Upregulation of HOXA3 by isoform-specific Wilms tumour 1 drives chemotherapy resistance in acute myeloid leukaemia.

Upregulation of the Wilms' tumour 1 (WT1) gene is common in acute myeloid leukaemia (AML) and is associated with poor prognosis. WT1 generates 12 primary transcripts through different translation initiation sites and alternative splicing. The short WT1 transcripts express abundantly in primary leukaemia samples. We observed that overexpression of short WT1 transcripts lacking exon 5 with and without the KTS motif (sWT1+/- and sWT1-/-) led to reduced cell growth. However, only sWT1+/- overexpression resulted in decreased CD71 expression, G1 arrest, and cytarabine resistance. Primary AML patient cells with low CD71 expression exhibit resistance to cytarabine, suggesting that CD71 may serve as a potential biomarker for chemotherapy. RNAseq differential expressed gene analysis identified two transcription factors, HOXA3 and GATA2, that are specifically upregulated in sWT1+/- cells, whereas CDKN1A is upregulated in sWT1-/- cells. Overexpression of either HOXA3 or GATA2 reproduced the effects of sWT1+/-, including decreased cell growth, G1 arrest, reduced CD71 expression and cytarabine resistance. HOXA3 expression correlates with chemotherapy response and overall survival in NPM1 mutation-negative leukaemia specimens. Overexpression of HOXA3 leads to drug resistance against a broad spectrum of chemotherapeutic agents. Our results suggest that WT1 regulates cell proliferation and drug sensitivity in an isoform-specific manner.

Age-related change in task-evoked amygdala-prefrontal circuitry: A multiverse approach with an accelerated longitudinal cohort aged 4-22 years.

The amygdala and its connections with medial prefrontal cortex (mPFC) play central roles in the development of emotional processes. While several studies have suggested that this circuitry exhibits functional changes across the first two decades of life, findings have been mixed - perhaps resulting from differences in analytic choices across studies. Here we used multiverse analyses to examine the robustness of task-based amygdala-mPFC function findings to analytic choices within the context of an accelerated longitudinal design (4-22 years-old; N = 98; 183 scans; 1-3 scans/participant). Participants recruited from the greater Los Angeles area completed an event-related emotional face (fear, neutral) task. Parallel analyses varying in preprocessing and modeling choices found that age-related change estimates for amygdala reactivity were more robust than task-evoked amygdala-mPFC functional connectivity to varied analytical choices. Specification curves indicated evidence for age-related decreases in amygdala reactivity to faces, though within-participant changes in amygdala reactivity could not be differentiated from between-participant differences. In contrast, amygdala-mPFC functional connectivity results varied across methods much more, and evidence for age-related change in amygdala-mPFC connectivity was not consistent. Generalized psychophysiological interaction (gPPI) measurements of connectivity were especially sensitive to whether a deconvolution step was applied. Our findings demonstrate the importance of assessing the robustness of findings to analysis choices, although the age-related changes in our current work cannot be overinterpreted given low test-retest reliability. Together, these findings highlight both the challenges in estimating developmental change in longitudinal cohorts and the value of multiverse approaches in developmental neuroimaging for assessing robustness of results.

Experimental evidence for a child-to-adolescent switch in human amygdala-prefrontal cortex communication: A cross-sectional pilot study.

Interactions between the amygdala and prefrontal cortex are fundamental to human emotion. Despite the central role of frontoamygdala communication in adult emotional learning and regulation, little is known about how top-down control emerges during human development. In the present cross-sectional pilot study, we experimentally manipulated prefrontal engagement to test its effects on the amygdala during development. Inducing dorsal anterior cingulate cortex (dACC) activation resulted in developmentally-opposite effects on amygdala reactivity during childhood versus adolescence, such that dACC activation was followed by increased amygdala reactivity in childhood but reduced amygdala reactivity in adolescence. Bayesian network analyses revealed an age-related switch between childhood and adolescence in the nature of amygdala connectivity with the dACC and ventromedial PFC (vmPFC). Whereas adolescence was marked by information flow from dACC and vmPFC to amygdala (consistent with that observed in adults), the reverse information flow, from the amygdala to dACC and vmPFC, was dominant in childhood. The age-related switch in information flow suggests a potential shift from bottom-up co-excitatory to top-down regulatory frontoamygdala connectivity and may indicate a profound change in the circuitry supporting maturation of emotional behavior. These findings provide novel insight into the developmental construction of amygdala-cortical connections and implications for the ways in which childhood experiences may influence subsequent prefrontal function.

