Sensitive Periods Of Development Research Articles

A role for activity-dependent epigenetics in the development and treatment of major depressive disorder.

Chronic stressors, during developmental sensitive periods and beyond, contribute to the risk of developing psychiatric conditions, including major depressive disorder (MDD). Epigenetic mechanisms including DNA methylation and histone modifications, at key stress response and neurotrophin genes, are increasingly implicated in mediating this risk. Although the exact mechanisms through which stressful environmental stimuli alter the epigenome are still unclear, research from the learning and memory fields indicates that epigenomic marks can be altered, at least in part, through calcium-dependent signaling cascades in direct response to neuronal activity. In this review, we highlight key findings from the stress, MDD, and learning and memory fields to propose a model where stress regulates downstream cellular functioning through activity-dependent epigenetic changes. Furthermore, we suggest that both typical and novel antidepressant treatments may exert positive influence through similar, activity-dependent pathways.

Microglia: Driving critical periods and sexual differentiation of the brain.

The proverbial role of microglia during brain development is shifting from passive members of the brain's immune system to active participants that are able to dictate enduring outcomes. Despite these advances, little attention has been paid to one of the most critical components of early brain development-sexual differentiation. Mounting evidence suggests that the normal developmental functions microglia perform-cell number regulation and synaptic connectivity-may be involved in the sex-specific patterning of the brain during these early sensitive periods, and may have lasting sex-dependent and sex-independent effects on behavior. In this review, we outline the known functions of microglia during developmental sensitive periods, and highlight the role they play in the establishment of sex differences in brain and behavior. We also propose a framework for how researchers can incorporate microglia in their study of sex differences and vice versa. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 580-592, 2018.

The Influence of Early Olfactory Experience on Mate Choice in Mammals: Evolutionary Aspects

The present review addresses the results of behavioral studies in cross-fostered rodent pups and the evolutionary significance and consequences of imprinting and early olfactory experience. The ability to assess the degree of relation to a potential mate can prevent inbreeding and the associated accumulation of deleterious mutations. Rodents are capable of recognizing related individuals by smell. This ability is formed in postnatal ontogenesis as a result of different mechanisms: “preassociation” and phenotypic correlation. The ability to distinguish representatives of their own and closely related species forms at an early age and is the basis for precopulative isolation mechanisms. Some mammals show an altered response to the odor of conspecifics after being fostered by individuals of other species, whereas other mammalian species do not show these changes. Certain features of odor response modification by early olfactory experience are species- and sexspecific. The critical period of behavioral reaction modification in response to odors occurs during the synaptogenesis period, which is indicative of the possible formation of new neuronal connections and synapses under the influence of early olfactory experiences. Certain behavioral and physiological responses were shown to be autonomous, as had an innate character and could not be altered by olfactory experience, whereas the others could change. The results of the studies, taken in their entirety, indicate a high degree of plasticity in the mammalian olfactory system, especially during short, sensitive developmental periods.

The Epigenetics of Early Life Adversity: Current Limitations and Possible Solutions.

Adverse experiences during sensitive postnatal developmental periods can disrupt the calibration of fundamental systems and increase the risk of a wide range of adult disease states, including psychiatric illnesses. Accumulating evidence suggests that epigenetic modifications involving DNA methylation, posttranslational histone modifications, and noncoding RNAs may be a key mediating factor in this disruption. Accumulating evidence from both animal models and human studies suggests that early life adversity alters the epigenome at multiple loci across the genome, but that the specific alterations, and the associated transcriptomic and psychiatric outcomes may be dependent on multiple individual factors. Here we will review the current findings on early life adversity associated alterations of the epigenome in animal models and humans, discuss current limitations, and highlight possible solutions and future directions.

