PRECLINICAL STUDIES

We have a track record of improving predictive value in preclinical models through: a) unique RDoC-based rodent models and transgenic rat lines, b) causal cell and pathway specific neuronal manipulation though a unique viral library of >400 vectors for brain circuitry, neuropeptide and social psychiatry research, c) a powerful animal imaging facility with a 9.4T MRI scanner and PET including opto-fMRI harmonized with 3T PET-fMRI in humans, d) leading expertise in AI/ statistical machine learning (SML) approaches enabling biophysically realistic high throughput assessment of neuronal system dynamics, and e) human iPS cell models and patient cell-based phenotyping for drug discovery in Hector Institute for Translational Brain Research. 

Innovative and predictive animal models in psychiatry. Using transdiagnostic RDoC-based predictive animal models in conjunction with life-time behavioral phenotyping see Figure (automated 24/7 monitoring of socially housed rats) and longitudinal multi-modal neuroimaging, we apply multimodal time series analyses to get insights into dynamic disease trajectories. Innovative transgenic rat models are used to obtain cell-specificity for mechanism and neurocircuitry-based mapping of clinically relevant behaviors. We also emphasize on neuropeptide research into social function as well as the motivational domain related to addictions (Gass, Grinevich, Hannson, Sommer, Spanagel).

Platform for automated 24/7 monitoring of socially housed rats.

Our automated 24/7 monitoring of socially housed rats is used to assess longitudinal data of locomotor activity in terms, social interaction, body temperature, and time spent drinking and feeding.

We have established the 3R-Center Rhein-Neckar for animal experimentation in psychiatry, which is dedicated to establish the anchoring of animal welfare principles (3R: reduce, refine, replace) and to strengthen the validity, robustness, and rigor of preclinical data to enable a smoother, faster and safer transition from preclinical to clinical testing and drug approval (Spanagel).

Translational preclinical imaging platform. Multimodal neuroimaging of causally manipulated animal models significantly improves the informative value of directly comparable PET/MRI examinations in patients, aiding bench to bedside translation, understanding of risk mechanisms, and accelerating drug development (Ende, Sartorius).

A SML platform for neural dynamical systems identification. We translate animal and human data into a common dynamical systems language through data integration into recurrent neural networks by deep learning. This enables mechanistic interpretations of recordings, exploration of mechanisms via simulation of data-constrained models, and identification of new biomarker classes by dynamical systems analysis and identification of biophysical parameters (Durstewitz).

Molecular disease mechanisms through animal/human single cell analyses:

Using our large and growing brain bank (currently about 400 individuals with SUDs and controls) we will study post-mortem brain tissue in different regions of the addiction circuitry (left part of the figure) on a comparative multi-omics single cell level (using core facilities of DKFZ). Information will be converged with gene expression and chromatin accessibility data from human brain organoids and our predictive animal models and functionally validated by viral and transgenic animal models.

The stem cell platform in the Hector Institute for Translational Brain Research has established unique resources for multilevel assessment of network alterations and multi-omic characterization of iPS-derived models, organoids and compound screening (Koch).