Search

Experiences of early life adversity pose significant psychological and physical health risks to exposed individuals. Emerging evidence suggests that these health risks can be transmitted across generations; however, the mechanisms underlying the intergenerational impacts of maternal early-life trauma on child health remain unknown.The current study used a prospective longitudinal design to determine the unique and joint contributions of maternal childhood trauma (neglect and abuse) and maternal prenatal and postnatal mental health (anxiety and depressive symptoms) (N = 541) to children's resting frontoamygdala functional connectivity at 6 years (N = 89) and emotional health at 7-8 years, as indexed by parent-reported internalizing problems and child self-reported anxiety and depressive symptoms (N = 268-418).Greater maternal childhood neglect was indirectly associated with greater internalizing problems serially through a pathway of worse maternal prenatal and postnatal mental health (greater maternal anxiety and depressive symptoms). Worse maternal postnatal mental health was also uniquely associated with more negative child frontoamygdala resting-state functional connectivity, over and above maternal childhood trauma (both neglect and abuse) and prenatal mental health. More negative frontoamygdala functional connectivity was, in turn, associated with poorer child emotional health outcomes.Findings from the current study provide support for the existence of intergenerational influences of parental exposure to childhood trauma on childhood risk for psychopathology in the next generation and point to the importance of maternal factors proximal to the second generation (maternal prenatal and postnatal mental health) in determining the intergenerational impact of maternal early experiences.

Art exposure can influence children's emotional growth, but little is known about tools that aid emotional development in art museums. We implemented attentional and social manipulations to test whether (1) modifications to unscripted instructions and (2) caregiver prompts shape children's attentional focus towards either the emotional or elemental content (e.g., colour and medium) of paintings. These manipulations occurred within an on-going art museum education programme. Afterwards, children's (N = 60; ages 3-13 years) attentional focus towards emotions or elements was assessed by asking them to select words that best described the art. Children focused on emotion more, but the instructional manipulation successfully influenced word choices towards the targeted focus. Caregiver prompts also influenced focus towards the elements and away from emotions. These findings highlight that children's attention to art's emotional content can be altered by social context, which here was demonstrated within a museum programme.

Rodent studies have shown that the gut microbiota can influence threat and safety learning, which has been linked to anxiety phenotypes. In humans, it has been demonstrated that microbiota composition varies with anxiety disorders, but evidence showing an association with threat learning is lacking. Here, we tested whether individual variability in threat and safety learning was related to gut microbiota composition in healthy adults. We found that threat, but not safety learning varies with individuals’ microbiome composition. Our results provide evidence that the gut microbiota is associated with excitatory threat learning across species.Significance StatementLearning from threats and safety is a core mechanism of anxiety disorders, and studies in rodent models have shown that the gut microbiota can modulate such behaviors. Although previous literature on humans shows a relationship between emotional circuits and gut microbiota, the evidence linking learning and microbiota is lacking. In a Pavlovian threat conditioning paradigm, we show that patterns of gut microbiota composition in healthy humans relate to their patterns of threat learning, but not safety learning. Our findings suggest one mechanism by which the human gut microbiota is associated with anxiety-related behaviors.

Parental input shapes youth self-regulation development, and a lack of sensitive caregiving is a risk factor for youth mental health problems. Parents may shape youth regulation through their influence over biological (including neural) and behavioral development during childhood at both micro (moment-to-moment) and macro (global) levels. Prior studies have shown that micro-level parent-child interactions shape youth's biology contributing to youth mental health. However, it remains unclear whether prior disrupted/absent care affects those moment-to-moment parent-youth interactions in ways that increase risk for youth psychopathology. In the current study, we calculated transfer entropy on cardiac data from parent-youth dyads where the youth had either been exposed to disrupted care prior to adoption or not. Transfer Entropy (TE) tracks information flow between two signals, enhancing quantification of directional coupling, allowing for the examination of parent-child and child-parent influences. Using this novel approach, we identified lower cardiac information transfer from youth-to-parents in dyads where the youth had been exposed to disrupted/absent early care. Moreover we showed that the degree to which the parent's physiology changed in response to youth's physiology was negatively related to the youth's mental health, representing a potential pathway for elevated mental health risk in populations exposed to disrupted/absent early care.

The current study investigated the impacts of parental behaviors (threat communication and comforting) on children's COVID-19 fears and whether effects differed by age. Caregivers of 283 children (5.5-17 years, M = 10.17, SD = 3.25) from 186 families completed online measures assessing children's and parents' COVID-19-related fears, children's sources of COVID-19 threat information, and parents' engagement in behaviors to reduce child distress (i.e., comfort behaviors). Higher COVID-19 fear in parents was associated with greater communication of COVID-19 threat information, which was associated with higher COVID-19 fear in younger, but not older, children. Over and above parental fear and threat communication, greater exposure to COVID-19 threat information from community sources (e.g., media, school, friends) was associated with greater COVID-19 fear in children, regardless of age. Greater engagement of parental comfort behaviors buffered the association between community sources of COVID-19 threat information and COVID-19 fears in older, but not younger, children. These findings suggest that younger children might be more vulnerable to developing heightened COVID-19 fears as a result of increasing sources of COVID-19 threat information in their lives. This study highlights the importance of supporting the socioemotional well-being of children and families through the COVID-19 pandemic and beyond.

Observing others is an important means of gathering information by proxy regarding safety and danger, a form of learning that is available as early as infancy. In two experiments, we examined the specificity and retention of emotional eavesdropping (i.e., bystander learning) on cue-specific discriminant learning during toddlerhood. After witnessing one adult admonish another for playing with Toy A (with no admonishment for Toy B), toddlers learned to choose Toy B for themselves regardless of whether they were tested immediately or 2 weeks later (Experiment 1). However, if asked to make a toy choice for someone else (i.e., when toddlers' personal risk was lower), approximately half the toddlers instead selected Toy A (Experiment 2). However, such choices were accompanied by toddlers' social monitoring of the adults, suggesting that toddlers may have been attempting to safely gain (via surrogacy) more information about risk contingencies. These findings suggest that toddlers can learn to discriminate valence in a cue-specific manner through social observation.

