Glucocorticoid receptor-dependent regulation of adult hippocampal neurogenesis by stress and antidepressants

• Applicant: Christoph Anacker, Ph.D.
• Subject Area: Biological Psychiatry ; Molecular Biology and Physiology of Neurons and Glial Cells ; Pharmacology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 238510011

The neurobiological mechanisms underlying depression pathogenesis and successful antidepressant treatment response are poorly understood, limiting effective drug development. Of emerging relevance is adult hippocampal neurogenesis, that is, the continuous birth of new functional neurons from stem cells in the hippocampus of the adult brain. Recent evidence has demonstrated that hippocampal neurogenesis is crucial to attenuate the development of hormone abnormalities and depressive behaviour under stressful conditions. Accordingly, chronic stress decreases neurogenesis, thereby contributing to the development of depressive symptoms; while antidepressants increase neurogenesis, an effect critically important for their behavioural action. However, the molecular mechanisms by which stress and chemically different classes of antidepressants modulate adult hippocampal neurogenesis remain elusive. My previous research has demonstrated that stress hormones (glucocorticoids) and antidepressants differentially regulate the function of the glucocorticoid receptor (GR) in cultured hippocampal stem cells in vitro. However, whether this differential GR activation in stem cells mediates the opposing effects of stress and antidepressants on hippocampal neurogenesis, the hormone system and depressive behaviour in a living organism, is unknown. To address this question, I will generate an innovative transgenic mouse strain with adult-inducible knockout of the GR specifically in adult hippocampal stem cells and their progeny. I will then subject these mice to 8 weeks of chronic stress and to treatment with two chemically different antidepressants. I will examine changes in adult hippocampal neurogenesis, in the electrophysiological activity of the brain, in the function of the hormone system, and in depressive behaviour in mice with and without stem cell-specific deletion of the GR. This project will therefore examine the GR as a potentially crucial molecular mechanism underlying stress-induced depression, and identify novel targets for more efficient antidepressant treatments targeting neurogenesis and neuroplasticity in the brain of depressed patients.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Rene Hen, Ph.D.