An Extended Amygdala Path with Implications for Early Life Stress

延长的杏仁核路径对早期生活压力的影响

• 批准号: 8515778
• 负责人: Danielle M. deCampo
• 金额: $ 4.35万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-10 至 2016-07-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515778
• 关键词: Adult; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Area; Behavior; Behavioral; Biological Neural Networks; Brain; CREB1 gene; Cell Nucleus; Cells; Cyclic AMP-Responsive DNA-Binding Protein; Data; Development; Differentiation and Growth; Disease; Exposure to; Figs - dietary; Fright; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Hippocampus (Brain); Homologous Gene; Human; Impairment; Individual Differences; Injection of therapeutic agent; Label; Laboratories; Life; Life Stress; Location; Macaca; Maps; Mediating; Mental Depression; Molecular; Molecular Profiling; Monkeys; Mood Disorders; Neurons; Output; Pathogenesis; Pathway interactions; Pattern; Phenotype; Plastics; Primates; Property; Regulation; Relative (related person); Risk; Rodent; Role; Site; Stimulus; Stress; Structure of terminal stria nuclei of preoptic region; Techniques; Temperament; Tissue-Specific Gene Expression; Tracer; Transcript; Work; abuse neglect; base; density; juvenile animal; laser capture microdissection; maternal separation; migration; neural growth; neurodevelopment; neuron development; nonhuman primate; novel; relating to nervous system; response; stressor

DESCRIPTION (provided by applicant): Exposure to early life stress (ELS) including neglect, abuse, maternal separation or loss carries an increased risk for the development of anxiety and mood disorders. The overarching goal in my proposal is to examine gene expression profiles in a novel circuit through the primate amygdala that is implicated in persistent anxiety, and to determine how ELS may alter gene expression in this path. Neural networks involving the amygdala may exert effects on long-lasting anxiety behaviors through inputs to the bed nucleus of the stria terminalis (BNST). Recent work in rodents shows that the BNST important for the long-lasting ('tonic') effects of unconditioned stressors. In monkeys, BNST activity is correlated with individual differences in anxious temperament, a stable pattern of response to threatening stimuli. Our preliminary data indicate that a unique amygdala nucleus, known as the paralaminar nucleus (PL), may be a novel afferent input to the BNST in primates. Aim 1 will determine if the PL has direct connections to the BNST, thus forming a conduit by which the amygdala influences long-lasting anxiety responses in the primate. The PL in both human and nonhuman primates contains a unique subpopulation of immature-appearing neurons not found in other amygdala regions, suggesting a special role in circuits through the region. Our preliminary immunocytochemical and molecular data suggest that the PL has capabilities for neural growth not seen in other amygdala regions. This suggests that the PL has unique plastic properties that may be important in the afferent regulation of BNST targets, particularly during development. Aim 2 will examine the extent to which the PL is a distinct amygdala subregion based on enrichment in gene transcripts involved in neuronal development. Stress, including ELS, alters the maturation and survival of developing neurons. While classic studies on stress effects have largely focused on hippocampal development, changes in gene expression in the developing primate amygdala are also observed. Our preliminary data show that immature-appearing neurons in the PL constitutively express high levels of activated (CREB), a transcript known to be altered in ELS. We hypothesize that normal CREB expression in the PL has downstream effects on many transcripts involved in neural development, and is disrupted by ELS. Specifically, I hypothesize that ELS will alter the transcription of genes involved in CREB-related pathways that are involved in neural differentiation, growth, and migration. Aim 3 will examine changes in PL gene transcripts in young monkeys exposed to ELS, focusing on CREB-mediated pathways.

描述（由申请人提供）：暴露于早期生活压力（ELS），包括忽视、虐待、母亲分离或失去母亲，会增加患焦虑和情绪障碍的风险。我的提案的总体目标是检查灵长类杏仁核中与持续焦虑有关的新回路中的基因表达谱，并确定 ELS 如何改变该路径中的基因表达。涉及杏仁核的神经网络可能通过对终纹床核（BNST）的输入对长期焦虑行为产生影响。最近对啮齿类动物的研究表明，BNST 对于无条件应激源的长期（“补品”）作用非常重要。在猴子中，BNST 活性与焦虑气质的个体差异相关，焦虑气质是对威胁刺激的稳定反应模式。我们的初步数据表明，一种独特的杏仁核，称为副层核（PL），可能是灵长类动物 BNST 的新传入输入。目标 1 将确定 PL 与 BNST 是否有直接联系，从而形成杏仁核影响灵长类动物长期焦虑反应的管道。人类和非人类灵长类动物的 PL 都含有其他杏仁核区域中未发现的独特的未成熟神经元亚群，这表明该区域在回路中具有特殊作用。我们的初步免疫细胞化学和分子数据表明，PL 具有其他杏仁核区域所没有的神经生长能力。这表明 PL 具有独特的塑性特性，这对于 BNST 靶标的传入调节可能很重要，特别是在发育过程中。目标 2 将根据参与神经元发育的基因转录本的丰富程度来检查 PL 在多大程度上是一个独特的杏仁核亚区域。压力（包括 ELS）会改变发育中神经元的成熟和存活。虽然关于压力影响的经典研究主要集中在海马发育上，但也观察到发育中的灵长类杏仁核中基因表达的变化。我们的初步数据显示，PL 中看起来不成熟的神经元组成性表达高水平的激活 (CREB)，这是一种已知在 ELS 中发生改变的转录物。我们假设 PL 中的正常 CREB ​​表达对许多参与神经发育的转录本具有下游影响，并被 ELS 破坏。具体来说，我假设 ELS 将改变与 CREB ​​相关通路相关的基因的转录，这些通路涉及神经分化、生长和迁移。目标 3 将检查暴露于 ELS 的幼猴中 PL 基因转录物的变化，重点关注 CREB ​​介导的途径。