The influence of unpredictable,fragmented parental signals on the developing brain

Mental illnesses originate early in life, governed by environmental and genetic factors. Because parents are a dominant source of signals to the developing child, parental signals - beginning with maternal signals in utero - are primary contributors to children’s mental health. Existing literature on maternal signals has focused almost exclusively on their quality and valence (e.g. maternal depression, sensitivity). Here we identify a novel dimension of maternal signals: their patterns and especially their predictability/unpredictability, as an important determinant of children’s neurodevelopment. We find that unpredictable maternal mood and behavior presage risk for child and adolescent psychopathology. In experimental models, fragmented/unpredictable maternal care patterns directly induce aberrant synaptic connectivity and disturbed maturation of cognitive and emotional brain circuits, with commensurate memory problems and anhedonia-like behaviors. Together, our findings across species demonstrate that patterns of maternal signals influence brain circuit maturation, promoting resilience or vulnerability to mental illness.     

A psychoneuroimmunological perspective to Emil Kraepelins dichotomy

Recent findings of gene-environment interaction on child and adolescent anxiety generate interest in mechanisms through which genetic risks are expressed. Current findings from neuroscience suggest avenues for exploring putative mechanisms. Specifically recent documentations of abnormality in brain function among anxious adolescents may reflect the end-result of gene expression. In turn these inherited predispositions may increase the likelihood of psychopathology in the presence of stress. The aim of the current article is to consider putative mechanisms reflecting genetic sensitivity to the environment (G x E). Thus we review data implicating biased processing of threat information and anomalies in brain circuitry in the expression of pediatric anxiety. These data suggest that links across development among genes, brain, psychological processes, and behavior are far from established. Accordingly, the article proposes strategies for examining these links. Exploring these relationships during development is crucial, given that these early life processes may potentially shape longer-term patterns of emotional behavior, and therefore life-long trajectories of anxiety.     

Genetic and neural dissociation of individual responses to emotional expressions in human infants

Interacting with others by interpreting and responding to their facial expressions is an essential and early developing social skill in humans. We examined whether and how variation in catechol-O-methyltransferase (COMT) and serotonin transporter (5-HTTLPR) genes is associated with 7-month-old infants' electrocortical responses to facial expressions. The results revealed that COMT variants are associated with differences in infants' brain responses to fearful faces over centro-parietal regions, whereas 5-HTTLPR variants are associated with differences in infants' brain responses to happy faces over fronto-temporal regions. Further support for differential associations of these gene variants with emotional processing came from our analysis of infant behavioral temperament: variation in COMT was associated with differences in infants' recovery from distress, whereas variation in 5-HTTLPR was associated with infants' smiling and laughter. This pattern of findings indicates that, in infancy, these genetic variants influence distinct brain systems involved in the processing of either positive or negative emotions. This has wide reaching implications for our understanding of how genetic variation biases specific brain mechanisms, giving rise to individual differences in emotional sensitivity and temperament.     

The neurobiology of the emotional adolescent: From the inside out

Adolescents are commonly portrayed as highly emotional, with their behaviors often hijacked by their emotions. Research on the neural substrates of adolescent affective behavior is beginning to paint a more nuanced picture of how neurodevelopmental changes in brain function influence affective behavior, and how these influences are modulated by external factors in the environment. Recent neurodevelopmental models suggest that the brain is designed to promote emotion regulation, learning, and affiliation across development, and that affective behavior reciprocally interacts with age-specific social demands and different social contexts. In this review, we discuss current findings on neurobiological mechanisms of adolescents’ affective behavior and highlight individual differences in and social-contextual influences on adolescents’ emotionality. Neurobiological mechanisms of affective processes related to anxiety and depression are also discussed as examples. As the field progresses, it will be critical to test new hypotheses generated from the foundational empirical and conceptual work and to focus on identifying more precisely how and when neural networks change in ways that promote or thwart adaptive affective behavior during adolescence.     

