Behavioral analyses in translational neuropsychiatric research
Mouse models as tools to assess higher cognition and evaluate treatment effects
by Frank Martin Hindermann
Date of Examination:2024-05-31
Date of issue:2024-07-05
Advisor:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. Susann Boretius
Persistent Address:
http://dx.doi.org/10.53846/goediss-10590
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Abstract
English
Cognitive impairment frequently co-occurs in a variety of neuropsychological disorders, making it an increasing burden to the affected individuals, their relatives, and society in general. Diagnostic procedures usually consist of screening tests, interviewing the patient and the people in their social surroundings, as well as the observation of the affected individual’s behavior. In this regard and to study certain disorders as well as diseases in animal models, behavioral analysis remains the primary tool for scientists studying these disorders and diseases in animal models. The first part of this thesis aimed to investigate the impact of the haploinsufficiency of the transcription factor ZBTB20, which causes the rare Primrose syndrome. Since previous work of our group showed increased ZBTB20 expression in hippocampal CA1 neurons upon recombinant human erythropoietin (rhEPO) treatment, the effects of rhEPO as a trial treatment in this mouse model of neurodevelopmental disorder were additionally assessed. Histological analyses confirmed the reduced expression of functional ZBTB20. Behavioral analysis demonstrated autism-like phenotype in affected males by showing impaired sociability, reduced communication, and repetitive behavior. These are the primary domains of autism spectrum disorder, which is reportedly common among individuals with Primrose syndrome. Additional co-diagnosed symptoms such as reduced cognitive flexibility, hyposensitivity to nociception, and hyperactivity could also be demonstrated in this mouse model. The trial treatment of rhEPO improved sociability, cognitive flexibility, working memory, and the motivation to explore. Brain MRI revealed volumetric changes in various regions. This study is the first to report an in-depth behavioral characterization and MRI of ZBTB20 deficient mice. By reproducing most if its symptoms, the results indicate ZBTB20+/- mice to be a valuable model to further investigate Primrose syndrome. For the second part of this thesis, we characterized a mouse model of tamoxifen-induced and diphteria toxin-a (DTA) mediated loss of pyramidal neurons and subsequent gray matter inflammation, imitating encephalitis, to experimentally gain insight of the pathophysiological role of autoantibodies in neuroinflammation and the subsequent impact on behavior. Histological analysis and MRI confirmed structural damage to hippocampus and other brain regions. Applied behavior tests revealed impairments in hippocampal-dependent tests of spatial and social memory. Thermal recordings of a social experiment were utilized to assess the Centralization Index as a non-invasive stress readout. Here, DTA mice exhibited reduced stress responses in a situation of forced social interaction. The DTA mouse model in this project proved to be a valuable asset to investigate a standardized approach of inducible gray matter encephalitis, exhibiting a classic and expected phenotype and allowing the future investigation of the encephalitic phenotype. The third project of this thesis aimed to address the growing need for experimenter-independent cognitive research in a social and therefore stress reduced environment, and to manage the vast amount of raw data that requires analyses, by providing an automated pipeline to analyze raw data generated by the IntelliCage setup. This pipeline, IntelliR, and the additionally provided scripts of three designed challenges to assess spatial, episodic-like, and working memory will assist in improving time consuming analysis and data reproducibility beyond the function of IntelliCage Analyzer software. Furthermore, additional readouts were introduced, along with the Cognition Index, which allows performance comparison across different tasks and challenges. To demonstrate the ability of mice to learn the designed cognitive challenges, three independent cohorts of healthy female mice were utilized, showing significantly increased performance compared to random chance level. Additionally, to demonstrate the sensitivity of IntelliR to subtle impairments in disease models, a cohort of DTA mice underwent the IntelliCage protocol, exhibiting cognitive impairments in various readouts, such as slower learning rates, reduced cognitive flexibility, and declined working memory. IntelliR can be not only easily integrated and executed, but also adapted for individual research requirements. Subsequently, it can improve the time management and reproducibility of IntelliCage data analysis.
Keywords: Behavior; Mice; Autism Spectrum Disorder; Primrose Syndrome; Zbtb20; Encephalitis; IntelliCage
