Critical Periods in Development of Amygdala Inhibition: Effect of Prenatal Stress

杏仁核抑制发展的关键时期：产前压力的影响

• 批准号: 8126611
• 负责人: DAVID Edward EHRLICH
• 金额: $ 3.05万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-31 至 2014-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8126611
• 关键词: 3-aminobutyric acid; Ablation; Address; Adolescent; Adult; Affect; Affective; Age; Agonist; Aminobutyric Acids; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Behavior; Behavioral Paradigm; Birth; Brain; Brain Part; Brain region; Cells; Development; Disease; Elderly; Electrophysiology (science); Emotional; Emotions; Environmental Risk Factor; Equilibrium; Etiology; Fright; Kinetics; Knowledge; Lead; Learning; Life; Life Experience; Life Stress; Long-Term Effects; Measures; Mediating; Mental disorders; Modeling; Molecular; Neurotransmitters; Output; Phenotype; Plastics; Play; Prevalence; Process; Property; Proteins; Rattus; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Safety; Shapes; Signal Transduction; Site; Small Interfering RNA; Stress; Subfamily lentivirinae; Synapses; Synaptic Transmission; Syndrome; System; Targeted Research; Testing; Time; Transgenic Animals; Translating; Western Blotting; base; conditioned fear; critical developmental period; critical period; design; drug sensitivity; experience; mRNA Expression; neural circuit; neurodevelopment; neurotransmission; novel; patch clamp; postnatal; prenatal; prenatal stress; prevent; protein expression; receptor; relating to nervous system; research study; response; synaptic inhibition; zolpidem

DESCRIPTION (provided by applicant): Anxiety disorders are widespread, particularly in juveniles, and are increasingly considered disorders of development. These disorders often emerge during developmental "critical periods," windows when brain circuits are highly plastic. One region which plays a central role in the expression and treatment of anxiety, the basolateral amygdala (BLA), experiences a postnatal critical period that may contribute to the emergence of anxiety disorders. Fearful and anxious behaviors are regulated by a balance between excitatory and inhibitory neurotransmission in the BLA, in particular by activity of 3-aminobutyric acid A (GABAA) receptors. The functional properties of GABAA receptors are determined by their expression of different subunits, and changes in expression of 1-subunits during development leads to drastic changes in the effects of this neurotransmitter system. Expression of the 11 subunit, which emerges postnatally, not only influences GABAA receptors, but also plays a vitally important role to organize the timing of critical periods. Because it plays such an important role in brain development and in the normal function of the BLA, the 11 subunit may be a point of vulnerability in the developing BLA. Interestingly, manipulations of 11 expression early in life significantly impact emotional behavior, but manipulations in adulthood do not. In this proposal we will characterize the normal development of 11 expression in the BLA, determine its effects on BLA neurotransmission, and identify whether manipulating 11 expression in the developing BLA has long-term effects on BLA neurotransmission and anxiety-like behaviors. Furthermore, we will test whether prenatal stress, which is a well-documented risk factor for anxiety disorders that has numerous effects on BLA development, influences the expression of 11 in the developing BLA. In summary, these studies aim to identify how 11-subunit expression influences development of the BLA and of emotional behaviors. Because this subunit plays a critical role in shaping neurotransmission of the BLA and organizing neural development, it is a prime candidate to regulate emotional development. Expression of the 11-subunit is sensitive to various environmental factors, including stress, so influencing 11 may be a mechanism by which early-life experiences alter neural development to promote or prevent anxiety disorders. If successful, these experiments will identify this protein as a potential target for preventative treatments for anxiety disorders, as well as identify developmental changes in the BLA that may contribute to normal emotional maturation. PUBLIC HEALTH RELEVANCE: Early-life stress is a well-documented risk factor for anxiety disorders, but the developmental changes that underlie this effect are unknown. These experiments are designed to study the effects of early-life stress on the development of a brain region that processes emotion, the amygdala. We will use a rat model of prenatal stress to explore how stress-induced changes in the developing amygdala can impact the maturation of emotional behavior and promote later-life anxiety.

描述（由申请人提供）：焦虑症广泛存在，特别是在青少年中，并且越来越多地被认为是发育障碍。这些疾病通常出现在发育的“关键时期”，大脑回路高度可塑的窗口。基底外侧杏仁核（BLA）在焦虑的表达和治疗中起着核心作用的一个区域经历了一个出生后的关键时期，这可能有助于焦虑症的出现。恐惧和焦虑行为受BLA中兴奋性和抑制性神经传递之间的平衡调节，特别是3-氨基丁酸A（GABAA）受体的活性。GABAA受体的功能特性由其不同亚基的表达决定，并且在发育期间1-亚基表达的变化导致该神经递质系统的作用的急剧变化。出生后出现的11亚基的表达不仅影响GABAA受体，而且在组织关键时期的时间方面起着至关重要的作用。因为它在大脑发育和BLA的正常功能中起着如此重要的作用，11亚基可能是BLA发育中的脆弱点。有趣的是，在生命早期对11个表达的操纵会显著影响情绪行为，但成年后的操纵不会。在这项提案中，我们将描述BLA中11表达的正常发展，确定其对BLA神经传递的影响，并确定在发展中的BLA中操纵11表达是否对BLA神经传递和焦虑样行为具有长期影响。此外，我们将测试是否产前压力，这是一个有据可查的风险因素焦虑症，有许多影响BLA的发展，影响11在发展中的BLA的表达。总之，这些研究旨在确定11-亚基表达如何影响BLA和情绪行为的发展。由于该亚基在形成BLA的神经传递和组织神经发育中起着关键作用，因此它是调节情绪发育的主要候选者。11-亚基的表达对各种环境因素（包括压力）敏感，因此影响11可能是早期生活经历改变神经发育以促进或预防焦虑症的机制。如果成功，这些实验将确定这种蛋白质作为预防性治疗焦虑症的潜在目标，并确定BLA中可能有助于正常情绪成熟的发育变化。 公共卫生相关性：早期生活压力是焦虑症的一个有据可查的危险因素，但这种影响背后的发育变化尚不清楚。这些实验旨在研究早期生活压力对大脑中处理情绪的区域杏仁核发育的影响。我们将使用产前应激的大鼠模型来探索应激诱导的杏仁核发育中的变化如何影响情感行为的成熟并促进晚年焦虑。