Abstract
The glucocorticoid receptor (GR) is critically involved in regulation of stress responses [inhibition of the hypothalamic-pituitary-adrenal (HPA) axis], emotional behavior and cognition via interactions with forebrain corticolimbic circuity. Work to date has largely focused on GR actions in forebrain excitatory neurons; however, recent studies suggest a potential role mediated by interneurons. Here, we targeted GR deletion in forebrain GABAergic neurons, including the cortical interneurons, using a Dlx5/6-Cre driver line to test the role of forebrain interneuronal GR in HPA axis regulation and behavior. Our data indicate that GR deletion in GABAergic neurons causes elevated corticosterone stress responsiveness and decreased cross-over latencies in a passive avoidance task in females, but not males. Dlx5/6-Cre driven gene deletion caused loss of GR in interneurons in the prefrontal cortex (PFC) and hippocampus, but also in select diencephalic GABAergic neurons (including the reticular thalamic nucleus and dorsomedial hypothalamus). Our data suggest that GR signaling in interneurons is differentially important in females, which may have implications for GR-directed therapies for stress-related affective disease states.
Highlights
The glucocorticoid receptor (GR) is critical for control of hypothalamic-pituitary-adrenal (HPA) axis reactivity, affective state and emotional memory in mice
We found the number of glutamic acid decarboxylase 67 (Gad67) cells containing GR in the cortex are significantly decreased in Dlx5/6 GRKD mice compared to control mice (T(6) = 7.196; p < 0.001; Figure 1C)
Our study indicates that deletion of GR in populations of forebrain GABAergic neurons including the cortical interneurons resulted in HPA axis hyperactivity to an acute stress and impulsivity or impaired retention of passive avoidance learning in females
Summary
The glucocorticoid receptor (GR) is critical for control of hypothalamic-pituitary-adrenal (HPA) axis reactivity, affective state and emotional memory in mice. The CaMKII-Cre line used generally directs Cre expression in glutamatergic neurons ( CaMKII-Cre lines can direct GR deletion to non-glutamatergic cells in regions such as the striatum and bed nucleus of the stria terminalis; Klug et al, 2012; Jennings et al, 2013; Wang et al, 2013). These data have led to the hypothesis that glucocorticoids are essential for regulating behavior and HPA axis function via modulating the activity of glutamatergic neurons in forebrain. The role of GR in forebrain interneurons in the female brain has yet to be elucidated
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