Adults quickly orient toward sources of danger and deploy fight-or-flight tactics to manage threatening situations. In contrast, infants who cannot implement the safety strategies available to adults and depend heavily on caregivers for survival are more likely to turn toward familiar adults, such as their parents, to help them navigate threatening circumstances. However, work has yet to investigate how readily children and adolescents orient toward their parents in threatening or fearful contexts. The current work addressed this question using a visual search paradigm that included arrays of parents' and strangers' faces as target and distractor stimuli, preceded by a fear or neutral emotional priming procedure. Linear mixed-effects models showed that children and adolescents (N = 88, age range = 4-17 years; 42M/46F) were faster to search for the face of their parent than of a stranger. However, fear priming attenuated this effect of the parent on search times, such that children and adolescents were significantly slower to orient toward their parent in an array of strangers' faces if they were first primed with fear as opposed to a neutral video. This work indicates that fear priming may phasically interfere with parental orienting during childhood and adolescence, possibly because fear reallocates attention away from parents and toward (potentially threatening) unfamiliar people in the environment to facilitate the development of independent threat learning and coping systems.

Humans learn about their environments by observing others, including what to fear and what to trust. Observational fear learning may be especially important early in life when children turn to their parents to gather information about their world. Yet, the vast majority of empirical research on fear learning in youth has thus far focused on firsthand classical conditioning, which may fail to capture one of the primary means by which fears are acquired during development. To address this gap in the literature, the present study examined observational fear learning in youth (n=33; age range: 6-17years) as they watched videos of their parent and an "unfamiliar parent" (i.e., another participant's parent) undergo fear conditioning. Youth demonstrated stronger fear learning when observing their parent compared to an unfamiliar parent, as indicated by changes in their self-reported liking of the stimuli to which their parents were conditioned (CS+, a geometric shape paired with an aversive noise; CS-, a geometric shape never paired with an aversive noise) and amygdala responses. Parent trait anxiety was associated with youth learning better (i.e., reporting a stronger preference for the CS- relative to CS+), and exhibiting stronger medial prefrontal-amygdala connectivity. Neuroimaging data were additionally acquired from a subset of parents during firsthand conditioning, and parental amygdala and mPFC activation were associated with youth's neural recruitment. Together, these results suggest that youth preferentially learn fears via observation of their parents, and this learning is associated with emotional traits and neural recruitment in parents.

Gastrointestinal and mental disorders are highly comorbid, and animal models have shown that both can be caused by early adversity (e.g., parental deprivation). Interactions between the brain and bacteria that live within the gastrointestinal system (the microbiome) underlie adversity–gastrointestinal–anxiety interactions, but these links have not been investigated during human development. In this study, we utilized data from a population of 344 youth (3–18 years old) who were raised with their biological parents or were exposed to early adverse caregiving experiences (i.e., institutional or foster care followed by international adoption) to explore adversity–gastrointestinal–anxiety associations. In Study 1, we demonstrated that previous adverse care experiences were associated with increased incidence of gastrointestinal symptoms in youth. Gastrointestinal symptoms were also associated with concurrent and future anxiety (measured across 5 years), and those gastrointestinal symptoms mediated the adversity–anxiety association at Time 1. In a subsample of children who provided both stool samples and functional magnetic resonance imaging of the brain (Study 2, which was a “proof-of-principle”), adversity was associated with changes in diversity (both alpha and beta) of microbial communities, and bacteria levels (adversity-associated and adversity-independent) were correlated with prefrontal cortex activation to emotional faces. Implications of these data for supporting youth mental health are discussed.

There is a growing appreciation for the range of sensitive periods which occur across the brain. These sensitive periods give rise to sensory outcomes, as well as complex higher-order cognitive functions like learning and memory. More recently, an understanding that sensitive periods of development occur outside of the central nervous system (e.g., in the gastrointestinal microbiota) has emerged. Less well understood is how these peripheral sensitive periods may interact with those operating centrally to influence complex behavior. The goal of this paper is to put forward the view that sensitive periods of development occur across the entirety of the microbiota-gut-brain (MGB) axis, and that these nested sensitive periods may interact to influence learning and memory outcomes. Adopting this framework should promote a 'new wave' of thinking in the field which appreciates the complex central and peripheral forces acting on behavior, and uses that understanding to innovate therapies and interventions for disordered learning and memory systems.

Episodic memory is critical to human functioning. In adults, episodic memory involves a distributed neural circuit in which the hippocampus plays a central role. As episodic memory abilities continue to develop across childhood and into adolescence, studying episodic memory maturation can provide insight into the development and construction of these hippocampal networks, and ultimately clues to their function in adulthood. While past developmental studies have shown that the hippocampus helps to support memory in middle childhood and adolescence, the extent to which ongoing maturation within the hippocampus contributes to developmental change in episodic memory abilities remains unclear. In contrast, slower maturing regions, such as the PFC, have been suggested to be the neurobiological locus of memory improvements into adolescence. However, it is also possible that the methods used to detect hippocampal development during middle childhood and adolescence are not sensitive enough. Here, we examine how temporal covariance (or differentiation) in voxel representations within anterior and posterior hippocampus change with age to support the development of detailed recollection in male and female developing humans. We find age-related increases in the distinctiveness of temporal activation profiles in the posterior, but not anterior, hippocampus. Second, we show that this measure of granularity, when present during postencoding rest periods, correlates with the recall of detailed memories of preceding stimuli several weeks postencoding, suggesting that granularity may promote memory stabilization.SIGNIFICANCE STATEMENTStudying hippocampal maturation can provide insight into episodic memory development, as well as clues to episodic functioning in adulthood. Past work has shown evidence both for and against hippocampal contributions to age-related improvements in memory performance, but has relied heavily on univariate approaches (averaging activity across hippocampal voxels), which may not be sensitive to nuanced developmental change. Here we use a novel approach, examining time signatures in individual hippocampal voxels to reveal regionally specific (anterior vs posterior hippocampus) differences in the distinctiveness (granularity) of temporal activation profiles across development. Importantly, posterior hippocampus granularity during windows of putative memory stabilization was associated with long-term memory specificity. This suggests that the posterior hippocampus gradually builds the capacity to support detailed episodic recall.

