Brain Mechanisms Underlying the Congenital Predisposition to Helplessness

描述（由申请人提供）：无助是一种带有不可控感觉的被动行为状态，是抑郁症和创伤后应激障碍（PTSD）的常见组成部分。尽管压力在这些疾病中扮演着众所周知的角色，但仍有必要调查导致无助特质的先天（先天）神经生物学倾向，因为只有少数人在压力或创伤后患上抑郁症或PTSD。这项研究的主要目的是通过研究先天无助的大鼠来更好地理解先天易感性是如何改变大脑和行为的——先天无助是一种选择性繁殖的表现出无助特征的大鼠。第一个目标是通过对成年大鼠的单独测试来进一步表征该模型的行为特征，以确定先天无助的大鼠是否表现出与易患PTSD的个体相似的气质特征：对新环境的高度探索，对奖励的低敏感性，以及对引起恐惧的刺激的夸张反应。第二个目标是在关键发育阶段对先天无助的幼稚大鼠的大脑进行代谢图谱，以确定潜在的大脑改变。根据初步数据预测，新生儿先天无助大鼠的大脑会表现出先天的脑活动区域间相关性的减少，特别是前脑和脑干区域之间的相关性。这种先天性改变可能随后损害下丘脑-垂体-肾上腺（HPA）轴的反馈。第三个目标是绘制抗抑郁药氟西汀对先天无助大鼠大脑的影响。假设氟西汀的抗抑郁作用可能是通过降低侧链的代谢来介导的。缰核可能通过其输入海马隔区和单胺能系统对下丘脑轴提供主要的调节作用。脑代谢效应将通过细胞色素氧化酶的定量组织化学来评估，因为这种方法为绘制神经生物学易感性的变化提供了重要的优势。细胞色素氧化酶的独特之处在于，它标志着累积的、长期的神经元活动，因此使其成为评估不同遗传品系动物大脑基线差异和对慢性抗抑郁药的反应的理想选择。更多地了解先天无助倾向背后的大脑机制，将有助于开发更有效的情感障碍治疗方法。

DESCRIPTION (provided by applicant): Helplessness, a behavioral state of passivity with feelings of uncontrollability, is a common component of depression and post-traumatic stress disorder (PTSD). Even though stress plays a well-understood role in these disorders, there is a need to investigate congenital (inborn) neurobiological predispositions that underlie the helplessness trait, because only a minority of people develops depression or PTSD following stress or trauma. The broad objective of the proposed research is to better understand how congenital predisposition alters brain and behavior by studying the congenitally helpless rat - a selectively bred strain which shows the helplessness trait. The first aim is to further characterize this model behaviorally with separate tests in adult rats to ascertain whether congenitally helpless rats show a temperamental profile resembling individuals susceptible to PTSD: high exploration in novel environments, low reward sensitivity, and an exaggerated response to fear-evoking stimuli. The second aim is to metabolically map the brains of naive congenitally helpless rats at critical developmental stages in order to identify the underlying brain alterations. It is anticipated based on preliminary data that brains of newborn congenitally helpless rats will show innate reductions in interregional correlations of brain activity, particularly between forebrain and brainstem regions. This congenital alteration may subsequently impair feedback to the hypothalamic-pituitary-adrenal (HPA) axis. The third aim is to map the effects of the antidepressant fluoxetine on the brains of congenitally helpless rats. It is hypothesized that fluoxetine antidepressant effects may be mediated by decreasing metabolism in the lateral habenula. The habenula may provide a major modulatory influence on the HPA axis through its inputs to septohippocampal and monoaminergic systems. Brain metabolic effects will be evaluated with quantitative histochemistry of cytochrome oxidase because this method offers important advantages for mapping changes in neurobiological predispositions. Cytochrome oxidase is unique in that it marks cumulative, long-term neuronal activity, thus making it ideal for assessing baseline brain differences in animals from different genetic strains and in response to chronic antidepressant administration. Greater knowledge of brain mechanisms underlying the congenital predisposition to helplessness would be beneficial to develop more effective treatments for affective disorders.