Understanding behavioral effects of early life stress using the reactive scope and allostatic load models

The mechanisms through which early life stress leads to psychopathology are thought to involve allostatic load, the "wear and tear" an organism is subjected to as a consequence of sustained elevated levels of glucocorticoids caused by repeated/prolonged stress activations. The allostatic load model described this phenomenon, but has been criticized as inadequate to explain alterations associated with early adverse experience in some systems, including behavior, which cannot be entirely explained from an energy balance perspective. The reactive scope model has been more recently proposed and focuses less on energy balance and more on dynamic ranges of physiological and behavioral mediators. In this review we examine the mechanisms underlying the behavioral consequences of early life stress in the context of both these models. We focus on adverse experiences that involve mother-infant relationship disruption, and dissect those mechanisms involving maternal care as a regulator of development of neural circuits that control emotional and social behaviors in the offspring. We also discuss the evolutionary purpose of the plasticity in behavioral development, which has a clear adaptive value in a changing environment.     

The effect of adverse intrauterine and newborn environments on cognitive development: the experiences of premature delivery and diabetes during pregnancy

The prenatal and early postnatal periods constitute a time of rapid development when the brain is in a state of both heightened plasticity and vulnerability. Premature infants and infants of diabetic mothers represent two experiments of nature that allow researchers to observe how the developing brain responds to early biological challenge of either a global or regionally specific nature. We outline a set of organizing principles for conceptualizing the mechanisms by which early adverse experience may be encoded in the brain and subsequently expressed in behavior. We then review the available literature on developmental outcomes for infants born premature and infants of diabetic mothers. Research examining the relative influence of experience and maturation in the development of preterm infants indicates that advance experience does not accelerate the advent of specific cognitive capacities, but may enhance performance once the particular ability has emerged. Long-term follow-up of preterm infants also reveals evidence for plasticity and cognitive improvement into early adolescence for later maturing executive functions. Finally we offer an integrated model for investigating cognitive outcomes in infants of diabetic mothers that incorporates data from animal, electrophysiological, and behavioral measures.     

Differential emotional experience induces elevated spine densities on basal dendrites of pyramidal neurons in the anterior cingulate cortex of Octodon degus.

It appears likely that, in analogy to the synaptic development of sensory and motor cortices, which critically depends on sensory or motor stimulation (Rosenzweig and Bennett, 1996), the synaptic development of limbic cortical regions are modulated by early postnatal cognitive and emotional experiences. The very first postnatal experience, which takes place in a confined and stable familial environment, is the interaction of the newborn individual with the parents and siblings (Gray, 1958). The aim of this quantitative morphological study was to analyze the impact of different degrees of juvenile emotional experience on the synaptic development in a limbic cortical area, the dorsal anterior cingulate cortex, a region which is involved in the perception and regulation of emotions. We study the precocious trumpet-tailed rat (Octodon degus) as the animal model, because, like human babies, this species is born with functional visual and acoustic systems and the pups are therefore capable of detecting even subtle environmental changes immediately after birth (Reynolds and Wright, 1979; Poeggel and Braun, 1996; Braun et al., 2000; Ovtscharoff and Braun, 2001). The results demonstrate that already a subtle disturbance of the familial environment such as handling induced significantly elevated spine densities on the basal dendrites of layer III cortical pyramidal neurons. More severe disturbances of the emotional environment, such as periodic parental deprivation with or without subsequent chronic social isolation, resulted in an elevation of spine densities of similar magnitude as seen after handling and in addition, altered spine densities confined to specific dendritic segments were observed in these groups. These observations unveil the remarkable sensitivity of the dorsal anterior cingulate cortex towards environmental influences and behavioral experiences during phases of postnatal development. The behavioral consequences of these experience-induced synaptic changes still need to be analyzed further to assess if they are beneficial or detrimental to the animals cognitive and emotional capacities in later life.     

The effects of neonatal stress on brain development: implications for psychopathology.

