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Endocrinology, doi:10.1210/en.2008-0615
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Endocrinology Vol. 149, No. 12 6343-6355
Copyright © 2008 by The Endocrine Society

Effects of Prenatal Dexamethasone Treatment on Physical Growth, Pituitary-Adrenal Hormones, and Performance of Motor, Motivational, and Cognitive Tasks in Juvenile and Adolescent Common Marmoset Monkeys

Jonas Hauser1, Alana Knapman1, Nicole R. Zürcher, Sonia Pilloud, Claudia Maier, Rochellys Diaz-Heijtz, Hans Forssberg, Andrea Dettling, Joram Feldon and Christopher R. Pryce

Behavioural Neurobiology Laboratory (J.H., A.K., N.R.Z., S.P., C.M., A.D., J.F., C.R.P.), Swiss Federal Institute of Technology-Zurich, CH-8603 Schwerzenbach, Switzerland; Behavioural Neuroscience Laboratory (R.D.-H.), Karolinska Institute, S-17177 Stockholm, Sweden; and Karolinska Institute (H.F.), Astrid Lindgren Children’s Hospital, S-17176 Stockholm, Sweden

Address all correspondence and requests for reprints to: Joram Feldon, Behavioural Neurobiology Laboratory, Swiss Federal Institute of Technology Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland. E-mail: feldon{at}behav.biol.ethz.ch; or Christopher Pryce, Novartis Pharma AG, Novartis Institutes for BioMedical Research Basel, 4002 Basel, Switzerland. E-mail: christopher.pryce{at}novartis.com.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Synthetic glucocorticoids such as dexamethasone (DEX) are commonly used to prevent respiratory distress syndrome in preterm infants, but there is emerging evidence of subsequent neurobehavioral abnormalities (e.g. problems with inattention/hyperactivity). In the present study, we exposed pregnant common marmosets (Callithrix jacchus, primates) to daily repeated DEX (5 mg/kg by mouth) during either early (d 42–48) or late (d 90–96) pregnancy (gestation period of 144 days). Relative to control, and with a longitudinal design, we investigated DEX effects in offspring in terms of physical growth, plasma ACTH and cortisol titers, social and maintenance behaviors, skilled motor reaching, motivation for palatable reward, and learning between infancy and adolescence. Early DEX resulted in reduced sociability in infants and increased motivation for palatable reward in adolescents. Late DEX resulted in a mild transient increase in knee-heel length in infants and enhanced reversal learning of stimulus-reward association in adolescents. There was no effect of either early or late DEX on basal plasma ACTH or cortisol titers. Both treatments resulted in impaired skilled motor reaching in juveniles, which attenuated in early DEX but persisted in late DEX across test sessions. The increased palatable-reward motivation and decreased social motivation observed in early DEX subjects provide experimental support for the clinical reports that prenatal glucocorticoid treatment impairs social development and predisposes to metabolic syndrome. These novel primate findings indicate that fetal glucocorticoid overexposure can lead to abnormal development of motor, affective, and cognitive behaviors. Importantly, the outcome is highly dependent upon the timing of glucocorticoid overexposure.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
SINCE ITS FIRST reported use in 1972 (1), prenatal treatment with synthetic glucocorticoid (GC), dexamethasone (DEX) being a major example, is commonly used as a prophylactic treatment of neonatal morbidity associated with preterm birth (2) and is advocated by the National Institutes of Health (3). A metaanalysis of the human studies reported an absence of negative side effects of such treatment on the physical status of neonates (4). Despite these encouraging findings at birth, the potential risks of prenatal GC treatment are indicated by studies of the long-term effects of prenatal stress, in which elevated endogenous GC is an important component, including increased risk of schizophrenia, increased risk of neurodevelopmental delay, increased emotionality and deficiency in orbito-frontal performance (5, 6, 7). Indeed, putative mechanisms of action and comparative empirical evidence, summarized below, indicate the need for increased understanding of whether or not prenatal GC exposure exerts long-term effects on development. This is particularly required for repeated GC administration (8), which is in fact the most common clinical treatment used (9, 10).

Synthetic GCs act via binding to GC receptors (GR), resulting in regulation of expression of genes with a glucocorticoid response element in their promoter (11). One of the major effects of GC binding to GR is inhibition of the hypothalamo-pituitary-adrenal (HPA) axis (11). In addition to this immediate effect, synthetic GCs have been shown to result in prenatal programming of GR expression level (12). Prenatal programming is the setting up of levels in adulthood of receptor expression based on availability of ligand during development and is proposed as a mediating mechanism for the phenotypes observed in adult animals exposed to prenatal DEX treatment (13). In rats, prenatal synthetic GC exposure results in reduced birth weight (14), impaired infantile motor reflexes (15), increased HPA axis reactivity to a stressor in adulthood (16), and memory impairment in young and mature adulthood (17, 18). Reported effects on adult behavior in the Porsolt forced swim test, a putative assay for distress, are equivocal (16, 19, 20). In nonhuman primates, GC treatment led to an acute reduction in fetal weight in the rhesus macaque but no change in birth weight in rhesus macaque, vervet monkey, or common marmoset (21, 22, 23). It led to increased locomotion and feeding in infancy in common marmoset (24), and increased HPA axis stressor reactivity in 8- to 9-month-old (infant) rhesus macaques and vervet monkeys (23, 25). Prenatal GC led to hippocampal abnormalities in both preterm and near-term fetuses and 20-month-old (juvenile) rhesus macaques (25, 26) and also to reduced cell proliferation, but not to impaired neuronal differentiation, in the dentate gyrus of neonatal common marmosets (22). To our knowledge (see also Ref. 27), there have been no further studies of postnatal effects of prenatal GC exposure in nonhuman primates.