Mind and gut: Associations between mood and gastrointestinal distress in children exposed to adversity.

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.

Friendship and social functioning following early institutional rearing: The role of ADHD symptoms.

Early institutional rearing is associated with increased risk for subsequent peer relationship difficulties, but the underlying mechanisms have not been identified. Friendship characteristics, social behaviors with peers, normed assessments of social problems, and social cue use were assessed in 142 children (mean age = 10.06, SD = 2.02; range 7-13 years), of whom 67 were previously institutionalized (PI), and 75 were raised by their biological families. Anxiety and attention-deficit/hyperactivity disorder (ADHD) symptoms, often elevated among PI children, were examined as potential mediators of PI status and baseline social functioning and longitudinal follow-ups (2 and 4 years later). Twenty-seven percent of PI children fell above the Child Behavior Checklist Social Problems cutoff. An examination of specific social behaviors with peers indicated that PI and comparison children did not differ in empathic concern or peer social approach, though parents were more likely to endorse aggression/overarousal as a reason that PI children might struggle with friendships. Comparison children outperformed PI children in computerized testing of social cue use learning. Finally, across these measures, social difficulties exhibited in the PI group were mediated by ADHD symptoms with predicted social problems assessed 4 years later. These findings show that, when PI children struggle with friendships, mechanisms involving attention and behavior regulation are likely contributors.

Previous Institutionalization Is Followed by Broader Amygdala-Hippocampal-PFC Network Connectivity during Aversive Learning in Human Development.

UNLABELLED: Early institutional care can be profoundly stressful for the human infant, and, as such, can lead to significant alterations in brain development. In animal models, similar variants of early adversity have been shown to modify amygdala-hippocampal-prefrontal cortex development and associated aversive learning. The current study examined this rearing aberration in human development. Eighty-nine children and adolescents who were either previously institutionalized (PI youth; N = 46; 33 females and 13 males; age range, 7-16 years) or were raised by their biological parents from birth (N = 43; 22 females and 21 males; age range, 7-16 years) completed an aversive-learning paradigm while undergoing functional neuroimaging, wherein visual cues were paired with either an aversive sound (CS+) or no sound (CS-). For the PI youth, better aversive learning was associated with higher concurrent trait anxiety. Both groups showed robust learning and amygdala activation for CS+ versus CS- trials. However, PI youth also exhibited broader recruitment of several regions and increased hippocampal connectivity with prefrontal cortex. Stronger connectivity between the hippocampus and ventromedial PFC predicted significant improvements in future anxiety (measured 2 years later), and this was particularly true within the PI group. These results suggest that for humans as well as for other species, early adversity alters the neurobiology of aversive learning by engaging a broader prefrontal-subcortical circuit than same-aged peers. These differences are interpreted as ontogenetic adaptations and potential sources of resilience. SIGNIFICANCE STATEMENT: Prior institutionalization is a significant form of early adversity. While nonhuman animal research suggests that early adversity alters aversive learning and associated neurocircuitry, no prior work has examined this in humans. Here, we show that youth who experienced prior institutionalization, but not comparison youth, recruit the hippocampus during aversive learning. Among youth who experienced prior institutionalization, individual differences in aversive learning were associated with worse current anxiety. However, connectivity between the hippocampus and prefrontal cortex prospectively predicted significant improvements in anxiety 2 years following scanning for previously institutionalized youth. Among youth who experienced prior institutionalization, age-atypical engagement of a distributed set of brain regions during aversive learning may serve a protective function.

Stimulus-Elicited Connectivity Influences Resting-State Connectivity Years Later in Human Development: A Prospective Study.