Recent studies have focused on the behavioral and neurobiological sequella of exposure to early adverse events. We hypothesize that early adverse experiences result in an increased sensitivity to the effects of stress later in life and render an individual vulnerable to stress-related psychiatric disorders. This vulnerability may be mediated by persistent changes in corticotropin-releasing-factor (CRF)-containing neurons, the hypothalamic-pituitary-adrenal axis, and the sympathetic nervous system. We therefore present an overview of the CRF system and its role as a mediator in the development of the stress response, major depression, and posttraumatic stress disorder. The literature pertaining to behavioral and neurobiological alterations associated with exposure to early adverse life events in rodents, nonhuman primates, and humans is reviewed. We focus on animal models that precipitate depressive and anxiety symptoms while producing neuroendocrine alterations that mimic those seen in adults with those disorders. The literature integrating neurobiological and behavioral consequences of early life stress is also reviewed, focusing primarily on infants born to mothers with depression and on infants who were abused or neglected.     

Effects of polychlorinated biphenyls on maternal odor conditioning in rat pups

Polychlorinated biphenyls (PCBs) are pervasive environmental contaminants that can have damaging effects on physiologic, motoric and cognitive function. Results from studies on PCBs and behavior have shown that exposure can alter learning and memory processes and that these shifts in cognitive abilities can be related to changes in hormonal and neural function. Little experimentation has been done on the impact of exposure to PCBs on social and emotional development. Previous work has shown that exposure to PCBs in children can alter play behavior. Importantly, exposure to PCBs has been found to change aspects of maternal-offspring interactions in rodents. The present study examined the impact of PCBs on maternal odor conditioning in rat pups 12-14 days of age. A modified version of the conditioned place preference paradigm was used that incorporated a maternal-associated odor cue (lemon scent) as the conditioned stimulus. PCBs significantly depressed the preference for the maternal-associated cue but did not impair discrimination for a novel odor. These effects could arise due to changes in the social dynamics between the dam and offspring after co-exposure to PCBs. For example, dams exposed to PCBs during gestation have been found to show elevated grooming directed towards pups exposed to PCBs. This change in maternal care can have dramatic effects on behavioral and hormonal systems in the developing rat pup. In conclusion, perinatal PCBs alter important social behaviors of both the mother and pup, and these alterations could have long-lasting effects on behavioral, cognitive and emotional development.     

Imbalance of immunohistochemically characterized interneuron populations in the adolescent and adult rodent medial prefrontal cortex after repeated exposure to neonatal separation stress

Experimental studies in various animal models have revealed convincing evidence that stressful experience during early developmental periods produces a variety of behavioral, neuroanatomical and endocrine alterations, which are reminiscent of human mental disorders such as depression and various types of anxiety disorders. Since these mental disorders are assumed to be associated with altered GABAergic inhibition in cortical and subcortical brain regions, the current study tested the hypothesis that early postnatal adverse emotional experience (separation stress) interferes with the establishment and functional maturation of distinct inhibitory interneuron populations in different subregions of the medial prefrontal cortex (mPFC) of the precocious rodent degu (Octodon degus). At the age around puberty early stressed animals displayed significantly lower densities of calbindin-D28k-immunoreactive interneurons in the anterior cingulate (down to 79%) and in the precentral medial (down to 64%) subregions of the mPFC compared with age-matched unstressed controls. At this age the densities of two other interneuron types characterized by their expression of the calcium-binding proteins parvalbumin or calretinin remained at control levels. In adulthood, i.e. after an extended period without stress exposure, the density of calbindin-D28k-immunoreactive interneurons in the stressed animals was back to control numbers, whereas parvalbumin-immunoreactive interneurons displayed significantly elevated density in the anterior cingulate (up to 138%) and in the precentral medial cortex (up to 137%) of the stressed animals. In both age groups the density of calretinin- and corticotropin releasing hormone-immunoreactive interneurons did not differ between stressed and control animals, and the prelimbic and infralimbic subregions of the medial prefrontal cortex remained unaffected by stress experience. These results confirm that early adverse emotional experience induces long lasting age-, region- and neuron-specific imbalance of inhibitory systems in some, but not all subregions of the medial prefrontal cortex of the degu.     

