Investigating the neural circuits and molecular mechanisms which regulate emotional behaviour and cognitive affective bias

情绪在认知功能中的作用是神经科学的一个重要领域，但我们的理解是有限的。对动物和人类的观察表明，情绪可以改变行为。在动物身上，这些类型的行为通常是通过观察恐惧行为(如冻结或逃跑)或奖励行为(如奖励学习)来研究的。情绪如何影响行为要比这复杂得多，最近用于研究动物情绪行为的方法的发展表明，积极和消极情绪状态对认知的复杂而微妙的影响。对人类的研究表明，情绪状态会影响他们体验环境的方式，也会影响他们做出的决定。这些通常被称为认知情感偏差。这些偏见已被证明会影响注意力、学习和记忆、回忆、解释和决策，而这些过程中的功能障碍与情绪障碍有关。最近，研究人员已经开发了一些方法，使研究人员能够证明在动物中也发现了类似的认知情感偏差，并且情绪状态(通常被称为动物的情感状态)可以在蜜蜂、小鼠、大鼠、绵羊、狗和灵长类动物中诱导乐观或悲观的认知行为。我们的研究项目推进了利用动物研究情绪行为的方法的进展，并集中在认知情感偏差的一个方面：情绪对决策的影响。我们的研究小组一直是发展啮齿动物判断偏差任务的领导者之一。在这项任务中，训练动物将特定的线索与积极或消极的情绪结果联系起来。一旦学习了这些参考线索，就会通过向动物呈现一个中间的模棱两可的线索并观察动物的反应来测试认知情感偏差。乐观的动物在对积极事件的预期中做出更多的反应，而悲观的动物在预期负面事件时做出更多的反应。然后，我们可以操纵动物的情绪状态，并观察这项任务中的偏见是如何变化的。我们已经证明，这种类型的方法与人类的行为有很好的关系，因为我们在人类参与者身上测试了几乎相同的任务。当我们在这项任务中观察抗抑郁药物时，我们也有了一个令人兴奋的发现，并发现在这项测试中使用的治疗方法的有效性和起效速度与此密切相关。例如，延缓起效的抗抑郁药氟西汀不会立即让大鼠变得更加乐观，但如果每天给药超过一周，就会变得更加乐观。这一点，以及最近发现的快速起效的抗抑郁剂氯胺酮，可以让老鼠在这项任务中立即变得更加乐观，这构成了这一应用中拟议的研究的基础。我们的目标是推进这些发现，并建立对导致这些乐观和悲观行为的大脑机制的更好理解。我们提出的实验将使用不同的药物治疗和对大脑小区域的直接操作，试图了解调节情绪行为的大脑回路。我们还将能够利用我们的行业合作伙伴提供的专业知识和额外资源，对关键感兴趣区域的特定路径和神经元亚群进行更复杂的分析。这些研究将把遗传操作与基因测序研究结合起来，预计将对分子和神经电路产生详细的见解。这些将有助于确定新的药物目标，以便进一步验证，并有可能纳入药物开发计划。

The role of emotions in cognitive function is an important area of neuroscience but one where our understanding is limited. Observations of animals and humans have shown that emotions can modify behaviour. In animals, these types of behaviours are classically studied by looking at fear behaviours such as freezing or escape, or reward behaviours such as reward learning. How emotions affect behaviour is much more complex than this and recent developments in the methods used to study emotional behaviour in animals suggest complex and subtle effects of both positive and negative emotional states on cognition. Studies in humans have shown that the emotional state can influence the way they experience their environment and also the decisions they make. These are often referred to as cognitive affective biases. These biases have been shown to influence attention, learning and memory, recall, interpretation and decision-making and dysfunction in these process are linked to emotional disorders. Recently, methods have been developed which have enabled researchers to show that similar cognitive affective biases are found in animals and that emotional state (often referred to as affective state in animals) can induce optimistic or pessimistic cognitive behaviours in animals as diverse as honey bees, mice, rats, sheep, dogs and primates.Our research project takes forward the advances in methods to study emotional behaviour using animals and focusses on one aspect of cognitive affective bias: the impact of emotions on decision-making. Our research group has been one of leaders in the development of the judgement bias task for rodents. In this task animals are trained to associated specific cues with an emotional outcome, either positive or negative. Once these reference cues are learnt, cognitive affective biases are tested by presenting the animal with an intermediate ambiguous cue and observing how the animal responds. Optimistic animals make more responses in anticipation of the positive event whilst pessimistic animals make more responses in anticipation of the negative event. We can then manipulate the animal's emotional state and observe how the bias in this task changes. We have already shown that this type of methodology relates well to behaviour in humans as we have tested an almost identical task in human participants. We have also made an exciting discovery when looking at antidepressant drugs in this task and found that the effectiveness, and rate of onset of action of the treatments used in people, is mirrored closely in this test. For example, the delayed onset antidepressant fluoxetine does not immediately make rats more optimistic but does if the dosing is given daily for more than a week. This, and the recent discovery that the rapid onset antidepressant, ketamine, can make rats immediately more optimistic in this task forms the basis for the proposed studies in this application.Our aim is to take forward these discoveries and build towards a better understanding of the brain mechanisms which cause these optimistic versus pessimistic behaviours. Our proposed experiments will use different drug treatments and direct manipulations of small regions of the brain to try to understand the brain circuits which regulate emotional behaviour. We will also be able to utilise the expertise and additional resources provided by our industrial collaborator to undertake a much more sophisticated analysis of specific pathways and neuronal sub-populations in key regions of interest. These studies will combine genetic manipulations with gene sequencing studies and are anticipated to yield a detailed insight into the molecular and neural circuits. These will help identify novel drug targets to take forward for further validation and potentially into a drug development programme.