Understanding how psychedelic drugs affect brain and behaviour in rodents

了解迷幻药物如何影响啮齿类动物的大脑和行为

• 批准号: 2897454
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2897454
• 关键词: Understanding; how; psychedelic; drugs; affect

The profound perception-, emotion- and cognition-altering properties of psychedelic drugs have been hailed as a "breakthrough therapy" for pervasive, difficult-to-treat neuropsychiatric conditions such as major depressive disorder. As such, drugs such as psilocybin have unique potential to treat the causes of psychiatric illness and enable recovery (1). However, the mechanisms by which psychedelics impact brain function remain poorly understood.In human diseases such as major depression the communication between brain regions appears to become too rigid. This results in patients being 'stuck in a rut', unable to 'break out' of repetitive negative thoughts and feelings as well as expressing high anxiety, poor self-esteem and self-blaming. These thought patterns may arise from the abnormal dominance of certain brain states, often due to hyperactive 'top down' focus on negative thoughts. Psychedelics may act to reverse this state by increasing the variety of brain states through temporarily reorganizing how brain regions interact, thereby, enabling the formation of new, long-range communication patterns (1, 2). This, in turn, may lead to more flexible cognition and emotional breakthroughs in patients (3). Such an effect may 're-program' maladaptive thinking patterns by enhancing bottom-up information transmission, allowing the emergence of a new, potentially brighter, cognitive perspective (4). However, it is difficult to investigate this hypothesis purely via human brain scanning, as this is an indirect measure of brain activity; thus, invasive approaches to record the activity of neurons directly are required and this can only be accomplished using rodents.To reveal the neural and synaptic effects of psychedelics the student on this project will record from multiple regions of the rodent brain during psychedelic drug challenge. Recordings will target brain regions including the prefrontal and parietal cortices, hippocampus and amygdala, as well as early stages of sensory systems. Recordings in freely moving animals will allow us to correlate drug effects in the brain with changes in motor, sensory and cognitive functions (such as fear and anxiety). The student will also learn how to explore these large datasets using powerful analytical techniques (such as information theory (5)) to reveal whether psychedelics do indeed increase the number, strength and direction of links between brain regions. The positive effects of psychedelics in patients persist long after drug treatment, suggesting that they produce equally long-term brain changes. The student will explore this through protein and epigenetic changes in our targeted brain regions at various delays after drug challenge. Finally, it will be important to translate the project's findings to the clinical setting, so the student will also carry out non-invasive imaging of brain activity in rodents under psychedelic challenge (e.g., fMRI and magnetic resonance spectroscopy). This will correlate their earlier invasive, direct measures of brain activity with indirect but clinically relevant measures of global brain function and neurochemistry.

致幻药物具有深刻的感知、情绪和认知改变特性，被誉为治疗严重抑郁症等普遍且难以治疗的神经精神疾病的“突破性疗法”。因此，裸盖菇素等药物具有治疗精神疾病病因并促进康复的独特潜力 (1)。然而，人们对迷幻药影响大脑功能的机制仍知之甚少。在重度抑郁症等人类疾病中，大脑区域之间的沟通似乎变得过于僵化。这导致患者“墨守成规”，无法“摆脱”重复的消极想法和感受，并表现出高度焦虑、自尊心差和自责。这些思维模式可能是由于某些大脑状态的异常主导而产生的，通常是由于过度活跃的“自上而下”的消极思维关注所致。迷幻药可能会通过暂时重组大脑区域的相互作用来增加大脑状态的多样性，从而逆转这种状态，从而形成新的远程通信模式 (1, 2)。反过来，这可能会导致患者更灵活的认知和情感突破 (3)。这种效应可能会通过增强自下而上的信息传递来“重新编程”适应不良的思维模式，从而出现一种新的、可能更光明的认知视角 (4)。然而，纯粹通过人脑扫描来研究这一假设是很困难的，因为这是对大脑活动的间接测量。因此，需要采用侵入性方法来直接记录神经元的活动，而这只能通过啮齿动物来实现。为了揭示迷幻药的神经和突触效应，该项目的学生将在迷幻药物挑战期间从啮齿动物大脑的多个区域进行记录。录音将针对大脑区域，包括前额叶和顶叶皮质、海马体和杏仁核，以及感觉系统的早期阶段。对自由活动的动物进行记录将使我们能够将大脑中的药物作用与运动、感觉和认知功能（例如恐惧和焦虑）的变化联系起来。学生还将学习如何使用强大的分析技术（例如信息论 (5)）探索这些大型数据集，以揭示迷幻药是否确实增加了大脑区域之间联系的数量、强度和方向。迷幻药对患者的积极作用在药物治疗后持续很长时间，这表明它们也会产生同样长期的大脑变化。学生将通过药物挑战后不同延迟时间我们目标大脑区域的蛋白质和表观遗传变化来探索这一点。最后，将该项目的研究结果转化为临床环境也很重要，因此学生还将在迷幻挑战下对啮齿类动物的大脑活动进行非侵入性成像（例如功能磁共振成像和磁共振波谱）。这将把他们早期侵入性的、直接的大脑活动测量与间接但临床相关的整体大脑功能和神经化学测量联系起来。