Understanding how psychedelic drugs affect brain and behaviour in rodents

致幻剂具有深刻的感知、情感和认知改变特性，被誉为治疗普遍存在的、难以治疗的神经精神疾病（如重度抑郁症）的“突破性疗法”。因此，像裸盖菇素这样的药物在治疗精神疾病的原因并使其恢复方面具有独特的潜力(1)。然而，致幻剂影响大脑功能的机制仍然知之甚少。在人类疾病中，如重度抑郁症，大脑区域之间的交流似乎变得过于僵化。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、缺乏自尊和自责。这些思维模式可能源于某些大脑状态的异常主导，通常是由于过度活跃的“自上而下”的消极思想。致幻剂可以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，从而使新的远程通信模式得以形成，从而逆转这种状态（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加强自下而上的信息传递来“重新编程”适应不良的思维模式，从而产生一种新的、可能更明亮的认知视角(4)。然而，单纯通过人脑扫描来研究这一假设是困难的，因为这是对大脑活动的间接测量；因此，需要直接记录神经元活动的侵入性方法，而这只能在啮齿动物身上完成。为了揭示迷幻药对神经和突触的影响，这个项目的学生将在迷幻药的刺激下记录啮齿动物大脑的多个区域。录音将针对包括前额叶和顶叶皮质、海马体和杏仁核在内的大脑区域，以及感觉系统的早期阶段。对自由活动的动物进行记录，将使我们能够将药物对大脑的影响与运动、感觉和认知功能（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（如信息论）来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。在药物治疗后，致幻剂对患者的积极作用会持续很长时间，这表明它们会产生同样长期的大脑变化。学生将通过在药物挑战后不同延迟时间内我们的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，将该项目的发现转化为临床环境将是很重要的，因此学生还将在迷幻挑战下对啮齿动物的大脑活动进行非侵入性成像（例如，fMRI和磁共振波谱）。这将把他们早期的侵入性、直接的脑活动测量与间接的、临床相关的脑功能和神经化学测量联系起来。

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.