The cellular and synaptic mechanisms for the effects of psychedelics on flexible memory representations in the hippocampus

迷幻疗法为治疗包括抑郁、焦虑、成瘾和创伤后应激障碍在内的许多心理健康状况提供了一种潜在的范式转换方法。然而，致幻剂的作用机制仍然知之甚少，这导致了新的投资和兴趣，不仅研究致幻剂的临床效果，而且研究它们的基础生物学。明显受益于迷幻治疗的心理障碍的异质性对理解潜在机制提出了挑战，并突出了研究跨诊断机制（跨不同诊断组共享）的重要性。此外，致幻剂通常表现出复杂的药理学特征，并与许多不同的受体群体相互作用。目前对迷幻药作用机制的理解，如裸盖菇素，强调其作为5-HT2A受体拮抗剂的能力，并引起突触可塑性和认知灵活性的增强。这些急性效应可能导致记忆表征的改变，从而维持不良的精神健康状态。致幻剂影响神经可塑性的机制尚不完全清楚，重要的是，它在调节认知和行为变化方面的功能重要性尚不清楚。在这个项目中，我们的目标是通过研究迷幻药对海马体记忆表征的影响，整合啮齿动物行为、体内成像和脑切片电生理学方面的专业知识，来解决这些未知问题。我们已经开发了一种方法，直接测量认知记忆表征在啮齿动物海马的神经活动使用双光子成像监测海马CA1位置细胞的活动，因为他们在虚拟现实中导航的小鼠。我们和其他人已经证明，海马体位置细胞的表征适应环境中确定的变化，特别是奖励位置等显著特征，这些适应对指导学习行为至关重要。通过与COMPASS Pathways的合作，我们将通过分析位置细胞适应虚拟现实环境的速度和程度，结合不同程度的不确定性，探索COMP360（正在进行的临床试验中使用的裸盖菇素合成制剂）对记忆表征和由此产生的行为的影响。在体内的工作将通过进一步测试裸盖菇素对海马切片突触可塑性的影响来补充，使用紧密模拟体内情况的范例，通过刺激树突状钙信号事件。我们将使用电生理学和双光子成像相结合的方法来测试裸盖菇素对钙事件和突触可塑性的影响。

Psychedelic therapies offer a potentially paradigm-shifting approach to the treatment of many mental health conditionsincluding depression, anxiety, addiction and post-traumatic stress disorder. However, the mechanism of action ofpsychedelics remains poorly understood, and this has led to new investment and interest in not only studying the clinicaleffects of psychedelics, but also their fundamental biology. The heterogeneity of psychological disorders whichapparently benefit from psychedelic therapy presents a challenge to understanding underlying mechanisms andhighlights the importance of studying mechanisms which are transdiagnostic (shared across different diagnostic groups).Furthermore, psychedelics typically exhibit complex pharmacological profiles, and interact with many different receptorpopulations.Current understanding of the mechanism of action of psychedelics, such as psilocybin, emphasises its ability to act as anagonist at the 5-HT2A receptor and cause an enhancement of both synaptic plasticity and cognitive flexibility. Theseacute effects may enable changes in the memory representations that maintain states of poor mental health. Themechanisms by which psychedelics affect neural plasticity are not completely known, and importantly its functionalimportance for mediating change in cognition and behaviour is poorly characterised. In this project we aim to addressthese unknowns by investigating the effects of psychedelics on representations of memory in the hippocampus,integrating expertise in rodent behaviour, in vivo imaging and brain slice electrophysiology. We have developed a method to directly measure cognitive memory representations in the neural activity of the rodenthippocampus using 2-photon imaging to monitor hippocampal CA1 place cell activity in mice as they navigate in virtualreality. We and others have shown that hippocampal place cell representations adapt to defined changes in theenvironment, particularly for salient features such as reward locations and that these adaptations are crucial for guidinglearned behaviour. Through our collaboration with COMPASS Pathways, we will explore the effects of COMP360 (asynthetic formulation of psilocybin used in ongoing clinical trials) on memory representations and resulting behaviourby analysing the speed and extent of place cell adaptations in response to precise manipulations of the virtual realityenvironment, incorporating varying levels of uncertainty. In vivo work will be complemented by further testing theeffects of psilocybin on synaptic plasticity in hippocampal slices using paradigms that closely model the in vivo situationby stimulating dendritic calcium signalling events. We will test the effects of psilocybin on calcium events and synapticplasticity using a combination of electrophysiology and 2-photon imaging.