UNLABELLED: Although the functional architecture of the brain is indexed by resting-state connectivity networks, little is currently known about the mechanisms through which these networks assemble into stable mature patterns. The current study posits and tests the long-term phasic molding hypothesis that resting-state networks are gradually shaped by recurring stimulus-elicited connectivity across development by examining how both stimulus-elicited and resting-state functional connections of the human brain emerge over development at the systems level. Using a sequential design following 4- to 18-year-olds over a 2 year period, we examined the predictive associations between stimulus-elicited and resting-state connectivity in amygdala-cortical circuitry as an exemplar case (given this network's protracted development across these ages). Age-related changes in amygdala functional connectivity converged on the same regions of medial prefrontal cortex (mPFC) and inferior frontal gyrus when elicited by emotional stimuli and when measured at rest. Consistent with the long-term phasic molding hypothesis, prospective analyses for both connections showed that the magnitude of an individual's stimulus-elicited connectivity unidirectionally predicted resting-state functional connectivity 2 years later. For the amygdala-mPFC connection, only stimulus-elicited connectivity during childhood and the transition to adolescence shaped future resting-state connectivity, consistent with a sensitive period ending with adolescence for the amygdala-mPFC circuit. Together, these findings suggest that resting-state functional architecture may arise from phasic patterns of functional connectivity elicited by environmental stimuli over the course of development on the order of years. SIGNIFICANCE STATEMENT: A fundamental issue in understanding the ontogeny of brain function is how resting-state (intrinsic) functional networks emerge and relate to stimulus-elicited functional connectivity. Here, we posit and test the long-term phasic molding hypothesis that resting-state network development is influenced by recurring stimulus-elicited connectivity through prospective examination of the developing human amygdala-cortical functional connections. Our results provide critical insight into how early environmental events sculpt functional network architecture across development and highlight childhood as a potential developmental period of heightened malleability for the amygdala-medial prefrontal cortex circuit. These findings have implications for how both positive and adverse experiences influence the developing brain and motivate future investigations of whether this molding mechanism reflects a general phenomenon of brain development.

Altered ventral striatal-medial prefrontal cortex resting-state connectivity mediates adolescent social problems after early institutional care.

Early caregiving adversity is associated with increased risk for social difficulties. The ventral striatum and associated corticostriatal circuitry, which have demonstrated vulnerability to early exposures to adversity, are implicated in many aspects of social behavior, including social play, aggression, and valuation of social stimuli across development. Here, we used resting-state functional magnetic resonance imaging to assess the degree to which early caregiving adversity was associated with altered coritocostriatal resting connectivity in previously institutionalized youth (n = 41) relative to youth who were raised with their biological families from birth (n = 47), and the degree to which this connectivity was associated with parent-reported social problems. Using a seed-based approach, we observed increased positive coupling between the ventral striatum and anterior regions of medial prefrontal cortex (mPFC) in previously institutionalized youth. Stronger ventral striatum-mPFC coupling was associated with parent reports of social problems. A moderated-mediation analysis showed that ventral striatal-mPFC connectivity mediated group differences in social problems, and more so with increasing age. These findings show that early institutional care is associated with differences in resting-state connectivity between the ventral striatum and the mPFC, and this connectivity seems to play an increasingly important role in social behaviors as youth enter adolescence.

Positive valence bias and parent-child relationship security moderate the association between early institutional caregiving and internalizing symptoms.

Institutional caregiving is associated with significant deviations from species-expected caregiving, altering the normative sequence of attachment formation and placing children at risk for long-term emotional difficulties. However, little is known about factors that can promote resilience following early institutional caregiving. In the current study, we investigated how adaptations in affective processing (i.e., positive valence bias) and family-level protective factors (i.e., secure parent-child relationships) moderate risk for internalizing symptoms in previously institutionalized (PI) youth. Children and adolescents with and without a history of institutional care performed a laboratory-based affective processing task and self-reported measures of parent-child relationship security. PI youth were more likely than comparison youth to show positive valence biases when interpreting ambiguous facial expressions. Both positive valence bias and parent-child relationship security moderated the association between institutional care and parent-reported internalizing symptoms, such that greater positive valence bias and more secure parent-child relationships predicted fewer symptoms in PI youth. However, when both factors were tested concurrently, parent-child relationship security more strongly moderated the link between PI status and internalizing symptoms. These findings suggest that both individual-level adaptations in affective processing and family-level factors of secure parent-child relationships may ameliorate risk for internalizing psychopathology following early institutional caregiving.

