Neural Circuits Underlying Adaptive Behavior and Addiction

适应性行为和成瘾背后的神经回路

基本信息

批准号：
8493950
负责人：
Gero Miesenboeck
金额：
$ 23.19万
依托单位：
UNIVERSITY OF OXFORD
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8493950
关键词：
Adaptive Behaviors Address Algorithms Amphetamines Animals Architecture Aversive Stimulus Behavior Behavioral Biological Brain Cells Choice Behavior Cocaine Cues Decision Making Dopamine Drosophila melanogaster Drug abuse Electrophysiology (science)Event Functional Imaging Future Genetic Goals Intelligence Learning Link Location Logic Mammals Maps Memory Methods Methylphenidate Molecular Monitor Mushroom Bodies Nature Neurons Odors Olfactory Learning Optics Output Pattern Pharmaceutical Preparations Physiological Play Positive Reinforcements Process Psychological reinforcement Punishment Resolution Rewards Role Signal Transduction Site Source Sterile coverings Stimulus Synapses System Testing Update addiction aversive conditioning base conditioning dopaminergic neuron drug of abuse expectation experience fly improved neural circuit new technology optical imaging optogenetics patch clamp postsynaptic presynaptic programs promoter relating to nervous system research study response tool

Adaptive Behaviors Address Algorithms Amphetamines Animals Architecture Aversive Stimulus Behavior Behavioral Biological Brain Cells Choice Behavior Cocaine Cues Decision Making Dopamine Drosophila melanogaster Drug abuse Electrophysiology (science)Event Functional Imaging Future Genetic Goals Intelligence Learning Link Location Logic Mammals Maps Memory Methods Methylphenidate Molecular Monitor Mushroom Bodies Nature Neurons Odors Olfactory Learning Optics Output Pattern Pharmaceutical Preparations Physiological Play Positive Reinforcements Process Psychological reinforcement Punishment Resolution Rewards Role Signal Transduction Site Source Sterile coverings Stimulus Synapses System Testing Update addiction aversive conditioning base conditioning dopaminergic neuron drug of abuse expectation experience fly improved neural circuit new technology optical imaging optogenetics patch clamp postsynaptic presynaptic programs promoter relating to nervous system research study response tool

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项目摘要

DESCRIPTION (provided by applicant): Learning requires the updating of predictions based on experience, a process thought to be driven by error signals carried by dopaminergic neurons. The short-circuiting of this process by many drugs of abuse is an important factor in addiction. Despite this, the neural circuits that calculate changes in expectation and act upon conditioning dopamine signals remain largely unknown. As in mammals, dopamine plays an instructive role in the adaptive behavior of the fly, Drosophila melanogaster. We have previously identified a subset of dopaminergic neurons sufficient to provide conditioning error signals during olfactory learning, and have anatomically mapped the source of reinforcement to a single cluster of 12 cells, the PPL1 neurons. This project will take advantage of the numerical simplicity and genetic tractability of the fly brain and use the PPL1 cluster as the point of entry into the conserved mechanisms underlying adaptive behavior. Using a combination of genetic, neuroanatomical and optogenetic approaches along with functional optical imaging, electrophysiology and behavioral analysis, we will address four Specific Aims: 1) We will target optogenetic tools to restricted subsets of PPL1 neurons and establish which cells are necessary, and which sufficient, to drive learning. 2) We will use optical and electrophysiological recordings to monitor the activity of PPL1 neurons before, during, and after learning, allowing us to test the hypothesis that PPL1 output represents a prediction error signal. The effect of cocaine, methylphenidate, and amphetamine on this learning process will be determined, revealing the effects of these drugs of abuse on an identified learning circuit. 3) We will trace PPL1 projections to the storage sites of associative memories, analyze the biophysical changes underlying memory formation, and identify the circuit components that relay the contents of memory to downstream decision-making centers. 4) We will identify and manipulate synaptic inputs to PPL1 neurons in an effort to dissect the biological algorithm that regulates dopamine release. The project thus addresses fundamental questions about the neural principles underpinning adaptive behavior and addiction, using powerful new technologies in an eminently tractable experimental system.

描述（由申请人提供）：学习需要基于经验的预测进行更新，这一过程被认为是由多巴胺能神经元携带的错误信号驱动的。许多滥用药物对这一过程的短路是成瘾的重要因素。尽管如此，计算预期变化并在调节多巴胺信号方面起作用的神经回路仍然在很大程度上未知。与哺乳动物一样，多巴胺在果蝇的适应性行为中起着启发性的作用。我们先前已经确定了足以在嗅觉学习过程中提供条件误差信号的多巴胺能神经元的子集，并在解剖学上将增强源映射到一个由12个细胞的单个群集PPL1神经元映射到PPL1神经元。该项目将利用苍蝇大脑的数值简单性和遗传障碍性，并使用PPL1簇作为进入自适应行为基础的保守机制的点。使用遗传，神经解剖学和光遗传学方法以及功能性影像学，电生理学和行为分析的结合，我们将解决四个具体目标：1）我们将靶向限制PPL1神经元的限制子集并确定哪些细胞是必不可少的，并且有足够的细胞来驱动学习。 2）我们将使用光学和电生理记录来监测PPL1神经元的活性，然后才能学习，从而使我们能够测试PPL1输出代表预测误差信号的假设。将确定可卡因，哌醋甲酯和苯丙胺对这一学习过程的影响，从而揭示了这些滥用药物对确定的学习电路的影响。 3）我们将将PPL1的投影追踪到关联记忆的存储位点，分析内存形成的生物物理变化，并确定将内存内容传递到下游决策中心的电路组件。 4）我们将识别并操纵PPL1神经元的突触输入，以剖析调节多巴胺释放的生物学算法。因此，该项目解决了有关适应性行为和成瘾基础的神经原理的基本问题，并使用强大的新技术在非常易于处理的实验系统中。