Plasticity of thalamocortical axons is regulated by serotonin levels modulated by preterm birth.

Sensory inputs are conveyed to distinct primary areas of the neocortex through specific thalamocortical axons (TCA). While TCA have the ability to reorient postnatally to rescue embryonic mistargeting and target proper modality-specific areas, how this remarkable adaptive process is regulated remains largely unknown. Here, using a mutant mouse model with a shifted TCA trajectory during embryogenesis, we demonstrated that TCA rewiring occurs during a short postnatal time window, preceded by a prenatal apoptosis of thalamic neurons-two processes that together lead to the formation of properly innervated albeit reduced primary sensory areas. We furthermore showed that preterm birth, through serotonin modulation, impairs early postnatal TCA plasticity, as well as the subsequent delineation of cortical area boundary. Our study defines a birth and serotonin-sensitive period that enables concerted adaptations of TCA to primary cortical areas with major implications for our understanding of brain wiring in physiological and preterm conditions.

Peripuberty Is a Sensitive Period for Prefrontal Parvalbumin Interneuron Activity to Impact Adult Cognitive Flexibility.

INTRODUCTION: Developmental windows in which experiences can elicit long-lasting effects on brain circuitry and behavior are called "sensitive periods" and reflect a state of heightened plasticity. The classic example of a sensitive period comes from studies of sensory systems, like the visual system, where early visual experience is required for normal wiring of primary visual cortex and proper visual functioning. At a mechanistic level, loss of incoming visual input results in a decrease in activity in thalamocortical neurons representing the affected eye, resulting in an activity-dependent reduction in the representation of those inputs in the visual cortex and loss of visual perception in that eye. While associative cortical regions like the medial prefrontal cortex (mPFC) do not receive direct sensory input, recent findings demonstrate that changes in activity levels experienced by this region during defined windows in early development may also result in long-lasting changes in prefrontal cortical circuitry, network function, and behavior. For example, we recently demonstrated that decreasing the activity of mPFC parvalbumin-expressing (PV) interneurons during a period of time encompassing peripuberty (postnatal day P14) to adolescence (P50) led to a long-lasting decrease in their functional inhibition of pyramidal cells, as well as impairments in cognitive flexibility. While the effects of manipulating mPFC PV interneuron activity were selective to development, and not adulthood, the exact timing of the sensitive period for this manipulation remains unknown. METHODS: To refine the sensitive period in which inhibiting mPFC PV cell activity can lead to persistent effects on prefrontal functioning, we used a chemogenetic approach to restrict our inhibition of mPFC PV activity to two distinct windows: (1) peripuberty (P14-P32) and (2) early adolescence (P33-P50). We then investigated adult behavior after P90. In parallel, we performed histological analysis of molecular markers associated with sensitive period onset and offset in visual cortex, to define the onset and offset of peak-sensitive period plasticity in the mPFC. RESULTS: We found that inhibition of mPFC PV interneurons in peripuberty (P14-P32), but not adolescence (P33-P50), led to an impairment in set-shifting behavior in adulthood manifest as an increase in trials to reach criterion performance and errors. Consistent with a pubertal onset of sensitive period plasticity in the PFC, we found that histological markers of sensitive period onset and offset also demarcated P14 and P35, respectively. The time course of expression of these markers was similar in visual cortex. CONCLUSION: Both lines of research converge on the peripubertal period (P14-P32) as one of heightened sensitive period plasticity in the mPFC. Further, our direct comparison of markers of sensitive period plasticity across the prefrontal and visual cortex suggests a similar time course of expression, challenging the notion that sensitive periods occur hierarchically. Together, these findings extend our knowledge about the nature and timing of sensitive period plasticity in the developing mPFC.

Early life exposure to queen mandibular pheromone mediates persistent transcriptional changes in the brain of honey bee foragers.

