Investigating serotonergic modulation of affective biases and emotional behaviour in rodents using psychedelic drugs

人类在其历史上一直使用迷幻药物作为文化实践的一部分，或者最近作为精神障碍的潜在治疗方法。迷幻体验是一种独特的心理状态，与情绪的深刻、积极的变化有关。人们对迷幻药物的潜在临床用途重新产生了兴趣。研究这些药物如何影响大脑也是更好地理解情绪的基本生物学的一条途径。研究大脑及其如何控制我们的行为是复杂的，认知和情感行为是神经科学中最大的挑战之一。需要在动物身上进行实验，以了解大脑的特定部分、大脑化学物质和涉及的药物靶点。动物实验对于发展有关正常心理学的知识也非常重要，这样我们就可以了解这些变化是如何以及为什么在病理状态下发生变化的。在情绪行为的背景下，最近的研究表明，测量啮齿动物的相关行为是可行的，这个项目将使用我们实验室开发的一种测试方法--情感偏差测试--来建立这个基础。我们将利用我们的测试来研究生物和心理机制之间的相互作用，这一机制的基础是有证据表明，认知上的偏差，即所谓的情感偏差，对正常和病态的情绪行为都有贡献。情感偏差是认知神经科学中使用的一个术语，它描述了认知被情绪状态改变的心理过程。研究表明，影响学习、记忆、决策和解释的负面情感偏差是抑郁症的常见特征。我们最近发现，传统的延迟型抗抑郁药和快速起效的抗抑郁药都能调节情感偏向，但它们的作用方式截然不同。发现药物治疗可以对情绪产生快速和持续的影响，这是该领域的一项重大进展。这导致了一种提议，即存在一类具有这些特征的小分子。由于这些药物的作用持续时间超过药物在体内的时间，它们必须能够产生适应性变化，有证据表明这些可塑性变化发生在特定的神经网络中，并导致它们的统称为精神增塑剂。迷幻剂被认为是精神成形剂，这个项目将探索它们是否具有改变情感偏见的能力，就像我们在这一类药物中观察到的那样。我们计划的研究将集中在两种关键的迷幻药物-裸盖菇素和MDMA的作用上。这两种药物都作用于大脑的化学信号通路之一--5-羟色胺，但作用方式不同。我们的目标不仅是研究它们对行为的影响，然后探索这些影响是如何产生的。这将涉及到研究，我们使用特定的化学物质来阻断我们认为涉及的途径的组成部分。我们还将通过将药物直接输送到感兴趣的区域来观察涉及到的大脑区域。除了行为方面的工作，我们还与在记录细胞电特性和神经元生理学适应性变化方面拥有专业知识的同事合作。这将揭示迷幻药物如何影响我们感兴趣区域内单个细胞的特性。在人类中，我们所知道的关于药物如何影响大脑特定区域的大部分信息都是通过脑功能成像(FMRI)获得的。在我们的最后一个工作包中，我们计划使用一种与fMRI等效的方法，即氧气安培法。使用这种方法，我们可以记录特定脑区的氧气使用情况，作为神经活动和相关回路之间联系的指示器。通过整合通过这些不同方法获得的所有数据，我们将能够将分子/细胞和神经回路与相关的情绪行为联系起来。

Humans have used psychedelic drugs throughout their history as part of cultural practises or more recently as potential treatments for psychiatric disorders. The psychedelic experience is a unique psychological state associated with profound, positive changes in mood. There has been a resurgence in interest in the potential clinical uses for psychedelic drugs. Research into how these drugs affect the brain is also a route to better understanding the fundamental biology of emotions. Studying the brain and how it controls our behaviour is complicated and cognitive and affective behaviours represent one of the biggest challenges in neuroscience. Experiments in animals are needed to understand the specific parts of the brain, brain chemistry and drug targets involved. Animal tests are also very important for the development of knowledge about normal psychology so we can understand how and why these change in pathological states. In the context of emotional behaviour, recent research has shown it is feasible to measure relevant behaviours in rodents and this project will build on this using an assay developed in our laboratory, the affective bias test. We will use our test to investigate the interaction between biological and psychological mechanisms building on evidence that biases in cognition, termed 'affective biases', contribute to both normal and pathological emotional behaviour. Affective bias is a term used in cognitive neuroscience which describes the psychological process whereby cognition is modified by emotional state. Research has shown that negative affective biases affecting learning, memory, decision-making and interpretation, are a common feature of depression. We have recently discovered that both conventional delayed onset antidepressants and rapid-acting antidepressants modulate affective biases, but they do this in very different ways. The discovery that pharmacological treatments can induce rapid and sustained effects on mood is a major development for the field. It has led to the proposal that there is a class of small molecules which share these characteristics. Because these drugs have effects which are sustained beyond the time the drug is in the body, they must be able to generate adaptive changes and evidence suggest these plasticity changes arise within specific neural networks and has led to their collective name of 'psychoplastogens'. Psychedelics are thought to be psychoplastogens and this project will explore whether they share the ability to modify affective biases as we have observed with other drugs from this class. Our planned research will focus on the effects of two key psychedelic drugs, psilocybin and MDMA. These drugs both act on one of the brains chemical signalling pathways, serotonin, but do so in different ways. We aim to not only study their effects on behaviour but then explore how these effects arise. This will involve studies where we use specific chemicals to block components of the pathways we think are involved. We will also look at the brain regions involved by delivering the drugs directly to the region of interest. Alongside the behavioural, work we are collaborating with colleagues with expertise in recording the electrical properties of cells and adaptive changes in neuronal physiology. This will reveal how psychedelic drugs affect the properties of single cells within our regions of interest. In humans much of what we know about how drugs affect specific regions of the brain are obtained from function brain imaging (fMRI). In our final work package, we plan to use an equivalent method to fMRI known as oxygen amperometry. Using this approach, we can record oxygen use with specific brain region as an indicator of neural activity and the connections between relevant circuits. By integrating all the data obtained across these different approaches we will be able to relate the molecular/cellular and neural circuits with a relevant emotional behaviour.