Behavioral and neural representation of emotional facial expressions across the lifespan

Humans' experience of emotion and comprehension of affective cues varies substantially across the lifespan. Work in cognitive and affective neuroscience has begun to characterize behavioral and neural responses to emotional cues that systematically change with age. This review examines work to date characterizing the maturation of facial expression comprehension, and dynamic changes in amygdala recruitment from early childhood through late adulthood while viewing facial expressions of emotion. Recent neuroimaging work has tested amygdala and prefrontal engagement in experimental paradigms mimicking real aspects of social interactions, which we highlight briefly, along with considerations for future research.     

Sleep,Circadian Rhythms,and Risk Across Health Domains in Adolescents With an Evening Circadian Preference

Sleep and circadian rhythm changes during adolescence contribute to increased risk across emotional, behavioral, cognitive, social, and physical health domains. This study examines if sleep and dim light melatonin onset (DLMO) are related to greater risk in these 5 health domains. Participants were 163 (93 female, age = 14.7 years) adolescents with an evening circadian preference from a study funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Sleep and circadian measures included weekday total sleep time (TST), bedtime, and shut-eye time assessed via sleep diary, the Children’s Morningness–Eveningness Preferences scale, and DLMO. Health domains included self-reported emotional, cognitive, behavioral, social, and physical health. Later DLMO was significantly associated with shorter weekday TST, later weekday bedtime, and later weekday shut-eye time, as well as lower risk in the behavioral domain. At the trend level, later DLMO was related to fewer physical health problems. Earlier DLMO combined with a later bedtime, later shut-eye time, or shorter TST predicted greater risk in the cognitive domain. Later DLMO and shorter TST or a later bedtime predicted worse physical health. DLMO timing was not related to the emotional or social domain. There is evidence that a discrepancy between sleep behaviors and the endogenous circadian rhythm may be related to risk in the cognitive domain for adolescents with an evening circadian preference. Preliminary evidence also indicated that a delayed DLMO and shorter TST or a later bedtime may be related to vulnerability to physical health risk.     

Experimental dissociation of behavioral and cardiovascular outcome in the borderline hypertensive rat

F1 Offspring of hypertensive and normotensive rats (BHR) were reared with either hypertensive (SHR) or normotensive (WKY) cagemates, and observations were conducted at two developmental periods to assess the effects of rearing condition on the social environment and the behavior of BHR subjects. SHR displayed significantly more agonistic behavior during development than WKY, and BHR subjects reared with SHR were the targets of significantly more agonistic behavior than BHR subjects reared with WKY cagemates. BHR reared with SHR initiated twice as much agonistic behavior as BHR reared with WKY. When heart rate and blood pressure were assessed at 75-80 days of age, however, neither the alterations in developmental social environment nor the alterations in the behavioral characteristics of BHR were associated with differences in cardiovascular variables. The results do not support a causal connection between behavioral characteristics and cardiovascular outcome.     

Does Cognitive Impairment Explain Behavioral and Social Problems of Children with Neurofibromatosis Type 1?

Thirty NF1-patients (mean age 11.7 years, SD = 3.3) and 30 healthy controls (mean age 12.5 years, SD = 3.1) were assessed on social skills, autistic traits, hyperactivity-inattention, emotional problems, conduct problems, and peer problems. Cognitive control, information processing speed, and social information processing were measured using 5 computer tasks. GLM analyses of variance showed significant group differences, to the disadvantage of NF1-patients, on all measures of behavior, social functioning and cognition. General cognitive ability (a composite score of processing speed, social information processing, and cognitive control) accounted for group differences in emotional problems, whereas social information processing accounted for group differences in conduct problems. Although reductions were observed for group differences in other aspects of behavior and social functioning after control for (specific) cognitive abilities, group differences remained evident. Training of cognitive abilities may help reducing certain social and behavioral problems of children with NF1, but further refinement regarding associations between specific aspects of cognition and specific social and behavioral outcomes is required.     

