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: 8703181
• 负责人: Danielle M. deCampo
• 金额: $ 4.4万
• 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/8703181
• 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、母亲分离或丧失，会增加患焦虑和情绪障碍的风险。我的建议的首要目标是检查通过灵长类杏仁核的一个与持续焦虑有关的新回路中的基因表达谱，并确定ELS如何改变这一途径中的基因表达。涉及杏仁核的神经网络可能通过输入终纹床核（BNST）对长期焦虑行为产生影响。最近对啮齿动物的研究表明，BNST对非条件应激源的持久（“滋补”）效应很重要。在猴子中，BNST活动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，被称为平行核（PL），可能是灵长类动物BNST的一种新的传入输入。目的1将确定脑后皮层是否与脑后皮层有直接联系，从而形成一个通道，通过该通道杏仁核影响灵长类动物的长期焦虑反应。人类和非人类灵长类动物的PL都包含一个独特的未成熟神经元亚群，在其他杏仁核区域中没有发现，这表明该区域的电路具有特殊作用。我们初步的免疫细胞化学和分子数据表明，PL具有其他杏仁核区域未见的神经生长能力。这表明PL具有独特的塑性特性，可能在BNST目标的传入调节中很重要，特别是在发育过程中。目的2将检查在何种程度上PL是一个独特的杏仁核亚区基于富集参与神经元发育的基因转录物。应激，包括ELS，会改变发育中的神经元的成熟和存活。虽然关于应激效应的经典研究主要集中在海马的发育上，但也观察到灵长类动物发育中的杏仁核基因表达的变化。我们的初步数据显示，PL中出现的未成熟神经元组成性地表达高水平的激活（CREB），这是一种已知在ELS中被改变的转录物。我们假设PL中正常的CREB表达对许多参与神经发育的转录本有下游影响，并被ELS破坏。具体来说，我假设ELS会改变参与creb相关通路的基因转录，这些通路涉及神经分化、生长和迁移。目的3将研究暴露于ELS的年轻猴子中PL基因转录物的变化，重点关注creb介导的途径。