Thus, across species, there is evidence that prenatal GR activation is associated with motor impairments, prefrontal cortex dysfunction, and possibly disturbed mood. Based on these observations, and given the common use of prenatal GC treatment in antenatal medicine, there is a clear need for more experimental and translational evidence for the effects of prenatal GC on neuropsychological development in nonhuman primates. The present study was conducted with the common marmoset (Callithrix jacchus) to investigate the long-term effects of prenatal DEX in a nonhuman primate in terms of growth, HPA endocrinology, social behavior, and neuropsychological function. This New World monkey is small (350–450 g), exhibits dizygotic twinning, hemochorial placentation with chimerism, a gestation period of 144 d, well-developed sensory and motor function at birth, weaning at month 3, and sexual maturation at 15–18 months (28). The marmoset exhibits GC resistance, such that endogenous levels are high and high doses of DEX are required in HPA challenge tests (29). Nonetheless, the marmoset also exhibits typical HPA characteristics such as the diurnal rhythm and stress responses (30), and there is high homology between the marmoset GR gene and those of other mammals including human (31). DEX was administered daily during gestation wk 7 (late first trimester), likely targeting the maturational stage of maximal neurogenesis in this primate (32) and therefore a putative sensitive period for inducing acute central effects with long-term consequences, or gestation wk 13 (late second trimester), likely targeting the maturational stage similar to that at which the human fetus at risk for preterm delivery is exposed to synthetic GC as a prophylactic clinical measure and therefore of particular translational relevance. Although it is not the typical clinical regimen, which is once-weekly GC dosing (33), daily dosing was used because this is the regimen that has often been used in rat, sheep, and monkey studies.

When the monkeys were juvenile (months 4–8) and/or adolescent (months 9–12), we measured the long-term effects of prenatal DEX on physical growth, basal ACTH and cortisol titers, species-typical behaviors, skilled reaching motor performance using an adaptation of the rat version of this test (34), motivation for reward and shifts in reward value using various reinforcement schedules, and simple discrimination and reversal learning.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects and DEX treatment
Subjects were 12 pairs of common marmoset twins provided by 12 different breeding pairs. Further details of breeding and offspring are given in Hauser et al. (24). Social groups were housed in a dedicated facility (humidity 66 ± 2% and temperature 22 ± 1 C, lights on 0800–1900 h, 15 min UV light, infrared light in dark). Home cages (3 m3) were equipped with supports, a wire-mesh inner cage (40 x 40 x 80 cm) (35), a protruding sleeping/test box (30 x 30 x 20 cm), and sawdust on the floor. Social groups were fed high-protein mash (Premix; Nafag Animal Nutrition and Feeds, Gossau, Switzerland), complemented with crickets, fruits, and eggs twice per week. Commercial high-protein pellets (Kliba3450, 4.5 mm; Kliba, Kaiseraugst, Switzerland) and water were available ad libitum. Conception date was estimated based on breeding females plasma estrone conjugate titers (24, 36).

Based on a pilot study conducted at the German Primate Center (E. Fuchs, personal communication), a dose of 5 mg/kg · d was selected for this study; this dose led to reduced maternal plasma cortisol titers and was half of the dose that inhibited fetal growth but also induced abortion in some pilot study females. In the present study, pregnant females were allocated randomly to one of the treatment groups and were administered per os DEX (5 mg/kg · d, DEX tablets; Jenapharm, Jena, Germany) or syrup vehicle, during estimated gestation d 42–48 (early DEX) and 90–96 (late DEX) as follows: vehicle (VEH at both treatment windows), early DEX (EDEX, DEX early and VEH late), late DEX (LDEX, VEH early and DEX late). There were five male subjects in VEH and EDEX, and four in LDEX, and for females, the sample size was three VEH, three EDEX, and four LDEX (see also Ref. 24). Tail hair of one offspring subject per group was shaved to facilitate identification.

Morphometric and physiological sampling
At 1200 h on wk 20, 24, 28, 32, 36, 40, 44, and 48, offspring were caught on subsequent days and blood sampled (0.2 ml) (24). We then measured body weight and knee-heel length and shaved the tail hairs. Blood plasma was kept at –80 C until radioimmunoassay (RIA).

Home cage behavioral observation
Home cage behaviors were measured during postnatal month 5, 7, 9, and 12, using the ethogram of Stevenson and Poole (37). Three observations (60 min) were performed per month. Data were entered into a computer (Workabout; PSION, London, UK), running Observer mobile support package software (Noldus Information Technology, Wageningen, The Netherlands). Behaviors were recorded using all-occurrence (frequency) or 30-sec instantaneous (percent time of observation) sampling. Behavior elements investigated were eating solid food, exploration, mobility, scratch with hand or foot, self-grooming, social grooming, social play, solitary play, and tail hair piloerection.

Motor skilled reaching task
Apparatus.
Apparatus and design were adapted from a rat paradigm (34). Subjects were enclosed in the inner cage. The test box front wall was replaced by a transparent Plexiglas screen with a 1.7- x 1.5-cm opening in its center and a protruding 20- x 13- x 1-cm platform (6 cm above floor) with four round indentations [diameter = 7 mm, depth = 0.2 mm, either left or right (2.5 or 3.5 cm from center) and far or close (5 or 3 cm from opening)]. The front wall and platform were enclosed in a dimly illuminated (25 W) Wisconsin general test apparatus (40 x 42 x 45 cm) (35, 38), equipped with access hatch, semiopaque window, and opening shutter.

Training and testing.
Subject training (5–11 d) began at age 22 wk, immediately followed by testing (4–6 d). After a 3-h mash deprivation, subjects were tested, using a counterbalanced design, at either 1200 or 1400 h. The reward used was 5 cm3 dry cracker cube (Zwieback; HUG AG, Malters, Switzerland) soaked in banana milk drink (Emmi, Lucerne, Switzerland). Training comprised stepwise habituation to apparatus and reward, being enclosed in the inner cage, physical separation from the parents and the twin, sequential presentation of rewards in front of the opening, and finally to the use of the Wisconsin general test apparatus shutter. The progression to the next stage of training occurred when the subject was picking up and eating rewards; at the last stage of training, where conditions were identical to the test situation apart from the location of the reward, consumption of 12 rewards of 16 presented was required for the subject to progress to testing.

