Neural Correlates of Emotion

描述(由申请者提供)：该项目的长期目标是开发和使用一种具有临床相关性的攻击行为动物模型。我们假设低5-羟色胺诱导的攻击性与(1)其他情绪行为的改变和(2)杏仁核神经元膜兴奋性的增加有关。据报道，冲动攻击型的人焦虑程度较低，对恐惧条件反射也不那么敏感。与人类相似，有人认为焦虑行为和恐惧学习与攻击性和低血清素水平有关。此外，攻击性被认为是边缘区域癫痫样过程的结果。杏仁核是一种边缘结构，在癫痫和情绪方面都有明确的作用，涉及杏仁核的癫痫发作活动可能与人类的攻击性有关。因此，杏仁核神经元兴奋性的细胞机制可能在攻击行为中起作用。支持这一观点的临床研究表明，抗惊厥药物对监狱囚犯和精神病患者有抗侵略性作用。在这个项目中，大鼠长期使用PCPA治疗，PCPA是一种竞争性的5-羟色胺合成抑制剂，显著抑制5-羟色胺的合成。低5-羟色胺被广泛认为与许多物种的攻击性有关。攻击性行为是通过一种简单的啮齿动物攻击性测试来量化的，其特征是容易识别的刻板印象行为。初步数据显示，在这个模型中，攻击行为被抗惊厥药物苯妥英抑制，就像其他人在人类攻击行为中所显示的那样。该项目的具体目标是(1)定义建立冲动性攻击模型所需的显著自变量，并研究攻击性、脑5-羟色胺降低与杏仁核依赖的情绪行为变化(如焦虑和恐惧学习)之间的关系；以及(2)使用全细胞电压钳技术比较对照和攻击性动物的杏仁核神经元膜特性和神经传递。此外，攻击性的神经关联被用细胞生理学方法来研究，这在以前从未被用来研究攻击性行为。这项创新的建议研究了与人类精神病理学相关的异常情绪行为的基本生物学机制。通过建立这种动物模型，未来的研究工作可以对攻击性等复杂情绪行为的细胞神经生物学产生重要的见解，并可能对治疗涉及不适当攻击性的精神障碍，如双相情感障碍、边缘人格障碍或反社会人格障碍具有重要的临床意义。

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop and use a clinically relevant animal model of aggressive behavior. We hypothesize that low serotonin-induced aggression is associated with (1) changes in other emotional behavior and (2) increased membrane excitability in amygdala neurons. Impulsive-aggressive humans reportedly have low anxiety and are less sensitive to fear-conditioning. Similar to humans, it is proposed that anxious behaviors and fear-learning are correlated with aggression and low serotonin levels. In addition, aggression has been suggested to result from epilepsy-like processes in limbic areas. One limbic structure, the amygdala, has well-defined roles in both epilepsy and emotion, and seizure activity that involves the amygdala may be associated with aggression in humans. Thus, cellular mechanisms of neuronal excitability in the amygdala may have a functional role in aggressive behavior. Supporting this idea are clinical studies showing anti-aggressive effects of anticonvulsants in prison inmates and psychiatric patients. In this project rats are chronically treated with PCPA, a competitive inhibitor of serotonin synthesis, to significantly inhibit serotonin synthesis. Low serotonin is widely-implicated in aggression in many species. Aggressive behavior is quantified using a simple test of rodent aggression characterized by easily recognized, stereotypical behaviors. Preliminary data have shown that aggressive behavior in this model is inhibited by the anticonvulsant phenytoin, as others have shown with human aggression. The specific aims of this project are to (1) define the salient independent variables required to model impulsive aggression, and to examine the relationship between aggression, low brain serotonin, and changes in amygdala-dependent emotional behaviors such as anxiety and fear-learning; and (2) compare amygdala neuron membrane properties and neurotransmission in control and aggressive animals using whole cell voltage-clamp.An animal model is developed that shares behavioral, neurochemical, and pharmacological similarities with impulsive-aggression in humans. Also, the neural correlates of aggression are investigated using cellular physiological methods never before used to study aggressive behavior. This innovative proposal examines basic biological mechanisms of aberrant emotional behavior that are relevant to human psychopathology. By developing this animal model, future research efforts can yield important insight into the cellular neurobiology of complex emotional behaviors such as aggression, and may have important clinical implications for the treatment of psychiatric disorders involving inappropriate aggression such as bipolar disorder, borderline personality disorder or antisocial personality disorder.