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）：矛盾的是，儿童对虐待他们的照顾者形成了强烈的依恋，这些儿童在童年时期和成年后患精神疾病的风险很高。尽管这是一个重要的伦理/社会和心理健康问题，但这种矛盾的依恋如何发生仍然是一个谜。具体来说，这种矛盾依恋的神经学基础尚不清楚。然而，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调节（气味-休克配对）对虐待依恋的神经生物学进行了建模。我们发现，厌恶气味的休克配对会在新生大鼠发育的敏感时期产生气味偏好，但会在年长的幼鼠和成年大鼠中产生厌恶。幼鼠在 10 天左右时，皮质酮自然升高，似乎使杏仁核“上线”，并将婴儿转变为成人的回避气味休克条件反射的反应。具体来说，我们可以通过系统地或选择性地分别降低或升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长期持续的，它们可能会引起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：首先，当学习到偏好或厌恶时，有害输入会引起哪些基因表达变化？这详细描述了杏仁核在从偏好转变为厌恶之前和之后如何做出不同的反应。其次，由于控制 CORT 水平，杏仁核中的基因表达发生了哪些变化，同时也改变了敏感期？第三，厌恶或偏好学习的长期变化是什么，这些变化会持续到成年并改变其他动机行为的参与程度？年龄特异性学习和 CORT（改变偏好学习转变为厌恶学习的年龄）的结合使用，提供了一个强大的工具，可以在年龄依赖和独立范式中评估杏仁核候选基因。我们的初步研究表明，敏感期期间和之后多巴胺标记物发生了对比变化，后续研究进一步表明多巴胺在厌恶刺激的习得偏好中的作用。