Discrimination of amygdala response predicts future separation anxiety in youth with early deprivation.

BACKGROUND: Significant disruption in caregiving is associated with increased internalizing symptoms, most notably heightened separation anxiety symptoms during childhood. It is also associated with altered functional development of the amygdala, a neurobiological correlate of anxious behavior. However, much less is known about how functional alterations of amygdala predict individual differences in anxiety. Here, we probed amygdala function following institutional caregiving using very subtle social-affective stimuli (trustworthy and untrustworthy faces), which typically result in large differences in amygdala signal, and change in separation anxiety behaviors over a 2-year period. We hypothesized that the degree of differentiation of amygdala signal to trustworthy versus untrustworthy face stimuli would predict separation anxiety symptoms. METHODS: Seventy-four youths mean (SD) age = 9.7 years (2.64) with and without previous institutional care, who were all living in families at the time of testing, participated in an fMRI task designed to examine differential amygdala response to trustworthy versus untrustworthy faces. Parents reported on their children's separation anxiety symptoms at the time of scan and again 2 years later. RESULTS: Previous institutional care was associated with diminished amygdala signal differences and behavioral differences to the contrast of untrustworthy and trustworthy faces. Diminished differentiation of these stimuli types predicted more severe separation anxiety symptoms 2 years later. Older age at adoption was associated with diminished differentiation of amygdala responses. CONCLUSIONS: A history of institutional care is associated with reduced differential amygdala responses to social-affective cues of trustworthiness that are typically exhibited by comparison samples. Individual differences in the degree of amygdala differential responding to these cues predict the severity of separation anxiety symptoms over a 2-year period. These findings provide a biological mechanism to explain the associations between early caregiving adversity and individual differences in internalizing symptomology during development, thereby contributing to individualized predictions of future clinical outcomes.

Early developmental emergence of human amygdala-prefrontal connectivity after maternal deprivation.

Under typical conditions, medial prefrontal cortex (mPFC) connections with the amygdala are immature during childhood and become adult-like during adolescence. Rodent models show that maternal deprivation accelerates this development, prompting examination of human amygdala-mPFC phenotypes following maternal deprivation. Previously institutionalized youths, who experienced early maternal deprivation, exhibited atypical amygdala-mPFC connectivity. Specifically, unlike the immature connectivity (positive amygdala-mPFC coupling) of comparison children, children with a history of early adversity evidenced mature connectivity (negative amygdala-mPFC coupling) and thus, resembled the adolescent phenotype. This connectivity pattern was mediated by the hormone cortisol, suggesting that stress-induced modifications of the hypothalamic-pituitary-adrenal axis shape amygdala-mPFC circuitry. Despite being age-atypical, negative amygdala-mPFC coupling conferred some degree of reduced anxiety, although anxiety was still significantly higher in the previously institutionalized group. These findings suggest that accelerated amygdala-mPFC development is an ontogenetic adaptation in response to early adversity.

"The Cooties Effect": Amygdala Reactivity to Opposite- versus Same-sex Faces Declines from Childhood to Adolescence.

One of the most important social identities that children learn to define themselves and others by is sex, becoming a salient social category by early childhood. Although older children begin to show greater flexibility in their gendered behaviors and attitudes, gender rigidity intensifies again around the time of puberty. In the current study, we assessed behavioral and neural biases to sex across a wide age group. Ninety-three youth (ages 7-17 years) provided behavioral rating of same- and opposite-sex attitudes, and 52 youth (ages 4-18 years) underwent an fMRI scan as they matched the emotion of same- and opposite-sex faces. We demonstrate significant age-related behavioral biases of sex that are mediated by differential amygdala response to opposite-sex relative to same-sex faces in children, an effect that completely attenuates by the teenage years. Moreover, we find a second peak in amygdala sensitivity to opposite-sex faces around the time of puberty. Thus, the amygdala codes for developmentally dependent and motivationally relevant social identification across development.

Normative development of ventral striatal resting state connectivity in humans.

