Title: In vivo imaging of cerebral epigenetic changes following 5HT-2AR modulation

PhD-student: Lene Lundgaard Donovan, NRU

Abstract:

Recent evidence suggests that use of psilocybin (a classic hallucinogen and 5-HT2AR agonist) can have long term beneficial effects on mood and behaviour. We have published that the recreational use of 5-HT2AR agonists is associated with reduced 5-HT2AR binding in neocortex. However, the molecular processes by which these compounds induce their lasting effects are unknown. We hypothesize that 5-HT2AR activation induces epigenetic changes via modulation of HDAC enzyme levels. HDACs are a family of epigenetic enzymes that regulate chromatin condensation level and thus gene transcription.

The aim of this project is to investigate if serotonin 2A receptor (5-HT2AR) ligands induce epigenetic modifications. These alterations can lead to downstream changes in gene expression, which in turn can cause secondary lasting effects on receptor levels and behaviour. The project takes a completely novel approach by combining in vivo and ex vivo investigations of these epigenetic and 5-HT2AR modulations.

We will target the 5-HT2AR with the agonist psilocybin and the antagonist clozapine to investigate how this influences the HDAC levels and 5-HT2AR density in the pig brain. We will use the in vivo imaging technique PET to measure HDAC levels ([11C]Martinostat) and 5-HT2AR ([11C]Cimbi-36) density. In the same brains, we will look at functional consequences of altered HDAC levels by determining chromatin modifications in the form of histone acetylation, gene transcription levels and biochemical isolation of HDAC complexes.