Child-facing professionals in a variety of settings have identified a lack of confidence in recognizing mental health symptoms as a major barrier to treatment for youth. The aim of this study was to investigate the generalizability and predictive validity of known associations between gastrointestinal (GI) symptoms and youth anxiety to establish their utility in community mental health decision-making. We analyzed data from youth ages 3-21 years in volunteer samples collected in Los Angeles (N=327) and New York City (N =102), as well as the community-referred Healthy Brain Network sample (N=1957). Youth gastrointestinal distress was measured through the parent-reported Child Behavior Checklist (CBCL), and youth anxiety was measured through (1) the parent-proxy form of the Screen for Anxiety Related Disorders (SCARED), (2) the child-report form of the SCARED, or (3) clinician-consensus diagnoses (2 and 3 in the Healthy Brain Network cohort only). We examined generalizability of GI-anxiety associations across cohorts and anxiety reporters, then evaluated performance of GI models predicting youth anxiety in holdout data. Consistent with previous work, higher levels of gastrointestinal complaints were associated with more parent-reported youth anxiety behaviors in the Los Angeles (β = 5.02, 95% CI [3.46, 6.52]), New York (β = 5.49, 95% CI [2.85, 8.10]), and Healthy Brain Network (β = 3.88, 95% CI [3.37, 4.38]) cohorts. In the Healthy Brain Network cohort, gastrointestinal symptoms were also associated with more child-reported (β = 1.79, 95% CI [1.07, 2.51]) anxiety behaviors and higher probability of a clinician-evaluated anxiety diagnosis (β = 0.28, 95% CI [0.19, 0.37]). Models trained on one cohort predicted parent-reported (q2 = 0.139, 95% CI [0.036, 0.23], p = .0001) and child-reported (q2= 0.073, 95% CI [0.005, 0.135], p = .0001) anxiety behaviors, as well as clinician-evaluated anxiety diagnoses (AUC = .634, 95% CI [0.577, 0.69], p = .001) at above chance levels in holdout data. Models based on gastrointestinal symptoms often, but not always, outperformed models based on age and sex alone in predicting youth anxiety. Based on the generalizability and predictive validity of GI-anxiety associations investigated here, gastrointestinal complaints may be an effective tool in the hands of child-facing professionals for identifying children at risk for anxiety.

Highlights • Maternal separation did not accelerate maturation of PNNs in amygdala or PFC. • Maternal separation did not affect PV density in infant and juveniles. • No sex differences were observed in effects of maternal separation on PNNs or PV. • Impact of early adversity may be more easily seen with functional neural measures., Early life adversity impacts on a range of emotional, cognitive, and psychological processes. A recent theoretical model suggests that at least some of these effects are due to accelerated maturation of specific physiological systems and/or neural circuits. For example, maternal separation (MS), a model of early life adversity in rodents, accelerates maturation of memory systems, and here we examined its impact on maturation of perineuronal nets (PNNs) and parvalbumin (PV)-containing inhibitory interneurons. PNNs are specialized extracellular matrix structures suggested to be involved in stabilizing long-term memories and in the closure of a sensitive period in memory development. PV-containing inhibitory interneurons are the type of cell that PNNs preferentially surround, and are also thought to be involved in memory. In Experiment 1, with male rats, there was an increase in PNNs in both the amygdala and prefrontal cortex with age from infancy to juvenility. Contrary to prediction, MS had no impact on either PNN or PV expression. The same pattern was observed in female rats in Experiment 2. Taken together, these data show that the early maturation of memory in MS infants is not due to an accelerated maturation of PNNs or PV-containing cells in either the amygdala or prefrontal cortex.

Background: Development and implementation of effective family-based intervention and treatment strategies during COVID-19, and future public health crises, will require a detailed understanding of the ways that COVID-19 has affected parents, children, and families. Qualitative and mixed-methods research is an important means of gaining such detailed information, particularly in the early phases of the pandemic, when the research community continues to explore the meaning of this experience. Methods: We employed thematic analysis to identify themes in parents’ and children’s reflective writing about COVID-19, and explored how citation of certain themes mapped onto quantitative measures of distress commonly used in past psychosocial research on pandemics. Data were collected from N = 56 parents and N = 43 children between April to May 2020.Findings: Analysis of parent and child written reports revealed positive and negative thematic content, though parents expressed more positive themes than children. The most common themes identified from parent reports surrounded concerns about the impact of COVID-19 on their children, health concerns for others, and the stressful balancing act of parenting, schooling, and working from home. In addition, many parents reported gratitude for what they had, and reflected on the upsides of the pandemic for family relations. For children, the most common themes identified surrounded missing school and social relationships. When children expressed positive themes, they tended to be more egocentric reflections (e.g. learning to ride a bike). Both parent and child thematic content mapped onto parent-proxy and parent-self reported quantitative dimensions of parent and child distress. Finally, we observed that parents who reflected on gratitude in their written reports exhibited a decrease in negative affect pre- to -post-writing.Interpretation: Both parents and children are suffering from reduced wellbeing during the COVID-19 pandemic, particularly with the burdens imposed by the closure of in-person schooling. The psychosocial impact of the pandemic on families would likely be even greater in magnitude within less advantaged populations. Future research and policy should focus on identifying how to fulfill children’s social needs and lessen the caregiving burdens during this time.