Behavioural regulation in insect societies remains a fundamental question in sociobiology. In hymenopteran societies, the queen plays a crucial role in regulating group behaviour by affecting individual behaviour and physiology through modulation of worker gene expression. Honey bee (Apis mellifera) queens signal their presence via queen mandibular pheromone (QMP). While QMP has been shown to influence behaviour and gene expression of young workers, we know little about how these changes translate in older workers. The effects of the queen pheromone could have prolonged molecular impacts on workers that depend on an early sensitive period. We demonstrate that removal of QMP impacts long-term gene expression in the brain and antennae in foragers that were treated early in life (1 day post emergence), but not when treated later in life. Genes important for division of labour, learning, chemosensory perception and ageing were among those differentially expressed in the antennae and brain tissues, suggesting that QMP influences diverse physiological and behavioural processes in workers. Surprisingly, removal of QMP did not have an impact on foraging behaviour. Overall, our study suggests a sensitive period early in the life of workers, where the presence or absence of a queen has potentially life-long effects on transcriptional activity.

Bedtime to the brain: how infants' sleep behaviours intertwine with non-rapid eye movement sleep electroencephalography features.

Adequate sleep is critical for development and facilitates the maturation of the neurophysiological circuitries at the basis of cognitive and behavioural function. Observational research has associated early life sleep problems with worse later cognitive, psychosocial, and somatic health outcomes. Yet, the extent to which day-to-day sleep behaviours (e.g., duration, regularity) in early life relate to non-rapid eye movement (NREM) neurophysiology-acutely and the long-term-remains to be studied. We measured sleep behaviours in 32 healthy 6-month-olds assessed with actimetry and neurophysiology with high-density electroencephalography (EEG) to investigate the association between NREM sleep and habitual sleep behaviours. Our study revealed four findings: first, daytime sleep behaviours are related to EEG slow-wave activity (SWA). Second, night-time movement and awakenings from sleep are connected with spindle density. Third, habitual sleep timing is linked to neurophysiological connectivity quantified as delta coherence. And lastly, delta coherence at 6 months predicts night-time sleep duration at 12 months. These novel findings widen our understanding that infants' sleep behaviours are closely intertwined with three particular levels of neurophysiology: sleep pressure (determined by SWA), the maturation of the thalamocortical system (spindles), and the maturation of cortical connectivity (coherence). The crucial next step is to extend this concept to clinical groups to objectively characterise infants' sleep behaviours 'at risk' that foster later neurodevelopmental problems.

Sight restoration in congenitally blind humans does not restore visual brain structure.

It is unknown whether impaired brain structure after congenital blindness is reversible if sight is restored later in life. Using structural magnetic resonance imaging, visual cortical surface area and cortical thickness were assessed in a large group of 21 sight-recovery individuals who had been born blind and who months or years later gained sight through cataract removal surgery. As control groups, we included 27 normally sighted individuals, 10 individuals with permanent congenital blindness, and 11 sight-recovery individuals with a late onset of cataracts. Congenital cataract-reversal individuals had a lower visual cortical surface area and a higher visual cortical thickness than normally sighted controls. These results corresponded to those of congenitally permanently blind individuals suggesting that impaired brain structure did not recover. Crucially, structural brain alterations in congenital-cataract reversal individuals were associated with a lower post-surgery visual acuity. No significant changes in visual cortex structure were observed in sight-recovery individuals with late onset cataracts. The results demonstrate that impaired structural brain development due to visual deprivation from birth is not fully reversible and limits functional recovery. Additionally, they highlight the crucial importance of prevention measures in the context of other types of aberrant childhood environments including low socioeconomic status and adversity.

Twin Data Support a Sensitive Period for Singing Ability.

As with many other musical traits, the social environment is a key influence on the development of singing ability. While the familial singing environment is likely to be formative, its role relative to other environmental influences such as training is unclear. We used structural equation modeling to test relationships among demographic characteristics, familial environmental variables (early and current singing with family), vocal training, and singing ability in a large, previously documented sample of Australian twins (N = 1163). Notably, early singing with family, and to a lesser extent vocal training, predicted singing ability, whereas current singing with family did not. Early familial singing also mediated the relationship between sex and singing ability, with men who sang less with family during childhood showing poorer ability. Bivariate twin models between early familial singing and singing ability showed the phenotypic correlation was largely explained by shared environmental influences. This raises the possibility of a sensitive period for singing ability, with sociocultural expectations around singing potentially differentiating the developmental trajectories of this skill for men and women.

Contributions of dysfunctional plasticity mechanisms to the development of atypical perceptual processing.

