STRESS AND THE DEVELOPING BRAIN: A CROSS-SPECIES EXAMINATION OF THE NEURODEVELOPMENTAL IMPACTS OF EARLY ADVERSITY
Chairs & Presenters:
Heidi Meyer Chair/Discussant
Details of Research Subjects: Neurodevelopment and Plasticity including imaging work, Learning, Memory, Stress, Adversity
Ages of Research Subjects: prenatal, adolescence
Topics: Neurodevelopment and Plasticity including imaging work, Learning, Memory, Stress, Adversity
Early adversity has been shown to alter trajectories of brain development, which can permanently impact neural and behavioral functioning, and increase the risk for psychiatric disease. Evidence that outcomes following stress exposure can markedly differ in accordance with the timing of exposure suggests sensitive periods for environmental impact and encourages research at multiple developmental stages. This cross-species symposium will highlight immediate and long-term effects of stress on neurodevelopment and behavior from the prenatal period through adolescence. Beginning with the earliest stage of development, Madeleine Allen will examine how the prenatal environment influences the neonatal brain and sets the stage for further maturation. Next, the impact of childhood trauma on threat and safety discrimination, and the underlying circuitry will be considered. Dr. Hilary Marusak will discuss short-term extinction recall and corresponding altered signaling in cortical regions of trauma-exposed children. In a complementary presentation, Dr. Dylan Gee will discuss long-term extinction recall in maltreatment-exposed children and adolescents, and age-related differences in amygdala, hippocampus, and cingulate cortex activity. Emphasizing a translational perspective, Dr. Kevin Bath will demonstrate profound impacts of pre-adolescent stress on fear memory expression in mice, with a mechanistic link to disrupted prefrontal and amygdala connectivity. Finally, Dr. Danielle Gerhard will present evidence from mice of robust, sex-specific decreases in sociality following pre-adolescent stress exposure, which persist into adulthood. This symposium includes a geographically diverse group of researchers using a range of methods across species. By incorporating these varied perspectives, we will provide novel insight into the neurodevelopmental effects of stress and provide a platform to discuss best practices for integrating contemporary research findings across early development.
A MULTIVARIATE APPROACH TO EXAMINING ASSOCIATION BETWEEN THE PRENATAL ENVIRONMENT, MATERNAL-PLACENTAL-FETAL BIOLOGY, AND OFFSPRING BRAIN CONNECTIVITY
Chair/Discussant: Heidi Meyer (Weill Cornell Medicine, Department of Psychiatry)
Madeleine Allen (Oregon Health & Science University, Department of Psychiatry)
Co-authors: Eric Feczko, Jerod M. Rasmussen, Sonja Entringer, Pathik D. Wadhwa, Claudia Buss, Damien A. Fair, Alice M. Graham
Maternal psychological stress, socioeconomic status, life history, health, and nutrition are associated with differential offspring brain outcomes. These aspects of the prenatal environment are hypothesized to influence the developing fetal brain via stress-sensitive aspects of maternal-placental-fetal biology (MPF), which we have previously shown to be associated with altered offspring brain connectivity in the neonatal period. However, previous research has centered around univariate analyses that do not consider the wide array of preconceptional and prenatal factors with potential to influence MPF biology and the developing fetal brain. We seek to add to this research by identifying potential biological pathways for environmental effects on offspring brain outcomes using canonical correlation analysis (CCA) with a high-dimensionality dataset. Drawing from a longitudinal study of maternal-fetal/infant-dyads (N=138), biological samples were collected at two timepoints during pregnancy to derive the average across pregnancy of 34 stress-sensitive biological markers. Features of maternal life history, demographics, and lifestyle were surveyed throughout pregnancy. Resting state functional connectivity MRI in neonates was examined. CCA results show a significant canonical pair demonstrating covariance between several aspects of maternal physical and mental health during pregnancy (body mass index, gestational weight gain, and perceived social standing), and MPF biology (cortisol, C-reactive protein, and macrophage inflammatory protein). Multivariate analyses examining newborn infant brain networks in relation to MPF biology are in progress as the next phase of this study. This work advances understanding of potential biological pathways through which aspects of the prenatal environment can influence offspring brain development and subsequent developmental outcomes.
Hilary Marusak (Wayne State University, Department of Psychiatry and Behavioral Neurosciences)
TRAUMA EXPOSURE AND POSTTRAUMATIC STRESS SYMPTOMS LINKED TO ALTERATIONS IN FEAR-EXTINCTION NEURAL CIRCUITRY IN CHILDREN
Exposure to childhood trauma is extremely common (>60%) and is a leading risk factor for anxiety and posttraumatic stress disorder. Trauma-related disorders are characterized by deficits in fear-extinction and dysfunction in fear-extinction neural circuitry. Given the strong and pervasive link between childhood trauma and the development of psychopathology, fear-extinction may be a key mechanism. The present study tests the impact of childhood trauma and posttraumatic stress symptoms (PTSS) on fear-extinction and underlying neural circuitry. Children (N = 44; 45% trauma-exposed; 6-11 yrs) completed a novel two-day virtual reality fear-extinction experiment. On day one, participants underwent fear conditioning and extinction. Twenty-four hours later, participants completed a test of extinction recall during fMRI. Conditioned fear was measured throughout the experiment using skin conductance, subjective ratings, and approach/avoidant behavior, and activation in fear-relevant brain regions was estimated during recall. There were no group differences in conditioned fear responses during fear conditioning or extinction learning. During extinction recall, however, trauma-exposed children failed to approach the previously extinguished cue (p = 0.91). This avoidant behavioral response was accompanied by higher activation to the previously extinguished cue in fear-relevant brain regions, including the dorsal anterior cingulate cortex (pFWE = 0.001) and anterior insula (pFWE = 0.032), in trauma-exposed relative to control children. Children with higher PTSS showed poorer differentiation between threat and safety cues during fear conditioning and extinction recall (ps < 0.05). Alterations in fear-extinction and underlying neural circuitry may be a core mechanism through which childhood trauma confers heightened vulnerability to psychopathology.