Differential effects of childhood neglect and abuse during sensitive exposure periods on male and female hippocampus

The hippocampus is a highly stress susceptible structure and hippocampal abnormalities have been reported in a host of psychiatric disorders including major depression and post-traumatic stress disorder (PTSD). The hippocampus appears to be particularly susceptible to early life stress with a graded reduction in volume based on number of types (multiplicity) or severity of maltreatment. We assessed whether the most important predictors of adult hippocampal volume were multiplicity, severity or duration of exposure or timing of maltreatment during developmental sensitive periods. 3T MRIs were collected on 336 unmedicated, right-handed subjects (132M/204F, 18–25 years). Exposure to broad categories of abuse and neglect during each year of childhood were assessed using the Maltreatment and Abuse Chronology of Exposure scale and evaluated using artificial intelligence and predictive analytics. Male hippocampal volume was predicted by neglect, but not abuse, up through 7 years of age. Female hippocampal volume was predicted by abuse, but not neglect, at 10, 11, 15 and 16 years. Exposure at peak age had greater predictive importance than multiplicity, severity or duration. There were also marked gender differences in subfields and portions (head, body or tail) affected by exposure. History and symptoms of major depression, PTSD or anxiety disorders were not predictive of hippocampal volume once maltreatment was accounted for. Neglect appears to foster inadequate hippocampal development in males while abuse appears to produce a stress-related deficit in females. Studies assessing hippocampal volume in psychiatric disorders need to control for the gender-specific effects of abuse and neglect.

Neonatal programming with testosterone propionate reduces dopamine transporter expression in nucleus accumbens and methylphenidate-induced locomotor activity in adult female rats

Research in programming is focused on the study of stimuli that alters sensitive periods in development, such as prenatal and neonatal stages, that can produce long-term deleterious effects. These effects can occur in various organs or tissues such as the brain, affecting brain circuits and related behaviors. Our laboratory has demonstrated that neonatal programming with sex hormones affects the mesocorticolimbic circuitry, increasing the synthesis and release of dopamine (DA) in striatum and nucleus accumbens (NAcc). However, the behavioral response to psychostimulant drugs such as methylphenidate and the possible mechanism(s) involved have not been studied in adult rats exposed to sex hormones during the first hours of life. Thus, the aim of this study was to examine the locomotor activity induced by methylphenidate (5mg/kg i.p.) and the expression of the DA transporter (DAT) in NAcc of adult rats exposed to a single dose of testosterone propionate (TP: 1mg/50μLs.c.) or estradiol valerate (EV: 0.1mg/50μLs.c.) at postnatal day 1. Our results demonstrated that adult female rats treated with TP have a lower methylphenidate-induced locomotor activity compared to control and EV-treated adult female rats. This reduction in locomotor activity is related with a lower NAcc DAT expression. However, neither methylphenidate-induced locomotor activity nor NAcc DAT expression was affected in EV or TP-treated adult male rats. Our results suggest that early exposure to sex hormones affects long-term dopaminergic brain areas involved in the response to psychostimulants, which could be a vulnerability factor to favor the escalating doses of drugs of abuse.

Dynamic stress-related epigenetic regulation of the glucocorticoid receptor gene promoter during early development: The role of child maltreatment.

Epigenetics processes may play a vital role in the biological embedding of early environmental adversity and the development of psychopathology. Accumulating evidence suggests that maltreatment is linked to methylation of the glucocorticoid receptor gene, nuclear receptor subfamily 3, group C, member 1 (NR3C1), which is a key regulator of the hypothalamus-pituitary-adrenal axis. However, prior work has been exclusively cross-sectional, greatly constraining our understanding of stress-related epigenetic processes over time. In the current study, we examined the effect of maltreatment and other adversity on change in NR3C1 methylation among at-risk preschoolers to begin to characterize within-child epigenetic changes during this sensitive developmental period. Participants were 260 preschoolers (3-5 years old, 53.8% female), including 51.5% with moderate to severe maltreatment in the past 6 months. Child protection records, semistructured interviews, and parent reports were used to assess child stress exposure. Methylation of exons 1D and 1F of NR3C1 via saliva DNA were measured at two time points approximately 6 months apart. Results indicate that maltreated children evidence higher baseline levels of NR3C1 methylation, significant decreases in methylation over time, and then at follow-up, lower levels of methylation, relative to nonmaltreated preschoolers. Findings from the current study highlight the complex nature of stress-related epigenetic processes during early development.

