Brain Mechanisms Underlying the Congenital Predisposition to Helplessness

描述（由申请人提供）：无助，一种被动的行为状态，具有不可控的感觉，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了一个很好的角色，但有必要调查作为无助特质基础的先天性（天生）神经生物学倾向，因为只有少数人在压力或创伤后会患上抑郁症或创伤后应激障碍。拟议研究的广泛目标是通过研究先天无助的大鼠-一种显示无助特征的选择性繁殖品系-更好地了解先天性易感性如何改变大脑和行为。第一个目的是进一步表征这个模型的行为与单独的测试在成年大鼠，以确定是否先天性无助的大鼠表现出类似于个人易患创伤后应激障碍的气质：高探索新的环境，低奖励的敏感性，和夸大的反应引起恐惧的刺激。第二个目标是代谢地图幼稚先天无助大鼠在关键发育阶段的大脑，以确定潜在的大脑变化。根据初步数据，预计新生先天无助大鼠的大脑将显示大脑活动的区域间相关性先天减少，特别是前脑和脑干区域之间。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。第三个目标是绘制抗抑郁药氟西汀对先天无助大鼠大脑的影响。据推测，氟西汀的抗抑郁作用可能是通过降低外侧缰核的代谢来介导的。缰可能提供了一个主要的调节影响HPA轴通过其输入隔海马和单胺能系统。将采用细胞色素氧化酶的定量组织化学评价脑代谢效应，因为该方法在绘制神经生物学易感性变化方面具有重要优势。细胞色素氧化酶是独特的，因为它标志着累积的，长期的神经元活动，从而使其成为理想的评估基线脑差异的动物从不同的遗传品系和响应慢性抗抑郁药给药。更多地了解先天性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.