Is the microbiome a promising adjunct, a potential panacea, or a distraction from feasible treatments for neurodevelopmental disorders? Taking a developmental approach may get us closer to understanding the data and give us pause in trying to translate this nascent field to the clinic right now.

The perinatal brain is well equipped to react to the environment during sleep. Several lines of research in animals and humans prior to and immediately after birth have documented the capability to respond, to process and remember patterns of stimulation. In this article, we will summarize recent findings as well as previous work documenting the memory and learning capacities of the developing brain during sleep and wake states. The role of these sleep state dependent processes may play in the ability to adapt to the postnatal environment will be discussed.Au cours de la période périnatale, le cerveau est en mesure de réagir à l’environnement pendant le sommeil. Plusieurs recherches menées avant et immédiatement après la naissance chez des modèles animaux non-humains (oiseaux et rongeurs) et chez les humains montrent en effet que des capacités de réponse opèrent envers des stimulations auditives et olfactives, de même que des traitements associatifs et mnésiques. Cet article résume les données récentes aussi bien que des travaux plus classiques sur les aptitudes d’apprentissage et de mémoire du cerveau en développement au cours des phases d’éveil aussi bien qu’au cours du sommeil. Le rôle de ces processus précoces d’acquisition pendant le sommeil est discuté dans le cadre de l’adaptation immédiate aux conditions sensorielles de l’environnement postnatal.

Exposure to adverse events affects the development of stress and threat response systems, and emerging evidence suggests that these effects are transmitted to future generations. How such effects are transmitted, and, similarly, how they can be ameliorated, is the topic of this article. Recent evidence demonstrates generational transmission of traits acquired following environmental exposures such as stress (e.g., parental deprivation) and dietary change (e.g., famine, high-fat diet). These diverse environmental exposures often affect both mental and physical health and appear to be transmitted through similar epigenetic and behavioral mechanisms. This convergence suggests an interesting possibility—dietary/gut-directed manipulations may work to prevent the transgenerational transmission of adversity. Although future research is required, gastrointestinal treatments show early promise in the treatment of generational mental health and are both economic and globally accessible.

Children's development is largely dependent on caregiving; when caregiving is disrupted, children are at increased risk for numerous poor outcomes, in particular psychopathology. Therefore, determining how caregivers regulate children's affective neurobiology is essential for understanding psychopathology etiology and prevention. Much of the research on affective functioning uses fear learning to map maturation trajectories, with both rodent and human studies contributing knowledge. Nonetheless, as no standard framework exists through which to interpret developmental effects across species, research often remains siloed, thus contributing to the current therapeutic impasse. Here, we propose a developmental ecology framework that attempts to understand fear in the ecological context of the child: their relationship with their parent. By referring to developmental goals that are shared across species (to attach to, then, ultimately, separate from the parent), this framework provides a common grounding from which fear systems and their dysfunction can be understood, thus advancing research on psychopathologies and their treatment.

Background The human brain remains highly plastic for a protracted developmental period. Thus, although early caregiving adversities that alter amygdala development can result in enduring emotion regulation difficulties, these trajectories should respond to subsequent enriched caregiving. Exposure to high-quality parenting can regulate (i.e., decrease) children’s amygdala reactivity, a process that, over the long term, is hypothesized to enhance emotion regulation. We tested the hypothesis that even following adversity, the parent–child relationship would be associated with decreases in amygdala reactivity to parent cues, which would in turn predict lower future anxiety. Methods Participants were 102 children (6–10 years of age) and adolescents (11–17 years of age), for whom data were collected at one or two time points and who either had experienced institutional care before adoption (n = 45) or had lived always with their biological parents (comparison; n = 57). We examined how amygdala reactivity to visual cues of the parent at time 1 predicted longitudinal change (from time 1 to time 2) in parent-reported child anxiety across 3 years. Results At time 1, on average, amygdala reactivity decrements to parent cues were not seen in children who had received institutional care but were seen in children in the comparison group. However, some children who previously experienced institutional care did show decreased amygdala reactivity to parent cues (∼40%), which was associated with greater child-reported feelings of security with their parent. Amygdala decreases at time 1 were followed by steeper anxiety reductions from time 1 to time 2 (i.e., 3 years). Conclusions These data provide a neurobiological mechanism by which the parent–child relationship can increase resilience, even in children at significant risk for anxiety symptoms.

Gut microbial research has recently opened new frontiers in neuroscience and potentiated novel therapies for mental health problems (Mayer, et al., 2014). Much of our understanding of the gut microbiome's role in brain function and behavior, however, has been largely derived from research on nonhuman animals. Even less is known about how the development of the gut microbiome influences critical periods of neural and behavioral development, particularly adolescence. In this review, we first discuss why the gut microbiome has become increasingly relevant to developmental cognitive neuroscience and provide a synopsis of the known connections of the gut microbiome with social-affective brain function and behavior, specifically highlighting human developmental work when possible. We then focus on adolescence, a key period of neurobiological and social-affective development. Specifically, we review the links between the gut microbiome and six overarching domains of change during adolescence: (a) social processes, (b) motivation and behavior, (c) neural development, (d) cognition, (e) neuroendocrine function, and (f) physical health and wellness. Using a developmental science perspective, we summarize key changes across these six domains to underscore the promise for the gut microbiome to bidirectionally influence and transform adolescent development.

