Using cross-species comparisons and a neurobiological framework to understand early social deprivation effects on behavioral development.

Building upon the transactional model of brain development, we explore the impact of early maternal deprivation on neural development and plasticity in three neural systems: hyperactivity/impulsivity, executive function, and hypothalamic-pituitary-adrenal axis functioning across rodent, nonhuman primate, and human studies. Recognizing the complexity of early maternal-infant interactions, we limit our cross-species comparisons to data from rodent models of artificial rearing, nonhuman primate studies of peer rearing, and the relations between these two experimental approaches and human studies of children exposed to the early severe psychosocial deprivation associated with institutional care. In addition to discussing the strengths and limitations of these paradigms, we present the current state of research on the neurobiological impact of early maternal deprivation and the evidence of sensitive periods, noting methodological challenges. Integrating data across preclinical animal models and human studies, we speculate about the underlying biological mechanisms; the differential impact of deprivation due to temporal factors including onset, offset, and duration of the exposure; and the possibility and consequences of reopening of sensitive periods during adolescence.

Increased behavioral output but intact goal-directed and habitual responding for food reward following early-life social deprivation in rats.

Early-life social adversity, such as child neglect and institutionalized rearing, is associated with later-life difficulties of inhibitory control that may reflect altered attribution of salience to external stimuli. Studies in rats demonstrate that early-life social deprivation results in enhanced responsiveness to reward stimuli and conditioned reward cues. This study examined whether these effects are related to fundamental changes in appetitive conditioning processes involving instrumental goal-directed and habitual responding for food reward. Rats were reared either by the mother (maternal rearing; MR) or in complete isolation from the mother and litter (artificial rearing; AR) and tested as adults in two appetitive conditioning tasks. AR and MR rats did not differ in the amount of goal-directed effort they exerted to obtain food reward on progressive ratio schedules of reinforcement. AR and MR rats also did not differ in the shift from goal-directed to habitual responding on a random interval schedule and they were equally sensitive to changes in reward value. The major difference between AR and MR rats was that AR rats exhibited more non-instrumental responses (empty food magazine entries, ineffective lever presses). Thus, early-life social deprivation of rats through AR affects the expression of unreinforced extraneous behaviors when motivational requirements are high, but does not affect conditioned goal-directed and habitual responding to reward. The findings have implications for understanding what aspects of responsiveness to external stimuli may be selectively affected in disorders of inhibition associated with early-life social adversity.

Inadequate early social experience increases the incentive salience of reward-related cues in adulthood.

The mechanisms by which childhood abuse and/or neglect become risk factors for the development of drug addiction, problem gambling, and other disorders of behavioral inhibition are unknown. The loss of behavioral inhibition is often triggered by reward-related cues that acquire incentive salience. This study examined whether inadequate early-life social experience in rats affects the incentive salience of reward-related cues. Rats were deprived of early-life social experience with the mother and litter through artificial-rearing (AR). A group of AR rats (AR+STM) received additional tactile stimulation that mimicked maternal licking, a critical component of rat maternal care. Control rats were maternally reared (MR). The incentive salience attributed to a food cue was measured in adult rats using a conditioned approach task, where a conditional stimulus (CS; lever) was paired with food delivery, and in a conditional reinforcement task. The dependent measures were approach towards the CS (sign-tracking) versus approach towards the place of food delivery (goal-tracking) and instrumental responding for the CS. AR rats made significantly more sign-tracking responses than MR rats. AR rats also made more instrumental responses when reinforced with the CS. AR+STM rats' responses were intermediate to MR and AR rats. Thus, inadequate early-life social experience enhanced the incentive salience of a reward-related cue in adulthood. Replacement of maternal licking partially reversed this effect. These results highlight a potential link between early-life social adversity and susceptibility to disorders of behavioral inhibition.

Moderate prenatal alcohol exposure and serotonin genotype interact to alter CNS serotonin function in rhesus monkey offspring.

