Neural circuits and mechanisms of context specific conditioned inhibition

学习和记忆的能力构成了哺乳动物大脑的两个重要功能。 大多数生物体拥有的一个基本的学习和记忆功能是区分不同线索和环境的能力。 特别令人感兴趣的是，在辨别学习过程中，强化线索获得兴奋性，非强化线索获得抑制性联想。 我们一直在研究这些学习过程中的大鼠使用视觉辨别范式（VDP）。 我们证明，成功地执行这一工具性任务需要大鼠学习一个特定的刺激和运动反应，反复加强之间的兴奋性关联，这种行为是不特定的上下文，并依赖于背外侧纹状体。 我们还发现，对非强化线索的抑制性关联是获得的，显示出上下文特异性，并且依赖于腹侧海马（VH）。 这项研究计划的目的是发展一个清晰的理解的神经回路和神经机制所需的上下文特异性条件抑制。 我们的假设是，一个神经回路，包括VH和核丘脑核心（NAc）是必不可少的。 我们将使用不同层次的分析提供证据，VH和NA是一个功能电路介导的上下文特异性抑制。 这些技术将包括使用选择性神经毒性病变或可逆性病变，以证明VH和NAc之间的功能性相互作用。 我们还将评估在获取VDP期间VH和NAc中的信息处理。 这将在自由行为大鼠中使用高密度、多部位电生理记录技术来实现。 最后，我们将探讨情境特异性抑制效应的神经化学基础。 这一目标将通过在辨别学习期间阻断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，试图解释暴露于特定事件和环境条件以及负责的神经系统如何塑造行为。 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性质和原因的理解，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，许多重要的问题，条件反射过程仍然未知。 不同形式的抑制性条件反射，它们的神经底物和介导它们的生化机制还没有得到很好的理解，在这一基础研究领域仍然有很大的发现，创新和影响空间。

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.********