| Popis: |
Neuropsychiatric diseases are very heterogeneous and comorbid characterized by overlapping symptom domains. Globally, mental illnesses are drastically increasing demonstrating the enormous societal burden and the urge for new treatment options. Early discovery and developmental programs for new therapeutics demand state-of-the-art multidimensional approaches and translatable biomarkers to assess the therapeutic potential of new therapeutic concepts, aiming to reduce clinical attrition rates. The overarching aim of the present project was to setup a multidimensional radiotelemetry system that enables the direct combination and thus evaluation of physiologic parameters and behavior to investigate new therapeutic targets in the field of neuropsychiatric diseases. Besides central activity assessment (cortical electroencephalography (EEG) and local field potential recordings (LFPs)), peripheral readouts, as electrocardiography (ECG) and subsequent heart rate variability (HRV) analysis, were implemented as profound addition to investigate new therapeutic compounds. Three individual studies were conducted investigating new therapeutic concepts in the field of neuropsychiatric diseases. For this purpose, we took advantage of telemetric EEG and/or ECG recordings to reveal pharmacological induced alterations in EEG power spectra, sleep-wake architecture (vigilance states), locomotor activity, body temperature and/or HRV. Additionally, in vivo microdialysis, pharmacokinetic and exposure measurements as well as behavioral tests in social and cognition relevant domains enabled the respective assessment of pharmacological induced alterations in downstream signaling pathways, dose evaluation and the characterization of behavioral phenotype alterations post-treatment. The present studies demonstrated that the multidimensional combination of various readouts enables comprehensive assessment of central and peripheral functions, in line with the Research Domain Criteria (RDoC) concept. The established preclinical radiotelemetry system allows to investigate efficacy (internal activity) and tolerability in psychiatric drug discovery projects ranging from the detection of adverse side effects to the identification of potential translatable biomarkers to eventually bridge preclinical findings to clinical outcomes. Nevertheless, better standardization across laboratories in academia and industry in addition to advanced disease-relevant models, better mechanistic understanding in terms of circuit engagement, and an advanced (back-)translational stream are warranted to fully develop the potential of EEG- and overall biopotential recordings in preclinical CNS drug discovery and developmental programs. |
