Glucocorticoid receptor knockdown and adult hippocampal neurogenesis

Hooijdonk, L.W.A. van (2010)

Doctoral Thesis

The research in this thesis is aimed at the elucidation of the role of the glucocorticoid receptor (GR) in hippocampal neuroplasticity and functioning. To achieve this, we have developed a novel method to specifically knockdown GR in a discrete cell population of the mouse brain. In this thesis I report silencing of GR expression selectively in a population of neuronal progenitors and immature neurons of the dentate gyrus, using RNA-interference (RNAi) delivered by a lentiviral vector. Characterization of these cells resulted in the discovery that GR knockdown causes a striking modulation of hippocampal neurogenesis and remodelling of hippocampal circuitry. Functional studies further revealed consequences of GR knockdown for contextual memory performance and behavioural coping strategies during stressful conditions. The results demonstrate the feasibility to apply RNAi in discrete cell populations for study of the action mechanism of glucocorticoids underlying control of neuroplasticity and behaviour.

• Cognitive performance
• Dentate gyrus
• Glucocorticoid receptor
• Hippocampus,
• Lentiviral vector
• Mouse model
• Neurogenesis
• Neuroplasticity
• RNA-interference

• All authors: Hooijdonk, L.W.A. van
• Supervisor: Kloet, E.R. de; Vreugdenhil, E.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center (LUMC), Leiden University
• Date: 2010-04-20
• ISBN (print): 9789088911521
• Sponsorship: Leiden/ Amsterdam Center for Drug Research (LACDR, NWO-DFG International Research and Training Program (IRTG) Leiden-Trier (NWO-DN 95-420) J.E. Jurriaanse Stichting Internationale Stichting Alzheimer Onderzoek