Glucocorticoid receptor-dependent regulation of adult hippocampal neurogenesis by stress and antidepressants
Molecular Biology and Physiology of Neurons and Glial Cells
Pharmacology
Final Report Abstract
In this DFG fellowship, I investigated the molecular mechanisms of antidepressant responses on adult hippocampal neurogenesis, depressive- and anxiety-like behavior, stress resilience, and the neuroendocrine system. While I had initially proposed to delete the Glucocorticoid Receptor (GR) from adult-born neurons in the hippocampal dentate gyrus, these same transgenic mice had already been generated by other research groups, which conducted similar experiments with these mice before I started my DFG fellowship. I therefore decided to use the same transgenic strategy and the same study design to delete the serotonin 1A receptor (5HT1AR) from adult-born neurons instead. The 5HT1AR is crucial for the effects of selective serotonin reuptake inhibitor antidepressants and a potential upstream effector of GR function in the dentate gyrus. Deletion of 5HT1AR in adult-born neurons did not affect depression and anxiety-like behavior, neurogenesis, or neuroendocrine responses to stress. However, deletion of 5HT1AR from mature granule cells abolished antidepressant effects on neurogenesis, behavior, and neuroendocrine responses. In addition, germline 5HT1AR knockout mice do not respond to antidepressants, while 5HT1AR knockout mice in which 5HT1AR expression is rescued specifically in the dentate gyrus do respond. Antidepressants decrease GR expression in the dentate gyrus and increase expression of neurotrophic factors via a 5HT1AR-dependent effect. Antidepressants may thus regulate hippocampal neurogenesis via 5HT1AR-dependent release of neurotrophic factors from mature granule cells. Increased neurogenesis and 5HT1AR activation both reduce activity of the dentate gyrus, an effect that is necessary and sufficient to mediate stress resilience both at the behavioral level and at the level of HPA axis regulation. Using structural MRI, I also investigated brain-wide neuroanatomical changes, which implicate hippocampal projections in determining stress susceptibility and resilience.
