Combination of deep behavioral phenotyping with brain region and cell type specific manipulations of FKBP51

Bordes, Joeri (2023): Combination of deep behavioral phenotyping with brain region and cell type specific manipulations of FKBP51. Dissertation, LMU München: Fakultät für Biologie

Abstract

The increasing prevalence of stress-related disorders, such as major depressive disorder (MDD) has become a significant global concern, with devastating effects on individuals' personal lives and societal well-being. The exposure to severe and chronic stressors is a major risk factor for the development of such disorders, and recent traumatic events have further exacerbated this mental health crisis. The susceptibility to MDD is determined by a complex interplay of genetic, epigenetic, and environmental factors. One specific gene of significance in this context is FKBP5 (Fkbp5 in rodents), encoding the co-chaperone FK506 binding protein 51 (FKBP51). The interplay between severe stress exposure and genetic risk variants of FKBP5 has been associated with an increased vulnerability to psychopathology. A significant symptom observed in individuals with MDD is social dysfunction, characterized by the avoidance of social interactions and the display of maladaptive behaviors, such as aggression or irritability. However, traditional preclinical assessment methods for stress-induced behavioral symptoms, such as social aversion, have faced criticism due to their reductionistic nature, often failing to capture ethologically relevant behavioral constructs. Advancements in high-throughput pose estimation tools have provided opportunities for comprehensive behavioral analysis through automatically annotated behavioral assessments. This thesis explores various tools for automatically annotated behavioral assessment in preclinical psychiatry research, employing both supervised classification and unsupervised clustering strategies. Applying the newly established ad validated deep phenotyping methods, the thesis further investigates the brain region and cell type specific role of FKBP51 across different stress models and uncovers the underlying neurobiological mechanisms and behavioral profiles using automatically annotated behavioral assessment. The effectiveness of both supervised classification and unsupervised clustering strategies is demonstrated in characterizing individual and social behavioral profiles in mice subjected to various stress conditions. Moreover, the thesis highlights the distinct sex-specific effects of different stress paradigms on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis, including the expression of Fkbp5 in several stress-related brain regions, in particular the Locus Coeruleus (LC). Taken together, the current thesis emphasizes the importance of brain region and cell type specific regulation of Fkbp5 and underscores the benefits of automatically annotated behavioral assessment tools. This is put into perspective with future research prospects, advocating for the integration of diverse data modalities, such as in vivo measurements of stress mediators and neuronal activity recordings. This integrated approach aims to enhance our understanding of complex behaviors and the underlying molecular mechanisms. Ultimately, this can contribute to a better comprehension of the behavioral phenotypes and associated neurobiological alterations in stress-related disorders. These insights hold potential to facilitate the development of novel treatments for psychiatric disorders.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: social behavior, stress, deep phenotyping, neuroscience, Fkbp5, Locus Coeruleus
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 10. November 2023
• 1. Bericht­erstatter:in: Schmidt, Mathias