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强烈的依恋，这些儿童在童年和成年后都有很高的精神疾病风险。虽然这是一个重要的伦理/社会和心理健康问题，但这种矛盾的依恋是如何发生的仍然是一个谜。具体来说，这种矛盾依恋的神经学基础尚不清楚；然而，有大量数据表明，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反射（气味-电击配对）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的敏感发育时期产生气味偏好，但在老年幼鼠和成年大鼠中产生厌恶。在10天大的幼鼠体内，皮质酮的自然升高似乎使杏仁核“上线”，并将婴儿转变为成人的反应，以避免气味休克条件。具体来说，我们可以通过系统地或选择性地分别降低或提高幼犬杏仁核内的内源性CORT水平来加速或延迟敏感期的结束。因为这些对厌恶刺激的习得偏好是持久的，它们可能涉及杏仁核内基因和蛋白质的变化。我们在这里使用微阵列来评估“敏感”时期和之后的基因表达，以了解杏仁核内部的机制。我们确定：首先，当学习偏好或厌恶时，有害输入引起的基因表达变化是什么？这详细描述了从偏好到厌恶转换前后杏仁核的不同反应。第二，扁桃体中基因表达的哪些变化是由于对CORT水平的操纵而导致的，这也改变了敏感期？第三，什么是厌恶或偏好学习的长期变化，持续到成年并改变其他动机行为的参与水平？结合使用年龄特异性学习和CORT（改变偏好学习转换为厌恶学习的年龄），在年龄依赖和独立范式中提供了评估杏仁核候选基因的强大工具。我们的初步研究表明，在敏感期和敏感期之后，多巴胺标记物发生了截然不同的变化，后续研究进一步揭示了多巴胺在习得性厌恶刺激偏好中的作用。

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.