For testing, all subjects were given 64 trials (maximum 16 trials per session per day), with rewards placed in a counterbalanced schedule in one of the four indentations. An experimenter scored the following behaviors: attempt, arm goes through opening; reward obtained, reward is retrieved and eaten; reward retouched, reward touched but not grasped; reward missed, arm reaching movement failed to touch the reward; reward dropped, reward is dropped after successful grasp; reward pushed away and reward pushed out of reach, reward is pushed away from subject or out of reach; reward dragged, reward is dragged; approach with mouth, subject approaches reward with the mouth; and use both hands, both arms go through opening. The following scores were calculated: single attempt success (SAS), subject obtains the reward in first attempt regardless of errors, and single grasp success (SGS), subject obtains the reward in first attempt without errors.

CANTAB
Monkey CANTAB apparatus.
The monkey version of the CANTAB (Cambridge Neuropsychological Test Automated Battery) system was used for motivational and cognitive testing (35, 39). Via a test box equipped with a transparent Plexiglas front containing holes, subjects accessed the touch-sensitive screen on which visual stimuli were presented. The reward dispenser was located in the middle of the screen and a video camera to the side. Subjects were tested in the inner cage within the home cage. The experimenter observed from an adjacent room.

Reinforcement and touch-screen training.
At age 10 months, after 3 h mash deprivation (except for progressive ratio), subjects were trained or tested three to four times weekly in 20-min daily sessions (progressive ratio, 25 min). The reward used was syrup diluted 1:4 in water (40). A 3-sec inter-trial interval was implemented in all training and testing sessions. The criterion to pass to next training stage was consumption of 50% of rewards. Training stages were 1) association of an 8-sec tone (4000 Hz) with syrup delivery (0.02 ml/sec), with tone-reward pairing maintained throughout training and testing; 2) touching of a large blue stimulus that filled the screen resulting in tone-reward; 3) touching one of two blue stimuli located either side of the dispenser resulting in tone-reward, and touching outside of either stimulus resulting in 3-sec punishment tone (500 Hz) and disappearance of stimuli; 4) stepwise reduction in stimulus size; 5) one stimulus randomly presented left or right of dispenser and rewarded. Completion of all steps resulted in subjects being tested on the following consecutive tests (age): progressive-ratio reinforcement schedule (11 months), fixed-ratio reinforcement schedule and negative shift in reward valence (12 months), and simple discrimination and reversal learning (14 months).

Progressive-ratio reinforcement schedule.
The progressive-ratio task (35, 39) used a large, single blue stimulus, with stimulus touches secondarily reinforced by the color changing to magenta (0.1 sec). A session ended if 5 min elapsed without a stimulus touch. The progressive ratio used was the same as previously described in Spinelli et al. (35). Total number of responses (stimulus touches), total rewards obtained, and breakpoint ratio (number of responses required for next reward when animal stopped responding) were measured.

Fixed-ratio reinforcement schedule and negative shift in reward valence.
Animals were trained to a stable level of responses on a fixed-ratio reinforcement schedule and subsequently exposed to a negative shift in reward valence, based on Flaherty’s reward contrast paradigm (41). Subjects were tested on a fixed-ratio 10 (FR10, 10 responses for one reward) schedule, using a large, single blue stimulus and 1:4 syrup as reward. After 10 stable sessions at FR10, 1:4 syrup was shifted to 1:12 for four sessions. Blood samples were taken after one 1:4 session and after the initial 1:12 session. Total responses and total rewards obtained were measured.

Simple discrimination and reversal learning.
Subjects were tested in two-way simple discrimination followed by reversal learning (maximum 60 trials per session), using five successive simple discrimination pairs of blue shapes. Touching the correct stimulus was reinforced with tone-reward compound and touching the incorrect stimulus with 3-sec punishment tone and a black screen. The learning criterion was eight consecutive correct responses. With the fourth and fifth stimulus pairs, the stimulus-reward pairing was reversed upon achievement of the learning criterion. Total number of errors made to attain the learning criterion was measured.

RIA of plasma ACTH and cortisol
Plasma ACTH titers were determined in a single 25-µl sample aliquot using a modified commercial RIA kit (DiaSorin, Stillwater, MN) according to the method in Pryce et al. (42). Assay sensitivity was 16.3 pg/ml, intraassay precision was 9.0% (n = 10), and interassay precision was 10.6% (n = 7). Plasma unconjugated cortisol titers were determined in duplicate using an in-house RIA detailed in Pryce et al. (30). Assay sensitivity was 250 µg/dl, intraassay precision was 5.3% (n = 8), and interassay precision was 4.8% (n = 8).

