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）：奇怪的是，儿童对虐待他们的照顾者形成强烈的依恋，这些儿童在儿童时期和成年后都有患精神疾病的高风险。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如何发生仍然是一个谜。具体来说，这种自相矛盾的依恋的神经基础尚不清楚;然而，有大量数据表明，杏仁核在成人和婴儿的恐惧/厌恶学习中具有重要的调节作用。我们使用新生大鼠和恐惧条件反射（气味休克配对）建立了虐待性依恋的神经生物学模型。我们发现，气味厌恶休克配对产生的气味偏好在一个敏感的时期的发展，在新生大鼠，但在老年人和成年人的厌恶。在10天左右的幼鼠中，皮质酮的自然升高似乎使杏仁核“在线”，并使婴儿转向回避气味休克条件反射的成人反应。具体来说，我们可以加速或延迟敏感期的结束，简单地通过分别降低或提高幼犬的内源性CORT水平，无论是系统性的或选择性的杏仁核内。因为这些习得的对厌恶刺激的偏好是持久的，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”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：第一，什么是有害输入诱导的基因表达的变化时，偏好或厌恶的学习？这就详细描述了杏仁核在从偏好到厌恶的转换前后的不同反应。第二，在杏仁核中，由于CORT水平的改变，基因表达发生了什么变化，也改变了敏感期？第三，厌恶或偏好学习的长期变化是什么，这些变化持续到成年，并改变了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），提供了一个强大的工具，以评估杏仁核候选基因的年龄依赖性和独立的范式。我们的初步研究表明，在敏感期内和敏感期后多巴胺标记物的对比变化和后续研究进一步暗示了多巴胺在厌恶刺激的学习偏好中的作用。