Experimental studies of sensory plasticity during development in birds and mammals have highlighted the importance of sensory experiences for the construction and refinement of functional neural circuits. We discuss how dysregulation of experience-dependent brain plasticity can lead to abnormal perceptual representations that may contribute to heterogeneous deficits symptomatic of several neurodevelopmental disorders. We focus on alterations of somatosensory processing and the dynamic reorganization of cortical synaptic networks that occurs during early perceptual development. We also discuss the idea that the heterogeneity of strengths and weaknesses observed in children with neurodevelopmental disorders may be a direct consequence of altered plasticity mechanisms during early development. Treating the heterogeneity of perceptual developmental trajectories as a phenomenon worthy of study rather than as an experimental confound that should be overcome may be key to developing interventions that better account for the complex developmental trajectories experienced by modern humans.

Early-life exposure to PM2.5 leads to ASD-like phenotype in male offspring rats through activation of PI3K-AKT signaling pathway.

Previous studies have shown that early-life exposure to fine particulate matter (PM2.5) is associated with an increasing risk of autism spectrum disorder (ASD), however, the specific sensitive period of ASD is unknown. Here, a model of dynamic whole-body concentrated PM2.5 exposure in pre- and early-postnatal male offspring rats (MORs) was established. And we found that early postnatal PM2.5 exposed rats showed more typical ASD behavioral characteristics than maternal pregnancy exposure rats, including poor social interaction, novelty avoidance and anxiety disorder. And more severe oxidative stress and inflammatory responses were observed in early postnatal PM2.5 exposed rats. Moreover, the expression level of phosphatase and tensin homolog deleted on chromosome ten (PTEN) was down-regulated and the ratios of p-PI3K/PI3K and p-AKT/AKT were up-regulated in early postnatal PM2.5 exposed rats. This study suggests that early postnatal exposure to PM2.5 is more susceptible to ASD-like phenotype in offspring than maternal pregnancy exposure and the activation of PI3K-AKT signaling pathway may represent underlying mechanisms.

Using cortico-cerebellar structural patterns to classify early- and late-trained musicians.

A body of current evidence suggests that there is a sensitive period for musical training: people who begin training before the age of seven show better performance on tests of musical skill, and also show differences in brain structure-especially in motor cortical and cerebellar regions-compared with those who start later. We used support vector machine models-a subtype of supervised machine learning-to investigate distributed patterns of structural differences between early-trained (ET) and late-trained (LT) musicians and to better understand the age boundaries of the sensitive period for early musicianship. After selecting regions of interest from the cerebellum and cortical sensorimotor regions, we applied recursive feature elimination with cross-validation to produce a model which optimally and accurately classified ET and LT musicians. This model identified a combination of 17 regions, including 9 cerebellar and 8 sensorimotor regions, and maintained a high accuracy and sensitivity (true positives, i.e., ET musicians) without sacrificing specificity (true negatives, i.e., LT musicians). Critically, this model-which defined ET musicians as those who began their training before the age of 7-outperformed all other models in which age of start was earlier or later (between ages 5-10). Our model's ability to accurately classify ET and LT musicians provides additional evidence that musical training before age 7 affects cortico-cerebellar structure in adulthood, and is consistent with the hypothesis that connected brain regions interact during development to reciprocally influence brain and behavioral maturation.

Maternal social support during and after pregnancy and child cognitive ability: examining timing effects in two cohorts.

BACKGROUND: Maternal anxiety, depression, and stress during and after pregnancy are negatively associated with child cognitive development. However, the contribution of positive maternal experiences, such as social support, to child cognitive development has received less attention. Furthermore, how maternal experience of social support during specific developmental periods impacts child cognitive development is largely unknown. METHODS: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 5784) and the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study (PREDO; n = 420), we investigated the associations between maternal perceived social support during and after pregnancy and child's general cognitive ability at 8 years of age, assessed with the Wechsler Intelligence Scale for Children (WISC). Bayesian relevant life course modeling was used to investigate timing effects of maternal social support on child cognitive ability. RESULTS: In both cohorts, higher maternal perceived social support during pregnancy was associated with higher performance on the WISC, independent of sociodemographic factors and concurrent maternal symptoms of depression and anxiety. In ALSPAC, pregnancy emerged as a sensitive period for the effects of perceived social support on child cognitive ability, with a stronger effect of social support during pregnancy than after pregnancy on child cognitive ability. CONCLUSIONS: Our findings, supported from two prospective longitudinal cohorts, suggest a distinct role of maternal perceived social support during pregnancy for cognitive development in children. Our study suggests that interventions aimed at increasing maternal social support during pregnancy may be an important strategy for promoting maternal and child well-being.