YOUTH EXPOSED TO MALTREATMENT SHOW AGE-RELATED ALTERATIONS IN HIPPOCAMPAL-FRONTOAMYGDALA FUNCTION DURING EXTINCTION RECALL
Dylan Gee (Yale University, Department of Psychology)
Exposure to childhood trauma is a major risk factor for psychiatric disorders. Delineating the neurodevelopmental mechanisms linking early-life trauma to psychopathology is critical for the early identification of risk and optimizing interventions to promote resilience. Maltreatment-exposed youth show alterations in fear conditioning and related hippocampal-frontoamygdala circuitry, yet much remains unknown about extinction and extinction recall, which are central to discriminating threat from safety following trauma. Youth ages 8-17 years old (N=161) with or without exposure to maltreatment completed fear acquisition and extinction. Within one week, participants completed extinction recall and re-extinction during fMRI scanning. Given hypotheses about maltreatment and frontolimbic development, we tested for group differences in age-related patterns of activation in the amygdala, hippocampus, and subgenual anterior cingulate cortex (sgACC) during extinction recall and re-extinction. Maltreatment-exposed youth showed altered age-related activation in the amygdala (F(1,125)=5.40, p=.022) and hippocampus (F(1,125)=4.58, p=.034) during extinction recall. Whereas non-exposed youth showed stable activation, maltreatment-exposed youth showed age-related increases in amygdala and hippocampus activation to the CS- (vs. CS+). A maltreatment x age x sex interaction (F(1,125)=4.86, p=.029) revealed that maltreatment-exposed females (but not males) had altered age-related sgACC activation to the CS+ (vs. CS-) during re-extinction. Childhood maltreatment may alter the development of fear extinction and related brain activation. In particular, findings suggest that maltreatment-exposed youth fail to discriminate between threat and safety in an age-expected manner. Altered hippocampal and frontoamygdala function may underlie difficulties learning or integrating environmental cues signaling safety that could increase risk for psychopathology during development.
EARLY LIFE ADVERSITY DECREASES FEAR EXPRESSION IN PRE-ADOLESCENCE BY ACCELERATING AMYGDALAR PARVALBUMIN CELL DEVELOPMENT
Kevin Bath (Brown University, Cognitive, Linguistic & Psychological Sciences)
Resource insecurity represents a significant form of adversity and can be a potent source of stress. Early life adversity (ELA), in the form of resource insecurity during childhood, has been associated with increased risk for developing stress-related disorders later in life, including major depressive disorder and anxiety. Although the link between ELA and increased risk for psychopathology has been well established, the developmental mechanisms remain unclear. Using a mouse model of resource insecurity, limited bedding and nesting materials (LB), we tested the effects of LB on the development of fear learning and on key neuronal structures involved in emotional regulation, the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). LB delayed the ability of peri-weanling mice (21 days of age) to express, but not form, an auditory conditioned fear memory. LB disrupted typical fear circuit development, accelerating parvalbumin positive (PV+) inhibitory interneuron maturation in the BLA and delaying the maturation of connections between the mPFC and BLA. The decreased fear expression in LB reared mice during early development was rescued through optogenetic inactivation of PV+ cells in the BLA. Together our data demonstrate that LB has profound effects on mPFC and BLA development, decreasing threat-associated behavior expression, but not learning early in life. The current results provide a rodent model to probe the neural underpinnings of transiently blunted emotional reactivity in early life, and the emergence of fear-associated memories and pathology later in development.
PREADOLESCENT STRESS HAS ENDURING EFFECTS ON SOCIABILITY IN FEMALE MICE
Danielle Gerhard (Weill Cornell Medicine, Department of Psychiatry) Psychiatric disorders peak in prevalence during childhood and adolescence, and adverse experiences early in life increase the lifelong risk for psychopathology. Impairment in social behaviors is a key feature of many psychiatric disorders. Notably, adolescence is a time when social reorientation (from caregiver to peers) takes place, and social skills mature ‚Äì setting the stage for critical maturational milestones. To explore the enduring effects of pre-adolescent stress on the maturation of social behaviors and the neural systems mediating them, we used an acute variable foot shock stress (P28-P30) or a chronic unpredictable stress (P22-P31) paradigm followed by behavioral tests to measure sociability. We found that acute and chronic pre-adolescent stress exposure led to reduced sociality and altered social communication (measured by ultrasonic vocalizations) towards a novel conspecific in adulthood in female, but not male, mice. These deficits are not apparent during adolescence, but instead emerge during the transition to early adulthood. Our findings suggest that the pre-adolescent/pre-pubertal window is a sensitive period for social development in female mice. The nucleus accumbens has been implicated in social reward and motivation, and adults with major depressive disorder exhibit reduced activity of the nucleus accumbens in response to rewarding stimuli. Ongoing fiber photometry and molecular studies are investigating the effects of pre-adolescent stress on developing dopamine and glutamate systems in the nucleus accumbens.