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Dissecting the functional and morphological contributions of the glucocorticoid receptor gene in neural progenitor cells of the hippocampus


Stress hormones are known as one of the strongest and most ecologically relevant mediators of adult neurogenesis. A lingering question in adult neurogenesis is whether these hormones, known as corticosteroids (cortisol in humans, corticosterone in rodents), act directly on neural progenitor cells (NPCs), or indirectly through secreted factors or changes in network activity. Additionally, the functional contributions of this impact are largely speculative. To address these unknowns, we generated a transgenic mouse model whose glucocorticoid receptors (GRs) could be inducibly inactivated specifically in NPCs. GRs are the main target that corticosteroids bind to when elevated during stress. We investigated the effect of this cell-specific GR knockout model on hippocampal survival and differentiation and found them to be similarly affected by chronic corticosterone treatment compared to controls. This implies that corticosterone-suppressed neurogenesis and its impact on morphology is indirect, and GR in other cells may be mediating the effects. Furthermore, mice with GR inactivation in newborn neurons behaved similarly to controls in all tasks observed under basal levels of corticosterone. When mice were chronically treated with corticosterone, however, controls exhibited an anxious phenotype in novelty-suppressed feeding (NSF), light/dark box, and elevated Omaze, whereas transgenic mice behaved like untreated control groups in all anxiety measures except latency to feed in NSF. Neither corticosterone nor inactivation of GR in adult-born neurons altered depression-like behaviors in the forced swim test, nor percent freezing in contextual fear discrimination. Lastly, we found that corticosterone increased the rate of learning in 1-trial contextual fear conditioning, an effect not mediated by reducing GR signaling in the neurogenic pool. These results highlight the functional contributions of adult neurogenesis as well as how their GRs mediate anxiety-relevant behaviors irrespective of suppressed neurogenesis.

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