Circuit principles of demotivation in the decision to switch behaviors

决定改变行为时动机丧失的电路原理

• 批准号: 10612399
• 负责人: Michael A Crickmore
• 金额: $ 40.71万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10612399
• 关键词: Animals; Behavior; Behavior Disorders; Behavioral; Biological Assay; Biological Models; Brain; Calcium; Complement; Computer Models; Copulation; Data; Decision Making; Disease; Dopamine; Drosophila genus; Drowsiness; Drug Addiction; Environmental Wind; Etiology; Goals; Grant; Human; Hunger; Image; Individual; Investigation; Left; Logic; Mammals; Mental Depression; Modality; Modeling; Mood Disorders; Motivation; Neurons; Partner in relationship; Preparation; Probability; Process; Regulation; Role; Severities; Sex Behavior; Stimulus; System; Testing; Time; Work; behavioral response; data modeling; dopaminergic neuron; flexibility; male; mating behavior; motivated behavior; neural circuit; novel; optogenetics; premature; prevent; response; tool

Project Summary: The decision to commence a new behavior often requires termination of the ongoing behavior. This implies that the many drive states produced by an animal impact not only the neural circuits underlying their directly associated behaviors, but also those of many other behaviors. My lab has shown that the mating behaviors of male Drosophila are under motivational control and may be abandoned in the presence of stimuli evoking competing drives—depending on the relative intensities of the contending drives. These behaviors are motivated by dopaminergic neurons, one of many features shared with human motivational control. I present preliminary data demonstrating that multiple competing drives integrate synergistically to cause male Drosophila to prematurely terminate copulations that would last ~23 minutes if left undisturbed. This integration occurs at a set of eight male-specific, GABAergic Copulation Demotivating Neurons (CDNs) that cause immediate termination when stimulated beyond a threshold and can integrate diverse inputs over long timescales. During the first 5 minutes of mating, even the most severe threats cannot stimulate the CDNs and therefore do not cause termination; but as the mating progresses the CDNs become more accessible to diverse demotivating stimuli, gradually permitting termination in response to weaker and weaker inputs. I present a computational model for synergistic integration of competing inputs at behavior-specific demotivating neurons, demonstrating how this circuit logic can promote either behavioral stability, or flexibility, depending on the individual strengths of the full complement of drive states. I also propose a novel hypothesis for how behavior- specific demotivating neurons increase their sensitivity as the goals of the behavior are achieved. These experimental findings place the rarely studied topic of demotivation at the center of behavioral decision making and our computational work suggests several novel and testable hypotheses. The main goals of this grant are i) to understand how information from competing drives is processed and delivered to behavior-specific demotivation circuitry; and ii) to understand how this information is integrated with the motivational state of the ongoing behavior to decide whether or not to switch behaviors. This work will establish a new, front-line model system for high-order interactions between multiple motivations, with strong indications that the principles and models we derive will provide a framework for understanding motivations and decision making in humans. Project Relevance: This project explores a fundamental but understudied principle of motivational regulation: demotivation as goals are achieved and circumstances change. Dysregulation of motivation is central to drug addiction, depression, compulsive disorders, among many other behavior and mood disorders. The robust behaviors and precise manipulations in this proposal will relate neuronal activity to behavior and allow a direct attribution of causality. The data collected will be used to extend our circuit and computational models that are generalizable across animals and behaviors.

项目概要：决定开始一个新的行为往往需要终止正在进行的 行为这意味着动物产生的许多驱动状态不仅影响神经回路， 这不仅是他们直接相关行为的基础，也是许多其他行为的基础。我的实验室证明 雄性果蝇的交配行为是在动机控制下进行的， 刺激引起的竞争驱动器依赖于竞争驱动器的相对强度。这些 行为是由多巴胺能神经元激发的，这是与人类动机控制共有的许多特征之一。 我目前的初步数据表明，多个竞争驱动器协同整合，导致男性 果蝇提前终止交配，如果不受干扰，交配将持续约23分钟。这种集成 发生在一组八个男性特异性的GABA能交配失活神经元（CDN）， 当刺激超过阈值时立即终止，并能长时间整合各种输入 时间尺度。在交配的前5分钟，即使是最严重的威胁也不能刺激CDN， 因此不会导致终止;但随着交配的进展，CDN变得更容易被各种各样的人所接受。 去激励刺激，逐渐允许终止响应越来越弱的输入。我提出了一个 用于在行为特异性去激励神经元处的竞争输入的协同整合的计算模型， 演示了这种电路逻辑如何促进行为稳定性或灵活性，这取决于 充分补充驱动器状态的个人优势。我还提出了一个新的假设，关于行为- 特定的去激励神经元随着行为目标的实现而增加它们的敏感性。这些 实验结果将很少被研究的动机丧失置于行为决策的中心 我们的计算工作提出了几个新颖且可验证的假设。该补助金的主要目标是i） 了解来自竞争驱动器的信息是如何处理并传递给特定行为的 去激励电路;和ii）了解这些信息是如何与动机状态相结合的。 正在进行的行为，以决定是否切换行为。这项工作将建立一个新的，前线的模式 系统的高阶相互作用之间的多种动机，与强烈的迹象表明，原则和 我们得出的模型将为理解人类的动机和决策提供框架。 项目相关性：本项目探讨了动机调节的基本但未充分研究的原则： 随着目标的实现和环境的变化，动机失调是毒品的核心 成瘾，抑郁，强迫症，以及许多其他行为和情绪障碍。鲁棒 行为和精确的操作将把神经元活动与行为联系起来， 因果关系的归属。收集的数据将用于扩展我们的电路和计算模型， 在动物和行为中普遍化。