History of childhood mistreatment and the psychological health consequences of COVID-19 for older adults.

OBJECTIVES: We examine the associations between childhood mistreatment (emotional abuse, physical abuse, sexual abuse, and emotional neglect) and older adults' changes in depressive symptoms from before to during the COVID-19 pandemic (September 2018-June 2020). METHODS: Using a community-based sample of older adults in North Florida (N = 581), we used ordinary least-squares regression to estimate associations between childhood mistreatments and depressive symptoms in June 2020, controlling for baseline symptoms and demographic characteristics. Additional models tested whether emotion regulation and social support attenuated associations between childhood mistreatments and depressive symptoms. RESULTS: Older adults exposed to emotional neglect in childhood saw a greater increase in depressive symptoms than those who did not experience childhood mistreatment. Those reporting childhood physical abuse had higher baseline depressive symptoms, but they did not increase during the pandemic. These associations remained stable after controlling for emotion regulation and social support, coping resources thought to contribute to linkages between childhood mistreatment and psychological health in adulthood. CONCLUSION: Childhood mistreatment might inform the psychological consequences of major stressors in later life. Thus, early life interventions for children experiencing mistreatment could be especially important for long-term psychological health outcomes and responses to major stressful events. Identifying older people with histories of childhood mistreatment could also help clinicians gauge patients' risk of psychological decline during times such as the COVID-19 pandemic and tailor psychological health interventions.

Mediolateral Postural Control Mechanisms and Proprioception Improve With Kicking Sports Training During Adolescence.

Sensorimotor stimulation during the sensitive period is crucial for proper brain development. Kicking sports (KS) training stimulates these sensorimotor functions. The purpose of this study was to investigate if incorporating specific sensorimotor stimulation in mediolateral axis and proprioceptive inputs during KS training will improve the specific sensorimotor performance in adolescents. We assessed stability limits in 13 KS practitioners and 20 control participants. Starting from an upright position, subjects were asked to lean as far as possible (forward, backward, rightward, and leftward). Three sensory conditions were tested: (1) eyes open, (2) eyes closed, and (3) eyes closed while standing on a foam mat. We analyzed the maximal center of pressure excursion and the root means square of the center of pressure displacements. Results showed that KS group had smaller root means square and larger maximal center of pressure excursions than those of control participants in mediolateral axis in all sensory conditions. Furthermore, the results also revealed a significant smaller root means square excursion in KS group under foam mat condition compared to control group ML axis. This study provides evidence that KS training improved the lateral balance control and proprioceptive integration.

Development of infants' neural speech processing and its relation to later language skills: A MEG study.

The 'sensitive period' for phonetic learning (∼6-12 months) is one of the earliest milestones in language acquisition where infants start to become specialized in processing speech sounds in their native language. In the last decade, advancements in neuroimaging technologies for infants are starting to shed light on the underlying neural mechanisms supporting this important learning period. The current study reports on a large longitudinal dataset with the aim to replicate and extend on two important questions: 1) what are the developmental changes during the 'sensitive period' for native and nonnative speech processing? 2) how does native and nonnative speech processing in infants predict later language outcomes? Fifty-four infants were recruited at 7 months of age and their neural processing of speech was measured using Magnetoencephalography (MEG). Specifically, the neural sensitivity to a native and a nonnative speech contrast was indexed by the mismatch response (MMR). They repeated the measurement again at 11 months of age and their language development was further tracked from 12 months to 30 months of age using the MacArthur-Bates Communicative Development Inventory (CDI). Using an a priori Region-of-Interest (ROI) approach, we observed significant increases for the Native MMR in the left inferior frontal region (IF) and superior temporal region (ST) from 7 to 11 months, but not for the Nonnative MMR. Complementary whole brain comparison revealed more widespread developmental changes for both contrasts. However, only individual differences in the left IF and ST for the Nonnative MMR at 11 months of age were significant predictors of individual vocabulary growth up to 30 months of age. An exploratory machine-learning based analysis further revealed that whole brain time series for both Native and Nonnative contrasts can robustly predict later outcomes, but with very different underlying spatial-temporal patterns. The current study extends our current knowledge and suggests that native and nonnative speech processing may follow different developmental trajectories and utilize different mechanisms that are relevant for later language skills.

