Primate early life stress leads to long-term mild hippocampal decreases in corticosteroid receptor expression.

BACKGROUND: Expression of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) genes are moderately reduced in several brain regions in depression. These reductions could be partly due to early life stress (ELS), which predicts emotional disorders. Controlled primate studies are important to test whether ELS sufficient to induce long-term emotional changes also induces long-term altered MR and/or GR brain expression. METHODS: In the common marmoset, ELS of daily 30-120-min social isolation across month-1 resulted in some long-term changes in homeostasis and emotional behavior. In some of these same subjects, the aim of this study was to use marmoset-specific riboprobes to determine whether ELS produced long-term effects on brain MR and GR gene expression. RESULTS: At adolescence, relative to control subjects, ELS marmosets exhibited mildly reduced messenger RNA signal for both MR (-15%, p = .05) and GR (-13%, p = .02) in hippocampus-primarily CA1-2-but not in prefrontal cortex, other cortical regions, or hypothalamus. CONCLUSIONS: In adolescent marmoset monkey brains, reduced hippocampal expression of MR and GR are consistent chronic-indicators of ELS. It is unlikely that these chronic, mild, specific reductions were acute-mediators of the observed long-term emotional effects of ELS. However, they do suggest involvement of hippocampal MR/GR in the neurodevelopmental effects of ELS.

Behavioral and physiological effects of an infant-neglect manipulation in a bi-parental, twinning primate: impact is dependent on familial factors.

Experimental animal studies and epidemiological and clinical human studies demonstrate that atypical infant-caregiving can exert short- and long-term effects on offspring phenotype, including increased long-term risk of affective disorders. Whilst the early environment is therefore a major determinant of behavioral, physiological and neurobiological phenotypes, the effects of early adversity exhibit individual variation, presumably due to differences in environment-genotype interactions. Twin studies provide a powerful model with which to study such interactions. However, human twin studies rarely include analysis of genotype-environment interactions or of individuals exposed to extreme environments, and rat studies have rarely attempted to utilize littermates (i.e. dizygotic twins) to investigate environment-genotype interactions. Here, we report on the effects of repeated deprivation of caregiving in the common marmoset, a primate that exhibits dizygotic twinning and bi-parental care. Breeding pairs each contributed early deprived (ED) twins and control (CON) twins, thereby allowing for the study of effects of ED, parentage and ED-parentage interaction. Significant ED x parentage interaction effects were obtained for basal urinary, plasma and cerebrospinal-fluid cortisol titers (infancy-adolescence), and basal levels of social and maintenance behaviors (juveniles); basal urinary cortisol titers during a 2-week period of repeated psychosocial challenge (juveniles), and social and exploratory behavior during psychosocial challenge (juveniles). Significant main effects of ED were obtained for: basal levels of time spent in contact with parents (ED>CON; juveniles) and in locomotor activity (EDCON; juveniles); time spent in locomotor activity (EDCON) during psychosocial challenge (juveniles). This study provides evidence for long-term effects of early environment on bio-behavioral traits and states in marmosets specifically, and the importance of including parental factors in developmental studies in mammals generally.

Long-term effects of early-life environmental manipulations in rodents and primates: Potential animal models in depression research.

Depression is one of the most common human illnesses and is of immense clinical and economic significance. Knowledge of the neuro-psychology, -biology and -pharmacology of depression is limited, as is the efficacy of antidepressant treatment. In terms of depression aetiology, whilst the evidence for causal mechanisms is sparse, some genomic and environmental factors associated with increased vulnerability have been identified. With regards to the latter, the environments in which human infants and children develop are fundamental to how they develop, and parental loss, emotional and physical neglect, and abuse have been shown to be associated with: traits of depression, traits of predisposition to depression triggered by subsequent life events, and associated physiological abnormalities, across the life span. Studies of postnatal environmental manipulations in rodents and primates can potentially yield evidence that abnormal early-life experience leading to dysfunction of the neurobiology, physiology and behaviour of emotion is a general mammalian characteristic, and therefore, that this approach can be used to develop animal models for depression research, with aetiological, face, construct and predictive validity. The establishment of models with such validity, if at all achievable, will require a sophisticated combination of (1) appropriate postnatal manipulations that induce acute stress responses in the infant brain which in turn lead to long-term neurobiological consequences, and (2) appropriate behavioural and physiological assays to identify and quantify any depression-like phenotypes resulting from these long-term neurobiological phenotypes. Here, we review some of the evidence-positive and negative-that neglect-like environments in rat pups and monkey infants lead to long-term, depression-like behavioural traits of reduced motivation for reward and impaired coping with adversity, and to altered activity in relevant physiological homeostatic systems.

Deprivation of parenting disrupts development of homeostatic and reward systems in marmoset monkey offspring.