Author(s): Simpson, Carra A; Schwartz, Orli S; Eliby, Djamila; Butler, Catherine A; Huang, Katherine; O'Brien-Simpson, Neil; Callaghan, Bridget L; Dashper, Stuart G; Gooley, Paul R; Whittle, Sarah; Haslam, Nick; Simmons, Julian G | Abstract: IntroductionResearch has highlighted relationships between the micro-organisms that inhabit our gastrointestinal tract (oral and gut microbiota) with host mood and gastrointestinal functioning. Mental health disorders and functional gastrointestinal disorders co-occur at high rates, although the mechanisms underlying these associations remain unclear. The Bugs and Brains Study aims to investigate complex relationships between anxiety/depression and irritable bowel syndrome (IBS) in two ways. First, its primary component will compare the gut and oral microbiota in females with anxiety/depression and/or IBS relative to controls, and investigate underlying physiological, endocrine and immune factors, as well as associations with diet and psychosocial factors. In an ancillary component, the study will also investigate gastrointestinal and mental health symptoms in a larger sample, and explore relationships with diet, exercise, oral health, substance use, medical history, early life adversity and psychosocial factors.Methods and analysisThe Bugs and Brains Study aims to recruit 160 females to the primary component: (1) 40 controls; (2) 40 participants with a depressive/anxiety disorder, but no IBS; (3) 40 participants with IBS, but no depressive/anxiety disorder and (4) 40 participants with both depressive/anxiety disorder and IBS. Participation is completed within 1 month, and involves comprehensive questionnaires, anthropometrics, a diagnostic clinical interview, collection of two saliva samples, and stool, urine and hair samples. This study aims to use a systems biology approach to characterise oral and gut microbial composition and function using 16S rRNA gene sequencing and nuclear MR spectroscopy. As part of the ancillary component, it will collect questionnaire data from 1000 participants aged 18-40 years, capturing mental health, gastrointestinal health, oral health, diet and psychosocial factors.Ethics and disseminationApproval was granted by the University of Melbourne Human Research Ethics Committee (#1749221). All participants voluntarily provided informed consent. Results will be published in peer-reviewed journals and presented at scientific conferences.

Early-life adversity is a potent risk factor for mental-health disorders in exposed individuals, and effects of adversity are exhibited across generations. Such adversities are also associated with poor gastrointestinal outcomes. In addition, emerging evidence suggests that microbiota-gut-brain interactions may mediate the effects of early-life stress on psychological dysfunction. In the present study, we administered an early-life stressor (i.e., maternal separation) to infant male rats, and we investigated the effects of this stressor on conditioned aversive reactions in the rats' subsequent infant male offspring. We demonstrated, for the first time, longer-lasting aversive associations and greater relapse after extinction in the offspring (F1 generation) of rats exposed to maternal separation (F0 generation), compared with the offspring of rats not exposed to maternal separation. These generational effects were reversed by probiotic supplementation, which was effective as both an active treatment when administered to infant F1 rats and as a prophylactic when administered to F0 fathers before conception (i.e., in fathers' infancy). These findings have high clinical relevance in the identification of early-emerging putative risk phenotypes across generations and of potential therapies to ameliorate such generational effects.

The importance of early experiences for mental health across the lifespan is well recognized. In particular, there is a strong association between adverse caregiving experiences and mental illness. However, relative to studies assessing outcomes in adults, there are far fewer studies assessing the earlier emerging manifestations of caregiving adversity during development. This lack of developmental research limits an understanding of the mechanisms that link adversity with mental illness. Adoption of a developmental approach to research in this field will yield greater insights into the factors that tie adversity to poor emotion function across a lifespan. In this review, we focus on recent findings that have used a developmental approach in the examination of mental health and early adversity. These studies are notable in that, across numerous species, they converge on the idea that early adversity leads to accelerated maturation of emotion circuits in the brain and in the behaviors supported by these regions. We propose that these 'stress acceleration' effects are evidence of early system adaptation.

Infantile forgetting is a well-established, and ubiquitous, phenomenon that occurs in nearly all species, including humans. Despite this, recent advances have shown that apparently forgotten memories of early experiences can impact later behavior as well as the neurobiology underlying later learning. In addition, there is growing evidence that early-life adversity leads to faster maturation of the memory system, resulting in early experiences being explicitly recalled for longer periods of time. Understanding the neural mechanisms underpinning these effects may bring us closer to identifying novel treatment approaches for reversing the effects of early-life stress on memory and reducing subsequent risk for psychological disorders.

The adverse effects of early-life stress are pervasive, with well-established mental and physical health consequences for exposed individuals. The impact of early adverse experiences is also highly persistent, with documented increases in risk for mental illness across the life span that are accompanied by stable alterations in neural function and hormonal responses to stress. Here, we review some of these 'stress phenotypes', with a focus on intermediary factors that may signal risk for long-term mental health outcomes, such as altered development of the fear regulation system. Intriguingly, recent research suggests that such stress phenotypes may persist even beyond the life span of the individuals, with consequences for their offspring and grand-offspring. Phenotypic characteristics may be transmitted to future generations via either the matriline or the patriline, a phenomenon that has been demonstrated in both human and animal studies. In this review, we highlight behavioral and epigenetic factors that may contribute to this multigenerational transmission and discuss the potential of various treatment approaches that may halt the cycle of stress phenotypes.

Early experiences critically shape the structure and function of the brain. Perturbations in typical/species-expected early experiences are known to have profound neural effects, especially in regions important for emotional responding. Parental care is one species-expected stimulus that plays a fundamental role in the development of emotion neurocircuitry. Emerging evidence across species suggests that phasic variation in parental presence during the sensitive period of childhood affects the recruitment of emotional networks on a moment-to-moment basis. In addition, it appears that increasing independence from caregivers cues the termination of the sensitive period for environmental input into emotion network development. In this review, we examine how early parental care, the central nervous system, and behavior come together to form a ‘neuro-environmental loop,' contributing to the formation of stable emotion regulation circuits. To achieve this end, we focus on the interaction of parental care and the developing amygdala–medial prefrontal cortex (mPFC) network—that is at the core of human emotional functioning. Using this model, we discuss how individual or group variations in parental independence, across chronic and brief timescales, might contribute to neural and emotional phenotypes that have implications for long-term mental health.

