Parasite/Host Interactions and the Neurobiology of Fear

寄生虫/宿主相互作用和恐惧的神经生物学

• 批准号: 7051367
• 负责人: ROBERT M. SAPOLSKY
• 金额: $ 15.69万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-08 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7051367
• 关键词: Toxoplasma gondii; anxiety; behavioral /social science research tag; conditioning; cues; dendrites; ethology; fear; green fluorescent proteins; host organism interaction; intraperitoneal injections; laboratory rat; life cycle; limbic system; nervous system infection; neural plasticity; neurobiology; neuropsychological tests; olfactions; parasitism; preference; protozoal infection; urine

DESCRIPTION (provided by applicant): Parasites have evolved various mechanisms for manipulating host behavior for the benefit of the parasite. This proposal concerns an example relevant to understanding fear and anxiety. The protozoan Toxoplasma gondii reproduces sexually in a two-species life cycle. The parasite reproduces in cats, and is then excreted. Infected feces are eaten by rodents, in which Toxoplasma forms cysts in muscle and the CNS. The life cycle is completed when the rodent is predated by a cat. Recent reports indicate that Toxoplasma alters the behavior of infected rodents so as to increase the likelihood of their being predated by cats. Specifically, the parasite blunts the innate aversion of rats for the urine of cats, producing instead an attraction towards cat pheromones. This appears to be a rather specific effect (rather than merely being secondary to damage to the olfactory system or to the CNS in general). Moreover, additional observations suggest that Toxoplasma decreases ethologically-relevant fear in other mammals as well. These findings suggest that Toxoplasma is selectively able to interfere with circuits of fear and anxiety in the rodent, a possibility unstudied to date, to my knowledge. The purpose of this exploratory grant is to examine how broadly Toxoplasma is able to suppress fear-related behaviors in rodents, and to begin to understand the neurobiology of this effect; potentially, this could pave the way for novel approaches to the treatment of anxiety disorders. In Specific Aim 1, we will test the generality of these Toxoplasma effects, examining the behavior of infected rats with a battery of tests of differing facets of fear and anxiety. Controls will be mocked infected or infected with Sarcocystis neurona, a related protozoa that does not reproduce in a carnivore. In Specific Aim 2, we will use a Toxoplasma strain that expresses a reporter gene during its phase of forming CNS cysts in order to do a detailed examination of the neuroanatomy of infection. We hypothesize that Toxoplasma infects brain regions involved in the circuitry of fear and anxiety (in particular, the amygdala). In Specific Aim 3, we will examine the effects of Toxoplasma infection on cell number and volume, and on dendritic morphology in brain regions implicated in the prior two Specific Aims in the effects of Toxo.

描述（由申请人提供）：寄生虫已经进化出各种机制来操纵宿主行为以使其受益。该提案涉及一个与理解恐惧和焦虑相关的例子。原生动物弓形虫在两个物种的生命周期中进行有性繁殖。这种寄生虫在猫体内繁殖，然后被排出体外。啮齿动物吃掉受感染的粪便，其中弓形虫在肌肉和中枢神经系统中形成包囊。当啮齿动物被猫捕食时，生命周期就完成了。最近的报告表明，弓形虫会改变受感染啮齿动物的行为，从而增加它们被猫捕食的可能性。具体来说，这种寄生虫削弱了老鼠对猫尿液的天生厌恶，反而产生了对猫信息素的吸引力。这似乎是一种相当特殊的影响（而不仅仅是对嗅觉系统或一般中枢神经系统损害的次要影响）。此外，其他观察结果表明，弓形虫也能减少其他哺乳动物与行为学相关的恐惧。 这些发现表明，弓形虫能够选择性地干扰啮齿动物的恐惧和焦虑回路，据我所知，迄今为止尚未研究过这种可能性。这项探索性资助的目的是检查弓形虫能够在多大程度上抑制啮齿类动物的恐惧相关行为，并开始了解这种效应的神经生物学；这可能为治疗焦虑症的新方法铺平道路。 在具体目标 1 中，我们将测试这些弓形虫效应的普遍性，通过一系列恐惧和焦虑不同方面的测试来检查受感染老鼠的行为。对照组将被模拟感染或感染神经元肉孢子虫，这是一种不能在食肉动物中繁殖的相关原生动物。在具体目标 2 中，我们将使用在形成中枢神经系统囊肿阶段表达报告基因的弓形虫菌株，以便对感染的神经解剖学进行详细检查。我们假设弓形虫感染涉及恐惧和焦虑回路的大脑区域（特别是杏仁核）。在具体目标 3 中，我们将检查弓形虫感染对细胞数量和体积的影响，以及对弓形虫影响的前两个具体目标所涉及的大脑区域树突形态的影响。