Cell-specific effects of mineralocorticoid receptor

Yang, Huanqing (2024): Cell-specific effects of mineralocorticoid receptor: the effects of mineralocorticoid receptor deletion in glutamatergic or GABAergic neurons on emotional and cognitive functions. Dissertation, LMU München: Fakultät für Biologie

Abstract

Stress is a normal response to situational pressures or demands. Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis and leads to the release of corticosteroids, which act in the brain via two distinct receptors: mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). MR plays a key role in cognitive and emotional function, making it a key player in the body's response to stress. This thesis aims to investigate the effects of MR on emotional behavior and cognitive function in specific cell types (glutamatergic neurons and GABAergic neurons). Therefore, I first performed baseline behavioral testing in mice lacking MR in glutamatergic neurons as well as in GABAergic neurons. Lack of MR in glutamatergic neurons results in an anxiety-like phenotype, whereas lack of MR in GABAergic neurons appears to affect cognitive function. Following, further cognitive behavioral experiments were carried out on mice lacking MR in GABAergic neurons, and it was found that mice lacking MR in GABAergic neurons performed better in stressful experiments. Then, electrophysiological experiments were used to observe whether the neuronal functions of glutamatergic neurons and GABAergic neurons lacking MR were changed. Morphological changes of glutamatergic neurons lacking MR were observed by Golgi staining. Then I conducted behavioral tests on these two strains of mice after chronic social stress, not only on male mice, but also on female mice, in order to observe the emotional behavior and cognitive behavior of mice of different sexes after experiencing chronic stress. Whether the performance is consistent. Furthermore, in single-cell RNA sequencing data we found the gene of interest Fam107a, which was significantly downregulated in MR-deficient glutamatergic neurons. By virus-mediated overexpression of Fam107a, we found that it partially rescued the genotype. In the single-cell RNA sequencing data of GABAergic neurons lacking MR, we found that the Npy gene was significantly down regulated. In the future, we will observe its effect on mice lacking MR in GABAergic neurons by manipulating the Npy gene. Given the central role of MR in cognitive and emotional functioning, and its importance as a target for promoting resilience, future research should investigate how MR modulation can be used to alleviate disturbances in emotion and behavior, as well as cognitive impairment, in patients with stress-related psychiatric disorders.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Stress, Mineralocorticoid receptor, Anxiety, Behavior, Cognition, Sex
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 22. Februar 2024
• 1. Bericht­erstatter:in: Schmidt, Mathias