Incentives play a crucial role in guiding behavior throughout our lives, but perhaps no more so than during the early years of life. The ventral striatum is a critical piece of an incentive-based learning circuit, sharing robust anatomical connections with subcortical (e.g., amygdala, hippocampus) and cortical structures (e.g., medial prefrontal cortex (mPFC), insula) that collectively support incentive valuation and learning. Resting-state functional connectivity (rsFC) is a powerful method that provides insight into the development of the functional architecture of these connections involved in incentive-based learning. We employed a seed-based correlation approach to investigate ventral striatal rsFC in a cross-sectional sample of typically developing individuals between the ages of 4.5 and 23-years old (n=66). Ventral striatal rsFC with the mPFC showed regionally specific linear age-related changes in connectivity that were associated with age-related increases in circulating testosterone levels. Further, ventral striatal connectivity with the posterior hippocampus and posterior insula demonstrated quadratic age-related changes characterized by negative connectivity in adolescence. Finally, across this age range, the ventral striatum demonstrated positive coupling with the amygdala beginning during childhood and remaining consistently positive across age. In sum, our findings suggest that normative ventral striatal rsFC development is dynamic and characterized by early establishment of connectivity with medial prefrontal and limbic structures supporting incentive-based learning, as well as substantial functional reorganization with later developing regions during transitions into and out of adolescence.

Early-life adversity and adolescent depression: mechanisms involving the ventral striatum.

Early-life adversity is a well-established risk factor for the development of depression later in life. Here we discuss the relationship between early-life adversity and depression, focusing specifically on effects of early-life caregiver deprivation on alterations in the neural and behavioral substrates of reward-processing. We also examine vulnerability to depression within the context of sensitive periods of neural development and the timing of adverse exposure. We further review the development of the ventral striatum, a limbic structure implicated in reward processing, and its role in depressive outcomes following early-life adversity. Finally, we suggest a potential neurobiological mechanism linking early-life adversity and altered ventral striatal development. Together these findings may help provide further insight into the role of reward circuitry dysfunction in psychopathological outcomes in both clinical and developmental populations.

Exploration-exploitation strategy is dependent on early experience.

Traditional conceptualizations of early adversity characterize behavioral outcomes as maladaptive. However, conditional adaptation theory proposes that differing behavioral phenotypes following early experience are appropriate for the expected environment (e.g., behaviors likely to result in the best outcome based on environmental expectations). In the present study, youth with (n = 46) and without (n = 91) a history of previous institutionalization completed a laboratory-based experimental paradigm in which exploration-exploitation strategy was examined, a phenotype relevant to environmental expectations. Previous institutionalization was associated with decreased exploration and increased exploitation. A strategy favoring exploration resulted in greater success in the generous task condition whereas a strategy favoring exploitation produced greater success in the restricted task condition. These results suggest that exploration-exploitation strategy may be influenced by early experience, and the resulting success of strategy choice is context dependent and in line with expectations of the future environment based on early experience.

A developmental shift from positive to negative connectivity in human amygdala-prefrontal circuitry.

Recent human imaging and animal studies highlight the importance of frontoamygdala circuitry in the regulation of emotional behavior and its disruption in anxiety-related disorders. Although tracing studies have suggested changes in amygdala-cortical connectivity through the adolescent period in rodents, less is known about the reciprocal connections within this circuitry across human development, when these circuits are being fine-tuned and substantial changes in emotional control are observed. The present study examined developmental changes in amygdala-prefrontal circuitry across the ages of 4-22 years using task-based functional magnetic resonance imaging. Results suggest positive amygdala-prefrontal connectivity in early childhood that switches to negative functional connectivity during the transition to adolescence. Amygdala-medial prefrontal cortex functional connectivity was significantly positive (greater than zero) among participants younger than 10 years, whereas functional connectivity was significantly negative (less than zero) among participants 10 years and older, over and above the effect of amygdala reactivity. The developmental switch in functional connectivity was paralleled by a steady decline in amygdala reactivity. Moreover, the valence switch might explain age-related improvement in task performance and a developmentally normative decline in anxiety. Initial positive connectivity followed by a valence shift to negative connectivity provides a neurobiological basis for regulatory development and may present novel insight into a more general process of developing regulatory connections.

Early experience shapes amygdala sensitivity to race: an international adoption design.

