Synaptic Microcircuits Underlying Associative Learning

关联学习背后的突触微电路

• 批准号: 10187661
• 负责人: Michael Nitabach
• 金额: $ 39.14万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10187661
• 关键词: Acute; Animal Model; Animals; Anxiety; Behavioral; Brain; Brain region; Cells; Chemosensitization; Clinical; Cues; Data; Drosophila genus; Exhibits; Extinction (Psychology); Failure; Genetic; Goals; Image; Interneurons; Learning; Learning Disorders; Measures; Memory; Mental Depression; Mental disorders; Modeling; Molecular; Mushroom Bodies; Nervous system structure; Neuronal Plasticity; Neurons; Odors; Output; Phase; Play; Recurrence; Resolution; Rewards; Role; Schizophrenia; Sensory; Shock; Signal Transduction; Synapses; Testing; Update; Visualization; base; cell type; classical conditioning; design; dopaminergic neuron; experimental study; flexibility; fly; in vivo; insight; learning extinction; novel; optogenetics; relating to nervous system; response; tool; voltage

Animals learn to associate otherwise neutral sensory cues with positive or negative contingencies and rely on those associations to make adaptive decisions. Flexible updating of these acquired associations as contingencies change is also important. Failure to update internal representations plays a causal role in some mental disorders, including schizophrenia and anxiety. While the neural substrates of acquiring and updating associations have been studied in mammalian models, the complexity of the mammalian brain has made it difficult to obtain precise cellular and synaptic mechanistic understanding. Drosophila flies exhibit flexible associative learning: they learn to avoid an odor paired with electric shock, and extinguish that learned association when the odor is later presented without shock. Flies have powerful genetic tools to allow precise manipulation and visualization of neural activity with cellular resolution in the mushroom body brain region (MB), where neural plasticity underlying learning occurs. Our long-term goal is to use Drosophila to gain mechanistic insight into how acquisition and extinction are implemented by synaptic microcircuits of the MB. Our novel hypothesis is that plasticity of dopamine neurons embedded in a recurrent synaptic microcircuit residing in the fly mushroom body underlies extinction of odor-shock associations. To test this hypothesis we employ in vivo Ca2+ imaging and optogenetics to visualize and manipulate dynamic changes in neural activity of specific genetically targeted MB cell types as a fly acquires and extinguishes an association between a neutral odor and aversive electric shock.

动物学会将其他中性的感官暗示与积极或消极的偶然性联系起来，并依赖于 做出适应性决策。将这些已获得的关联灵活更新为 意外情况的变化也很重要。未能更新内部表示在某些情况下起到了因果作用 精神障碍，包括精神分裂症和焦虑。而获取和更新的神经底物 在哺乳动物模型中已经研究过关联，哺乳动物大脑的复杂性使其 很难获得准确的细胞和突触机制的了解。果蝇表现出柔韧性 联想学习：他们学会避免伴随着电击的气味，并消除所学到的气味 当气味随后呈现时，没有电击，就会产生联想。苍蝇拥有强大的基因工具，可以精确地 利用细胞分辨率操纵和可视化蘑菇体脑区域的神经活动 (MB)，学习发生神经可塑性的地方。我们的长期目标是利用果蝇来获得 机械洞察获得和灭绝是如何通过MB的突触微电路实现的。 我们的新假设是，多巴胺神经元的可塑性嵌入到一个经常性的突触微电路中 生活在苍蝇蘑菇体内是气味-休克联系消亡的基础。为了检验这一假设，我们 利用体内钙离子成像和光遗传学来可视化和操纵神经活动的动态变化 当苍蝇获得和消除中性细胞之间的关联时，特定的基因靶向MB细胞类型的 气味和令人厌恶的电击。