Data analysis
Data were analyzed using the Statistical Package for the Social Sciences version 13 (SPSS, Chicago, IL). Distribution normality of data sets, e.g. males and females, was assessed using the Kolmogorov-Smirnov test. Only one data set (discrimination and reversal learning errors) exhibited a significant deviation from normality, and normality was attained with this data set using ln transformation. ANOVA was based on the general linear model. Treatment (VEH, EDEX, and LDEX) and sex were systematically used as between-subject factors. Morphometric measurements, ACTH and cortisol titers and home-cage behavioral elements were analyzed using age as within-subject factor. Scores from the skilled reaching task were analyzed using eight-trial blocks as within-subject factor and were analyzed with analysis of covariance (ANCOVA), with the rewards obtained and SAS as covariate in SAS and SGS ANCOVA, respectively. Multiple Pearson’s product-moment correlations were performed for exploration, solitary play, and social play at month 5 (age at testing) vs. reward obtained, SAS, and SGS in the skilled reaching task. Behavioral measures in CANTAB tasks were analyzed with session (progressive-ratio schedule, fixed-ratio schedule), session type (negative shift in reward valence), stimulus pair (simple discrimination), and stimulus pair and session type (reversal learning) as within-subject factors. Significance was set at P < 0.05 and a trend to significance at P < 0.1. Significant main or interaction effects of treatment were further analyzed post hoc using Fisher’s least significant difference (LSD) test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Physical and endocrine status
All three physical development measures increased monotonically, as supported by a main effect of age on body weight [F(7,133) = 201.23; P < 0.001; Fig. 1AGo], knee-heel length [F(7,133) = 312.12; P < 0.001; Fig. 1BGo] and body weight to knee-heel length ratio [F(7,133) = 101.69; P < 0.001, data not presented]. There were no effects of sex or treatment on body weight (P > 0.1; Fig. 1AGo). For knee-heel length, there was a significant treatment x age interaction [F(14,133) = 2.59; P < 0.05]; LDEX offspring had higher knee-heel length than EDEX and VEH, which were similar, at wk 44 and 48 (as supported by separate one-way ANOVA, P < 0.01; Fig. 1BGo).


Figure 1
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  		FIG. 1. Anthropometric and endocrine measures (mean ± SEM; n = 4, 5, and 5 for VEH, EDEX, and LDEX males and 4, 3, and 3 for VEH, EDEX, and LDEX females, respectively) in common marmosets aged 20–48 wk: A, body weight; B, knee-heel length; C, plasma ACTH titers; D, plasma cortisol titers. In B, there was a significant increase of knee-heel length in LDEX subjects at 44 and 48 wk of age (age x treatment interaction, P < 0.05).

 
There was no significant effect involving age, treatment, or sex on basal plasma ACTH titers (P >0.1; Fig. 1CGo). There was a significant effect of age on plasma cortisol titers [F(8,96) = 3.79; P < 0.05; Fig. 1DGo], with plasma cortisol titers being higher starting from wk 40. Individual comparison revealed a significant difference between wk 40 and wk 24, 28, 32 and 36 (all P values < 0.05).

Home cage behavior
The average scores for each behavior per treatment are given in Table 1Go. Regarding age effects, there was an increase in mobility between month 5 and months 7, 9, and 12 [age effect: F(3,54) = 278.14; P < 0.001]. For time spent eating solid food, subjects showed an inverted U-shaped curve, peaking at month 9 [age effect: F(3,54) = 4.19; P < 0.05]. Approach [F(3,54) = 5.32; P < 0.01], and contact [F(3,54) = 2.65; P < 0.05] showed a similar pattern, with a high level during month 5, reduction during month 7, increase during month 9, and reduction during month 12. A similar pattern of occurrence was observed for gnawing behavior [age effect: F(3,54) = 3.95; P < 0.05]. Subjects exhibited significantly reduced follow [F(3,54) = 7.13; P < 0.005], initiate play [F(3,54) = 8.11; P < 0.001], tail hair piloerection [F(3,54) = 19.96; P < 0.001], social play [F(3,54) = 3.78; P < 0.05], and solitary play [F(3,54) = 5.02; P < 0.01] behaviors with aging.


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  		TABLE 1. Home-cage behavioral scores

 
LDEX subjects showed significantly more gnawing than both VEH and EDEX subjects [F(2,18) = 4.43; P < 0.05]. Approach [F(2,18) = 4.81; P < 0.05], follow [F(2,18) = 4.25; P < 0.05], and leave [F(2,18) = 4.72; P < 0.05] were each significantly reduced in EDEX offspring vs. VEH (LSD P < 0.05) and vs. LDEX for follow only (LSD P < 0.05). As they increased in age, VEH subjects exhibited an increase in time spent in contact with other social group members, whereas both EDEX and LDEX exhibited a decrease in the same parameter as they increased in age, as reflected in a significant age x treatment interaction [F(6,54) = 2.65; P < 0.05]. Finally, both EDEX and LDEX subjects initiated less play bouts than did VEH [F(2,18) = 7.48; P < 0.005].

Motor skilled reaching task
There were no consistent treatment-group differences in the number of sessions subjects required to progress through training (VEH, 7.0 ± 0.7; EDEX, 6.4 ± 0.3; LDEX, 6.0 ± 0.4; P > 0.1) or testing (VEH, 4.1 ± 0.1; EDEX, 4.3 ± 0.2; LDEX, 4.3 ± 0.3; P > 0.1).

The test performance of subjects in the skilled reaching task improved across test sessions, that is, with experience. This was indicated by a significant main effect of blocks for several measures, including increasing number of rewards obtained [F(7,126) = 2.88; P < 0.05; Fig. 2AGo], increasing SAS [F(7,126) = 6.20; P < 0.001; Fig. 2AGo], increasing SGS [F(7,126) = 6.96; P < 0.001; Fig. 2AGo], decreasing number of misses [F(7,126) = 4.42; P < 0.01, data not presented], and decreasing number of retouches [F(7,126) = 2.85; P < 0.05, data not presented] (together, misses and retouches accounted for 78% of the total number of errors).


Figure 2
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  		FIG. 2. Skilled reaching task scores in juvenile common marmosets (mean ± SEM; n = 4, 5, and 5 for VEH, EDEX, and LDEX males and 4, 3, and 3 for VEH, EDEX, and LDEX females, respectively). A, Overall scores for the performance indices, rewards obtained, single attempt success, and single grasp success, across eight eight-trial blocks each measure demonstrated a main effect of block. B, SAS scores according to treatment and block; inset gives average scores collapsed across blocks. LDEX subjects reached a lower asymptotic performance compared with EDEX and VEH subjects (blocks x treatment, P < 0.05) C, SGS scores according to treatment and block; inset gives average scores collapsed across blocks. EDEX showed a delayed improvement with training, whereas LDEX showed no improvement with training (blocks x treatment, P < 0.05). D and E, Scores for percentage rewards obtained (D) and reward pushed out of reach (E), split by treatment and by sex [for males (M), n = 4, 5, and 5 for VEH, EDEX, and LDEX, respectively; for females (F), n = 4, 3, and 3 for VEH, EDEX, and LDEX, respectively]. *, Significant effect of treatment, P < 0.05.

