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Early life stress effects on threat-learning

早期生活压力对威胁学习的影响

基本信息

批准号：
10321307
负责人：
Kevin George Bath
金额：
$ 39.98万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-10-23 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321307
关键词：
Address Adolescent Adult Adverse event Affective American Amygdaloid structure Anatomy Animals Anxiety Anxiety Disorders Area Automobile Driving Bathing Behavior Behavioral Brain Cardiovascular Diseases Caring Cell Proliferation Cell physiology Cells Child Child Abuse Childhood Country Development Developmental Course Developmental Process Emotional Emotional Disturbance Environment Evaluation Event Exposure to Extinction (Psychology)Female Freezing Fright Genetic Goals Growth Hippocampus (Brain)Histologic Human Impaired cognition Impairment Individual Interneurons Label Learning Life Long-Term Effects Measures Medial Mediating Medical Mental Depression Mental Health Methods Modeling Molecular Genetics Mus Neurobiology Panic Disorder Pathologic Pathology Persons Plant Roots Post-Traumatic Stress Disorders Prefrontal Cortex Regulation Research Risk Role Site Stress Structure Techniques Teenagers Testing Trauma Work World Health Organization anxiety-like behavior base behavior measurement behavioral outcome burden of illness cellular development classical conditioning cortico-limbic circuits cost depressive symptoms diagnostic criteria early life adversity early life stress endophenotype experience insight lens lifetime risk maladaptive behavior male mature animal mouse model neurobiological mechanism neurodevelopment neuron development neuropsychiatric disorder novel optogenetics pediatric trauma pup relating to nervous system resilience response stem stress related disorder stressor

项目摘要

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.

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