Amygdala Gene Expression: Learning in a Sensitive Period

杏仁核基因表达：敏感期的学习

• 批准号: 7146421
• 负责人: GORDON Alfred BARR
• 金额: $ 25.94万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146421
• 关键词: amygdala; animal developmental psychology; behavioral /social science research tag; behavioral genetics; caregivers; child abuse; conditioning; corticosterone; developmental genetics; developmental neurobiology; disease /disorder model; dopamine; early experience; electrostimulus; ethology; fear; gene expression; immunocytochemistry; in situ hybridization; laboratory rat; microarray technology; newborn animals; olfactory stimulus; parent offspring interaction; preference; western blottings

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.

描述（由申请人提供）：自相矛盾的是，儿童对虐待护理人员形成强烈的依恋，这些孩子在儿童期和成年人期间都有精神疾病的高风险。尽管这是一个重要的道德 /社会和心理健康问题，但这种自相矛盾的依恋如何发生仍然是一个谜。具体来说，这种矛盾的附着的神经学基础尚不清楚。但是，有大量的数据表明，杏仁核在成人和婴儿中的恐惧/厌恶学习中都具有重要的调节作用。我们已经使用新生大鼠和恐惧调节（气味震动配对）对虐待依恋的神经生物学进行了建模。我们发现，在新生大鼠的敏感时期内，厌恶性的冲击配对会产生气味偏好，但在老年幼犬和成年人中厌恶。大鼠幼犬大约10天大的皮质酮中天然存在的升高似乎将杏仁核带来“在线”，并将婴儿切换为成年人因气味震动条件的回避反应。具体而言，我们可以通过分别在杏仁核内或选择性地降低或选择性地降低或提高幼犬的内源性皮质水平，从而加速或延迟敏感周期的末端。由于这些对厌恶刺激的偏好是持久的，因此他们可能会在杏仁核内参与基因和蛋白质的变化。我们在这里使用微阵列评估“敏感”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，当学习偏好或厌恶时，有害输入引起的基因表达的变化是什么？这提供了有关杏仁核在从偏好转变为厌恶之前和之后的响应方式不同的详细说明。其次，由于操纵CORT水平也改变了敏感时期，基因表达发生了什么变化？第三，持续到成年并修改其他动机行为的水平的厌恶或偏好学习的长期变化是什么？特定年龄的学习和Cort的联合使用（改变了偏好学习的年龄切换到厌恶学习），提供了一种有力的工具来评估依赖性和独立范式中的杏仁核候选基因。我们的初步研究表明，在敏感时期内和之后，多巴胺标志物的对比变化，随访研究进一步暗示了多巴胺在学习厌恶刺激的学习偏好中的作用。