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

描述(由申请人提供)：焦虑症很普遍，尤其是在青少年中，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“关键期”，也就是大脑回路高度可塑性的时期。杏仁基底外侧核(BLA)在焦虑的表达和治疗中起着核心作用，它经历了一个出生后的关键期，这可能是导致焦虑症出现的原因之一。恐惧和焦虑行为是由BLA中兴奋性和抑制性神经传递之间的平衡调节的，特别是通过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，而1-亚基在发育过程中表达的变化导致这一神经递质系统的作用发生剧烈变化。出生后出现的11个亚基的表达不仅影响GABAA受体，而且在组织关键时期的时间安排方面起着至关重要的作用。由于它在大脑发育和血乳酸的正常功能中发挥着重要作用，因此11亚基可能是血乳酸发育中的一个薄弱环节。有趣的是，在生命早期对11种表情的操控显著影响情绪行为，但成年后的操控不会。在这项建议中，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，并确定在发育中的BLA中操纵11表达是否对BLA神经传递和焦虑样行为有长期影响。此外，我们将测试产前应激是否会影响11在发育中的BLA的表达。产前应激是焦虑症的一个有充分证据的危险因素，对BLA的发展有许多影响。综上所述，这些研究旨在确定11个亚基的表达如何影响BLA和情绪行为的发展。因为这个亚基在形成BLA的神经传递和组织神经发育方面起着关键作用，所以它是调节情绪发育的最佳候选者。11亚基的表达对包括压力在内的各种环境因素很敏感，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一种机制。如果成功，这些实验将确定这种蛋白质作为焦虑症预防性治疗的潜在靶点，并确定可能有助于正常情绪成熟的血乳酸的发育变化。

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.