Social isolation and chronic handling alter endocannabinoid signaling and behavioral reactivity to context in adult rats

Social deprivation in early life disrupts emotionality and attentional processes in humans. Rearing rats in isolation reproduces some of these abnormalities, which are attenuated by daily handling. However, the neurochemical mechanisms underlying these responses remain poorly understood. We hypothesized that post-weaning social isolation alters the endocannabinoid system, a neuromodulatory system that controls emotional responding. We characterized behavioral consequences of social isolation and evaluated whether handling would reverse social isolation-induced alterations in behavioral reactivity to context and the endocannabinoid system. At weaning, pups were single or group housed and concomitantly handled or not handled daily until adulthood. Rats were tested in emotionality- and attentional-sensitive behavioral assays (open field, elevated plus maze, startle and prepulse inhibition). Cannabinoid receptor densities and endocannabinoid levels were quantified in a separate group of rats. Social isolation negatively altered behavioral responding. Socially-isolated rats that were handled showed less deficits in the open field, elevated plus maze, and prepulse inhibition tests. Social isolation produced site-specific alterations (supraoptic nucleus, ventrolateral thalamus, rostral striatum) in cannabinoid receptor densities compared to group rearing. Handling altered the endocannabinoid system in neural circuitry controlling emotional expression. Handling altered endocannabinoid content (prefrontal and piriform cortices, nucleus accumbens) and cannabinoid receptor densities (lateral globus pallidus, cingulate and piriform cortices, hippocampus) in a region-specific manner. Some effects of social isolation on the endocannabinoid system were moderated by handling. Isolates were unresponsive to handling-induced increases in cannabinoid receptor densities (caudal striatum, anterior thalamus), but were sensitive to handling-induced changes in endocannabinoid content (piriform, prefrontal cortices), compared to group-reared rats. Our findings suggest alterations in the endocannabinoid system may contribute to the abnormal isolate phenotype. Handling modifies the endocannabinoid system and behavioral reactivity to context, but surmounts only some effects of social isolation. These data implicate a pivotal role for the endocannabinoid system in stress adaptation and emotionality-related disturbances.     

Cognitive Behavioral Psychotherapy With Older Adults

Cognitive behavioral psychotherapy is readily adaptable to use with older adults. This review integrates discussion of cognitive and behavioral intervention techniques with recent research and clinical observations in the field of gerontology. Cognitive changes with aging, personality and emotional development, cohort effects, and the social environment of older adults are discussed in relation to psychotherapy. Applications of cognitive behavior therapy to specific late-life problems such as chronic illness and disability, depression, alcoholism, and insomnia are presented. The effectiveness of cognitive and behavioral techniques in treating these disorders in older adults is discussed.     

Repeated cross-fostering affects maternal behavior and olfactory preferences in rat pups

Disturbances in early mother–infant relationships are strongly associated with changes in the development of a number of physiological and behavioral systems in the neonate that can create a complex change in patterns of vulnerability throughout life. Institutionalized children, despite receiving adequate care, display important behavioral changes in adult life, and such changes are strongly associated with a lack of selective and consistent attachment to the maternal figure in early life. It is not yet clear how human adoption processes alter the mother–infant relationship early in life. Here, to mimic the situation of human adoption and explore the impact on the formation of attachment between the infant and a caregiver, we use a repeated cross-fostering (RCF) model in rodents in two postnatal periods, postnatal days (PND) 1 to 3 (early RCF) and 9 to 11 (late RCF). Early exposure but not late exposure to RCF reduces the pups' preference for the odor of the mother figure. Moreover, early exposure and slightly later exposure to RCF reduce maternal care and motivation in collecting the pups and bringing them to the nest. The RCF protocol creates an unstable environment for mother–pup interaction, but it seems to affect learned attachment to the mother only when it occurs during the corresponding sensitive period of development.     

Aspects of social and emotional competence in adult attention-deficit/hyperactivity disorder

Social and emotional competence were evaluated using self-report and behavioral measures in adults with attention-deficit/hyperactivity disorder (ADHD) and controls. Adults with ADHD viewed themselves as less socially competent but more sensitive toward violations of social norms than controls. Films depicting emotional interactions were used to assess linguistic properties of free recall and perceived emotional intensity. Although adults with ADHD used more words to describe the scenes, they used fewer emotion-related words, despite rating the emotions depicted as more intense than did controls. In contrast, no group differences for words depicting social or cognitive processes were observed. Overall, adults with ADHD appear more aware of their problems in social versus emotional skills. Findings may have implications for improving the psychosocial functioning of these adults.     