 
For SAS, there was a significant treatment x blocks interaction [F(7,126) = 2.08; P < 0.001; Fig. 2BGo]. VEH subjects scored highest in early blocks, with EDEX intermediate and LDEX lowest; VEH and EDEX attained similar, relatively high SAS in the final block, whereas LDEX attained a lower asymptote. For SGS, there was also a significant treatment x blocks interaction [F(7,126) = 6.96; P < 0.001; Fig. 2CGo]; this reflected a delay in improvement of performance in EDEX compared with VEH and the absence of improvement in LDEX subjects compared with both VEH and EDEX. A posteriori one-way ANOVA for each treatment yielded a significant effect of block for VEH [F(7,42) = 3.87; P < 0.05) and EDEX [F(7,42) = 5.70; P < 0.01] but not for LDEX (P > 0.1). For number of rewards obtained, there was a significant treatment x sex interaction [F(2,18) = 5.04; P > 0.05]; female LDEX subjects obtained fewer rewards than VEH and EDEX female subjects and VEH, EDEX, and LDEX male subjects (Fig. 2DGo). This reduced performance co-occurred with an increased reward pushed out of reach score in female LDEX subjects compared with all other groups, confirmed by a significant treatment x sex interaction [F(2,18) = 5.05; P < 0.05; Fig. 2EGo].

The score for rewards obtained, SAS and SGS, when compared pair-wise using product-moment correlation, demonstrated significant positive correlations in all cases (r ≥ +0.665; df = 24; P < 0.01). This was expected, but it is nonetheless important to present the findings for all three measures, given that they provide progressively increasing sensitivity in terms of measuring skilled performance, i.e. SGS more than SAS more than rewards obtained. To assess this interdependence and its influence on our findings, rewards obtained and SAS were used as covariates in ANCOVA for SAS and SGS, respectively. This yielded a close to significant treatment x blocks interaction for SAS (P = 0.051) and SGS (P = 0.057) and a significant treatment main effect for SGS (P < 0.05).

To study possible associations between home cage behaviors that are putatively highly dependent on motor skills and performance of the skilled reaching task, correlations were calculated for skilled motor SGS scores at age 5 months and scores at the same age for three behaviors selected a priori, namely exploration, solitary play, and social play. Correlation coefficients were less than or equal to 0.35 and nonsignificant (P > 0.1).

Reward motivation and stimulus-reward association using monkey CANTAB tasks
There were no treatment group differences in number of CANTAB training sessions required until the final criterion to begin testing was achieved: VEH, 22.9 ± 3.4; EDEX, 27.6 ± 2.9; LDEX, 23 ± 2.5 (P > 0.1).

In the progressive-ratio schedule of reinforcement, there was no significant effect of treatment, sex, or session on total responses (Fig. 3AGo), rewards obtained (Fig. 3BGo), breakpoint ratio (Fig. 3CGo), or any other measure (P > 0.05).


Figure 3
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  		FIG. 3. Average performance across 10 sessions on a progressive-ratio schedule of reinforcement (mean ± SEM; n = 4 per treatment for males and 4, 3, and 2 for VEH, EDEX, and LDEX females). A, Total number of responses; B, total number of rewards obtained; C, breakpoint ratio reached. Neither EDEX nor LDEX treatment affected behavioral performance.

 
Subjects’ responding on a fixed-ratio schedule of reinforcement was stable across the 10 sessions, indicated by the absence of a significant effect of session on each dependent measure, including total responses and rewards obtained (P > 0.1). There was a significant main effect of treatment on total number of responses [F(2,9) = 9.01; P < 0.01; Fig. 4Go, A and B] and total number of rewards obtained [F(2,9) = 8.87; P < 0.01; Fig. 4Go, C and D] with EDEX subjects showing more responses and obtaining more rewards than VEH and LDEX subjects (which were similar) as confirmed by post hoc LSD (for both total number of responses and total number of rewards obtained, P < 0.005 for EDEX vs. VEH and EDEX vs. LDEX). Female subjects obtained more rewards than males [F(1,9) = 6.93; P < 0.05]. There were no treatment or sex effects on the time elapsed at which animals made the last response (P > 0.05).


Figure 4
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  		FIG. 4. Average performance across 10 sessions on a fixed-ratio schedule of reinforcement (mean ± SEM; n = 3 per treatment for males and 4, 3, and 1 for VEH, EDEX, and LDEX females). A, Total number of responses by males; B, total number of responses by females; C, total number of rewards obtained by males; D, total number of rewards obtained by females. EDEX subjects showed increased performance in terms of total responses performed and, therefore, total rewards obtained, relative to VEH and LDEX. Females showed increased total responses performed and therefore total rewards obtained relative to males. *, Significant effect of treatment, P < 0.05.

