Early life stress effects on threat-learning

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ABSTRACT' ! Early life stress (ELS) significantly increases the risk for emotional disturbance and affective pathology. Sixty- four percent of individuals will experience at least one significant stressor in childhood, and this single adverse event increases the lifetime risk for panic disorder, depression, or anxiety disorders by ~30%. Experiencing three or more early life stressors doubles the lifetime risk for stress-related pathology. Anxiety disorders alone cost the American people approximately $42 billion a year, which is approximately one third of the total $148 billion spent on mental health. Further, according to the World Health Organization, the burden of disease for neuropsychiatric disorders on the country exceeds that of any other medical condition, even doubling that of cardiovascular disease, and anxiety disorders pose the greatest threat to mental health worldwide. In the U.S. nearly 29% of people will develop some form of anxiety disorder in their lifetime. Despite the enormous burden of stress-related disorders, relatively little is known regarding the neurobiological underpinnings of pathology development. For many, the roots of later emotional disturbance may lie in altered development and long term functioning of cortico-limbic circuits that regulate emotional reactivity and threat evaluation, including the basolateral amygdala (BLA), the site of threat learning, and the infralimbic (IL) and prelimbic (PL) cortices. Elegant work in control reared animals have shown that these regions are late maturing and in adult animals these regions have been shown to be highly sensitive to stress. In recent work, we and other have found that ELS can drive precocious emergence of some forms of threat-associated learning. However, the extent of ELS effects on regional maturation, connectivity, and behavioral development are still not known. By investigating developmental process, we have the potential to identify novel effects of ELS on the maturation and assembly of this brain circuit, and to understand how altering timing of key neurodevelopmental events may impact the development of threat assessment and risk for later stress-related pathology. In AIM 1, we will determine the effects of stress genetic and histological markers of maturation, including connectivity between BLA, IL and PL. In AIM 2 we will test the hypothesis that ELS alters the developmental profile of threat associated learning and emergence of anxiety-like behavior. In AIM 3, we will test the specific prediction that ELS drives asymmetrical cortico-limbic maturation, resulting in a developmental disruption in the ability express threat-associated learning, with implications for risk for later emotional disturbance. Through the lens of ELS, the broad intellectual significance of this work is in its promise for informing the mechanisms driving risk for pathology and the impact of the environment on brain and behavioral development. The questions addressed here are relevant to a broad scientific audience and also have immediate impact on the development of translational programming aimed at identifying factors mediating risk and resilience in children and animals exposed to early adversity.