Brain Mechanisms Underlying the Congenital Predisposition to Helplessness

描述(申请人提供)：无助，一种被动的行为状态，感觉无法控制，是抑郁症和创伤后应激障碍(PTSD)的常见组成部分。尽管压力在这些障碍中扮演着众所周知的角色，但仍有必要调查作为无助特征基础的先天性(天生)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创伤后应激障碍。这项拟议研究的广泛目标是通过研究先天无助的大鼠--一种选择性繁殖的表现无助特征的品系--来更好地了解先天易感如何改变大脑和行为。第一个目的是通过在成年大鼠身上进行单独的测试来进一步描述这一模型的行为特征，以确定先天无助的大鼠是否表现出类似于创伤后应激障碍易感个体的气质特征：在新环境中的高探索性，低奖励敏感度，以及对引起恐惧的刺激的夸大反应。第二个目标是对处于关键发育阶段的幼稚的先天无助的大鼠的大脑进行代谢映射，以确定潜在的大脑变化。根据初步数据，新生的先天性无助大鼠的大脑将显示出区域间脑活动相关性的先天减少，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对下丘脑-垂体-肾上腺(HPA)轴的反馈。第三个目的是绘制抗抑郁剂氟西汀对先天性无助大鼠大脑的影响。推测氟西汀的抗抑郁作用可能是通过降低外侧缰核的代谢来实现的。缰核可能通过其对隔-海马和单胺能系统的输入对HPA轴产生重要的调制影响。脑代谢的影响将通过细胞色素氧化酶的定量组织化学来评估，因为这种方法在绘制神经生物学倾向的变化方面具有重要的优势。细胞色素氧化酶的独特之处在于它标记了累积的、长期的神经元活动，从而使其成为评估来自不同基因品系的动物的基线大脑差异和对长期服用抗抑郁药物的反应的理想方法。更多地了解先天性无助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.