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

迷幻药对海马灵活记忆表征影响的细胞和突触机制

• 批准号: 2886127
• 金额: --
• 依托单位: University of Bristol
• 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-2886127
• 关键词: cellular; synaptic; mechanisms; effects; psychedelics

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.

迷幻疗法为许多精神健康疾病的治疗提供了一种潜在的范式转换方法，包括抑郁、焦虑、成瘾和创伤后应激障碍。然而，迷幻剂的作用机制仍然知之甚少，这导致了新的投资和兴趣，不仅研究迷幻剂的临床效果，而且研究它们的基础生物学。从迷幻治疗中获益的心理障碍的异质性对理解潜在的机制提出了挑战，并突显了研究跨诊断机制的重要性。此外，迷幻药通常表现出复杂的药理特征，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了解，如裸盖菇素，强调其作为5-HT2A受体激动剂的能力，并导致突触可塑性和认知灵活性的增强。这些剧烈的影响可能会导致记忆表征的变化，从而维持糟糕的心理健康状态。致幻剂影响神经可塑性的机制尚不完全清楚，更重要的是，迷幻剂在调节认知和行为变化方面的功能重要性还没有得到充分的描述。在这个项目中，我们的目标是通过研究迷幻剂对海马区记忆表征的影响来解决这些未知问题，结合啮齿动物行为、活体成像和脑片电生理学的专业知识。我们已经开发了一种方法，使用双光子成像来监测小鼠在虚拟现实中导航时海马区CA1区细胞的活动，从而直接测量轮状脑区神经活动中的认知记忆表征。我们和其他人已经证明，海马区的位置细胞表征适应环境中的明确变化，特别是对于奖励位置等显著特征，并且这些适应对于指导学习行为至关重要。通过与Compass Path的合作，我们将探索COMP360(正在进行的临床试验中使用的裸盖菇素的合成配方)对记忆表征和结果行为的影响，方法是分析放置细胞适应虚拟现实环境的精确操作的速度和程度，其中包含不同程度的不确定性。在体内的工作将通过进一步测试裸盖菇素对海马片突触可塑性的影响来补充，使用通过刺激树突状细胞钙信号事件来接近模拟体内情况的范式。我们将使用电生理学和双光子成像相结合的方法测试裸盖菇素对钙事件和突触可塑性的影响。