 
The negative shift in reward valence, from a 1:4 to 1:12 syrup solution, induced a clear decrease in responses relative to the mean of preshift FR values. Therefore, for total number of responses and total number of rewards obtained, there was a significant main effect of session type [F(4,44) = 8.32; P < 0.001, and F(4,44) = 8.39; P < 0.001; Fig. 5Go]. Pair-wise comparison of sessions revealed a significant difference between session 1 (average of the FR10 sessions) and each of the following sessions (including the shift session and the three postshift sessions, all P values< 0.05; Fig. 5Go). The significant main effect of treatment obtained with FR10 and 1:4 syrup (Fig. 4Go) persisted after the negative shift, in terms of both total number of responses and total number of rewards obtained; thus, there was a significant main effect of treatment on total number of responses and total number of rewards obtained [F(2,11) = 6.10; P < 0.05, and F(2,11) = 5.91; P < 0.05], again due to increased responses and rewards obtained by EDEX relative to LDEX and VEH, which were similar (for both total number of responses and total number of rewards obtained, LSD P < 0.05 for EDEX vs. VEH and EDEX vs. LDEX). For time elapsed to last press, there was a significant sex x session interaction [F(8,44) = 3.43; P < 0.05], reflecting decreased time in postshift session 1 vs. preshift and in males specifically; sex-specific analysis revealed a significant effect of session in males only [F(3,44) = 3.75; P < 0.05]. Plasma ACTH and cortisol measurements measured during preshift and postshift sessions did not show any effect of session or treatment or sex (data not presented).


Figure 5
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  		FIG. 5. Negative shift effect on fixed-ratio schedule of reinforcement performance (mean ± SEM; n = 3, 3, and 3 for VEH, EDEX, and LDEX males and 4, 3, and 1 for VEH, EDEX, and LDEX females, respectively). The negative shift effect was present in all groups (session type, P < 0.05). EDEX subjects showed an increased number of rewards obtained relative to VEH and LDEX independent of session type (treatment, P < 0.05).

 
Successive simple discrimination learning and reversal learning
ANOVA of total errors committed to reach the learning criterion across four successive stimulus pairs yielded a significant main effect of stimulus pair [F(3,33) = 6.84; P < 0.05], with subjects committing fewer errors as they progressed across pairs. There were no significant effects of treatment or sex on errors committed to reach learning criterion (P > 0.5; Fig. 6AGo).


Figure 6
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  		FIG. 6. Two-choice discrimination learning set and reversal learning set performance (mean ± SEM; n = 3, 3, and 3 for VEH, EDEX, LDEX males and 4, 3, and 1 for VEH, EDEX, and LDEX females, respectively; ln transformation was applied to achieve normality of data distribution). A, Number of errors to reach criterion for discrimination learning, according to stimulus pair and treatment; B and C, number of errors to reach criterion for discrimination and reversal for stimulus pair 4 (B) and stimulus pair 5 (C), according to treatment. There was no effect of treatment on acquisition. Each treatment group made significantly more errors to criterion at reversal vs. discrimination with stimulus pair 4, and this was also the case in VEH and EDEX subjects, but not LDEX subjects, with stimulus pair 5. *, Significant effect of reversal, P < 0.05.

 
When, with stimulus pairs 4 and 5, the stimulus-reward contingency was reversed after attainment of the simple discrimination criterion, subjects made more errors to attain the reversed criterion, as indicated by a significant main effect of session type [F(1,7) = 10.70; P < 0.05; Fig. 6Go, B and C]. There was a significant treatment x session type x stimuli pair interaction [F(2,7) = 11.79; P < 0.01], due to a relatively attenuated reversal effect observed with stimulus pair 5 in LDEX subjects.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This report describes the effects of prenatal DEX exposure on physical, endocrine, and in particular, behavioral traits in juvenile and adolescent common marmosets. In a previous report on the same monkeys in infancy (24), we described that EDEX infants were heavier and spent more time locomoting and more time eating than LDEX and VEH infants, which were similar. There were no effects of prenatal DEX on HPA axis activity assessed in terms of basal plasma ACTH and basal urinary and plasma cortisol levels in infants. In juveniles and adolescents, as reported here, there were also no effects of prenatal DEX on basal plasma ACTH and cortisol levels. The effect of EDEX on body weight observed in infancy was no longer present, whereas LDEX adolescents demonstrated a moderate increase in knee-heel length compared with VEH and EDEX. EDEX and LDEX juveniles/adolescents demonstrated a constellation of differences at the behavioral level relative to VEH and in some cases also relative to each other. EDEX made a reduced contribution to social relationships in that they approached and left the proximity of other family members less and initiated play less, relative to VEH and LDEX. EDEX juveniles demonstrated a deficit in skilled reaching, revealed by the measure single grasp success, relative to VEH. EDEX adolescents demonstrated increased motivation to obtain palatable reward on a fixed-ratio schedule (but not on a progressive-ratio schedule) relative to VEH and LDEX. LDEX juveniles/adolescents exhibited increased gnawing behavior relative to VEH and EDEX. LDEX juveniles demonstrated a deficit in skilled reaching, revealed by rewards obtained in LDEX females, by single attempt success relative to VEH and EDEX, and by SGS relative to VEH. LDEX adolescents demonstrated enhanced reversal learning of simple stimulus-reward associations relative to VEH and EDEX.

We observed no significant effect of either prenatal treatment on the body weight of the subjects at ages 20–48 wk and only a moderate increase of knee-heel length in the LDEX subjects at wk 44 and 48. Similarly in rhesus macaque, prenatal DEX exposure at 132 and 133 d gestation did not lead to an effect on body weight at age 20 months (25). In the vervet monkey, prenatal exposure to DEX, from midgestation to parturition, resulted in reduced body weight and skeletal growth at ages 8 and 12 months (23). Taken together, and notwithstanding that different primate species are being compared, these data suggest that the effect of prenatal DEX on physical growth is dose-duration dependent.

There was no effect of either prenatal DEX treatment on basal plasma levels of ACTH or cortisol in juvenile/adolescent marmosets. In the rhesus macaque study, prenatal DEX led to increased basal and stressed (30 min isolation) levels of plasma cortisol in adulthood (25). In the vervet monkey study (23), there was no effect of prenatal DEX on basal levels of plasma ACTH or cortisol, but there was an increased plasma cortisol response to a mild stressor in infancy in the highest DEX-dose group; there was no effect of prenatal DEX on plasma cortisol levels after a DEX suppression test, suggesting that HPA axis negative feedback as mediated via pituitary-gland GR was intact. Therefore, the effects of prenatal DEX on marmoset behavior, as discussed below, occurred in the absence of altered basal levels of ACTH or cortisol.