Beyond Pink and Blue: The Complexity of Early Androgen Effects on Gender Development.

Why do girls and women differ from boys and men? Gender development is typically considered to result from socialization, but sex hormones present during sensitive periods of development, particularly prenatal androgens, play an important role. Data from natural experiments, especially from females with congenital adrenal hyperplasia, show the complexity of the effects of androgens on behavior: Prenatal androgens apparently have large effects on interests and engagement in gendered activities; moderate effects on spatial abilities; and relatively small or no effects on gender identity, gender cognitions, and gendered peer involvement. These differential effects provide an opportunity to move beyond identifying sources of variation in behavior to understanding developmental processes. These processes include links among gendered characteristics, psychological and neural mechanisms underlying development, and the joint effects of biological predispositions and social experiences.

Approaches to modeling the development of physiological stress responsivity.

Influential biopsychosocial theories have proposed that some developmental periods in the lifespan are potential pivot points or opportunities for recalibration of stress response systems. To date, however, there have been few longitudinal studies of physiological stress responsivity and no studies comparing change in physiological stress responsivity across developmental periods. Our goals were to (a) address conceptual and methodological issues in studying the development of physiological stress responsivity within and between individuals, and (b) provide an exemplar for evaluating development of responsivity to stress in the parasympathetic nervous system, comparing respiratory sinus arrhythmia (RSA) responsivity from middle to late childhood with middle to late adolescence. We propose the use of latent growth modeling of stress responsivity that includes time-varying covariates to account for conceptual and methodological issues in the measurement of physiological stress responsivity. Such models allow researchers to address key aspects of developmental sensitivity including within-individual variability, mean level change over time, and between-individual variability over time. In an empirical example, we found significant between-individual variability over time in RSA responsivity to stress during middle to late childhood but not during middle to late adolescence, suggesting that childhood may be a period of greater developmental sensitivity at the between-individual level.

27.0 Considerations in the Assessment and Treatment of Transitional Age Youth Across the Diagnostic Spectrum

The transition from adolescence into early adulthood reflects a sensitive developmental period of risk across the diagnostic spectrum. This period of development can be impacted by accumulated impairments from inadequately treated childhood and adolescent psychopathology and marks an age of risk for the emergence of acute symptoms. Moreover, treatment considerations can be complicated when a young person turns age 18 years. This Clinical Perspective provides an overview of the specific challenges that arise during this time period, as well as strategies for assessment, triage, and treatment of emerging adults.

Rapid plasticity of visually evoked responses in rat monocular visual cortex.

Sensory cortical circuits are shaped by experience during sensitive periods in development. In the primary visual cortex (V1) altered visual experience results in changes in visual responsiveness of cortical neurons. The experience-dependent refinement of the circuit in V1 is thought to rely on competitive interactions between feedforward circuits driven by the two eyes. However, recent data have provided evidence for an additional role of cortico-cortical circuits in this process. Indeed, experience-dependent changes in intracortical circuits can be induced rapidly and may result in rapid-onset functional changes. Unilateral occlusion of vision rapidly alters visual responsiveness, synaptic strength and connectivity of local circuits in the binocular region of V1 (V1b), where the inputs from the two eyes converge. In the monocular region of rodent V1 (V1m), where feedforward inputs from the ipsilateral eye are virtually absent, visual deprivation induces rapid plasticity in local circuits; however, functional changes seem to occur only after long periods of deprivation. In V1m there is currently no evidence for functional changes occurring within a time window compatible with that of local circuit plasticity. Here, we probed the visual responsiveness of neurons in rat V1m and assessed the effect of one day unilateral eye lid suture on single neuron visual responses. We report a novel form of plasticity within V1m that occurs on a timescale consistent with the earliest known changes in synaptic strength. Our data provide new insights into how sensory experience can rapidly modulate neuronal responses, even in the absence of direct competition between feedforward thalamocortical inputs.

