Investigation of the effect of psychedelic substances on neuronal three-dimensional cell cultures.

• Applicant: Professorin Dr.-Ing. Christiane Thielemann
• Subject Area: Experimental and Theoretical Network Neuroscience
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518810023

Clinical studies suggest that psychedelic substances such as LSD, DMT, ayahuasca, or psilocybin are promising candidates for the treatment of mental illness. The basic understanding of the effects of serotonergic psychedelics is largely based on preclinical studies in in vivo and in vitro animal models, which provide clear evidence of modified neuroplasticity. However, due to species-specific differences, it is questionable to what extent these findings are transferable to humans. Non-invasive studies (EEG, fMRI) on the human brain are also available, but show partly controversial results. Against this background, it becomes clear that the effect of serotonergic psychedelics on the human brain is not sufficiently understood and that there is an urgent need for systematic investigations. Our own preliminary work has shown that electrophysiological analyses of neuronal cell cultures are suitable to investigate the acute effects of 1-propionyl-lysergic acid diethylamide (1P-LSD) on functional network properties. In order to pursue this promising approach, the research project will present for the first time a well-characterized serotonergic cell culture model, which on the one hand is of human origin and on the other hand allows a systematic structural and functional investigation after the application of psychedelic substances. Stem cell-based in vitro cell cultures (hiPSC), whose population contains serotonergic neurons, are particularly suitable as a model with a human background. Here, a three-dimensional model is proposed as it can be cultured for months and allows the observation of long-term effects that are particularly relevant for therapy. High resolution methods such as high density MEA chips and light sheet microscopy in combination with calcium imaging will be employed to investigate the effects of LSD and DMT on the serotonergic hiPSC model. From the collected imaging and electrophysiological data, after further processing steps, network models will be built in the form of graph structures, features will be extracted and investigated using machine learning methods.

• DFG Programme: Research Grants