BACKGROUND: Moderate prenatal alcohol exposure can contribute to neurodevelopmental impairments and disrupt several neurotransmitter systems. We examined the timing of moderate level alcohol exposure, serotonin transporter gene polymorphic region variation (rh5-HTTLPR), and levels of primary serotonin and dopamine (DA) metabolites in cerebrospinal fluid (CSF) in rhesus monkeys. METHODS: Thirty-two 30-month old rhesus monkeys (Macaca mulatta) from 4 groups of females were assessed: (i) early alcohol-exposed group (n = 9), in which mothers voluntarily consumed 0.6 g/kg/d alcohol solution on gestational days 0 to 50; (ii) middle-to-late gestation alcohol-exposed group (n = 6), mothers consumed 0.6 g/kg/d alcohol solution on gestational days 50 to 135; (iii) a continuous-exposure group (n = 8), mothers consumed 0.6 g/kg/d alcohol solution on gestational days 0 to 135; and (iv) controls (n = 9), mothers consumed an isocaloric control solution on gestational days 0 to 50, 50 to 135, or 0 to 135. Serotonin transporter promoter region allelic variants (homozygous s/s or heterozygous s/l vs. homozygous l/l) were determined. We examined CSF concentrations of the 5-HT and DA metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), respectively, at baseline and 50 hours after separation from cage-mates, when the monkeys were 30 months old. RESULTS: Early- and middle-to-late gestation-alcohol exposed monkeys carrying the short allele had lower concentrations of 5-HIAA in CSF relative to other groups. Concentrations of 5-HIAA in CSF were lower for s allele carriers and increased from baseline relative to pre-separation values, whereas 5-HIAA levels in l/l allele carriers were not affected by separation. Monkeys carrying the short allele had lower basal concentrations of HVA in CSF compared with monkeys homozygous for the long allele. CONCLUSION: Carrying the s allele of the 5-HT transporter increased the probability of reduced 5-HIAA in early- and middle-to-late gestation alcohol-exposed monkeys and reduced HVA at baseline. These findings that prenatal alcohol exposure altered central 5-HT activity in genetically sensitive monkeys raise questions about whether abnormal serotonin biological pathways could underlie some of the psychiatric disorders reported in fetal alcohol spectrum disorder.

Interactions between the effects of early isolation rearing and complex housing on adult locomotor activity and sensitivity to amphetamine in rats involve noradrenergic neurotransmission.

Increased sensitivity to the locomotor-activating effects of amphetamine in rats with a history of early-life social isolation is commonly attributed to alteration of the dopamine system. The locomotor response to amphetamine may also be due to effects on the noradrenergic system and particularly alpha-adrenergic receptors. The present study examined whether noradrenergic neurotransmission mediates the increased sensitivity to the locomotor effects of amphetamine resulting from early social isolation and whether this effect can be reversed by later-life social housing experience. Rats reared in complete social isolation (artificially reared, AR) exhibited higher levels of locomotor activity than maternally reared (MR) rats in response to amphetamine (0.25mg/kg). Increased sensitivity to the locomotor effects of amphetamine in AR rats was reduced by the alpha-adrenergic receptor antagonist prazosin (0.5mg/kg). Prazosin alone reduced activity in AR rats to the level of MR rats. Group housing in cages that were more complex than standard laboratory cages reduced activity in both AR and MR rats. Group housing did not decrease the sensitivity of AR rats to the locomotor effects of either amphetamine or prazosin. Differences in activity between rats in standard and complex housing conditions were not altered by drug treatments. These findings indicate that pre-weaning social experience alters the responsiveness of the noradrenergic system to drug challenges, whereas post-weaning housing experience may not, even though ongoing activity is affected. Increased activity and sensitivity to amphetamine resulting from social isolation in early life may be mediated by changes in noradrenergic alpha-receptor mediated neurotransmission.

Pilot study investigating infant vagal reactivity and visual behavior during object perception.

