Susceptibility and Resilience to Adverse Childhood Experiences: A Role for Perineuronal Nets

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SUMMARY: Over 60% of children experience severe stress and are exposed to traumatic events including interpersonal violence, sexual abuse, accidents and injuries – adverse childhood experiences – but there is a mismatch between their exposure to these experiences and the prevalence of subsequent psychopathology. This mismatch, in which most children who experience traumatic events do not show psychopathology, may result from resilience to the events, a lack of diagnosis, or forgetting about the experiences. Resilience to adverse events involves responding with minimal distress or an early and effective return to normal levels of function. Forgetting about traumatic events in the very young – referred to as infantile amnesia – has been associated with critical periods in development involving the formation and strengthening of perineuronal nets surrounding neurons in specific areas of the brain related to memory formation for highly stressful events. Disrupting these perineuronal nets may extend or renew critical periods and help allow the memory of adverse experiences to be erased. Using a new model of hyperarousal in young rats to model adverse childhood experiences, we will determine the ontogeny, mechanisms, and treatment of hyperarousal. Our overarching goal is to understand the hyperarousal that results from stressful events. We will test the hypothesis that resilience to and forgetting about learning-induced hyperarousal is a function of perineuronal nets that form and strengthen during development around neurons in the circuits underlying associative learning. To test this hypothesis, we focus on three specific aims: (1) Characterize the ontogeny of hyperarousal and determine the underlying neural mechanisms, (2) Determine behavioral strategies to “treat” or mitigate hyperarousal in young rats and delineate the neural mechanisms involved, and (3) Determine the role of perineuronal nets in hyperarousal and its treatment. We will conduct a series of experiments in which we characterize hyperarousal in young rats, determine treatments, and then manipulate perineuronal nets before acquisition or extinction of aversive associative learning to determine whether we can manipulate critical periods to impair the development or facilitate the forgetting of hyperarousal as well as the conditioned emotional responding to cues associated with adverse events. The proposed experiments constitute a concerted effort to fill an important gap in our understanding of the developmental trajectory of hyperarousal that occurs in children following adverse events – an area of growing concern as the incidence of interpersonal violence, accidents and injuries to children continues to escalate both in the United States and abroad. We will focus on mechanistic studies that reveal the underlying neural processes, the role of perineuronal nets, and elucidate age-specific behavioral and pharmacological treatment strategies.