Early-life caregiving shapes the architecture and function of the developing brain. The fact that the infant-caregiver relationship is critically important for infant functioning across all altricial species, and that the anatomical circuits supporting emotional functioning are highly preserved across different species, suggests that the results of studies examining the role of early adversity and emotional functioning should be translatable across species. Here we present findings from four different research laboratories, using three different species, which have converged on a similar finding: adversity accelerates the developmental trajectory of amygdala-prefrontal cortex (PFC) development and modifies emotional behaviors. First, a rodent model of attachment learning associated with adversity is presented showing precocial disruption of attachment learning and emergence of heightened fear learning and emotionality. Second, a model of infant-mother separation is presented in which early adversity is shown to accelerate the developmental emergence of adult-like fear retention and extinction. Third, a model of early life adversity in Rhesus monkeys is presented in which a naturally occurring variation in maternal-care (abuse) is shown to alter the functioning of emotion circuits. Finally, a human model of maternal deprivation is presented in which children born into orphanages and then adopted abroad exhibit aberrant development of emotion circuits. The convergence of these cross-species studies on early life adversity suggests that adversity targets the amygdala and PFC and has immediate impact on infant behavior with the caregiver, and emotional reactions to the world. These results provide insight into mechanisms responsible for caregiver induced mental health trajectory alterations. © 2014 Wiley Periodicals, Inc. Dev Psychobiol 56: 1635–1650, 2014.

Revealing the engram is one of the greatest challenges in neuroscience. Many researchers focus on understanding the cellular and molecular mechanisms underlying the formation and maintenance of the engram, but an underutilized approach has been to investigate analogous processes associated with forgetting. Infant rodents present an ideal model for this purpose because they display a rapid form of non-pathological forgetting known as infantile amnesia (IA). Despite the widespread importance of this interesting phenomenon, the study of the neural bases of IA has remained largely neglected. Here, we consider what IA can tell us about memory. We argue that to understand the mechanisms underlying the engram we must also gain an appreciation of the mechanisms that drive forgetting.

Early adversity increases the risk of nearly all mental health disorders. Although tractable animal models exist to probe the psychobiology of early adversity, the empirical research has focused largely on adult outcomes. In the current studies we examined how early exposure to the stress hormone corticosterone (CORT) affects the maturation of fear extinction in infant rats. Whereas juvenile and adult rodents exhibit extinction learning that is relapse-prone (i.e., they show renewal and reinstatement of extinguished fear), under typical rearing conditions the extinction system in infant rats appears to be relapse-resistant (i.e., extinction leads to a permanent reduction in conditioned fear). In the current studies we tested the hypothesis that chronically exposing infant rats to CORT, either indirectly (through maternal drinking water) or directly (via insertion of an osmotic pump), leads to an early transition into the adult-like extinction system (i.e., evidence of the renewal effect). Although some differences were observed between the 2 methods of CORT exposure, the data showed that infants exposed to CORT via either method exhibited premature emergence of adult-like extinction learning (i.e., they exhibited the renewal effect). The theoretical implications of these findings for typical and abnormal development of emotion learning systems, as well as their practical applications in the context of prevention and treatment of mental health disorders, are discussed.

Recent evidence has shown that pups exposed to maternal separation exhibit profound changes in their emotional development, for example, early emergence of adult-like fear retention and fear inhibition (Callaghan & Richardson, 2011; Callaghan & Richardson, 2012). Numerous studies have shown that maternal separation is also a significant stressor for the mother. However, no studies have examined how a mother's prior parenting experience affects emotion development of pups in her subsequent litters. In this study female rats were bred and were then separated from their pups (maternal separation, MS) or remained with their pups (standard rearing, SR). After those pups were weaned, females were bred again with all pups from the subsequent litters being standard reared. Hence, these subsequent litter pups had mothers that were either previously separated (MS) or not (SR) from their prior litter. Those pups underwent fear conditioning at postnatal Day 17 and tested for fear retention, or had their fear extinguished and then tested for the renewal effect. The results show that the MS infants respond similarly to infants that had been directly exposed to MS. That is, the MS infants exhibited better retention of fear and more relapse after extinction compared with SR infants. Further experiments demonstrated that MS rats were not more anxious than SR infants. Taken together, these experiments are the first to demonstrate that infant offspring exhibit atypical emotional development of fear conditioning (but not anxiety) as a consequence of their mother's prior exposure to stress. (PsycINFO Database Record

Adolescence is a period of heightened susceptibility to anxiety disorders, yet we have little experimental evidence on what factors may lead to psychopathology in adolescence. Preclinical models of extinction are commonly used to study the treatment of anxiety symptoms. Interestingly, recent research has shown that there are fundamental changes in the process of extinction across development, which may have implications for our understanding of psychopathology across the lifespan. Specifically, this research shows that the process of extinction parallels the nonlinear function of prefrontal cortex development, such that extinction behaviour is similar in juvenile and adult rats, but involves different processes in infancy and adolescence (periods of rapid growth and pruning, respectively). Our previous studies have shown that early-life stress accelerates the transition between infant and juvenile extinction systems. In the current series of experiments, we examined whether the same early-life stress, maternal separation (MS), would lead to an earlier transition between the juvenile and adolescent extinction systems, and between the adolescent and adult extinction systems. We show that MS adolescent rats exhibit more adult-like extinction behaviour, and that adolescent-like extinction emerges earlier in development (i.e. in pre-adolescent rats). These results may have important implications for the understanding and treatment of anxiety symptoms in adolescent populations.

