Dopaminergic modulation of CO2 response during starvation in C. elegans

线虫饥饿期间 CO2 反应的多巴胺能调节

基本信息

  • 批准号:
    8983841
  • 负责人:
  • 金额:
    $ 3.74万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-08-01 至 2018-07-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Sensory cues can be attractive or repulsive depending on the context in which they are present. To make contextually appropriate decisions, the brain must integrate sensory information in the environment with its own internal needs. Biogenic amines are small molecules that the brain releases that cause changes in neural circuit function and drive contextually appropriate behavior. Dopamine release encodes motivation and salience and regulates reward-driven behaviors. In humans, regulation of dopamine signaling is critical: too much dopamine signaling is implicated in schizophrenia, whereas decreased dopamine signaling is implicated in Parkinson's Disease. How dopamine dynamically modulates neural circuits to effect state-dependent changes on behavior is poorly understood. The experiments in this proposal will investigate how dopamine acts at the gene, cell, and circuit levels to alter CO2 response behavior as a function of starvation in C. elegans. We have found that, when fed, C. elegans adults avoid CO2, an evolutionarily advantageous strategy that may allow them to evade CO2-emitting predators. Within 3 hours of starvation, worms switch from avoiding CO2 to being attracted to it. We have implicated a role for dopamine in this switch. Worms with no dopamine are constitutively attracted to CO2 and worms with increased dopamine have attenuated attraction to CO2 even when starved. We have identified a dopamine receptor that is involved in mediating the switch from CO2 avoidance to attraction. We will investigate how dopaminergic signaling regulates CO2-evoked behavior using pharmacogenetics, quantitative worm tracking, and time-lapse imaging of dopaminergic neuron activity (Aim 1). We will then dissect how dopamine functionally alters the CO2 microcircuit by imaging activity of CO2 circuit neurons in wild-type worms and mutants with altered dopaminergic signaling (Aim 2). Finally, we will take a systems-based approach to image and perturb neural circuit function in intact, freely moving animals to determine how dopamine-mediated changes in neuronal activity directly translate to observable changes in behavior (Aim 3). These experiments will provide fundamental insights into how dopamine dynamically modulates neuronal circuits and may elucidate how dysregulation of dopaminergic signaling leads to sensory deficits seen in neuropsychiatric disease.
 描述(由申请人提供):感官暗示可能是吸引人的,也可能是令人厌恶的,这取决于它们所处的环境。为了做出与环境相适应的决定,大脑必须将环境中的感觉信息与自身的内在需求结合起来。生物胺是大脑释放的小分子,会导致神经回路功能的变化,并驱动与背景相适应的行为。多巴胺的释放编码动机和显着性,并调节奖励驱动的行为。在人类中,多巴胺信号的调节是至关重要的:太多的多巴胺信号与精神分裂症有关,而多巴胺信号的减少与帕金森病有关。多巴胺如何动态地调节神经回路,以影响行为的状态依赖变化,目前还知之甚少。这项提议中的实验将研究多巴胺如何在基因、细胞和电路水平上改变线虫的二氧化碳响应行为,作为饥饿的函数。 我们发现,当喂食线虫时,线虫的成虫会避免二氧化碳,这是一种进化上的有利策略,可能会让它们躲避排放二氧化碳的捕食者。在饥饿的3小时内,蠕虫从躲避二氧化碳转变为被二氧化碳吸引。我们已经暗示了多巴胺在这种转换中的作用。没有多巴胺的蠕虫天生就会被二氧化碳吸引,而多巴胺增加的蠕虫即使在饥饿的情况下也会减弱对二氧化碳的吸引力。我们已经确定了一种多巴胺受体,它参与了从避免二氧化碳到吸引二氧化碳的转换。我们将使用药物遗传学、定量蠕虫跟踪和多巴胺能神经元活动的时移成像来研究多巴胺能信号如何调节二氧化碳诱发的行为(目标1)。然后,我们将剖析多巴胺如何通过成像野生型蠕虫和多巴胺能信号改变的突变体中的二氧化碳电路神经元的活动来在功能上改变二氧化碳微电路(目标2)。最后,我们将采用一种基于系统的方法对完整、自由移动的动物的神经回路功能进行成像和干扰,以确定多巴胺介导的神经元活动变化如何直接转化为可观察到的行为变化(目标3)。这些实验将为多巴胺如何动态调节神经元电路提供基本的见解,并可能阐明多巴胺能信号的失调如何导致神经精神疾病中的感觉障碍。

项目成果

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