Developmental underpinnings of differences in rodent novelty-seeking and emotional reactivity

Innate differences in human temperament strongly influence how individuals cope with stress and also predispose towards specific types of psychopathology. The present study examines the developing brain in an animal model of temperamental differences to examine how altered neurodevelopment may engender differences in emotional reactivity that are stable throughout the animal's life. We utilize selectively-bred High Responder (bHR) and Low Responder (bLR) rats that exhibit dramatic emotional behavior differences, with bHRs exhibiting exaggerated novelty-exploration, aggression, impulsivity and drug self-administration, and bLRs showing marked behavioral inhibition and exaggerated anxiety-like and depressive-like behavior. Using Affymetrix microarrays, we assessed bLR and bHR gene expression in the developing brain on postnatal days (P)7, 14 and 21, focusing on the hippocampus and nucleus accumbens, two regions related to emotionality and known to differ in adult bLR and bHR rats. We found dramatic gene expression differences between bLR and bHR in the P7 and P14 hippocampus, with minimal differences in the nucleus accumbens. Some of the most profound differences involved genes critical for neurodevelopment and synaptogenesis. Stereological studies evaluated hippocampal structure in developing bHR and bLR pups, revealing enhanced hippocampal volume and cell proliferation in bLR animals. Finally, behavioral studies showed that the characteristic bHR and bLR behavioral phenotypes emerge very early in life, with exploratory differences apparent at P16 and anxiety differences present by P25. Together these data point to specific brain regions and critical periods when the bHR and bLR phenotypes begin to diverge, which may eventually allow us to test possible therapeutic interventions to normalize extreme phenotypes (e.g. the anxiety-prone nature of bLRs or drug addiction proclivity of bHRs).     

Different effects of acute neonatal stressors and long-term postnatal handling on stress-induced changes in behavior and in ornithine decarboxylase activity of adult rats

A transient increase in brain polyamine (PA) metabolism, termed the PA-stress-response (PSR), is a common response to stressful stimuli. Previous studies have implicated the PSR as a component of the adaptive and/or maladaptive brain response to stressful events. Ample evidence indicates that stressful experiences during early life can alter normal developmental processes and may result in pathophysiological and behavioral changes in the adult. The aim of the present study, therefore, was to determine whether strong acute neonatal stressors (3 mg/kg dexamethasone, or 2 h restraint stress at day 7), as compared to mild long-term intermittent maternal separation and handling (15 min, twice a day between postnatal days 2 and 25), would lead in adult Wistar rats to different PSR and behavioral reactivity to novelty stress. Changes in ornithine decarboxylase (ODC) activity and in tissue PA concentrations served as markers of the PSR, and behavioral alterations in an open-field arena indicated the reactivity to novelty stress. Animals subjected to acute neonatal stressors, showed reduced behavioral reactivity in the open-field test, indicative of increased emotional reactivity to novelty. In these animals, the increase in ODC activity after dexamethasone challenge was attenuated in the brain, but exaggerated in the liver. In the thymus and adrenal gland of these animals, the basal enzyme activity was significantly increased, but a similar reduction was observed after dexamethasone challenge. In contrast, long-term postnatal handling led in adults to novelty-induced changes indicative of reduced emotional behavior, yet the alterations in ODC activity after dexamethasone challenge in these animals were similar to those in animals after acute stressors. The concentrations of tissue polyamines in adults were not affected by any of the postnatal stressors. The results justify the following conclusions: (1) Strong acute neonatal stressors can lead to increased emotional behavior in adults, while mild long-term intermittent handling, may result in adaptation and reduced emotionality. (2) Attenuated stress-induced increase of ODC activity in the brain, but exaggerated increased activity in the liver, may be implicated in altered emotional behavior reactivity to stressors.     

Early life stress, the development of aggression and neuroendocrine and neurobiological correlates: What can we learn from animal models?