Multisensory Integration in Cochlear Implant Recipients.

Speech perception is inherently a multisensory process involving integration of auditory and visual cues. Multisensory integration in cochlear implant (CI) recipients is a unique circumstance in that the integration occurs after auditory deprivation and the provision of hearing via the CI. Despite the clear importance of multisensory cues for perception, in general, and for speech intelligibility, specifically, the topic of multisensory perceptual benefits in CI users has only recently begun to emerge as an area of inquiry. We review the research that has been conducted on multisensory integration in CI users to date and suggest a number of areas needing further research. The overall pattern of results indicates that many CI recipients show at least some perceptual gain that can be attributable to multisensory integration. The extent of this gain, however, varies based on a number of factors, including age of implantation and specific task being assessed (e.g., stimulus detection, phoneme perception, word recognition). Although both children and adults with CIs obtain audiovisual benefits for phoneme, word, and sentence stimuli, neither group shows demonstrable gain for suprasegmental feature perception. Additionally, only early-implanted children and the highest performing adults obtain audiovisual integration benefits similar to individuals with normal hearing. Increasing age of implantation in children is associated with poorer gains resultant from audiovisual integration, suggesting a sensitive period in development for the brain networks that subserve these integrative functions, as well as length of auditory experience. This finding highlights the need for early detection of and intervention for hearing loss, not only in terms of auditory perception, but also in terms of the behavioral and perceptual benefits of audiovisual processing. Importantly, patterns of auditory, visual, and audiovisual responses suggest that underlying integrative processes may be fundamentally different between CI users and typical-hearing listeners. Future research, particularly in low-level processing tasks such as signal detection will help to further assess mechanisms of multisensory integration for individuals with hearing loss, both with and without CIs.

A New Perspective on the Mechanisms of Neglect

Over the past two decades, substantial evidence demonstrates a strong relationship between child abuse and neglect and increased risk for psychopathology that persists across the life course. To date, most studies elucidating the underlying mechanism for this association have focused on the effects of child abuse and neglect on stress pathways and the limbic system ( 1 McLaughlin K.A. Sheridan M.A. Tibu F. Fox N.A. Zeanah C.H. Nelson 3rd, C.A. Causal effects of the early caregiving environment on development of stress response systems in children. Proc Natl Acad Sci U S A. 2015; 18: 5637-5642 Crossref Scopus (275) Google Scholar ). In this issue of Biological Psychiatry, McLaughlin et al. ( 2 McLaughlin K.A. Sheridan M.A. Nelson C.A. Neglect as a violation of species-expectant experience: Neurodevelopmental consequences. Biol Psychiatry. 2017; 82: 462-471 Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar ) propose a novel conceptual framework of child neglect as deprivation of experience-expectant learning that compromises neuronal processes during sensitive periods of development.

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits.

Overexpression of Dual‐specificity tyrosine‐phosphorylated regulated kinase 1A (DYRK1A), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS‐associated phenotypes have been largely unsuccessful. Epigallocatechin‐3‐gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to account for improvement of some DS‐associated phenotypes that have been reported in preclinical studies and clinical trials. However, the beneficial effects of EGCG are inconsistent and there is no direct evidence that any observed improvement actually occurs through Dyrk1a inhibition. Inconclusive outcomes likely reflect a lack of knowledge about the tissue‐specific patterns of spatial and temporal overexpression and elevated activity of Dyrk1a that may contribute to emerging DS traits during development. Emerging evidence indicates that Dyrk1a expression varies over the life span in DS mouse models, yet preclinical therapeutic treatments targeting Dyrk1a have largely not considered these developmental changes. Therapies intended to improve DS phenotypes through normalizing trisomic Dyrk1a need to optimize the timing and dose of treatment to match the spatiotemporal patterning of excessive Dyrk1a activity in relevant tissues. This will require more precise identification of developmental periods of vulnerability to enduring adverse effects of elevated Dyrk1a, representing the concurrence of increased Dyrk1a expression together with hypothesized tissue‐specific‐sensitive periods when Dyrk1a regulates cellular processes that shape the long‐term functional properties of the tissue. Future efforts targeting inhibition of trisomic Dyrk1a should identify these putative spatiotemporally specific developmental sensitive periods and determine whether normalizing Dyrk1a activity then can lead to improved outcomes in DS phenotypes.

