Allopregnanolone regulates neurogenesis and depressive/anxiety-like behaviour in a social isolation rodent model of chronic stress

Abstract

Chronic stress has been implicated as a causal factor in depression and anxiety, and is associated with neuroendocrine dysfunction and impaired hippocampal neurogenesis. The neurosteroid allopregnanolone (3α,5α-THP; ALLO) has been shown to be reduced in depressed patients. ALLO is "stress responsive" and plays a major role in regulating hypothalamic-pituitary-adrenal (HPA) axis function. We propose that reduced ALLO levels following chronic stress leads to HPA hyperactivity due to diminished ALLO regulation. This will result in increased glucocorticoid levels and reduced BDNF expression, leading to impaired hippocampal neurogenesis and the precipitation of depression/anxiety. To investigate this, chronic stress was induced using the social isolation model and depressive/anxiety-like behaviour assessed using the novelty-suppressed feeding test and forced-swim test. The social isolation model was associated with a significant reduction in endogenous ALLO levels and a depressive/anxiety-like behavioural profile. When exogenous ALLO was administered from the onset of isolation it prevented the development of depressive/anxiety-like behaviours and impairment of hippocampal neurogenesis. When treatment was initiated following six weeks of social isolation, behavioural profile was restored and deficits in BDNF and neurogenesis were not observed. Supporting our hypothesis we observed that socially isolated animals exhibited reduced HPA responsiveness, which was either prevented or normalised with ALLO treatment. Combined, these results indicate that administration of exogenous ALLO either during or following a period of chronic stress can prevent or normalise HPA dysfunction and impairment of hippocampal neurogenesis respectively, precluding the establishment of depressive/anxiety-like behaviours. ALLO may therefore provide a novel therapeutic target for the treatment of depression/anxiety.