Exposure to life stressors is a predisposing factor for states of depression and anxiety. Both behavioral control over stressor exposure and physical activity are potent modulators of the behavioral response to stress, and may operate through similar neurochemical mechanisms. Uncontrollable, but not controllable, stress produces long-term behavioral depression! anxiety or learned helplessness (LH) by sensitizing 5HT neurons in the dorsal raphe nucleus (DRN). The proposed research will test the hypothesis that behavioral control and physical activity both prevent LH by attenuating stress-induced locus coeruleus (LC) norepinephrine (NE) output to serotonin (5HT) neurons in the DRN, thereby preventing sensitization of the DRN. (1) We will determine if physical activity prevents two behavioral measures of LH (shuttle box escape and freezing). (2) We will determine if physical activity prevents sensitization of 5HT DRN neurons by (a) measuring stress-induced activation of 5HT neurons within the DRN using double immunohistochemical labeling for 5HT and c-Fos and (b) measuring stress-induced 5HT release within the DRN using in vivo microdialysis. (3) We will determine if both physical activity and behavioral control prevent sensitization of the DRN by reducing NE input from .the LC by (a) measuring stress-induced NE release in the DRN using in vivo microdialysis, (b) injecting a retrograde tracer (Flouro-Gold, FG) into the DRN and quantifying the number of active LC neurons that specifically innervate the DRN using immunohistochemical labeling for FG and c-Fos and, (c) driving the LC during stress to reverse the protective effect of physical activity and stressor control.