What Do Evolutionary Models Teach Us About Sensitive Periods in Psychological Development?

Abstract. Sensitive periods in development are widespread in nature. Many psychologists and biologists regard sensitive periods as byproducts of developmental processes. Although this view may be correct in some cases, it is unlikely to be the whole story. There is large variation in sensitive periods (a) between species in the same trait ( Beecher & Brenowitz, 2005 ), (b) between individuals of the same species ( Frankenhuis, Panchanathan, & Belsky, 2016 ), and (c) between different traits within a single individual ( Zeanah, Gunnar, McCall, Kreppner, & Fox, 2011 ). In this article, we discuss recent insights provided by formal models of the evolution of sensitive periods. These models help to identify the conditions in which sensitive periods are likely to evolve, and make predictions about the factors that affect their development. We conclude by discussing future directions for empirical research.

Sleep timing is associated with self-reported dietary patterns in 9- to 15-year-olds

ObjectiveTo examine sleep timing differences in self-reported dietary patterns of children and adolescents. DesignCross-sectional. ParticipantsStudents aged 9-15 years (n=119, 11.7±1.3 years, 76% female) attending a summer program for the gifted. The upper and lower quartiles of reported midsleep time (weighted weekday-weekend average) were used to identify early (n=28) and late (n=27) sleep timing groups. MethodsSleep patterns were assessed via self-report. Participants also rated their likelihood to consume 9 different categories of food and drinks on a 5-point scale ranging from “no likelihood” to “high likelihood.” Foods were grouped as follows: (1) sugary and caffeinated beverages; (2) high-energy-dense, nutrient-poor foods (ie, sugary, salty, fatty foods); and (3) low-energy-dense, nutrient-rich foods (ie, vegetables, proteins, carbohydrates, fruits). ResultsMidsleep time was 02:11±00:25 for the early and 06:14±01:00 for the late sleep timing groups. Participants reporting later sleep timing were more likely to consume sugary/caffeinated beverages and high-energy-dense, nutrient-poor foods throughout the day compared with their early sleep timing peers. The late vs the early sleep timing group also had a higher likelihood of overall consumption of foods and drinks from all categories into the evening and nighttime hours. ConclusionOur findings indicate that children and adolescents who exhibit late sleep timing are more likely to make poorer dietary choices, which may have important implications for understanding pathways to adiposity and obesity risk during this sensitive period of development.

Neurobiological Development in the Context of Childhood Trauma.

Neurobiological systems may be particularly susceptible to deleterious impact of childhood trauma, and the impact of childhood trauma on development and subsequent functional outcomes across the lifespan has been well-documented. The current review addresses the neurobiological impact of exposure to interpersonal trauma in childhood in the context of executive function, emotion regulation, and dissociation/interoceptive awareness. Subsequent risk for PTSD and depression is also discussed. The pathway of risk from childhood trauma to these cognitive, emotional, and psychiatric outcomes is addressed in terms of potential structural and functional alterations within the hippocampus, prefrontal cortex, and amygdala resulting from chronic or repeated activation of the hypothalamic-pituitary-adrenal (HPA) axis and its interaction with and influence on genetic and epigenetic processes during sensitive periods of development. Implications for practice are discussed.