In the current study, we investigated how complete infant deprivation to out-group race impacts behavioral and neural sensitivity to race. Although monkey models have successfully achieved complete face deprivation in early life, this is typically impossible in human studies. We overcame this barrier by examining youths with exclusively homogenous racial experience in early postnatal development. These were youths raised in orphanage care in either East Asia or Eastern Europe as infants and later adopted by American families. The use of international adoption bolsters confidence of infant exposure to race (e.g., to solely Asian faces or European faces). Participants completed an emotional matching task during functional MRI. Our findings show that deprivation to other-race faces in infancy disrupts recognition of emotion and results in heightened amygdala response to out-group faces. Greater early deprivation (i.e., later age of adoption) is associated with greater biases to race. These data demonstrate how early social deprivation to race shapes amygdala function later in life and provides support that early postnatal development may represent a sensitive period for race perception.

The development of human amygdala functional connectivity at rest from 4 to 23 years: a cross-sectional study.

Functional connections (FC) between the amygdala and cortical and subcortical regions underlie a range of affective and cognitive processes. Despite the central role amygdala networks have in these functions, the normative developmental emergence of FC between the amygdala and the rest of the brain is still largely undefined. This study employed amygdala subregion maps and resting-state functional magnetic resonance imaging to characterize the typical development of human amygdala FC from age 4 to 23years old (n=58). Amygdala FC with subcortical and limbic regions was largely stable across this developmental period. However, three cortical regions exhibited age-dependent changes in FC: amygdala FC with the medial prefrontal cortex (mPFC) increased with age, amygdala FC with a region including the insula and superior temporal sulcus decreased with age, and amygdala FC with a region encompassing the parahippocampal gyrus and posterior cingulate also decreased with age. The transition from childhood to adolescence (around age 10years) marked an important change-point in the nature of amygdala-cortical FC. We distinguished unique developmental patterns of coupling for three amygdala subregions and found particularly robust convergence of FC for all subregions with the mPFC. These findings suggest that there are extensive changes in amygdala-cortical functional connectivity that emerge between childhood and adolescence.

Maternal buffering of human amygdala-prefrontal circuitry during childhood but not during adolescence.

Mature amygdala-prefrontal circuitry regulates affect in adulthood but shows protracted development. In altricial and semialtricial species, caregivers provide potent affect regulation when mature neurocircuitry is absent. The present investigation examined a potential mechanism through which caregivers provide regulatory influences in childhood. Children, but not adolescents, showed evidence of maternal buffering, such that maternal stimuli suppressed amygdala reactivity. In the absence of maternal stimuli, children exhibited immature amygdala-prefrontal connectivity. However, in the presence of maternal stimuli, children's connectivity was more mature, resembling adolescents' connectivity. Children showed improved affect-related regulation in the presence of their mothers. Individual differences emerged, with greater maternal influence on amygdala-prefrontal circuitry associated with stronger mother-child relationships and maternal modulation of behavioral regulation. These findings suggest a neural mechanism through which caregivers modulate children's regulatory behavior by inducing more mature connectivity and buffering against heightened reactivity. Maternal buffering in childhood, but not adolescence, suggests that childhood may be a sensitive period for amygdala-prefrontal development.

Telomere Erosion and Depressive Symptoms Across Development Following Institutional Care.

OBJECTIVE: A large literature has identified exposure to early caregiving adversities as a potent risk for developing affective psychopathology, with depression, in particular, increasing across childhood into adolescence. Evidence suggests telomere erosion, a marker of biological aging, may underlie associations between adverse early-life experiences and later depressive behavior; yet, little is understood about this association during development. METHOD: The current accelerated longitudinal study examined concurrent telomere length and depressive symptoms concurrently, 2 and 4 years later, from the preschool period through adolescence among children exposed (n =116) and not exposed (n = 242) to early previous institutional (PI) care. RESULTS: PI care was associated with shorter telomeres on average and with quadratic age-related growth in depressive symptoms, indicating a steeper association between PI care and depressive symptoms in younger age groups that leveled off in adolescence. Contrary to studies in adult samples, telomere length was not associated with depressive symptoms, and it did not predict future symptoms. CONCLUSION: These findings indicate that early caregiving disruptions increase the risk for both accelerated biological aging and depressive symptoms, although these variables did not correlate with each other during this age range.