Recent studies in rats have shown that extinction occurring early in life is resistant to relapse and may represent the erasure of fear memories. In the present study we examined the effects of early life stress on extinction in the developing rat, which could have important implications for the treatment of anxiety disorders in those who have experienced early life stress. In the present study, we used maternal-separation on postnatal days (P) 2-14 as an early life stressor. On P17, maternally separated and standard-reared animals were trained to fear a noise associated with a footshock. The fear of this noise was then extinguished (through repeated nonreinforced noise presentations) on P18. Animals were tested for contextually mediated, stress-mediated, and GABA-mediated fear relapse the day after extinction. We found that young animals exposed to maternal-separation were more likely to exhibit context- and stress-mediated relapse after extinction than standard-reared animals (Experiments 1 and 2). Further, unlike standard-reared animals, maternally separated rats exhibited a return of fear when the inhibitory neurotransmitter GABA was blocked at test (Experiment 3). These effects were not the result of maternal separation increasing rats' sensitivity to footshock (Experiment 5) and may in part be related to superior long-term memory for contexts in P17 maternally separated rats (Experiment 4). Taken together, these results suggest that early life adversity may prepare young animals to respond more cautiously toward fear signals in their environment.

The parent-adolescent relationship is an important predictor of adolescent mental health, especially depressive disorders. This relationship is constructed in the context of maturing emotion neurobiology and could help shape such neurobiology in ways that are important for current and future mental health. Amygdala resting-state functional networks have been linked to depression, but whether such resting connectivity is associated with parent affective behaviors or acts as a salient mediator between parenting and risk for depressive disorder is unknown.In the present study of 128 individuals, a 7-year longitudinal design was used to examine how observed maternal aggressive behavior during mother-adolescent interactions in early adolescence (12 years) predicted amygdala (whole and subregion)-based resting connectivity in mid adolescence (16 years). In 101 of those participants, whether altered amygdala resting-state connectivity mediated the association between maternal aggressive behavior and the first onset of major depressive disorder (MDD) in late adolescence (19 years) was analyzed.Maternal aggression was related to resting-state functional connectivity between the amygdala and right superior temporal-posterior insula-Heschl gyri, bilateral visual cortex, and left temporal and insula cortices (the latter being driven by the centromedial amygdala subregion; p .001). Further, amygdala and centromedial amygdala connectivity with the temporal and insula cortices mediated the association between maternal aggression and late adolescent-onset MDD (CI 0.20 to 2.87; CI 0.13 to 2.40, respectively).These findings are consistent with previous literature documenting the importance of amygdala resting networks for adolescent depression but further suggest the importance of parental affective (particularly aggressive) behavior in the development of such functional connectivity patterns during this period of peak onset for mental health disorders.

Recently, scientific interest in the brain–gut axis has grown dramatically, particularly with respect to the link between gastrointestinal and psychiatric dysfunction. However, the role of gut function in early emotional dysregulation is yet to be examined, despite the prevalence and treatment resistance of early-onset psychiatric disorders. The present studies utilized a developmental rodent model of early-life stress (ELS) to explore this gap. Rats were exposed to maternal separation (MS) on postnatal days 2–14. Throughout MS, dams received either vehicle or a probiotic formulation (previously shown to reduce gastrointestinal dysfunction) in their drinking water. Replicating past research, untreated MS infants exhibited an adult-like profile of long-lasting fear memories and fear relapse following extinction. In contrast, probiotic-exposed MS infants exhibited age-appropriate infantile amnesia and resistance to relapse. These effects were not mediated by changes in pups’ or dams’ anxiety at the time of training, nor by maternal responsiveness. Overall, probiotics acted as an effective and non-invasive treatment to restore normal developmental trajectories of emotion-related behaviors in infant rats exposed to ELS. These results provide promising initial evidence for this novel approach to reduce the risk of mental health problems in vulnerable individuals. Future studies are needed to test this treatment in humans exposed to ELS and to elucidate mechanisms for the observed behavioral changes.

In recent years the gap between psychological and psychiatric research and practice has lessened. In turn, greater attention has been paid toward how psychological and pharmacological treatments interact. Unfortunately, the majority of research has indicated no additive effect of anxiolytics and antidepressants when combined with psychological treatments, and in many cases pharmacological treatments attenuate the effectiveness of psychological treatments. However, as psychology and psychiatry have come closer together, research has started to investigate the neural and molecular mechanisms underlying psychological treatments. Such research has utilised preclinical models of psychological treatments, such as fear extinction, in both rodents and humans to determine multiple neural and molecular changes that may be responsible for the long-term cognitive and behavioural changes that psychological treatments induce. Currently, researchers are attempting to identify pharmacological agents that directly augment these neural/molecular changes, and which may be more effective adjuncts to psychological treatments than traditional anxiolytics and antidepressants. In this review we describe the research that has led to this new wave of thinking about combined psychological/pharmacological treatments. We also argue that an increased emphasis on identifying individual difference factors that predict the effectiveness of pharmacological adjuncts is critical in facilitating the translation of this preclinical research into clinical practice.

Recent studies have shown that chronic early life stress results in precocious expression of the adult-like phenotype of fear retention and inhibition. However, it is unknown whether the experience of acute early trauma has the same effects as exposure to chronic early stress. In the present study, a 24-hr period of maternal deprivation on postnatal day (P) 9 was used as an acute early life stressor. In infancy (P16-17), maternally deprived and standard-reared rats were conditioned to fear a noise paired with shock. In Experiments 1 and 2, fear to the noise was then extinguished before rats were tested for context-mediated fear renewal or stress-induced fear reinstatement. In Experiments 3a and 3b, conditioned rats were tested for fear retention 1, 7, or 14 days after training. Whereas standard-reared infants exhibited relapse-resistant extinction and infantile amnesia (i.e., behaviors typical of their age), maternally deprived infants exhibited the renewal and reinstatement effects (i.e., relapse-prone extinction) and showed good retention of fear over the 7- and 14-day intervals (i.e., infantile amnesia was reduced). In other words, similar to rats exposed to chronic early life stress, rats exposed to acute early stress expressed an adult-like profile of fear retention and inhibition during infancy. These findings suggest that similar mechanisms might be involved in the effects of acute and chronic stress on emotional development, and may have implications for our understanding and treatment of emotional disorders associated with early adversity.

