquisition of the non-matching-to-sample task; (2) there was a positive correlation between attention on the infant neurobehavioral test and later learning of the non-matching-to-sample task, suggesting continuity between deficits in infancy and later cognitive deficits. This continuity suggests that early intervention could take advantage of early brain plasticity and the potential role of the environment in modifying brain development (Hannigan et al., 1993; Weinberg et al., 1995). Our findings also raise the importance of longitudinal follow-up of humans in the prospective study conducted by Huizink (2000), to explore whether there will be continuity from the early developmental deficits in mental and motor scales.

Neuroimaging Studies The recent development and availability of neuroimaging techniques has enabled noninvasive studies of brain structure and function. Rodent studies have suggested that certain areas of the brain may be especially sensitive to prenatal stress. Using the latest technology available to us, positron emission tomography (PET), we are examining the dopamine system, which regulates integrative functions, including motor control, attention, cognition, and emotional balance (Diamond, 1996). The dopamine system is implicated in changes due to prenatal stress in rats (Fride and Weinstock, 1989) as well as fetal alcohol effects in both rats and monkeys (Druse et al., 1990). We have examined a subgroup of offspring from six control mothers and eight mothers that were prenatally stressed and fetal alcohol exposed (Schneider et al., 1997). In our studies that combine prenatal stress with prenatal alcohol exposure, we used the same noise stress procedure that we used in other studies. The mothers in the alcohol + stress


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treatment group were also allowed access to 0.6 g kg alcohol solution per day throughout gestation in a Nutrasweet solution. Control monkeys were given an isocaloric sucrose solution. All monkeys were prescreened and selected for alcohol preference, and were randomly assigned to treatment groups. We began the dosing 5 days prior to breeding and stopped at the birth of the infant. With very few exceptions, the monkeys drank all the available alcohol solution. (For more details, see Schneider et al., 1997). We evaluated the striatum, a region with highest dopamine innervation, in separate scans in these monkeys when they were 4-5 years old. To assess dopamine synthesis, we use 6-[”F] fluoro-L-rn-tyrosine (6-FMT) as PET tracer (DeJesus et a/., 1997). This tracer, an analog of rn-tyrosine, enters brain neurons and provides very high specific-to-nonspecific uptakes for PET imaging of striatal areas. To assess post-synaptic dopamine D2 receptors, we use Fallypride (FAL), an F-18 labeled raclopride analog (Mukherjee et al., 1999). The ratio between these two measures reflects the balance between post-synaptic and pre-synaptic dopamine function in the striatum. Based on PET scans of 14 animals, the results show a marked increase in this measure of post-/pre-synaptic dopamine function in prenatally stress + fetal alcohol exposed offspring compared to controls (Roberts et al., 1999). This finding was not seen in fetal alcohol-exposed (without prenatal stress) monkeys and we have not yet scanned our prenatal stress-only monkeys. Our tentative interpretation is that prenatal stress might provide the context within which fetal alcohol has its most harmful consequences on brain dopaminergic function. It is interesting to note that rodent studies have also linked prenatal stress to long-term effects on dopaminergic system activity and dopamine-related behaviors as well as higher behavioral and endocrine reactivity to stress (Fride and Weinstock, 1989). It has been suggested that dopamine projections to the nucleus accumbens might serve, at least in part, as the neurobiological underpinning for the altered response to novelty noted in prenatally stressed rodents (Deminiere et al., 1992).

SUMMARY Our three prospective longitudinal studies provide evidence supporting the hypothesis that prenatal stress alters the development of monkey offspring, resulting in a range of effects, persisting into adolescence. There was support for the hypothesis that prenatal stress reduced attention and motor development in infancy and negatively affected learning in adolescence, in comparison to controls. These results are consistent with the findings of McIntosh et al. (19954, whose research indicated that prenatally stressed children would be more likely to show ADHD, as well as the work of Huizink (2000) reporting early deficits in mental and motor test outcomes in prenatally stressed children. The data in our three prospective studies also yielded evidence to support the hypothesis that prenatal stress would result in higher levels of disturbance behavior and altered HPA axis function, especially under conditions of challenge. Compared to controls, prenatally stressed monkeys consistently showed increased stereotypies and decreased exploration, locomotion, and play behavior, and increased HPA axis activation, under stressful conditions. As suggested by Maccari et al. (1995) and others, this finding may be the result of elevated maternal stress hormones during pregnancy having crossed the placenta “barrier” in the prenatal stress condition, resulting in decreased binding capacity of hippocampal type 1 and type I1 receptors in offspring, which could subsequently alter offspring negative feedback on the HPA axis (Barbazanges et al., 1996; Henry et al., 1994; Maccari et al., 1995). Taken together, these findings suggest that monkeys from mothers exposed to chronic stress or endocrine activation during pregnancy develop impairments in early attention and motor performance, as well as slower learning and emotion regulation during adolescence. Longitudinal studies following these monkeys into adulthood are in progress to determine the persistence of these effects. These results should be considered informative to pregnant women and health care providers, suggesting that the most


cautious course of action is to avoid stressful events during pregnancy, if possible.


Acknowledgements We thank Julie Larson for assistance in preparation of the manuscript and for technical assistance with data collection and Helen LeRoy for editorial assistance. The research reported in this paper was supported by grants from the National Institute of Alcohol Abuse and Alcoholism a 1 0 0 7 9 and AA12277, the W. T. Grant Foundation Faculty Scholars Award, National Institute of Mental Health MH48417 and Training Grant MCJ009102 from the Maternal and Child Health Bureau to Mary L. Schneider.

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