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

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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.