Early neurodevelopment origins of anxiety

焦虑的早期神经发育起源

• 批准号: 8475884
• 负责人: Richard J Davidson
• 金额: $ 213.43万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8475884
• 关键词: Accounting; Adolescence; Adolescent; Adult; Affect; Age of Onset; Age-Months; Age-Years; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Behavioral; Brain; Brain region; Cell Line; Cell Nucleus; Cell model; Cellular Neurobiology; Characteristics; Child; Childhood; Chronic; Data; Development; Disease; Early Intervention; Emotional; Environmental Risk Factor; Event; Fathers; Fiber; Fibroblasts; Functional Magnetic Resonance Imaging; Funding; Gene Expression Profile; Genes; Growth; Hormonal; Human; Hydrocortisone; Image; Individual; Infant; Intervention; Laboratories; Lateral; Life; Link; Macaca mulatta; Magnetic Resonance Imaging; Maintenance; Marriage; Measures; Mediating; Mental Depression; Mental disorders; Metabolism; Methods; Modeling; Molecular; Monkeys; Mood Disorders; Moods; Mothers; Multimodal Imaging; National Institute of Mental Health; Neuronal Plasticity; Neurons; Neurosciences; Parents; Pathway interactions; Pattern; Phenotype; Positron-Emission Tomography; Prefrontal Cortex; Primates; Principal Investigator; Prosencephalon; Psychiatry; Psychology; RNA Sequence Analysis; RNA Sequences; Recovery; Regulation; Research Personnel; Risk; Risk Factors; Rodent; Sampling; Severities; Staging; Stem cells; Structure; Substance Use Disorder; System; Temperament; Testing; Tissues; Translating; Twin Multiple Birth; Vision; Wisconsin; Work; affective neuroscience; age related; base; emotion regulation; gamma-Aminobutyric Acid; induced pluripotent stem cell; insight; interdisciplinary collaboration; neural circuit; neurobehavioral; neurodevelopment; neuromechanism; new therapeutic target; nonhuman primate; novel; novel strategies; novel therapeutics; peer; programs; public health relevance; response; screening; sound; tool

DESCRIPTION (provided by applicant): Childhood anxious temperament (AT) is a key risk factor for developing anxiety and co- morbid depression. In primates, AT is evident early in life, stable, and associated with increased threat reactivity. Early adversity is known to increase the risk of developing extreme AT. While adversity is common, the neural mechanisms linking it to AT are not understood. This understanding would permit identification of novel therapeutic targets with the potential for developing neuroscientifically-informed interventions. This proposal builds on work validating the AT phenotype and identifying the neural circuit underlying AT. Recent microarray and RNA sequencing (RNA-seq) work suggests the hypothesis that extreme AT reflects neuroplasticity deficits in the lateral division of the central nucleus of the amygdala (CeL), a key regulator of amygdalar outflow to regions that give rise to signs of anxiety, and the region most predictive of AT in our imaging work. This proposal aims to understand how peer rearing (PR), a controlled early adversity manipulation, causes extreme AT in primates, something not possible in human studies. The use of primates increases the likelihood that discoveries will translate to at-risk children. PR and maternally- reared (MR) animals will be longitudinally assessed, testing adversity's impact on the development of AT. Repeated multimodal imaging will assess adversity's impact on the development of amygdala reactivity and prefrontal-amygdala anxiety regulation circuits. Importantly, the primate model affords an opportunity to test whether adversity's harmful effects on AT are mediated by alterations in CeL neuroplasticity pathways. Immunohistochemical and RNA-seq analyses will be performed on CeL microdissected neurons. This novel synthesis of tools promises new insights into how adversity-induced molecular alterations manifest in brain function, connectivity, and structure, and how these macroscopic changes contribute to extreme AT- insights not readily available from molecular-level rodent or systems-level human studies. Further, a stem cell model of CeL GABAergic neurons will be created and compared to neurons from CeL. A valid stem cell model would enhance understanding of AT's molecular bases and accelerate the screening of new therapeutics.

描述（由申请人提供）：儿童焦虑气质（AT）是发展为焦虑和共病抑郁症的关键危险因素。在灵长类动物中，AT在生命早期明显，稳定，并与威胁反应增加有关。众所周知，早期的逆境会增加患极端AT的风险。虽然逆境很常见，但将其与AT联系起来的神经机制尚不清楚。这种理解将允许识别新的治疗靶点，并有可能开发神经科学知情的干预措施。这个提议