Early life stress (child and adolescent abuse, neglect and trauma) induces robust alterations in emotional and social functioning resulting in enhanced risk for the development of psychopathologies such as mood and aggressive disorders. Here, an overview is given on recent findings in primate and rodent models of early life stress, demonstrating that chronic deprivation of early maternal care as well as chronic deprivation of early physical interactions with peers are profound risk factors for the development of inappropriate aggressive behaviors. Alterations in the hypothalamic–pituitary–adrenocortical (HPA), vasopressin and serotonin systems and their relevance for the regulation of aggression are discussed. Data suggest that social deprivation-induced inappropriate forms of aggression are associated with high or low HPA axis (re)activity and a generally lower functioning of the serotonin system in adulthood. Moreover, genetic and epigenetic modifications in HPA and serotonin systems influence the outcome of early life stress and may even moderate adverse effects of early social deprivation on aggression. A more comprehensive study of aggression, neuroendocrine, neurobiological and (epi)genetic correlates of early life stress using animal models is necessary to provide a better understanding of the invasive aggressive deficits observed in humans exposed to child maltreatment.     

Sexual dimorphism in rats: effects of early maternal separation and variable chronic stress on pituitary-adrenal axis and behavior

The pituitary-adrenal axis response is gender-dependent, showing lower activity in male rats. Furthermore, males showed low emotional behavior and females high emotionality when exposed to such chronic stress situations. The gender of an animal is a relevant factor in the development of responses to stress. The aim of the present study was to investigate the influence of early maternal separation on the pituitary-adrenal activity and emotional behavior of adult male and female rats subjected to chronic variable stress. Male and female Wistar rats were isolated 4.5 h daily, during the three first weeks of life. At 48 days of age, the rats were exposed to variable chronic stress (five different stressors during 24 days). Non-maternally separated and maternally separated males showed lower levels of ACTH compared to females (p<0.01). In male rats exposed to variable chronic stress, the maternally separated animals showed a diminution in the levels of ACTH and Corticosterone (p<0.05) compared to non-maternally separated rats. In the Open Field test, the maternally separated and non-maternally separated-stressed males showed lower emotional reactivity compared with female rats. This was indicated by increase in ambulation (p<0.05) and decrease in defecation (p<0.05). Male rats subjected to variable chronic stress presented low emotional behavior seen in their lower defecation (p<0.05). Stressed females displayed decreased ambulation (p<0.05) and increased defecation (p<0.05), showing high emotional reactivity after exposure to chronic stress. Maternally separated males showed higher emotionality after the exposure to chronic variable stress. This was indicated by decrease in ambulation (p<0.05), decrease in rearing (p<0.05) and increase in defecation (p<0.05). Thus, maternal separation and variable chronic stress caused long-term gender-dependent alterations in pituitary-adrenal activity and emotional behavior.     

Brain mechanisms underlying emotional alterations in the peripartum period in rats

In the period before and after parturition, i.e., in pregnancy and lactation, a variety of neuroendocrine alterations occur that are accompanied by marked behavioral changes, including emotional responsiveness to external challenging situations. On the one hand, activation of neuroendocrine systems (oxytocin, prolactin) ensures reproduction-related physiological processes, but in a synergistic manner also ensures accompanying behaviors necessary for the survival of the offspring. On the other hand, there is a dramatic reduction in the responsiveness of neuroendocrine systems to stimuli not relevant for reproduction, such as the hypothalamo-pituitary-adrenal (HPA) axis responses to physical or emotional stimuli in both pregnant and lactating rats. With CRH being the main regulator of the HPA axis, downregulation of the brain CRH system may result in various behavioral, in particular emotional, adaptations of the maternal organisms, including changes in anxiety-related behavior. In support of this, the lactating rat becomes less emotionally responsive to novel situations, demonstrating reduced anxiety, and shows a higher degree of aggressive behavior in the test for agonistic behavior as well as in the maternal defense test. These changes in emotionality are independent of the innate (pre-lactation) level of anxiety and are seen in both rats bred for high as well as low levels of anxiety. Both brain oxytocin and prolactin, highly activated at this time, play a significant role in these behavioral and possibly also neuroendocrine adaptations in the peripartum period.