Altered resting-state functional network connectivity in profound sensorineural hearing loss infants within an early sensitive period: A group ICA study.

Data from both animal models and deaf children provide evidence for that the maturation of auditory cortex has a sensitive period during the first 2-4 years of life. During this period, the auditory stimulation can affect the development of cortical function to the greatest extent. Thus far, little is known about the brain development trajectory after early auditory deprivation within this period. In this study, independent component analysis (ICA) technique was used to detect the characteristics of brain network development in children with bilateral profound sensorineural hearing loss (SNHL) before 3 years old. Seven resting-state networks (RSN) were identified in 50 SNHL and 36 healthy controls using ICA method, and further their intra-and inter-network functional connectivity (FC) were compared between two groups. Compared with the control group, SNHL group showed decreased FC within default mode network, while enhanced FC within auditory network (AUN) and salience network. No significant changes in FC were found in the visual network (VN) and sensorimotor network (SMN). Furthermore, the inter-network FC between SMN and AUN, frontal network and AUN, SMN and VN, frontal network and VN were significantly increased in SNHL group. The results implicate that the loss and the compensatory reorganization of brain network FC coexist in SNHL infants. It provides a network basis for understanding the brain development trajectory after hearing loss within early sensitive period.

Why Is an Early Start of Training Related to Musical Skills in Adulthood? A Genetically Informative Study.

Experts in domains such as music or sports often start training early. It has been suggested that this may reflect a sensitive period in childhood for skill acquisition. However, it could be that familial factors (e.g., genetics) contribute to the association. Here, we examined the effect of age of onset of musical training on musical aptitude and achievement in professional musicians (n = 310) and twins (n = 7,786). In line with previous literature, results showed that an earlier age of onset was associated with higher aptitude and achievement in both samples. After we adjusted for lifetime practice hours, age of onset was associated only with aptitude (p < .001; achievement: p > .14). Twin analyses showed that the association with aptitude was fully explained by familial factors. Thus, these findings provide little support for a sensitive period for music but highlight that familiar factors play an important role for associations between age of onset of training and skills in adulthood.

The effects of early-life immune activation on microglia-mediated neuronal remodeling and the associated ontogeny of hippocampal-dependent learning in juvenile rats.

Many neurodevelopmental disorders and associated learning deficits have been linked to early-life immune activation or ongoing immune dysregulation (Laskaris et al., 2016; O'Connor et al., 2014; Frick et al., 2013). Neuroscientists have begun to understand how the maturation of neural circuits allows for the emergence of cognitive and learning behaviors; yet we know very little about how these developing neural circuits are perturbed by certain events, including risk-factors such as early-life immune activation and immune dysregulation. To answer these questions, we examined the impact of early-life immune activation on the emergence of hippocampal-dependent learning in juvenile male and female rats using a well-characterized hippocampal-dependent learning task and we investigated the corresponding, dynamic multicellular interactions in the hippocampus that may contribute to these learning deficits. We found that even low levels of immune activation can result in hippocampal-depedent learning deficits days later, but only when this activation occurs during a sensitive period of development. The initial immune response and associated cytokine production in the hippocampus resolved within 24 h, several days prior to the observed learning deficit, but notably the initial immune response was followed by altered microglial-neuronal communication and synapse remodeling that changed the structure of hippocampal neurons during this period of juvenile brain development. We conclude that immune activation or dysregulation during a sensitive period of hippocampal development can precipitate the emergence of learning deficits via a multi-cellular process that may be initiated by, but not the direct result of the initial cytokine response. SIGNIFICANCE STATEMENT: Many neurodevelopmental disorders have been linked to early-life immune activation or immune dysregulation; however, very little is known about how dynamic changes in neuroimmune cells mediate the transition from normal brain function to the early stages of cognitive disorders, or how changes in immune signaling are subsequently integrated into developing neuronal networks. The current experiments examined the consequences of immune activation on the cellular and molecular changes that accompany the emergence of learning deficits during a sensitive period of hippocampal development. These findings have the potential to significantly advance our understanding of how early-life immune activation or dysregulation can result in the emergence of cognitive and learning deficits that are the largest source of years lived with disability in humans.