In terms of development of maintenance and social behavior in the family group, there were some important effects of EDEX and LDEX. EDEX subjects exhibited less of some of the behaviors that mediate and maintain social interactions and relationships, namely approaching, following, and leaving (43), compared with both VEH and LDEX subjects. Both EDEX and LDEX juveniles/adolescents showed a reduction in time spent in social contact as they aged, in contrast to VEH subjects, which showed an increase in social contact as they aged. These findings suggest that EDEX and, to a lesser extent, LDEX both led to reduced social motivation. In humans, it has been reported that prenatal GC treatment, chronic prenatal DEX treatment for diagnosed congenital adrenal hyperplasia, leads in infants, children aged between 6 months and 5.5 yr, to reduced sociability and also to increased emotionality and shyness (7). In macaques, extended prenatal stress or prenatal ACTH administration resulted in long-term effects in terms of increased emotionality in social situations (44). Although emotionality was not tested per se in our study, several results argue against a similar explanation for the reduced sociability in EDEX and LDEX subjects. These juveniles/adolescents did not exhibit any alterations in home cage measures that could be interpreted as increased emotionality, e.g. tail hair piloerection and distress calling. In addition, when exposed to the negative shift in the FR schedule, subjects from the three treatment groups showed a similar response in terms of the negative shift in reward valence. Therefore, it seems unlikely that a change in emotionality per se explains the reduction in social behavior observed in the juvenile/adolescent marmosets in this study. Finally, the aforementioned findings of increased emotionality in humans and monkeys were the consequence of extended periods of prenatal GR stimulation, compared with the shorter treatment windows studied here.

Turning to conditioned behavioral readouts, it is worth emphasizing that all training and testing was carried out in the home cage, thereby eliminating any confounding effects of social isolation stress, which would be expected to be particularly marked in the immature animals studied here (45). It was possible to adapt the skilled reaching task developed for rats (34) to a nonhuman primate version, demonstrating that the paradigm is appropriate for comparative studies. Given the importance of the comparative approach in, for example, understanding the evolution of forelimb function (46) and development of translational models of movement disorders (e.g. Huntington’s disease and Parkinson’s disease), it is advantageous that a single task that retains consistency in terms of apparatus and behavioral readouts can be used to assess reach-to-grasp movement across different study species.

Our evidence for impairing effects of prenatal DEX on juvenile motor dexterity extends knowledge of this important developmental issue quite markedly, in terms of species, maturational stage, and treatment. Burlet and colleagues (15) demonstrated that prenatal DEX exposure leads to reduced righting reflex and grasping performance in 3- and 10-d-old rats, respectively. The most relevant previous primate evidence that prenatal GC exposure leads to important motor deficits was obtained in rhesus monkey neonates either after prenatal stress (47) or prenatal ACTH treatment (48), using the Brazelton Newborn Behavioral Assessment Scale (49). The use of neonatal neuromotor development assessment would have been an interesting addition to the current study, but we considered that it would also have been an additional stressor and therefore a potential confound.

The impairments observed in the two treatment groups in our study were qualitatively different; EDEX led to a performance deficit in terms of the most sensitive measure, SGS, specifically. LDEX led to a consistent impairment in ability to obtain rewards per se in females, to a consistent deficit in SAS despite improvement with task experience, and to an absence of improvement with task experience in SGS. It is noteworthy here that there were no alterations in home cage behaviors that are particularly motorically demanding, such as exploration, solitary play, and social play, in EDEX or LDEX, and also that these behaviors did not correlate with the motor dexterity indices of the skilled reaching task. The LDEX female-specific reduction in rewards obtained co-occurred with increased pushing rewards out of reach; this might have reflected high motor impulsivity, but we do not have an explanation as to why this would be female specific, particularly because all subjects would be expected to be prepubertal during skilled reaching task testing.

This dichotomy between the reduced performance in EDEX and LDEX infants in the skilled reaching task and normal motorically demanding home cage behavior suggests that the treatments do not impact on cortices that are required for basic motor tasks, such as motor and premotor area or supplementary motor area (50), but rather on modulatory areas. The fine modulation of a precise motor learning, such as in the skilled reaching task used in this study, was shown by lesion studies to depend upon the cerebellum and the dependent cerebello-thalamo-cortical pathway (51, 52) and upon the basal ganglia and the dependent striato-thalamo-cortical loop (53, 54, 55, 56). Prenatal GR activation, using synthetic GC treatment or prenatal stress, reduces neurogenesis and cellular interconnectivity in the cerebellum in rat (57, 58) and alters striatal dopaminergic activity in both rat and monkey (59, 60). These data clearly indicate that prenatal GR stimulation has an impact on the development of central nervous system (CNS) structures required for the development of fine motor control and motor learning, such as required in the skilled reaching task used here. Therefore, we hypothesize that the effects observed in EDEX and LDEX subjects in this study originate from the impact of the treatment on elements of the cerebello-thalamo-cortical and/or the striato-thalamo-cortical pathways.

We hypothesize that the qualitatively different effects of EDEX vs. LDEX on skilled reaching in the common marmoset originate from the difference in the stages of CNS maturation generally, and GR expression specifically, at the time of these two GR agonism treatments. Due to the lack of information on both brain maturation and GR ontogeny in the marmoset, we must turn to comparative evidence for insight into possible mechanisms. The brain regions relevant to skilled motor performance, namely the neocortex including the motor cortex, the basal ganglia, and the cerebellum, are identifiable from embryonic d 12 in rodents and from gestational wk 7 in humans (61). Regarding GR ontogeny, GR mRNA expression has been reported from embryonic d 12.5 in rodents (62) and continues to increase monotonically until the postnatal stress hyporesponsive period, i.e. postnatal d 14. Despite the inherent difficulties in extrapolating from rodent to marmoset, it is possible that a similar increase in GR expression occurs in marmoset. Therefore, we hypothesize that EDEX targeted both a less mature brain and relatively low expression of GR compared with LDEX. This hypothesis would appear to accord with the respective behavioral effects observed, with EDEX resulting in mild impairment that could be overcome with training and LDEX resulting in higher impairments that could not be attenuated with training.

