Brain Mechanisms Underlying the Congenital Predisposition to Helplessness

描述（由申请人提供）：无助是一种被动的行为状态，伴有无法控制的感觉，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发挥着众所周知的作用，但仍需要调查无助特征背后的先天性神经生物学倾向，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。拟议研究的总体目标是通过研究先天性无助的老鼠（一种表现出无助特征的选择性繁殖品系）来更好地了解先天性倾向如何改变大脑和行为。第一个目标是通过对成年大鼠进行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类似于易受创伤后应激障碍（PTSD）个体的气质特征：在新环境中的高度探索、低奖励敏感性以及对引起恐惧的刺激的夸张反应。第二个目标是绘制幼稚先天无助大鼠在关键发育阶段的大脑代谢图谱，以识别潜在的大脑变化。根据初步数据，预计新生先天性无助大鼠的大脑将表现出大脑活动区域间相关性的先天性降低，特别是前脑和脑干区域之间的相关性。这种先天性改变随后可能会损害下丘脑-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的老鼠大脑的影响。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。缰核可能通过其对隔海马和单胺能系统的输入对 HPA 轴产生主要的调节影响。将通过细胞色素氧化酶的定量组织化学来评估脑代谢效应，因为该方法为绘制神经生物学倾向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记了累积的长期神经元活动，因此非常适合评估来自不同遗传株的动物的基线大脑差异以及对长期抗抑郁药物的反应。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.