Stress-induced glucocorticoid receptor activation determines functional recovery following ischemic stroke

Adult male rats were pre-trained and tested in a skilled reaching task and received a focal ischemic motor cortex lesion. One group of animals received daily restraint stress starting one week pre-lesion up to three weeks post-lesion. Immuno-histochemical analysis of GR expression was performed to determine receptor activation.Stress reduced reaching success in na？ve animals and diminished recovery of limb use. Exaggerated functional loss in stressed rats was related to increased GR activation in the lesion hemisphere as indicated by nuclear GR location.These findings provide a mechanistic link between stress-induced motor disability and GR activation in a rat model of stroke. The elevated receptor activation proposes synergistic effects of stress and stroke to modulate the impact of glucocorticoids on motor system function at the genomic level. The modulation of GR biosynthesis may alter responsiveness to stroke treatment and compromise recovery.Common symptoms of stroke include motor disturbances, such as postural imbalance and disturbed skilled movement [1-3]. The degree of spontaneous functional recovery after stroke is determined by inflammatory processes, which are modulated by stress and activity of the hypothalamic-pituitary-adrenal (HPA) axis [4].Stress and high levels of glucocorticoids (GCs) are associated with poor stroke outcome and high morbidity [5-8]. The experience of psychological distress is associated with increased stroke risk and represents a predictor of fatal stroke [9-13]. Stress has been recognized as a critical variable in determining the success of stroke therapy and rehabilitative interventions [14,15]. Because adverse experience modulates neuronal plasticity [16,17] the intrinsic properties of the HPA axis, such as GR density, may explain the large variability in recovery rates among individual patients [18]. Because GC therapy also represents a potential treatment for stroke, investigation of glucocorticoid receptor (GR) regulation is