Short post-weaning social isolation induces long-term changes in the dopaminergic system and increases susceptibility to psychostimulants in female rats

Childhood and adolescence are sensitive periods of development, marked by high brain maturation and plasticity. Exposure to early life stress, such as social isolation, is able to prompt changes in sensitive brain circuitries, essentially in the mesolimbic dopaminergic system and increase the risk for addictive behaviors later in life. Post-weaning social isolation can stimulate the consumption of rewarding substances, like drugs of abuse and palatable foods. However, most studies analyze long periods of social isolation and very little is known about the effects of a brief social isolation in a sensitive period of development and its association with palatable food on the reward system sensitization. Furthermore, females are more susceptible to the reinforcing effect of drugs than males. Therefore, the aim of this study was to analyze the effects of a short post-weaning social isolation combined with a free access to a chronic high sugar diet (HSD) on the dopaminergic system, oxidative status and behavioral response to an amphetamine-like drug in adulthood. We used female Wistar rats that were socially isolated from post-natal days (PD) 21 to 35 and received free access to a HSD until PD 60. On PD 65, animals were submitted to a challenge with diethylpropion (DEP), an amphetamine-like drug and different responses were analyzed: locomotor activity, immmunocontent of dopamine related proteins, and the oxidative status in the striatum, before and after the DEP challenge. We showed that a short post-weaning social isolation (SI) increased the locomotor response to DEP, when compared with previous saline administration. Social isolation also increased dopamine transporter, tyrosine hydroxylase, and decreased dopamine D2 receptor immunocontent. Additionally, SI increased the overall oxidative status parameters after the challenge with DEP. Interestingly, the exposure to a HSD prevented the SI effects on locomotor response, but did not interfere in the dopaminergic parameters evaluated, despite having modified some oxidative parameters. This study showed for the first time that a short post-weaning social isolation was able to induce long-term changes in the striatal dopaminergic system and increased the response to psychostimulants. These results emphasize the importance of stressful experiences during a short period of development on programming susceptibility to psychostimulants later in life.

485. Childhood Maltreatment and Normal Adult Personality Traits: Evidence for Developmental Sensitive Periods of Exposure

485. Childhood Maltreatment and Normal Adult Personality Traits: Evidence for Developmental Sensitive Periods of Exposure

Impact of High-Fat Diet and Early Stress on Depressive-Like Behavior and Hippocampal Plasticity in Adult Male Rats.

During development, the brain goes through fundamental processes, including organization of neural networks and plasticity. Environmental interventions may change initial brain programming, leading to long-lasting effects and altering the susceptibility to psychopathologies, including depression disorder. It is known that depression is a psychiatric disorder with a high prevalence worldwide, including high rates among adolescents. In this study, we evaluated whether social isolation in the prepubertal period and chronic use of high-fat diet (HFD) may induce depressive-like behavior in male adult rats. We also investigated hippocampal plasticity markers and neurotransmitter systems. We found both social isolation and HFD induced a depressive-like behavior in the forced swimming task. Moreover, chronic HFD reduced synaptic markers in hippocampus, demonstrated by reductions in βIII-tubulin (neuronal marker), PSD-95, SNAP-25, and neurotrophin-3. The HFD group also presented decreased glutamatergic and GABAergic receptors subunits. On the other hand, stress affected hippocampal brain-derived neurotrophic factor (BDNF) signaling pathways, and increased expression of subunit of the NMDA receptor (NR2A). Both factors (stress and diet) decreased GR in the hippocampus without affecting plasma corticosterone at basal levels. Interactions between early stress and HFD access were observed only in the BNDF receptor(tropomyosin receptor kinase B; TrkB) and synaptophysin. In summary, these findings showed that a brief social isolation and chronic HFD, during a sensitive developmental period, cause depressive-like behavior in adulthood. The mechanisms underlying these behavioral effects may involve changes in the levels of synaptic proteins in hippocampus: HFD consumption appears to affect synaptic markers, while social isolation affected BDNF signaling more significantly.