Severe effects of the COVID-19 confinement on young children's sleep: A longitudinal study identifying risk and protective factors.

The COVID-19 confinement has dramatically altered daily routines, causing decreased sleep quality in adults. This necessitates careful observation, as sleep plays a crucial role in brain maturation and poor sleep increases the risk of psychopathology, particularly in the young population. Through an online survey with one baseline (April 2020) and two follow-up assessments (May and June 2020), we examined the effect of confinement on sleep quality in 452 babies (0-35 months) and 412 preschool children (36-71 months) from several, mainly European, countries. An acute decrease in sleep quality was found in both groups of children. However, at follow-up assessments, this effect rebounded to the level reported for the period before the confinement. Importantly, caregiver's stress level was identified as a substantial risk factor determining lower sleep quality in both groups of children across assessments. Protective factors conserving children's sleep quality included caregiver's engagement in mindfulness techniques or childcare, and the presence of siblings and pets. In the near future, we may repeatedly experience the circumstances of abruptly enforced confinement. Our findings reveal promising pathways of action to protect young children's sleep, with which to essentially mitigate the long-term consequences of the pandemic on brain development and mental health.

Timing-specific associations between income-to-needs ratio and hippocampal and amygdala volumes in middle childhood: A preliminary study.

It is well known that financial disadvantage is associated with alterations in brain development in regions critical to socioemotional well-being such as the hippocampus and the amygdala. Yet little is known about whether family income at different points in development is differentially associated with these structures. Furthermore, little is known about which environmental factors statistically mediate associations between income and subcortical structure. Using a longitudinal birth cohort and linear mixed-effects models, we identified associations between income-to-needs ratio (INR) at 6 timepoints throughout childhood and hippocampal and amygdala volumes at age 7-9 years (n = 41; 236 INR measurements; 41 brain measurements). Mediation analysis identified environmental sequelae of income that statistically accounted for INR-brain associations. Lower INR prior to age 4 was associated with smaller hippocampal volumes, whereas lower INR prior to age 2 was associated with smaller right amygdala volume. These associations were mediated by unmet basic needs (e.g., food, housing). These findings delineate the temporal specificity of associations between income and hippocampal and amygdala structures.

Gene manipulation to test links between genome, brain and behavior in developing songbirds: a test case.

Songbird research has made many seminal contributions to the fields of ethology, endocrinology, physiology, ecology, evolution and neurobiology. Genome manipulation is thus a promising new methodological strategy to enhance the existing strengths of the songbird system to advance and expand fundamental knowledge of how genetic sequences and regulation of genomic function support complex natural learned behaviors. In zebra finches (Taeniopygia guttata) in particular, a rich set of questions about the complex process of developmental song learning in juvenile males has been defined. This Review uses one area of zebra finch song learning to demonstrate how genome editing can advance causal investigations into known genome-brain-behavior relationships. Given the number and diversity of songbird species, comparative work leveraging genome manipulation would expand the influence of these birds in additional fields of ecology and evolution for song learning and other behaviors.

Oral contraceptive use in adolescence predicts lasting vulnerability to depression in adulthood.

BACKGROUND: Previous evidence suggests that use of oral contraceptives (OCs), especially during adolescence, may increase women's vulnerability to depression in the short term. Here, we investigate whether women who had first used OC in adolescence show an increased prevalence of depression in the long term. METHODS: We examined 1,236 women in the United States National Health and Nutrition Examination Survey for whom information on depression and age at first OC use was publicly available. We compared women who reported first use of OCs in adolescence to women who had never used OCs and women who had first used OCs in adulthood on 1-year prevalence of major depressive disorder (MDD) assessed by trained interviewers. RESULTS: Compared with women who had used OCs during adolescence, women who had never used OCs were less likely to meet the criteria for MDD within the past year in adulthood [odds ratio (OR) = 0.31, 95% CI = 0.16-0.60], and so were women who only started using OCs in adulthood (OR = 0.54, 95% CI = 0.30-0.95). Third factors that have previously been proposed to explain the relationship between OC use and depression risk such as age at sexual debut, and, importantly, current OC use, did not account for the results in propensity score analyses. CONCLUSIONS: We show a long-term association between adolescent OC use and depression risk in adulthood regardless of current OC use. Our findings suggest that adolescence may be a sensitive period during which OC use could increase women's risk for depression, years after first exposure.