Original articleRepeated parental deprivation in the infant common marmoset (callithrix jacchus, primates) and analysis of its effects on early development
Introduction
There is growing evidence that adverse early life events constitute one of the major risk factors for the development of mood and anxiety disorders in adolescence and adulthood Bernet and Stein 1999, Glaser 2000, Heim and Nemeroff 2001, Heim et al 1997, Wong and Licinio 2001. In interplay with the genome, the early environment regulates brain development and consequently the development of species-specific behavior, as well as individual differences in behavior Gottlieb 1998, Greenough et al 1987, Plomin 1994. In mammals, parental care is the major factor in the early environment, and there is compelling evidence that parental care commensurate with maintenance of the infant’s homeostasis is important for the short-term and long-term development and functioning of neurobiology, physiology, and behavior Hofer 1987, Hofer 1994b. This rodent and primate evidence is provided by observational studies of the consequences of spontaneous differences in maternal care and by experimental studies involving manipulation of the infant–mother dyad Kraemer et al 1989, Liu et al 2000, Meaney et al 1996, Pryce et al 2001a, Rosenblum et al 1994. This approach in animals could yield models of the short-term and long-term consequences of abuse and neglect in human parent–infant relationships. Models of the short-term consequences of early life stress will be directly relevant to child psychiatry. Studies of the long-term consequences can provide models of important symptoms of neuropsychiatric disorders, including mood disorders and psychoses, that can (but do not have to) include adverse early life events in their etiology.
Most experimental evidence for the enduring effects of manipulation of the infant’s maternal environment on its neurobehavioral development is based on rat studies. The effects of a number of different manipulation paradigms have been investigated. Early handling (EH) involves daily separation of pups from the mother, and in some laboratories also from the littermates, for a brief period (3–15 min), and its effects are studied typically in adulthood relative to mothers and pups that do not experience any environmental disturbance, so-called early non-handling (NH) (Levine 1960). Maternal separation (MS) involves daily separation of the intact litter from the mother for a prolonged period (3–6 hours), and early deprivation (ED) or isolation involves daily separation of pups from the mother and littermates for a prolonged period (3–6 hours). The effects of MS and ED have been studied relative to NH or to mothers and pups that experience the environmental disturbance, including occasional brief handling, of typical animal facility rearing (AFR). As adults, EH offspring demonstrate reduced stress-related neuroendocrine responses (hypothalamic–pituitary–adrenal [HPA] axis) and reduced fearfulness in comparison with NH Caldji et al 1998, Levine 1960, Levine 2000, Meaney et al 1996, Pryce et al 2001a. Early deprivation adult offspring exhibit reduced (i.e., EH-like) stress/fear-related endocrine and behavioral responses relative to NH Kosten et al 2000, Pryce et al 2001a and AFR offspring (Ogawa et al 1994).
In comparison to the large number of rat studies, the study of long-term effects of manipulation of the infant–mother dyad in nonhuman primates has, with some notable exception, received little attention. Primate studies could well provide an important complement to rodent studies in this research area. For example, the prefrontal cortex and amygdala are major brain areas in the regulation of emotion and motivation in nonhuman primates and humans, and have undergone considerable development in primates, leading to marked primate–rodent differences Drevets 2001, Rolls 2000. Second, the infant–parent relationship differs markedly between rodents and primates: for a rat pup, it is natural to be separated from the mother (but not the littermates) for periods of 15–30 min while the mother leaves the nest for foraging. In contrast, the 1–2 primate infants are in full and continuous body contact with the mother, or in the case of some primates, mother and father, throughout the first several weeks of life (Pryce 1996). Therefore, interrupting body contact for even brief periods is likely to constitute a severe stressor for a primate infant. Rats and primates also differ in their maturational state at birth, with rats being poorly developed at birth and undergoing rapid postnatal growth, and nonhuman primate infants being born well developed and undergoing relatively slow postnatal growth. Differences also exist in the postnatal state of the HPA system. Postnatal days 2–14 constitute the stress hypo-responsive period (SHRP) of the rat HPA. Maternal care is an important regulator of the SHRP, so that postnatal manipulations such as EH and ED might exert some of their long-term effects via SHRP disruption (Levine 2000). Primate infants do not demonstrate a SHRP, with neonates already capable of adult-like pituitary–adrenal stress responses Bowman and Wolf 1965, Gunnar 1989. In the common marmoset monkey, infants actually demonstrate high basal levels of adrenocorticotropic hormone (ACTH) and cortisol relative to those of older conspecifics (Pryce et al 2002).
