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

在相关事件之间形成联系所提供的日常思维的具体细节，使我们能够建立清晰的思路。联想学习机制是所有动物都共有的，它不仅支持对思想、言语和行为的暗示，还支持通过使用“心理刹车”来抑制不适当的想法和行为而犹豫不决的能力。当失去抑制联想产生的冲动的能力时，可能会出现各种症状。临床上，抑制调节受损被认为是导致一系列疾病的原因，包括成瘾、焦虑、肥胖和精神分裂症。无拘无束的行为也是正常年龄认知衰退特征的一个有充分证据的特征。在实验室大鼠中开发的学习程序提供了一个很好的模型系统来研究不想要的联想的门控。如果一个特定的事件预测了一个结果，学习通常通过动物对第一个事件的行为反应来证明。然而，如果第一个事件与另一个提示相结合，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。这种抑制的障碍可以解释各种症状，从吃得过多导致的后果不再令人愉快，到一些被认为是精神分裂症的混乱思维模式。我们建议在大鼠身上使用翻译程序，修改我们用来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。实验性的大脑治疗将精确地针对已知对行为调节重要的区域，这些区域接受包含大脑化学物质多巴胺的投射，多巴胺与抑制性学习的调节有关。我们将(1)检查暂时切断大脑小区域和相互连接的区域(注射短暂的灭活药物)的影响；(2)测试相互连接的大脑区域的电活动模式中的串扰；(3)使用药物治疗来选择性地操纵大脑化学物质多巴胺，以确定调节抑制性学习的确切途径；以及(4)检查观察到的行为影响如何依赖于相互连接的大脑区域之间的串扰。本项目将推进先前的发现，即我们将有选择地干扰特定大脑路径中的化学信号，通过将药物定向输送到最初被暂时使大脑小区域失活的区域。本项目的一个独特贡献将是描绘化学调节剂多巴胺在抑制学习所必需的神经回路中的作用。我们实验室的其他研究表明，对特定作用部位具有一定选择性的局部药物治疗可以对行为产生不同的影响，通常与相同大脑区域的一般脑损伤的影响截然不同。重要的是，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研究结果(反之亦然)。在老鼠身上进行的实验描绘了抑制学习的大脑基础，并提供了重要的线索，说明新的治疗方法应该在哪里和如何发挥作用，副作用最小。在进行实验计划的同时，我们将访问学校，利用中六外展计划，以及与精神健康专业人员和制药业的联系人联系，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了解。

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.