BACKGROUND: Early environment is a major determinant of long-term mental health, evidenced by the relationship between early-life neglect or abuse and chronically increased vulnerability to developmental psychopathology, including major depressive disorder (MDD). Animal studies can increase understanding of environmentally mediated causal risk processes. We describe how daily deprivation of biological parenting in primate infants disrupts development of homeostatic and reward systems central to MDD. METHODS: Nine breeding pairs of marmoset monkeys provided control twins (CON) and early-deprived twins (ED); the latter were socially isolated for 30-120 min/day on days 2-28. During the first year of life, basal urinary norepinephrine (NE) titers and cardiophysiologic activity were measured. At the end of year 1 (adolescence), automated neuropsychologic tests were conducted to measure responsiveness to changes in stimulus-reward association (simple/reversed visual discrimination learning) and to reward per se (progressive ratio [PR] reinforcement schedule). RESULTS: The ED monkeys exhibited increased basal urinary NE titers and increased systolic blood pressure relative to CON siblings. The ED monkeys required more sessions to reinstate stimulus-oriented behavior following reversal, suggesting increased vulnerability to perceived loss of environmental control; ED monkeys also performed less PR operant responses, indicating that reward was less of an incentive and that they were mildly anhedonic relative to CON. CONCLUSIONS: In marmoset monkeys, neglect-like manipulation of ED leads to chronic changes in homeostatic systems, similar to those in children and adolescents exposed to early-life adversity and in MDD, and to responses to environmental stimuli similar to those that characterize MDD.

Performance of the marmoset monkey on computerized tasks of attention and working memory.

The CAmbridge Neuropsychological Test Automated Battery (CANTAB) is a computerised battery of neuropsychological tests presented as stimuli on a touch-sensitive computer screen that has been used to assess a wide range of cognitive functions in neuropsychiatric patients, healthy volunteers, and species of non-human primate, primarily the rhesus macaque. The common marmoset is a small-bodied, tractable simian primate that breeds well under laboratory conditions. This primate has been quite extensively studied in terms of its abilities and limitations with respect to appetitive cognitive conditioning. However, the CANTAB versions of sustained/divided attention and working memory tasks have to-date not been studied in the marmoset. Here we describe adult marmoset performance on the CANTAB five-choice serial reaction time task, a delayed match-to-position task, and a task derived from the CANTAB visuo-spatial paired associates learning task that constituted two, concurrent delayed match-to-position tasks. The acquisition and stable longitudinal performance of these tasks provide strong evidence that the marmoset, in addition to the macaque, can be the species of choice for CANTAB-based drug and lesion studies of cognitive function, using tasks similar to those deployed in the study of human cognition and diagnosis of neuropsychiatric disorders.

Repeated parental deprivation in the infant common marmoset (Callithrix jacchus, primates) and analysis of its effects on early development.

BACKGROUND: We describe a successful demonstration that repeated early deprivation of parental care (ED), as used to study effects of early life stress in rats, can be performed in a primate and that it constitutes an early life stressor. METHODS: Seven breeding pairs of marmoset monkeys each provided control twins (CON) and twins that were subjected to ED for 30-120 min/day on postnatal days (PND) 2-28. Urine samples were obtained to monitor the acute effect of ED on cortisol and catecholamine levels. Behavior samples were obtained in the home cage to monitor the effects of ED on infant and infant-parent behavior. RESULTS: Early deprivation of parental care caused acute increases in cortisol, epinephrine, and norepinephrine. At PND 28, basal cortisol was reduced in ED compared with CON infants, and ED infants were smaller than CON infants. Early deprivation infants tended to spend more time in the suckling position than did CON. Early deprivation infants demonstrated more distress vocalization than CON infants, even though the parental care they received in the home cage was similar. Early deprivation infants tended to play less socially than did CON. CONCLUSIONS: To our knowledge, this is the first demonstration that a repeated early life stressor of the type developed in rats can also be applied to a primate species.

Early life stress: long-term physiological impact in rodents and primates.

Rat, monkey, and human infants have evolved to expect certain patterns of care. Spontaneous or experimental deviations of care from the norm result in infant stress responses. Hyperactivity of immature stress systems such as the limbic-hypothalamic-pituitary-adrenal axis and the limbic-sympatho-adrenomedullary axis can alter their subsequent reactivity across the life span.

Early deprivation and behavioral and physiological responses to social separation/novelty in the marmoset.

Long-term effects of adverse early environment on neurobehavioral development have been reported for rodents and primates. The present study used daily early deprivation (ED), a paradigm developed for rats, for the first time in a nonhuman primate, the common marmoset, and investigated its effects on the behavioral and physiological responses to social separation/novelty (SSN) challenge tests in juveniles. On postnatal days (PNDs) 2-28, infants (n=5 twin pairs) were removed from the parents and placed alone in an isolation chamber for 30-120 min (9 h/week). Parents and control subjects (n=5 twin pairs) were briefly restrained (CON). At Weeks 18-20, behavioral responses of ED and CON juveniles to six 60-min SSN tests in an isolated cage, comprising 45 min alone and 15 min reunion with the father, were measured. Baseline and post-test urine samples were collected for measurement of cortisol. ED subjects exhibited significantly lower basal SSN urinary cortisol than CON, whilst SSN response cortisol values were similar in ED and CON. When alone, ED subjects were significantly less mobile and emitted significantly less contact calls than CON. Following reunion, ED subjects were significantly less in contact with or being carried by the father than CON and demonstrated significantly more tail piloerection. Although they require validation by additional parameters (e.g. cardiovascular), these data strongly suggest that early-life stress alters endocrine and behavioral responsiveness to psychosocial challenge in this primate and in a direction that could model important changes in disorders of human affective state.