OBJECTIVE: The authors examined whether changes in vagal tone were related to infant visual attention during auditory and visual events paired (synchronous) and not paired (asynchronous) in time. They predicted that infants would demonstrate greater visual attention to the synchronous slideshow and that vagal tone would decrease with visual attention. METHOD: Nineteen infants, 3.5 months old, watched computer-generated synchronous or asynchronous slideshows of auditory and visual stimuli. Visual behavior and vagal tone data were collected. Vagal tone reflects physiological responses during attention or exposure to mild stressors. Repeated-measures analysis of variance examined differences in vagal tone across conditions. RESULTS: Visual behavior did not differ between the synchronous and asynchronous slideshow conditions. Vagal tone was significantly lower during the asynchronous slideshow. CONCLUSION: Infants may discriminate synchronous from asynchronous stimuli without changing visual behavior. Implications related to play with toys or objects are discussed.

Moderate level fetal alcohol exposure and serotonin transporter gene promoter polymorphism affect neonatal temperament and limbic-hypothalamic-pituitary-adrenal axis regulation in monkeys.

BACKGROUND: A length polymorphism in the serotonin (5-HT) transporter gene promoter region in humans and rhesus monkeys affects functional characteristics of the brain 5-HT system. Prenatal alcohol exposure (FA-exposure) can have an impact on brain and psychosocial development that could interact with genetic endowment. This study determined whether moderate FA-exposure interacts with polymorphism in the 5-HT transporter gene to increase the incidence or severity of fetal alcohol effects in rhesus monkeys. METHODS: The offspring of monkeys who did or did not consume moderate amounts of alcohol during pregnancy were assessed for temperament as neonates and adrenocorticotropic hormone (ACTH) and cortisol (CORT) in response to mother-infant separation at 6 months of age. Serotonin promoter region genotypes (homozygous s/s or heterozygous s/l versus homozygous l/l) were determined. RESULTS: Prenatal alcohol exposed carriers of the s allele exhibited increased neonatal irritability and increased ACTH and CORT compared with FA-exposed monkeys homozygous for the l allele and monkeys that were not FA-exposed regardless of genotype. CONCLUSIONS: The s allele of the 5-HT transporter increases the probability of neonatal irritability and increased stress responsiveness in FA-exposed monkeys, and this gene-environment interaction may affect psychosocial development. It is probable that FA-exposure contributes to 5-HT transporter gene-environment interactions in humans.

Moderate-level prenatal alcohol exposure alters striatal dopamine system function in rhesus monkeys.

BACKGROUND: Moderate prenatal alcohol exposure can cause impairments even in the absence of gross morphological defects associated with fetal alcohol syndrome. The basal ganglia, which include the dopamine-rich striatum, are sensitive to fetal alcohol-induced injury. In this study, we manipulated the timing of moderate-level alcohol exposure and compared the risk of adverse effects on striatal dopamine (DA) system function in rhesus monkeys. METHODS: Thirty-five young adult rhesus monkeys (Macaca mulatta) from four groups of females were assessed: (1) an early alcohol-exposed group (n=9), in which mothers voluntarily consumed 0.6 g/kg alcohol solution on gestational days 0 through 50; (2) a middle-to-late gestation alcohol-exposed group (n=7), in which mothers voluntarily consumed 0.6 g/kg alcohol solution on gestational days 50 through 135; (3) a continuous-exposure group (n=9), in which mothers voluntarily consumed 0.6 g/kg alcohol solution on days 0 through 135; and (4) controls (n=10), in which mothers voluntarily consumed an isocaloric control solution on gestational days 0 through 50, 50 through 135, or 0 through 135. We studied striatal DA system function by positron emission tomography in separate scans for trapping of [(18)F]fallypride and 6-[(18)F]fluoro-m-tyrosine to assess striatal DA D2 receptor (D2R) binding and DA synthesis, respectively, via dopadecarboxylase activity. RESULTS: Moderate-level alcohol exposure during early gestation and continuous exposure throughout gestation (early + middle-to-late exposure) reduced the striatal D2R binding to DA synthesis ratio, whereas middle-to-late alcohol gestation exposure increased the striatal D2R binding to DA synthesis ratio. The continuous-exposure group showed the largest effect. Moreover, the D2R binding/DA synthesis ratio was related to neonatal neurobehavior measures in control monkeys, but these relationships were disrupted in the fetal alcohol-exposed monkeys. CONCLUSION: These results suggest that the vulnerability of the DA system to the effects of moderate doses of alcohol during gestation depend on the timing of the alcohol exposure. Early-gestation moderate alcohol exposure resulted in a reduction or blunting of dopaminergic function in adulthood, whereas middle to late exposure (without early exposure) either induced the opposite pattern or heightened dopaminergic function. Continuously exposed monkeys showed the largest effect, suggesting that the sooner women stop drinking, the better it is for the fetus.

