Stress induces activation of stress-activated kinases in the mouse brain.

Stress is a part of daily life. However, molecular mechanisms underlying the activation of limbic-hypothalamic-pituitary-adrenal (LHPA) axis remains unknown. In this study, we explored whether activation of the mitogen-activated kinase kinase 4 (MKK4)-c-Jun-N-terminal kinase (JNK) signaling pathway may play a role in the activation of the LHPA axis. We found that forced-swim stress induced elevation of activated MKK4 in the hippocampal formation, amygdala, and hypothalamus. Unlike MKK4, a high basal level of JNK activity is present in many brain areas of unstressed mice. Forced-swim stress significantly elevated JNK activity in the hypothalamus and amygdala and, to a lesser extent, in the cortex, CA1 and CA3 regions, and the dentate gyrus. To further investigate the role of MKK4 and JNK in induction of stress responses, we investigated whether a different stress, namely, restraint stress, induced activation of MKK4 or JNK in the brain. We found that restraint stress also induced elevation of activated MKK4 and JNK in the hippocampal formation, amygdala, and hypothalamus. Because MKK4 and JNK were activated within 5 min following stress, we propose that the MKK4-JNK signaling may be an early neural event in the initiation of neuroendocrine, autonomic and behavioral stress responses.