Parasite / host interaction and the neurobiology of fear

寄生虫/宿主相互作用和恐惧的神经生物学

基本信息

批准号：
7866559
负责人：
ROBERT M. SAPOLSKY
金额：
$ 35.71万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7866559
关键词：
Acute Amygdaloid structure Animal Model Animals Anxiety Area Behavior Behavior Control Behavior Therapy Behavioral Biological Response Modifiers Brain Brain region Categories Cell Count Chronic Conditioned Culture Media Cyst Deltastab Dendrites Dopamine Eating Employee Strikes Family Felidae Feces Felis catus Fright Glutamates Goals Grant Immune response Infection Inflammation Inflammatory Infusion procedures Intestines Knowledge Learning Length Life Cycle Stages Light Maps Mediating Mental disorders Microglia Molecular Molecular Profiling Neurobiology Neuroglia Neurons Neurotransmitters Odors Oocysts Organism Paper Parasites Parasitology Pathway interactions Pheromone Process Proteome Rattus Reproduction Rewards Rodent Role Signal Transduction Smell Perception Structure Syndrome Time Tissues Toxoplasma Toxoplasma gondii Urine Vertebral column Work asexual base behavior change discount extracellular fitness gamma-Aminobutyric Acid in vivo interest mutant neurochemistry parasite genome protein expression public health relevance relating to nervous system reproductive reproductive success research study response theories

项目摘要

DESCRIPTION (provided by applicant): The behavioral manipulation hypothesis posits that parasites can change the behavior of hosts to increase the reproductive fitness of the parasite. The protozoan parasite Toxoplasma gondii fits this description well. Toxoplasma shuttles between an asexual life-cycle in rodents and a sexual life-cycle in cat intestine. In rodents, parasites preferentially localize to the brain. The parasite has evolved the capacity to, once having formed cysts in the brain, abolish the innate fear that rodents have of the odors of cats, and to convert that fear into an attraction; this increases the likelihood of the rodent being predated, thereby completing the parasite's life cycle. Our prior work has shown the robustness of this behavioral phenomenon, the preferential formation of Toxoplasma cysts in the amygdala, and the capacity of the parasite to reduce cell number and dendrite length in the basolateral amygdala. The present grant further explores the neurobiology of Toxoplasma's behavioral effects, in order to better understand both normal and pathological fear. Specific Aim 1 identifies brain regions that are candidates for mediating the behavioral effects of Toxoplasma. A time course study will indicate brain regions where Toxoplasma cysts form prior to the first emergence of the behavioral effects of the parasite. In addition, we will construct a map of brain regions activated in response to cat odor in control rats (using cFos expression as a marker), and then determine whether Toxoplasma blocks such activation in any of those regions. The candidate brain regions identified in this Specific Aim will be studied in the subsequent Aims. Specific Aim 2 studies whether Toxoplasma causes inflammation in local brain regions and whether that contributes to the behavioral syndrome. It will also investigate whether the parasite changes the number of cells (both neurons and glia) in different brain regions, and/or changes the complexity of dendritic processes in neurons. Finally, it will examine whether Toxoplasma blocks the effects of cat odor on extracellular concentrations of glutamate, GABA and dopamine in those candidate brain regions. Specific Aim 3 will explore the reductive bases of Toxoplasma's actions. The first part will be an analysis of protein expression profiles in brain regions implicated in the parasite's behavioral effects, and in the parasite as well. The second will be a conditioned medium experiment, determining whether the medium in which cultured Toxoplasma grows can have the same effects in the brain as the parasite itself. This will be a first step in determining whether a factor secreted by the parasite mediates the behavioral effects. PUBLIC HEALTH RELEVANCE Experiments proposed in this grant explore an unlikely intersection of parasitology and neurobiology, that is, loss of innate fear in rodents due to Toxoplasma infection. Pathological fear is central to several psychiatric disorders. Understanding how Toxoplasma abolishes fear will shed light on how fear is generated in the first place and how we can manage pathological fear.

描述（由申请人提供）：行为操纵假说认为寄生虫可以改变宿主的行为以提高寄生虫的繁殖适应性。原生动物寄生虫弓形虫很符合这个描述。弓形虫在啮齿动物的无性生命周期和猫肠道的有性生命周期之间穿梭。在啮齿类动物中，寄生虫优先定位于大脑。这种寄生虫已经进化出一种能力，一旦在大脑中形成囊肿，就能消除啮齿类动物对猫气味的天生恐惧，并将这种恐惧转化为吸引力。这增加了啮齿动物被捕食的可能性，从而完成了寄生虫的生命周期。我们之前的工作已经证明了这种行为现象的稳健性，弓形虫包囊在杏仁核中的优先形成，以及寄生虫减少基底外侧杏仁核中细胞数量和树突长度的能力。目前的资助进一步探讨了弓形虫行为影响的神经生物学，以便更好地理解正常和病理性的恐惧。具体目标 1 确定了介导弓形虫行为影响的候选大脑区域。时间进程研究将表明在寄生虫首次出现行为影响之前弓形虫包囊形成的大脑区域。此外，我们将构建对照大鼠响应猫气味而激活的大脑区域图（使用 cFos 表达作为标记），然后确定弓形虫是否阻止任何这些区域的此类激活。本特定目标中确定的候选大脑区域将在后续目标中进行研究。具体目标 2 研究弓形虫是否会引起局部大脑区域炎症以及是否会导致行为综合征。它还将研究寄生虫是否改变不同大脑区域的细胞（神经元和神经胶质细胞）数量，和/或改变神经元树突过程的复杂性。最后，它将检查弓形虫是否会阻止猫气味对这些候选大脑区域中谷氨酸、GABA 和多巴胺细胞外浓度的影响。具体目标 3 将探索弓形虫作用的还原基础。第一部分将分析与寄生虫行为影响有关的大脑区域以及寄生虫中的蛋白质表达谱。第二个是条件培养基实验，确定弓形虫生长的培养基是否能在大脑中产生与寄生虫本身相同的效果。这将是确定寄生虫分泌的因子是否介导行为影响的第一步。公共卫生相关性本次资助中提出的实验探索了寄生虫学和神经生物学之间不太可能的交叉点，即啮齿动物因弓形虫感染而丧失先天恐惧。病理性恐惧是多种精神疾病的核心。了解弓形虫如何消除恐惧将有助于了解恐惧最初是如何产生的以及我们如何管理病态恐惧。