Pause for thought: The role of corticostriatal circuitry and its dopamine innervation in the inhibitory modulation of associative learning

日常思维的具体细节，由相关事件之间形成的联系提供，使我们能够建立清晰的思路。所有动物共有的联想学习机制不仅支持思想、言语和行为的提示，还支持通过使用“心理刹车”来抑制不适当的思想和行为的犹豫能力。当失去抑制由联想产生的冲动的能力时，可能会出现各种症状。在临床上，抑制调节受损已被确定为导致许多疾病，包括成瘾、焦虑、肥胖和精神分裂症。去抑制行为也是正常衰老的认知衰退特征的一个充分记录的特征。在实验室大鼠中开发的学习程序为研究不良联想的门控提供了一个很好的模型系统。如果一个特定的事件预示着一个结果，学习通常是通过动物对第一个事件的行为反应来证明的。然而，如果第一个事件与另一个暗示同时出现，这意味着预期的结果现在不会发生，正常的行为和认知反应就会受到抑制。这种抑制能力的缺陷可以解释各种症状，从暴饮暴食（多吃的后果不再令人愉快）到精神分裂症的一些思维模式紊乱。我们建议在大鼠中使用翻译程序，采用我们用于测试人类抑制性学习的实验设计，以描绘参与抑制性学习的大脑区域。实验脑治疗将精确地针对已知对行为调节有重要作用的区域，这些区域接受含有与抑制性学习调节有关的脑化学物质多巴胺的投射。这种高度控制的实验对于确定抑制性学习缺陷的机制是必要的。我们将(1)检查暂时关闭小区域的皮层和相互连接的区域（注射短期灭活药物）的效果；(2)相互连接的脑区电活动模式的串扰测试；(3)利用药物治疗选择性地操纵大脑化学物质多巴胺，以确定抑制性学习被调节的精确途径；(4)研究观察到的行为效应如何依赖于相互连接的大脑区域之间的串扰。目前的项目将推进先前的发现，我们将有选择性地干扰特定大脑通路中的化学信号，通过靶向药物递送到首先通过暂时使大脑小区域失活来确定的区域。本项目的一个独特贡献将是描述化学调节剂多巴胺在抑制学习所需的神经回路中的作用。我们实验室的其他研究表明，局部药物治疗对特定作用部位具有一定的选择性，可以对行为产生明显的影响，这通常与同一大脑区域的一般脑损伤的影响完全不同。重要的是，在这个项目中使用的行为程序也适用于人类；尽管实验细节不同，但有足够的相似性将动物实验室的发现转化为临床（反之亦然）。在老鼠身上进行的实验描绘了抑制性学习的大脑基质，并提供了重要的线索，说明新的治疗方法应该在哪里以及如何起作用，并且副作用最小。在实施实验方案的同时，我们将访问学校，利用六年级外展方案，并与心理健康专业人员和制药行业的联系人联系，解释这类动物工作的重要性，以及它如何转化为我们对人类健康的理解。

The nuts and bolts of everyday thinking, provided by the formation of connections between related events, enable us to establish clear trains of thought. Associative learning mechanisms, common to all animals, support not only the cueing of thoughts, words and deeds, but also the ability to hesitate through the use of a 'mental brake' to suppress inappropriate thoughts and actions. When the ability to restrain the impulse generated by an association is lost, diverse symptoms may result. Clinically, impaired inhibitory modulation has been identified as contributing to a number of disorders, including addiction, anxiety, obesity and schizophrenia. Disinhibited behaviours are also a well-documented feature of the cognitive decline characteristic of normal ageing.Learning procedures developed in the laboratory rat provide an excellent model system to study the gating of unwanted associations. If a particular event predicts an outcome, learning is normally demonstrated by the animal's behavioural reaction to the first event. However, if the first event is presented in conjunction with another cue which means that the expected outcome will not now occur, the normal behavioural and cognitive reactions are inhibited. Impairments in such inhibition could explain a variety of symptoms, from over-eating when the consequences of eating more food will no longer be pleasant, to some of the disordered thought patterns identified with schizophrenia. We propose to use translational procedures in the rat, adapting the experimental design which we have used to test inhibitory learning in humans, in order to delineate the brain areas involved in inhibitory learning. The experimental brain treatments will be precisely targeted to areas known to be important for behavioural regulation and which receive projections containing the brain chemical dopamine implicated in the modulation of inhibitory learning. Highly controlled experiments of the kind proposed are necessary to identify the mechanisms underlying inhibitory learning deficits.We will (1) examine the effects of temporarily switching off small areas of cortex and interconnected areas (injecting a shortlived inactivating drug); (2) test for cross-talk in the patterns of electrical activity in interconnected brain areas; (3) use drug treatments to selectively manipulate the brain chemical dopamine, to determine the precise pathways through which inhibitory learning is modulated; and (4) examine how the observed behavioural effects depend on cross-talk between interconnected brain regions. The present project will advance previous findings in that we will selectively interfere with chemical signalling in specific brain pathways, by targeted drug delivery to areas first identified by temporarily inactivating small brain regions. One unique contribution of the present project will be the delineation of the role of the chemical modulator dopamine in the neural circuitry necessary for inhibitory learning. Other studies in our laboratory have shown that localised drug treatments with some selectivity to particular sites of action can have distinct effects on behaviour, often quite different to the effects of general brain damage in the same brain regions. Importantly, the behavioural procedures to be used in this project work in humans too; although the experimental details differ, there is sufficient similarity to translate findings from the animal laboratory to the clinic (and vice versa). Experiments in rats delineate the brain substrates of inhibitory learning and give vital clues as to where and how new treatments should work, with minimum side-effects.In parallel with the experimental programme, we will visit schools and use sixth form outreach programmes, as well as liaise with mental health professionals and contacts in the pharmaceutical industry, to explain the importance of animal work of this kind, and how it translates to our understanding of human health.