Genetic Analysis of Acoustic Startle Behavior and Circuits

声惊吓行为和电路的遗传分析

• 批准号: 8447646
• 负责人: Kurt C. Marsden
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447646
• 关键词: Acoustic Nerve; Acoustics; Adult; Affect; Aggressive behavior; Alleles; Animals; Antibodies; Anxiety; Anxiety Disorders; Autistic Disorder; Behavior; Behavioral; Behavioral Paradigm; Bilateral; Biochemical Pathway; Biological Models; Candidate Disease Gene; Cells; Characteristics; Chromosomes, Human, Pair 5; Code; Contralateral; Defect; Development; Disease; Drug Targeting; Exhibits; Fertilization; Fishes; Genes; Genetic; Genetic Programming; Genetic Recombination; Genetic Screening; Hyperactive behavior; Hypersensitivity; Image; Imagery; In Situ Hybridization; Individual; Injection of therapeutic agent; Ipsilateral; Larva; Maps; Mauthner' s neuron; Mediating; Messenger RNA; Modality; Molecular; Molecular Genetics; Motor Neurons; Mutation; NMDA receptor antagonist; Nature; Nervous System Part; Nervous system structure; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Play; Post-Traumatic Stress Disorders; Potassium Channel; Process; Proteins; Regulation; Role; Schizophrenia; Sensory; Site; Speed; Spinal Cord; Stimulus; Swimming; Synapses; Tail; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Transcription Coactivator; Transgenes; Transgenic Organisms; Translating; Vertebrates; Zebrafish; addiction; auditory stimulus; conditioned fear; drug testing; genetic analysis; hindbrain; in vivo; insight; kinematics; mutant; neural circuit; neuropsychiatry; novel; prepulse inhibition; research study; response; small molecule; sound; spatiotemporal

DESCRIPTION (provided by applicant): Survival depends on being able to accurately determine if an environmental stimulus requires a behavioral response. For example, the nervous system must set an appropriate behavioral threshold that an auditory stimulus must surpass in order to trigger a startle response. This threshold should be set such that potentially dangerous situations are detected and averted yet not so low that common sounds will elicit a response. Excessive startle responses are observed in many neuropsychiatric disorders including schizophrenia, post-traumatic stress disorder, anxiety disorders, and addiction. Furthermore, this threshold should be able to be modulated so that, for instance, an individual will become habituated to persistent loud stimuli. While the principle components of the hindbrain and spinal cord circuits that underlie the startle response are known and conserved among vertebrates, the molecular-genetic mechanisms that regulate startle threshold and modulation are not well understood. Here I propose to use the powerful zebrafish model system to investigate the mechanisms of startle regulation. In fish the acoustic startle response is initiated by the firing of one of two bilateral giant reticulospinal neurons, the Mauthner cells, which receive direct synaptic input from the ipsilateral auditory nerve. Upon firing, the Mauthner cell directly activates contralateral motor neurons to trigger a characteristic "C"-bend, initiating escape behavior. Through a recent genetic screen for mutants with defects in startle modulation we identified a mutant that is hypersensitive to acoustic startle stimuli. Without displaying hyperactivity or any other defects in startle kinematics, homozygous houdini larvae perform startle escape responses to low-level auditory stimuli that fail to elicit escapes in wild-type fish. This suggests that the houdini gene plays a role in setting the acoustic startle threshold. The aims in this proposal will determine the extent of houdini's role in regulating behavior and identify the mechanisms by which it modulates the acoustic startle threshold. In aim 1 I will analyze whether houdini larvae are also hypersensitive to stimuli in other sensory modalities and whether they show defects in startle modulation such as habituation and prepulse inhibition. I will also test houdini adults for hypersensitivity and in anxiety, aggression, and addiction paradigms. In aim 2 I will identify the houdini gene and characterize its spatiotemporal expression. And in aim 3 I will reveal molecular mechanisms by which houdini affects the excitability of the Mauthner cell startle circuit. The houdini mutant presents an exciting opportunity to understand, at least in part, how the nervous system "decides" whether to initiate a behavior. These experiments will open up avenues not only for further characterization of the startle pathway but also for potential therapeutic interventions in conditions such as anxiety disorders.

描述（由申请人提供）：生存取决于能否准确确定环境刺激是否需要行为反应。例如，神经系统必须设定适当的行为阈值，听觉刺激必须超过该阈值才能触发惊吓反应。该阈值的设置应能够检测并避免潜在的危险情况，但又不能太低以致常见的声音会引起响应。在许多神经精神疾病中观察到过度惊吓反应，包括精神分裂症、创伤后应激障碍、焦虑症和成瘾。此外，这个阈值应该能够被调节，以便，例如，一个人将习惯于持续的大声刺激。虽然构成惊吓反应的后脑和脊髓回路的主要组成部分在脊椎动物中是已知的并且是保守的，但调节惊吓阈值和调制的分子遗传机制尚不清楚。在这里，我建议使用强大的斑马鱼模型系统来研究惊吓调节机制。 在鱼类中，声惊吓反应是由两个双侧巨大网状脊髓神经元之一（毛特纳细胞）的放电引发的，毛特纳细胞接收来自同侧听觉神经的直接突触输入。放电后，毛特纳细胞直接激活对侧运动神经元，触发特征性的“C”形弯曲，从而启动逃跑行为。通过最近对惊吓调节缺陷突变体的遗传筛选，我们发现了一种对声音惊吓刺激高度敏感的突变体。纯合的胡迪尼幼虫在惊吓运动学上没有表现出过度活跃或任何其他缺陷，它们对低水平的听觉刺激执行惊吓逃生反应，而这种反应无法在野生型鱼类中引起逃生。这表明胡迪尼基因在设定声音惊吓阈值方面发挥着作用。 该提案的目标将确定胡迪尼在调节行为方面的作用程度，并确定其调节声惊吓阈值的机制。在目标 1 中，我将分析胡迪尼幼虫是否也对其他感觉方式的刺激过敏，以及它们是否在惊吓调节方面表现出缺陷，例如习惯化和前脉冲抑制。我还将测试胡迪尼成人的超敏性以及焦虑、攻击性和成瘾范式。在目标 2 中，我将识别 houdini 基因并表征其时空表达。在目标 3 中，我将揭示胡迪尼影响毛特纳细胞惊吓回路兴奋性的分子机制。胡迪尼突变体提供了一个令人兴奋的机会，至少可以部分地了解神经系统如何“决定”是否发起某种行为。这些实验不仅将为进一步表征惊吓通路开辟途径，而且还将为焦虑症等疾病的潜在治疗干预开辟途径。