Motivation of subjects to obtain palatable reward was assessed in three different tasks, the progressive-ratio schedule of reinforcement, fixed-ratio schedule of reinforcement, and negative shift of the reward reinforcement value. The brain circuitry of reward is well described, with important areas including prefrontal cortex, amygdala, ventral and dorsal striatum, and ventral tegmental area (63). Each of these areas expresses GR, including evidence for postnatal expression in the marmoset (31), and therefore could be susceptible to altered functioning with long-term effects on reward processing, after prenatal DEX exposure. The most striking finding was the increased motivation to obtain reward on a fixed-ratio schedule, specifically, in EDEX subjects. It is noteworthy that in each of the treatment groups, responses and rewards obtained were considerably higher on the fixed-ratio schedule than on the progressive-ratio schedule. This suggests that these marmoset subjects were sensitive to the within-session negative shift in reward relative to effort, which occurred as they ascended the progressive ratio. If this is the case, then there were no effects of prenatal DEX on this negative-shift sensitivity, an extrapolation that is supported by the finding of a lack of effect of prenatal DEX on response to a negative shift in reward value per se. Under conditions of consistent and predictable reinforcement, therefore, EDEX subjects exhibited relatively high motivation, or in other words, an increased appetite, for palatable reward. In infancy, that is, at the time of weaning, these same infants spent more time feeding on solid food, so that we have two developmental measures that the motivation to consume palatable food is increased by EDEX treatment in this primate. These findings are important given the extensive evidence that GC modulates appetite, feeding, and body weight (64, 65, 66, 67) and the proposed link between prenatal GC exposure and the human metabolic syndrome, of which obesity is a major component (68).

There was no effect of either EDEX or LDEX treatment on simple discrimination learning across five stimulus pairs of shapes. Reversal learning was studied in the final two stimulus pairs, and with the final pair, LDEX subjects demonstrated enhanced reversal learning. Using excitotoxic lesioning and a similar CANTAB task to that used here, it has been demonstrated in the common marmoset that reversal learning is impaired by lesioning of the orbitofrontal cortex, probably due to impaired inhibitory control of perseverative responding to the previously rewarded stimulus (69). It is possible therefore that LDEX treatment led to a long-term change in orbitofrontal cortex functioning that was commensurate with an increase in inhibitory control, thereby increasing the ability to alter behavior in response to changes in the emotional significance of stimuli.

Above, when discussing possible mechanisms mediating prenatal DEX effects on offspring traits, we have stated, or at least implied, that these have their origin in activation of GR in the maturing CNS of the fetal offspring directly. In line with this, the GR programming hypothesis (13), for example, represents a model for long-term effects of prenatal treatment with empirical support. However, the altered traits observed in EDEX and LDEX marmosets might also derive indirectly, that is, via DEX effects on maternal physiology (e.g. heart rhythm and HPA activity) and/or behavior, which then impact on offspring development. The only relevant evidence that we can present on this important issue is that maternal plasma cortisol levels recovered to VEH levels within 1 wk of EDEX and LDEX treatment, and there was no effect of EDEX or LDEX on maternal behavior (24).

The current study marks a major contribution to the evidence that exposure of the fetus to synthetic GR agonist, as used commonly in pediatric medicine, has a long-term postnatal impact on basic motor, motivational, and learning functions in nonhuman primates. By adapting a rodent skilled motor task to a primate version, we have demonstrated that DEX applied in the first or, in particular, late second trimester leads to persistent motor deficits. EDEX led to increased wanting of palatable reward under conditions of a stable and predictable relationship between the food stimulus and the operant behavior required to obtain it. These EDEX subjects were as sensitive as VEH and LDEX subjects to negative shifts in the yield of reward relative to operant behavior. This increase in feeding motivation in EDEX subjects co-occurred with a reduction in social motivation, based on reduced levels of behaviors that regulate interactions with the family group. LDEX led to enhanced reversal learning, suggesting reduced perseveration. These effects were obtained in juveniles or adolescents and were not concomitant with altered basal levels of ACTH or cortisol. Overall, these findings suggest that prenatal DEX acts on GR expressed at the time of treatment and, via one or more processes that might include prenatal programming of GR, leads to altered maturation and functioning of brain areas that express GR. The diversity of the behavioral processes affected is testimony to the fetus sensitivity to exogenous GC stimulation.


   Acknowledgments
 
We are extremely grateful to Jeanne Michel, Pascal Guela, Dana Ryser-Stokes, and Jonas Schwank for animal care and maintenance, to Peter Schmid and Marcel Morf for technical assistance, to Steve Petty for administrative assistance, and to Eberhard Fuchs for administrative and scientific assistance.


   Footnotes
 
This work was supported by the European Commission Human Potential Program, 5th Framework, Glucocorticoid Hormone Programming in Early Life and Its Impact on Adult Health (EUPEAH) Grant No. QLRI-CT-2002-02758.

Disclosure Statement: The authors have nothing to disclose.

First Published Online August 28, 2008

1 J.H. and A.K. contributed equally. Back

Abbreviations: ANCOVA, Analysis of covariance; CNS, central nervous system; DEX, dexamethasone; EDEX, early DEX; FR10, fixed-ratio 10; GC, glucocorticoid; GR, GC receptor; HPA, hypothalamo-pituitary-adrenal; LDEX, late DEX; LSD, least significant difference; RIA, radioimmunoassay; SAS, single attempt success; SGS, single grasp success; VEH, vehicle.

Received April 29, 2008.

Accepted for publication August 15, 2008.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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