Neural circuits and mechanisms of context specific conditioned inhibition

上下文特定条件抑制的神经回路和机制

• 批准号: RGPIN-2015-06347
• 负责人: McDonald, Robert
• 金额: $ 5.17万
• 依托单位: University of Lethbridge
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=614097
• 关键词: Neural; circuits; mechanisms; context; specific

The abilities to learn and remember constitute two important functions mediated by the mammalian brain.  One fundamental learning and memory function that most organisms possess is the ability to discriminate between different cues and contexts.  Of particular interest is the demonstration that during discrimination learning, reinforced cues acquire excitatory and non-reinforced cues acquire inhibitory associations.      We have been investigating these learning processes in rats using a visual discrimination paradigm (VDP).  We demonstrated that successful performance of this instrumental task requires the rat to learn an excitatory association between a particular stimulus and a motor response that is repeatedly reinforced, this behaviour was not context-specific, and was dependent on dorso-lateral striatum.  We also showed that an inhibitory association to the non-reinforced cue was acquired, showed context-specificity, and was dependent on the ventral hippocampus (VH).      The goal of this proposed research program is to develop a clear understanding of the neural circuits and neural mechanisms necessary for context-specific conditioned inhibition.  Our hypothesis is that a neural circuit encompassing the VH and nucleus accumbens core (NAc) is essential.  We will use various levels of analysis to provide evidence that the VH and NA are a functional circuit mediating context-specific inhibition.  These techniques will include the use of selective neurotoxic lesions or reversible lesions to demonstrate a functional interaction between the VH and NAc.  We will also evaluate information processing in VH and NAc during acquisition of the VDP.  This will be achieved using high density, multi-site electrophysiological recording techniques in freely-behaving rats.  Finally, we will investigate the neurochemical basis of the context-specific inhibition effect.  This aim will be achieved by blocking neurotransmitter systems in the VH or NAc during discrimination learning. Impact:  There has been an impressive scholarly effort and tradition of trying to account for how behaviour is shaped by exposure to specific events and environmental conditions and the neural systems responsible.  This undertaking has made many advances in our understanding of the conditions and mechanisms of learning in human and non-human animals and has had a huge impact on modern society.  For example, this work is revolutionizing our understanding of the nature and causes of psychiatric disorders including addiction, anxiety, post-traumatic stress disorder, and obesity.  Despite these and other contributions, many important issues concerning conditioning processes remain unknown.  Different forms of inhibitory conditioning, their neural substrates and biochemical mechanisms mediating them are not well understood and there is still significant room for discovery, innovation and impact in this area of basic research.

学习和记忆能力是由哺乳动物大脑调节的两个重要功能。大多数生物体拥有的一个基本学习和记忆功能是区分不同线索和背景的能力。特别有趣的是，在辨别学习过程中，强化的线索获得兴奋，而非强化的线索获得抑制联系。 此后，我们一直在使用视觉辨别范式(VDP)研究大鼠的这些学习过程。我们证明，这项工具任务的成功执行需要大鼠学习特定刺激和反复强化的运动反应之间的兴奋性联系，这一行为不是上下文特定的，依赖于背外侧纹状体。我们还表明，获得了对非强化线索的抑制性联系，表现出上下文特异性，并依赖于腹侧海马体(VH)。 因此，这项拟议的研究计划的目标是清楚地了解语境特定的条件抑制所必需的神经回路和神经机制。我们的假设是，围绕VH和伏隔核核心(NAC)的神经回路是必不可少的。我们将使用不同水平的分析来提供证据，证明VH和NA是调节语境特定抑制的功能回路。这些技术将包括使用选择性神经毒性损伤或可逆性损伤来证明VH和NAC之间的功能相互作用。我们还将评估VH和NAC在获取VDP期间的信息处理。这将使用高密度实现。自由行为大鼠的多部位电生理记录技术。最后，我们将探讨特定背景抑制效应的神经化学基础。这一目的将通过在辨别学习过程中阻断VH或NAC中的神经递质系统来实现。 影响：有一个令人印象深刻的学术努力和传统，试图解释暴露在特定事件和环境条件下的行为是如何形成的，以及负责的神经系统。这项工作在我们对人类和非人类动物学习的条件和机制的理解方面取得了许多进展，并对现代社会产生了巨大的影响。例如，这项工作正在彻底改变我们对精神疾病的本质和原因的理解，包括成瘾、焦虑、创伤后应激障碍和肥胖。尽管有这些和其他贡献，许多关于条件反射过程的重要问题仍然未知。不同形式的抑制性条件反射，它们的神经底物和调节它们的生化机制还没有被很好地理解，在这一基础研究领域仍然有很大的发现、创新和影响的空间。