Neurobiological regulation of extinction learning in appetitve conditioning

食欲调节中消退学习的神经生物学调节

• 批准号: RGPIN-2017-04802
• 负责人: Chaudhri, Nadia
• 金额: $ 1.82万
• 依托单位: Concordia University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=711221
• 关键词: Neurobiological; regulation; extinction; learning; appetitve

The capacity to inhibit actions and reactions when an anticipated environmental stimulus no longer occurs is critical for flexible, adaptive behaviour. The ensuing decrement in conditioned responding, referred to as extinction, has been extensively researched using aversive Pavlovian conditioning procedures in which a conditional stimulus (CS) is paired with a noxious unconditional stimulus (US), and then the US is withheld to induce extinction. Results suggest that extinction produces a new inhibitory memory that competes with the original learning for control over responding. Specifically, a new CS-no US memory is formed during extinction that competes with the original CS-US memory to suppress responding. My program of research seeks to understand how the brain regulates the formation and retention of extinction memory. This area of research is shaped by the influential hypothesis that distinct cortical projections originating in the infralimbic subregion of the medial prefrontal cortex and terminating in either the amygdala or nucleus accumbens shell mediate the extinction of responding associated with aversive or appetitive (positive) stimuli, respectively. However, a consideration that has been overlooked in the development of this hypothesis is that research using aversive stimuli is conducted using Pavlovian learning models, whereas research using appetitive stimuli has almost exclusively been conducted using instrumental conditioning procedures. In the latter, operant responding is reinforced by an appetitive stimulus, which is subsequently withheld to induce extinction. Given that the original memory is acquired via different learning processes, we propose that it may be the learning process (Pavlovian or instrumental) and not the nature of stimulus (aversive or appetitive) that recruits distinct projections from the infralimbic cortex during extinction. We will use a multidisciplinary approach to test this novel hypothesis in rats. Using immunohistochemistry we will examine the activation of infralimbic projections to the nucleus accumbens shell or basolateral nucleus of the amygdala by extinction in appetitive Pavlovian and instrumental conditioning procedures. Using innovative in vivo optogenetic and chemogenetic strategies we will dissect the roles of these two projections in the extinction of appetitive instrumental conditioning, and appetitive and aversive Pavlovian conditioning. Results from this timely proposal will form the basis for new research aimed at identifying the molecular, neurochemical and genetic processes within well-defined neural circuits that mediate the extinction of appetitive conditioned responding. Overall, this line of research will expand our understanding of how the brain regulates the inhibition of actions and reactions when anticipated environmental stimuli fail to occur.

当预期的环境刺激不再发生时，抑制行动和反应的能力对于灵活的适应性行为至关重要。随后的条件反应的递减，称为灭绝，已经被广泛研究使用厌恶巴甫洛夫条件反射程序，其中条件刺激（CS）与有害的无条件刺激（US）配对，然后US被扣留以诱导灭绝。结果表明，消退产生了一种新的抑制性记忆，与原始学习竞争对反应的控制。具体来说，一个新的CS-no US记忆是在灭绝过程中形成的，它与原来的CS-US记忆竞争，以抑制反应。我的研究项目旨在了解大脑如何调节灭绝记忆的形成和保持。 这一领域的研究是由一个有影响力的假设，即不同的皮质投射起源于内侧前额叶皮层的边缘下亚区，终止于杏仁核或杏仁核壳介导与厌恶或食欲（积极）刺激相关的反应消退。然而，在这个假设的发展过程中被忽视的一个考虑是，使用厌恶刺激的研究是使用巴甫洛夫学习模型进行的，而使用食欲刺激的研究几乎完全是使用工具条件反射程序进行的。在后者中，操作性反应被食欲刺激加强，随后被抑制以诱导灭绝。鉴于原始记忆是通过不同的学习过程获得的，我们提出，它可能是学习过程（巴甫洛夫或工具），而不是刺激的性质（厌恶或食欲），在灭绝过程中，从边缘下皮层招募不同的投射。 我们将使用多学科方法在大鼠中测试这一新假设。使用免疫组织化学，我们将检查激活的边缘下投射到杏仁核壳或基底外侧核的食欲巴甫洛夫和仪器条件反射程序中的灭绝。使用创新的体内光遗传学和化学遗传学策略，我们将剖析这两个预测在食欲工具条件反射和食欲和厌恶巴甫洛夫条件反射的消退中的作用。这一及时的提议的结果将为新的研究奠定基础，这些研究旨在确定介导食欲条件反应消退的明确神经回路中的分子、神经化学和遗传过程。总的来说，这一系列的研究将扩大我们对大脑如何在预期的环境刺激未能发生时调节行为和反应的抑制的理解。