The psychobiological theory of attachment: a viable frame of reference for early intervention providers.

Psychobiological Attachment Theory (PAT) (Kraemer, 1992) provides a way of thinking about caregiver-infant relationships for use in clinical practice. This manuscript describes how the theory translates into a frame of reference that can be used in practice within the context of natural environments. A discussion of the theoretical base, function/dysfunction criteria, postulates regarding change, and presentation of an evaluation guide, provides a practical tool for use in early intervention practice.

Moderate level alcohol during pregnancy, prenatal stress, or both and limbic-hypothalamic-pituitary-adrenocortical axis response to stress in rhesus monkeys.

This study examined the relationship between moderate-level prenatal alcohol exposure, prenatal stress, and postnatal response to a challenging event in 6-month-old rhesus monkeys. Forty-one rhesus monkey (Macaca mulatta) infants were exposed prenatally to moderate level alcohol, maternal stress, or both. Offspring plasma cortisol and adrenocorticotrophic hormone (ACTH) were determined from blood samples before maternal separation and after separation. Behavioral observations were made repeatedly across separation. Moderate-level prenatal alcohol exposure was associated with significantly higher plasma ACTH response to maternal separation. Offspring exposed to prenatal alcohol, prenatal stress, and prenatal alcohol and stress showed reduced behavioral adaptation to stress compared with controls. Baseline, 2-hr, and 26-hr plasma ACTH levels were intercorrelated and predicted behavior during separation.

Mothering begets mothering: the transmission of behavior and its neurobiology across generations.

Early experiences exert their effects on adult parental behavior in part by altering the development of neurobiological mechanisms that initiate or support the initiation and sustenance of adult parental behavior. The effects of parental behavior on sensory, perceptual and emotional mechanisms in offspring constitute an experientially based mechanism by which neurobiological factors regulating behavior can be transferred from generation to generation somewhat independently of genetic endowment.

The impact of prenatal stress, fetal alcohol exposure, or both on development: perspectives from a primate model.

The question of whether psychosocial stress during pregnancy (alone or in combination with fetal alcohol exposure) has negative consequences for offspring has not been clearly established in human studies. In this article, we present an overview of three prospective longitudinal studies. Using rhesus monkeys as subjects, a noise or hormone stressor, alone or in combination with moderate level alcohol solution, was presented daily during different stages of pregnancy. Prenatal stress resulted in lighter birth weights in two of three studies, and males from the alcohol plus noise stress condition had reduced birth weights. There were no significant effects of any of the prenatal treatments on gestation duration. Both prenatal stress and moderate fetal alcohol exposure reduced attention span and neuromotor capabilities of offspring during the first month of life, while early gestation prenatal stress, during the period of neuronal migration, emerged as a period of enhanced vulnerability for these effects. Under conditions of challenge, prenatally stressed monkeys showed more disturbance behaviors and reduced locomotion and exploration as well as altered hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. Fetal alcohol exposed monkeys also showed increased HPA axis activity in response to stressful conditions. Finally, altered patterns of alcohol consumption during adolescence were associated with prenatal stress.

Assessment of glucoregulation in rhesus monkeys sedated with ketamine.

Glucose, insulin, and cortisol were measured in the blood of rhesus monkeys under several conditions. Glucose and insulin concentrations were higher and cortisol lower shortly after the morning meal than after an overnight fast. Ketamine had no detectable effect on basal (fasting) glucose or insulin values in normal monkeys, even when sedation was maintained for more than 2 h. Ketamine did not appear to affect the response to a glucose load or to insulininduced hypoglycemia. It is concluded that ketamine is a useful agent for pharmacological restraint of rhesus monkeys during studies of glucoregulation.