The majority of primate studies have been conducted with macaques and based on maternal privation; that is, the complete and continuous absence of the biological mother. Following separation from the mother within the first few days after birth, infants are either nursery-reared without physical contact with any other monkey during the first 6 months of life, or peer-reared in age-matched groups of maternally deprived monkeys. In contrast to rat ED, maternal privation constitutes a chronic absence of maternal care rather than the repeated stress of temporary deprivation of such care. Maternal privation has chronic physiologic, neurochemical, and behavioral effects. In comparison to mother-reared macaques, juvenile-adolescent maternally deprived peer-reared macaques exhibited either lower basal and stress-related HPA activity (Clarke 1993) or higher basal HPA activity (Higley et al 1992), and a phase shift in the HPA circadian rhythm has also been proposed (Boyce et al 1995). Nursery-reared macaques demonstrate reduced basal cerebrospinal fluid (CSF) norepinephrine relative to mother-reared macaques Kraemer 1992, Kraemer et al 1989. Peer-reared macaques, in contrast, demonstrate increased basal CSF norepinephrine relative to mother-reared control macaques; stress-induced levels of CSF norepinephrine and metabolites were reduced, as were basal serotonin and dopamine metabolites Clarke et al 1996, Higley et al 1992. The chronic behavioral consequences of maternal privation include self-clutching, stereotyped body rocking, deficiencies in social behavior, and affective flattening Gandelman 1992, Kraemer 1992, Paul et al 2000.
Primate studies that have used repeated infant–mother separations have been performed with mature, semi-independent infants, for example in 3–7-month-old squirrel monkeys Coe et al 1983, Hennessy 1986 and 6-month-old rhesus macaques (Hinde and McGinnis 1977). These mature infants demonstrate a cortisol stress response to each separation, whereas distress vocalization decreases markedly across separations. Reunited infants spend more time in contact with the mother and less time playing. Repeated deprivation of 5 hours per week in 3–5-month-old squirrel monkeys led to increased glucocorticoid feedback sensitivity in adulthood (Lyons et al 2000).
Another approach used in primates is manipulation of maternal care received by mature infants via varying the feeding demands on the mother. When tested as young adults, bonnet macaque offspring of mothers exposed to unpredictable foraging demands exhibited elevated basal corticotropin-releasing factor levels in the CSF, increased noradrenergic and blunted serotonergic responses, and depression-like behavior, including reduced social inter-actions Rosenblum and Andrews 1994, Rosenblum et al 1994. Using the correlational approach, it has been demonstrated that the primate offspring of less responsive parents demonstrate higher stress reactivity Dettling et al 1998, Gunnar et al 1981.
To our knowledge, there has been no attempt to date to develop a repeated early deprivation procedure, such as that conducted with rat pups, in a nonhuman primate. Here we describe a study in which we successfully conducted daily ED across the first month of life in the common marmoset (Callithrix jacchus). This is a small-bodied neotropical primate that in terms of reproduction is characterized by twinning and biparental care (Pryce 1993). In contrast to rat pups, marmoset infants are in continuous body contact (i.e., being carried) with a caregiver for 24 hours per day throughout the first 2–3 weeks of life Ingram 1977, Pryce 1993, such that even a short period of ED is a nonbiological event. Further to the description and validation of ED per se, we describe some of the early effects of this manipulation in terms of stress-related endocrine responses to ED and infant–parent behavior in the family group.
Section snippets
Subjects and husbandry
This study was conducted under experimental permit in accordance with the Animal Protection Act (1978), Switzerland. Seven established breeding pairs of common marmosets each contributed two sets of twin offspring, which were the subjects of this study. Each study group comprised the breeding female, breeding male, and the study twin infants only. No previous offspring were present, and the first set of twins per group was euthanized (aged 1 year) before the birth of the second set. These
Results
Infants vocalized considerably during ED, primarily with the distress vocalization that they emit in the home cage in response to parental aggression and also with the long call that is emitted by all age groups in this species and functions to advertise location. We had the clear impression that the amount of time that infants spent vocalizing during ED decreased with age and repeated ED exposure. Early deprivation infant vocalizations were not audible to marmosets in the main colony rooms,
Discussion
The present study has demonstrated that repeated early deprivation, a postnatal environmental manipulation developed in the rat, can be applied to at least one nonhuman primate species, the common marmoset monkey. Primate studies based on repeated ED will represent an important complement to the rat ED studies, for investigation into the short-term and long-term effects of continuous disruption of the early infant–parent relationship on neurobehavioral maturation and development. Given the
Acknowledgements
This research was supported by the Swiss National Science Foundation, Grant No. 31–55618.98 (to CRP).
We are grateful to Jacqueline Kupper and Jeanne von Arx for veterinary care and husbandry, and Nina Nanz-Bahr and Corinne Späte for technical assistance.
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