Mechanisms underlying flexible behaviors

灵活行为背后的机制

• 批准号: 8985788
• 负责人: Alejandro I. Lopez
• 金额: $ 4.81万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8985788
• 关键词: Address; Affect; Animals; Area; Autistic Disorder; Behavior; Behavioral; C. elegans genome; Caenorhabditis elegans; Calcium; Candidate Disease Gene; Characteristics; Complex; Disease; Emotional; Environment; Excision; Food; Functional disorder; Future; Generations; Genes; Genetic; Genetic Screening; Goals; Human; Image; Individual; Invertebrates; Lead; Learning; Mediating; Mediator of activation protein; Mental disorders; Molecular; Monitor; Mood Disorders; Nature; Nematoda; Nervous system structure; Neuromodulator; Neuromodulator Receptors; Neurons; Neurotransmitter Receptor; Neurotransmitters; Outcome; Output; Pattern; Physicians; Property; Recording of previous events; Research; Schizophrenia; Scientist; Source; System; Testing; Time; Training; Work; base; experience; flexibility; in vivo; insight; neural circuit; optogenetics; public health relevance; time use; tool

 DESCRIPTION (provided by applicant): The generation of appropriate behaviors relies on the ability to modulate internal states based on context and recent experience, and this ability is often defective in mental illnesses such as schizophrenia. Understanding the cellular and molecular mechanisms of internal state modulation may therefore provide insight into the nature of these disorders. The nematode Caenorhabditis elegans offers an excellent system to address these questions. It has a simple nervous system consisting of exactly 302 neurons with known connectivity and multiple genetic tools are available to monitor and manipulate individual neurons in behaving animals. C. elegans contains many of the same neurotransmitters and neuromodulators found in mammalian systems, suggesting that its circuits possess evolutionarily conserved properties. These characteristics will allow us to elucidate basic mechanisms that circuits use to generate appropriate behaviors. C. elegans foraging off-food displays a behavioral sequence that allows it to maximize its encounter with food sources. When removed from food, for the first 15 minutes, C. elegans enters a behavioral state called local search in which it performs many reorientations, exploring a small area and maximizing its chance of locating the previous food source. After 15 minutes, if it fails to find food, it entersa state called dispersal in which it suppress reorientations, exploring large areas and maximizing its encounter with random food sources. This sequence, which occurs in a constant external environment, represents a transition in the internal state of the animal that allows it to use context and recent experience to generate an appropriate behavior. To understand the cellular and molecular mechanisms that mediate the off-food foraging behavioral transition, we propose the following specific aims: 1) to identify the neurons important for off-food foraging using optogenetics; 2) to correlate off-food neuronal activity patterns with behavior using in vivo calcium imaging in freely moving animals; 3) to identify genes necessary for the behavioral sequence by performing a candidate genetic screen. The completion of these specific aims will yield fundamental insight into how circuits can change internally to elicit flexible behaviors. Th approaches in this proposal provide a platform to train a future physician scientist to study neural circuitry and behavior.

 描述（由申请人提供）：适当行为的产生依赖于根据上下文和最近的经验调节内部状态的能力，这种能力在精神疾病（如精神分裂症）中通常是有缺陷的。 因此，了解内部状态调制的细胞和分子机制可以提供对这些疾病的性质的洞察。 线虫秀丽隐杆线虫提供了一个很好的系统来解决这些问题。 它有一个简单的神经系统，由302个已知连接的神经元组成，并且有多种遗传工具可用于监测和操纵行为动物中的单个神经元。 C.线虫含有许多在哺乳动物系统中发现的相同神经递质和神经调质，这表明它的神经回路具有进化上保守的特性。 这些特征将使我们能够阐明电路用于产生适当行为的基本机制。 C.秀丽隐杆线虫在觅食时表现出一种行为序列，使其能够最大限度地与食物源相遇。 当从食物中取出时，在前15分钟，C。秀丽线虫进入一种称为局部搜索的行为状态，在这种状态下，它会进行多次重新定位，探索一个小区域，并最大限度地提高找到先前食物来源的机会。 15分钟后，如果它找不到食物，它就会进入一种叫做分散的状态，在这种状态下，它会抑制重新定位，探索大面积的区域，并最大限度地与随机的食物源相遇。 这个序列发生在恒定的外部环境中，代表了动物内部状态的转变，允许它使用上下文和最近的经验来产生适当的行为。 为了了解介导离食觅食行为转变的细胞和分子机制，我们提出了以下具体目标：1）利用光遗传学鉴定对离食觅食重要的神经元; 2）在自由移动的动物中，利用体内钙成像将离食神经元活动模式与行为相关联; 3）通过进行候选基因筛选来鉴定行为序列所必需的基因。 这些具体目标的完成将产生对电路如何内部改变以引发灵活行为的基本见解。 该建议中的方法提供了一个平台，以培养未来的医生科学家研究神经回路和行为。