Parasite/Host Interactions and the Neurobiology of Fear

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的行为以造福于寄生虫。这项建议涉及一个与理解恐惧和焦虑有关的例子。原生动物弓形虫在两个物种的生活史中进行有性繁殖。这种寄生虫在猫身上繁殖，然后被排泄出来。受感染的粪便被啮齿动物吃掉，弓形虫在肌肉和中枢神经系统形成包囊。当啮齿动物被猫捕食时，它的生命周期就完成了。最近的报告表明，弓形虫改变了受感染的啮齿动物的行为，从而增加了它们被猫捕食的可能性。具体地说，这种寄生虫削弱了老鼠对猫尿的天生厌恶，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的损害)。此外，更多的观察表明，弓形虫也减少了其他哺乳动物在行为学上的恐惧。 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，这种可能性迄今为止还没有研究过。这项探索性拨款的目的是研究弓形虫在多大程度上能够抑制啮齿动物的恐惧相关行为，并开始了解这种影响的神经生物学；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的不同方面的测试来检查受感染大鼠的行为。对照组将被嘲弄感染或感染神经性肉孢子虫，这是一种相关的原生动物，不会在食肉动物中繁殖。在具体目标2中，我们将使用一株在形成中枢神经系统包囊阶段表达报告基因的弓形虫菌株，以详细检查感染的神经解剖学。我们假设弓形虫感染了与恐惧和焦虑有关的大脑区域(特别是杏仁核)。在特定目标3中，我们将研究弓形虫感染对细胞数量和体积的影响，以及对前两个特定目标所涉及的脑区树突形态的影响。

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.