While early experiences are proposed to be important for the emergence of anxiety and other mental health problems, there is little empirical research examining the impact of such experiences on the development of emotional learning. Of the research that has been performed in this area, however, a complex picture has emerged in which the maturation of emotion circuits is influenced by the early experiences of the animal. For example, under typical laboratory rearing conditions infant rats rapidly forget learned fear associations (infantile amnesia) and express a form of extinction learning which is relapse-resistant (i.e., extinction in infant rats may be due to fear erasure). In contrast, adult rats exhibit very long-lasting memories of past learned fear associations, and express a form of extinction learning that is relapse-prone (i.e., the fear returns in a number of situations). However, when rats are reared under stressful conditions then they exhibit adult-like fear retention and extinction behaviours at an earlier stage of development (i.e., good retention of learned fear and relapse-prone extinction learning). In other words, under typical rearing conditions infant rats appear to be protected from exhibiting anxiety whereas after adverse rearing fear learning appears to make those infants more vulnerable to the later development of anxiety. While the effects of different experiences on infant rats’ fear retention and extinction are becoming better documented, the mechanisms which mediate the early transition seen following stress remain unclear. Here we suggest that rearing stress may lead to an early maturation of the molecular and cellular signals shown to be involved in the closure of critical period plasticity in sensory modalities (e.g., maturation of GABAergic neurons, development of perineuronal nets), and speculate that these signals could be manipulated in adulthood to re-open infant forms of emotional learning (i.e., those that favour resilience).

Research first reported nearly 50 years ago demonstrated that infant and young animals (including humans) exhibit profoundly faster rates of forgetting (i.e., infantile amnesia) than do adults. In addition to these differences in retention, more recent research has shown that inhibition of fear learning is also very different in infancy than in adulthood. Specifically, extinction of fear early in life is much more resistant to relapse than is extinction later in life. Both of these findings suggest that young animals should be especially resilient to the emergence of mental health disorders, which appears to be at odds with the view that early-life experiences are particularly important for the development of later psychopathologies (such as anxiety disorders) and with the finding that the majority of anxiety disorders first emerge in adolescence or childhood. This apparent paradox might be resolved, however, if exposure to chronic stress early in life affects the maturation of the fear retention and extinction systems, leading to a faster transition to the adult form of each (i.e., long-lasting fear memories and relapse-prone extinction). In several recent studies we have found exactly this pattern; that is, infant rats exposed to maternal-separation stress exhibit adult-like fear and extinction learning early in development. Further, we have demonstrated that some of these effects can be mimicked by exposing the mother to the stress hormone corticosterone in their drinking water (in lieu of the separation procedure). These findings suggest that early-life exposure to stress and stress hormones may act as a general signal that can alter the developmental trajectory of emotional systems and potentially place animals at greater risk for the development of anxiety. The implications of these recent findings for our understanding of the developmental origins of health and disease, and for enhancing preventative and therapeutic treatments across the lifespan, are considered.

Aims To review and summarize existing prospective studies reporting on remission from dependence upon amphetamines, cannabis, cocaine or opioids. Methods Systematic searches of the peer-reviewed literature were conducted to identify prospective studies reporting on remission from amphetamines, cannabis, cocaine or opioid dependence. Searches were limited to publication between 1990 and 2009. Reference lists of review articles and important studies were searched to identify additional studies. Remission was defined as no longer meeting diagnostic criteria for drug dependence or abstinence from drug use; follow-up periods of at least three years were investigated. The remission rate was estimated for each drug type, allowing pooling across studies with varying follow-up times. Results There were few studies examining the course of psychostimulant dependence that met inclusion criteria (one for amphetamines and four for cocaine). There were ten studies of opioid and three for cannabis dependence. Definitions of remission varied and most did not clearly assess remission from dependence. Amphetamine dependence had the highest remission rate (0.4477; 95%CI 0.3991, 0.4945), followed by opioid (0.2235; 95%CI 0.2091, 0.2408) and cocaine dependence (0.1366; 95%CI 0.1244, 0.1498). Conservative estimates of remission rates followed the same pattern with cannabis dependence (0.1734; 95%CI 0.1430, 0.2078) followed by amphetamine (0.1637; 95%CI 0.1475, 0.1797), opioid (0.0917; 95%CI 0.0842, 0.0979) and cocaine dependence (0.0532; 95%CI 0.0502, 0.0597). Conclusions The limited prospective evidence suggests that “remission” from dependence may occur relatively frequently but rates may differ across drugs. There is very little research on remission from drug dependence; definitions used are often imprecise and inconsistent across studies and there remains considerable uncertainty about the longitudinal course of dependence upon these most commonly used illicit drugs.

Mental health problems are often assumed to have their roots in early-life experiences. However, memories acquired in infancy are rapidly forgotten in nearly all species (including humans). As yet, a testable mechanism on how early-life experiences have a lasting impact on mental health is lacking. In these experiments, we tested the idea that infant adversity leads to an early transition into adult-like fear retention, allowing infant memories to have a longer-lasting influence. Rats were exposed to maternal separation (3 h per day) across postnatal days (P) 2–14, or their mother was given corticosterone in her drinking water across the same period. Infant rats were then trained to fear a conditioned stimulus (CS) paired with an aversive unconditioned stimulus (US) on P17. Retention of the fear association was then tested 1–55 days later. When tested one day after the CS–US association was formed, both standard-reared (SR) and maternally-separated (MS) rats exhibited strong memory. However, when tested 10 days later, SR rats exhibited robust forgetting, whereas MS rats exhibited near-perfect retention. These effects were mimicked by exposing the mother to the stress hormone corticosterone in the drinking water. Finally, fear associations in P17 MS rats were retained for up to 30 days. Our findings point to differences in retention of fear as one factor that might underlie the propensity of stress-exposed individuals to exhibit early anxiety symptoms and suggest that manipulations of the corticosterone system may hold the key to ameliorating some of the effects of early stress on persistent retention of fear.