Early experience and depressive disorders: human and non-human primate studies

This paper reviews evidence from both human and non-human primate studies concerning the role of early adverse experiences in the onset and course of adult depressive disorders. Despite accumulating evidence that stressful life events can play a major role in precipitating the onset of depressive episodes in humans, the mechanisms by which early experiences mediate and moderate the risk for later affective illnesses are not fully understood. Experimental paradigms in primates have documented the important role of undeveloped (social deprivation) or disrupted attachment systems (social separation). Effects of early social deprivation can be seen in many domains. Behavioral effects include repetitive idiosyncratic behaviors, increased self-directed behaviors, inappropriate expression of aggressive behaviors, non-modulated patterns of consumption, and inappropriate sexual and maternal behaviors. Cognitively, such animals require longer habituation time for any task and demonstrate increased perseverance on tasks following non-reward. Physiological effects include an altered hypothalamic-pituitary-adrenal response to stress, changes in diurnal temperature regulation, and alterations in immune function. Neurochemical effects include abnormalities in noradrenergic, serotonergic, and dopaminergic systems. Even neuroanatomical changes following early social deprivation have been reported. Studies with primates have also confirmed that early maternal and peer separations are major behavioral and neurobiological events with both short- and long-term consequences that parallel human depression. Future utilization of experimental paradigms in non-human primates may assist in better understanding the role of early experiences in predisposing to the development of affective illnesses in humans. This review concludes by presenting a model for understanding a developmentally based vulnerability to adult depressions.     

Implications for neurobiological research of cognitive models of psychosis: a theoretical paper

BACKGROUND: Cognitive models of the positive symptoms of psychosis specify the cognitive, social and emotional processes hypothesized to contribute to their occurrence and persistence, and propose that vulnerable individuals make characteristic appraisals that result in specific positive symptoms. METHOD: We describe cognitive models of positive psychotic symptoms and use this as the basis of discussing recent relevant empirical investigations and reviews that integrate cognitive approaches into neurobiological frameworks. RESULTS: Evidence increasingly supports a number of the hypotheses proposed by cognitive models. These are that: psychosis is on a continuum; specific cognitive processes are risk factors for the transition from subclinical experiences to clinical disorder; social adversity and trauma are associated with psychosis and with negative emotional processes; and these emotional processes contribute to the occurrence and persistence of psychotic symptoms. There is also evidence that reasoning biases contribute to the occurrence of delusions. CONCLUSIONS: The benefits of incorporating cognitive processes into neurobiological research include more sophisticated, bidirectional and interactive causal models, the amplification of phenotypes in neurobiological investigations by including emotional processes, and the adoption of more specific clinical phenotypes. For example, there is potential value in studying gene x environment x cognition/emotion interactions. Cognitive models and their derived phenotypes constitute the missing link in the chain between genetic or acquired biological vulnerability, the social environment and the expression of individual positive symptoms.     

Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson's disease

In addition to classic motor symptoms, Parkinson's disease (PD) is characterized by cognitive and emotional deficits, which have been demonstrated to precede motor impairments. The present study addresses the question of whether a partial degeneration of dopaminergic neurons using 6-hydroxydopamine (6-OHDA) in rats is able to induce premotor behavioral signs. The time-course of nigrostriatal damage was evaluated by tyrosine hydroxylase immunohistochemistry and the levels of dopamine, noradrenaline, and 5-HT in various brain regions were analyzed by high performance liquid chromatography (HPLC). Behavioral tests that assessed a variety of psychological functions, including locomotor activity, emotional reactivity and depression, anxiety and memory were conducted on 6-OHDA lesioned rats. Bilateral infusion of 6-OHDA in the striatum of rats caused early (1 week) damage of dopaminergic terminals in striatum and in cell bodies in substantia nigra pars compacta. The nigrostriatal lesion was accompanied by early loss of dopamine in the striatum, which remained stable through a 3-week period of observation. In addition, a late (3 weeks) loss of dopamine in the prefrontal cortex, but not in the hippocampus, was seen. Additional noradrenergic and serotonergic alterations were observed after 6-OHDA administration. The results indicated that 6-OHDA lesioned rats show decreased sucrose consumption and an increased immobility time in the forced swimming test, an anhedonic-depressive-like effect. In addition, an anxiogenic-like activity in the elevated plus maze test and cognitive impairments were observed on the cued version of the Morris water maze and social recognition tests. These findings suggest that partial striatal dopaminergic degeneration and parallel dopaminergic, noradrenergic and serotonergic alterations in striatum and prefrontal cortex may have caused the emotional and cognitive deficits observed in this rat model of early phase PD.     

Influence of parental deprivation on the behavioral development in Octodon degus: modulation by maternal vocalizations

Repeated separation from the family during very early stages of life is a stressful emotional experience which induces a variety of neuronal and synaptic changes in limbic cortical areas that may be related to behavioral alterations. First, we investigated whether repeated parental separation and handling, without separation from the family, leads to altered spontaneous exploratory behavior in a novel environment (open field test) in 8-day-old Octodon degus. Second, we tested whether the parentally deprived and handled animals display different stimulus-evoked exploratory behaviors in a modified open field version, in which a positive emotional stimulus, the maternal call, was presented. In the open field test a significant influence of previous emotional experience was found for the parameters of running, rearing, and vocalization. Parentally deprived degus displayed increased horizontal (running) and vertical (rearing) motoric activities, but decreased vocalization, compared to normal and handled controls. The presentation of maternal vocalizations significantly modified running, vocalization, and grooming activities, which in the case of running activity was dependent on previous emotional experience. Both deprivation-induced locomotor hyperactivity together with the reduced behavioral response towards a familiar acoustic emotional signal are similar to behavioral disturbances observed in human attachment disorders.     

Positive emotions: exploring the other hemisphere in behavioral medicine

The search for the psychological antecedents of medical disorders has focused on the role of stress and negative emotional states. Previous research in this area has investigated relations between negative emotions and physiological adaptations (e.g., blood pressure elevations), adverse health behaviors (e.g., smoking), and social conditions (e.g., social isolation). In this discussion, we argue that more attention is needed to understand the effects of positive emotional states on health enhancement and disease prevention. In each of the areas cited previously, evidence is beginning to emerge that indicates that positive emotions can be associated with health promoting conditions. Interventions using cognitive behavioral strategies or meditation can increase positive emotional states that are maintained over time and that may benefit health and well-being. Implications for behavioral medicine are discussed. This article is based on a presentation given by the first author at the International Congress of Behavioral Medicine, Helsinki, Finland, August 2002. This work was supported by grants R01 MH57233 (Margaret A. Chesney, principal investigator) and P30-MH62246 (Thomas J. Coates, principal investigator) from the National Institute of Mental Health. The authors thank Susan Folkman and Judith Moskowitz at the Osher Center for Integrative Medicine at the University of California, San Francisco, for their collaboration and guidance in the theoretical aspects of enhancing positive affect and meaning through coping effectiveness training (CET). We also thank the dedicated staff members and participants of the CET research trials.     

Multiple sensitive periods in human visual development: evidence from visually deprived children

Psychophysical studies of children deprived of early visual experience by dense cataracts indicate that there are multiple sensitive periods during which experience can influence visual development. We note three sensitive periods within acuity, each with different developmental time courses: the period of visually-driven normal development, the sensitive period for damage, and the sensitive period for recovery. Moreover, there are different sensitive periods for different aspects of vision. Relative to the period of visually driven normal development, the sensitive period for damage is surprisingly long for acuity, peripheral vision, and asymmetry of optokinetic nystagmus, but surprisingly short for global motion. A comparison of results from unilaterally versus bilaterally deprived children provides insights into the complex nature of interactions between the eyes during normal visual development.