Validation of evidence-based severity assessment and refinement in neuroscience animal models with functional neurosurgery and intracranial tumours

• Applicant: Professorin Kerstin Schwabe, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 321137804

Within the first two funding periods, our group evaluated multiple measures for potential severity assessment in (1) the rat Parkinson model with intracranial injection of 6-hydroxydopamine (6-OHDA), followed by repeated L-Dopa injections to induce dyskinesias and the implantation of electrodes for cable-bound recording and stimulation of neural activity, and (2) in rats with intracranial brain tumours after injection of BT4Ca-rat glioma cells, followed by tumour resection or local intra-tumoural injection and final humane endpoint detection. Distinct measures were also collected in rat models with hearing loss or cerebellar lesions. So far, we identified promising core parameters that can be used for severity assessment in our models, either as a stand-alone parameter or in a combination supported by data science approaches. In the third funding period, we will use these data to evaluate promising readout parameters, such as voluntary wheel running (VWR), burrowing, open-field activity, body weight, and measures in the home cage, including heart rate (HR) and activity (Act) assessed via subcutaneous implanted telemetric devices for informative value, robustness, and generalisability within all group working with neuroscience models. All parameters will be evaluated in acute, subacute, and chronic states of different neuroscience rat models and procedures, as well as across rat strains in a cross-laboratory approach. The Relative Severity Assessment Score (RELSA) will be applied and optimised on data sets of different experimental phases of our neuroscience rat models and interventions, both on individual and on group level. With the data recorded via telemetric devices, support vector machine classification of HR and Act with unsupervised k-means clustering will be applied to different models. We will also evaluate, whether clustering of VWL and body weight data by k-means algorithms, preferably in a home-cage setting, will enable the grading of severity levels in neuroscience models, including humane endpoint detection in the intracranial rat glioma model. Humane endpoint detection methods will be compared with the approaches of other groups. The efficacy of carprofen administered by drinking water plus timed subcutaneous injections will be assessed in all rat models with intracranial surgery used in our group. Outcome will be shared with all groups addressing analgesia. The potential burden of sham groups, which are commonly used as control groups in neuroscientific research, will be assessed in a cross-laboratory approach.

• DFG Programme: Research Units
• Subproject of: FOR 2591: Severity assessment in animal-based research