Amygdala Gene Expression: Learning in a Sensitive Period

描述(由申请人提供)：矛盾的是，儿童对虐待他们的照顾者形成了强烈的依恋，这些儿童在儿童时期和成年后都有很高的精神障碍风险。虽然这是一个重要的伦理/社会和心理健康问题，但这种自相矛盾的依恋是如何发生的仍然是一个谜。具体地说，这种矛盾依恋的神经学基础尚不清楚；然而，大量数据表明，杏仁核在成人和婴儿的恐惧/厌恶学习中都起着重要的调节作用。我们用新生大鼠和恐惧条件作用(气味-休克配对)模拟了虐待依恋的神经生物学。我们发现，气味厌恶电击配对在新生大鼠发育的敏感期产生气味偏好，但在年龄较大的幼鼠和成年鼠中产生厌恶。幼鼠出生10天左右，皮质酮自然升高，似乎使杏仁核“在线”，并将婴儿切换到成人对气味休克条件反射的回避反应。具体地说，我们可以通过系统地或选择性地分别降低或提高幼崽在杏仁核内的内源性皮质醇水平，来加速或推迟敏感期的结束。由于这些习得的对厌恶刺激的偏好是持久的，它们很可能参与了杏仁核内基因和蛋白质的变化。我们使用这里的微阵列来评估“敏感期”期间和之后的基因表达，以了解杏仁核内的机制。我们确定：首先，当习得偏好或厌恶时，有害输入会导致哪些基因表达的变化？这提供了杏仁核在从偏好转换到厌恶前后的不同反应的详细描述。其次，由于皮质醇水平的改变也改变了敏感期，杏仁核中的基因表达发生了什么变化？第三，厌恶或偏好学习的长期变化会持续到成年，并改变其他动机行为的参与程度吗？年龄特异性学习和CORT(改变偏好学习切换到厌恶学习的年龄)的结合使用，为在年龄相关和独立的范式中评估杏仁核候选基因提供了一个强大的工具。我们的初步研究表明，在敏感期和敏感期之后，多巴胺标志物的变化进行了对比，后续研究进一步暗示了多巴胺在习得的对厌恶刺激的偏好中的作用。

DESCRIPTION (provided by applicant): Paradoxically, children form strong attachments to their abusive caregiver, and these children are at high risk for psychiatric disorders both during childhood and as adults. Although this is an important ethical /societal and mental health problem, how this paradoxical attachment can occur remains a mystery. Specifically the neurological underpinnings of this paradoxical attachment are not known; however there are substantial data showing that the amygdala has an important regulatory role in fear/aversion learning both in adults and infants. We have modeled the neurobiology of abusive attachment using neonatal rats and fear conditioning (odor-shock pairings). We found odor-aversive shock pairings produces an odor preference during a sensitive period of development in neonatal rats but an aversion in older pups and adults. The naturally occurring elevation in corticosterone that occurs around 10 days of age in the rat pup appears to bring the amygdala "on-line" and switch the infant to the adult response of avoidance from odor-shock conditioning. Specifically, we can either accelerate or retard the end of the sensitive period simply by respectively lowering or raising the pup's endogenous CORT levels either systemically or selectively within the amygdala. Because these learned preferences to aversive stimuli are long lasting they likely engage changes in genes and proteins within the amygdala. We use here microarrays to assess gene expression during and after the "sensitive" period to understand what the mechanisms are within the amygdala. We determine: First, what are the changes in gene expression induced by noxious input when preferences or aversions are learned? This provides a detailed description of how the amygdala responds differently before and after the switch from preference to aversion. Second, what changes in gene expression occur in the amygdala as a result of manipulation of CORT levels that also alter the sensitive period? Third, what are the long term changes in aversion or preference learning that persist into adulthood and modify levels of engagement in other motivated behaviors? The combined use of age-specific learning and CORT (altering the age that preference learning switches to aversion learning), provides a powerful tool to assess amygdala candidate genes in an age dependent and independent paradigm. Our preliminary studies show contrasting changes in dopamine markers during and after the sensitive period and follow-up studies implicate further the role of dopamine in the learned preferences to aversive stimuli.