The developmental impact of prenatal stress, prenatal dexamethasone and postnatal social stress on physiology, behaviour and neuroanatomy of primate offspring: studies in rhesus macaque and common marmoset

Abstract

Rationale: Exposure of the immature mammalian brain to stress factors, including stress levels of glucocorticoids, either prenatally or postnatally, is regarded as a major regulatory factor in short- and long-term brain function and, in human, as a major aetiological factor in neuropsychiatric disorders. Experimental human studies are not feasible and animal studies are required to demonstrate causality and elucidate mechanisms. A number of studies have been conducted and reviewed in rodents but there are relatively few studies in primates.

Objectives: Here we present an overview of our published studies and some original data on the effects of: (1) prenatal stress on hypothalamic-pituitary-adrenal (HPA) re/activity and hippocampus neuroanatomy in juvenile-adolescent rhesus macaques; (2) prenatal dexamethasone (DEX) on HPA activity, behaviour and prefrontal cortex neuroanatomy in infant-adolescent common marmosets; (3) postnatal daily parental separation stress on HPA re/activity, behaviour, sleep and hippocampus and prefrontal cortex neuroanatomy in infant-adolescent common marmoset.

Results: Prenatal stress increased basal cortisol levels and reduced neurogenesis in macaque. Prenatal DEX was without effect on HPA activity and reduced social play and skilled motor behaviour in marmoset. Postnatal social stress increased basal cortisol levels, reduced social play, increased awakening and reduced hippocampal glucocorticoid and mineralocorticoid receptor expression in marmoset.

Conclusions: Perinatal stress-related environmental events exert short- and long-term effects on HPA function, behaviour and brain status in rhesus macaque and common marmoset. The mechanisms mediating the enduring effects remain to be elucidated, with candidates including increased basal HPA function and epigenetic programming.

Fig. 1

Schematic showing the major developmental life-history stages of the rhesus macaque (a) and the common marmoset (b). Please note that the scale for the rhesus macaque is given in years and the one for the common marmoset in weeks

Fig. 2

Effects of prenatal stress, both early (EPNS) and late (LPNS) in pregnancy on behaviour, cortisol titres in basal condition and after DEX stimulation, on neurogenesis and hippocampal volume in rhesus macaque offspring generated from stressed and control pregnancies. Values are mean ± SEM; *p < 0.05, significantly different from control monkeys (with modifications from Coe et al. 2003)

Fig. 3

Effects of early deprivation on plasma cortisol titres in infancy. a Plasma cortisol titres in ED common marmosets (N = 6) in samples obtained immediately after removal of the infant from the carrying parent (Pre-ED, 1100 hours) and immediately after a 30-min ED session (Post-ED, 1130 hours). There was not a significant effect of condition on plasma cortisol titres. b. Comparison of plasma cortisol titres in ED and CON infant common marmoset twins (N = 6, 6) in samples obtained immediately after removal of the infant from the carrying parent (1100 hours). Titres were significantly greater in ED versus CON infants. Values are mean ± SEM

Fig. 4

Comparison of effects of social separation on plasma cortisol titres in juvenile ED and CON common marmoset twins (N = 6, 6). Values are mean ± SEM. There was not a significant effect of Manipulation on plasma cortisol titres

Fig. 5

Comparison of social behaviours that were significantly different in ED and CON infant common marmoset twins (N = 6, 6): a Frequency of maternal anogenital licking of infants aged 1–4 weeks. b Percent time being carried by parents in infants aged 5–8 weeks. c Frequency of initiating an episode of social play by infants aged 9 weeks. Values are mean ± SEM

Fig. 6

Cortisol titres in ED common marmosets (N = 9) in urine samples obtained immediately after removal of the infant from the carrying parent (Pre-ED) and immediately after an ED session. Titres were significantly greater in post-versus pre-ED urine samples. Values are mean ± SEM, with cortisol expressed relative to creatinine titres

Fig. 7

Comparison of effects of saline injection (physical) challenge on plasma cortisol titres in adolescent ED and CON common marmoset twins (N = 7, 7). Values are mean ± SEM. There was a significant manipulation × time interaction. The Δ (SAL 4 h—Basal) was significantly greater in ED versus CON juveniles on plasma cortisol titres. Values are mean ± SEM

Fig. 8

Comparison of the effects of saline injection and DEX/CRH neuroendocrine challenge on a plasma ACTH and b plasma cortisol titres, in adolescent ED and CON common marmoset twins (N = 6, 6). Values are mean ± SEM. For ACTH, there was a significant manipulation × sample interaction and a significant main effect of manipulation, with titres increased in ED versus CON subjects. For cortisol, there was a significant manipulation × sample interaction

Fig. 9

Nocturnal electrocorticographic (upper trace) and electromyographic (lower trace) signals characteristic of two different sleep stages as measured in freely moving juvenile common marmosets. a ECoG and EMG traces interpreted as typical for slow-wave sleep (stage 4) b ECoG and EMG traces interpreted as typical for rapid eye movement sleep