Stress induces activation of stress‐activated kinases in the mouse brain

Abstract

Stress is a part of daily life. However, molecular mechanisms underlying the activation of limbic-hypothalamic-pituitaryadrenal (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.

Hippocampal c-Jun-N-Terminal Kinases Serve as Negative Regulators of Associative Learning

“…This assumption is further corroborated by data showing selective activation of JNKs in the hippocampal formation, and in discrete nuclei of the hypothalamus and the amygdala, which represent brain regions that play a critical role in the induction and regulation of stress responses (McEwen, 2007). Moreover, that all the aforementioned studies demonstrate activation of JNKs in the hippocampus reinforces the likelihood that JNKs signaling is crucially involved in the formation of stressassociated emotional memories (Liu et al, 2004;Kim et al, 2006).…”

“…Although authors reported that two forms of acute stress yielded somewhat different regional patterns of JNKs activation, it might have been that these differences resulted from the different rodent species and stress procedures used. More importantly, such dependence of the pJNK expression pattern on the nature, and particularly, on the relative strength of acute stress (Liu et al, 2004) may explain why exposure to immediate foot shock alone did not elevate hippocampal pJNK levels in a manner similar to prolonged immobilization stress. This assumption is further corroborated by data showing selective activation of JNKs in the hippocampal formation, and in discrete nuclei of the hypothalamus and the amygdala, which represent brain regions that play a critical role in the induction and regulation of stress responses (McEwen, 2007).…”

“…Previous studies using acute restraint (Meller et al, 2003;Liu et al, 2004) or forced swim stress (Liu et al, 2004;Shen et al, 2004) have already demonstrated that exposure to acute stress leads to significant early increase of pJNKs in various brain regions (i.e., prefrontal cortex, discrete nuclei of the hypothalamus and the amygdala) (Liu et al, 2004;Shen et al, 2004), indicating that activation of the JNKs signaling pathway might be involved in initiation of stress responses. Although authors reported that two forms of acute stress yielded somewhat different regional patterns of JNKs activation, it might have been that these differences resulted from the different rodent species and stress procedures used.…”

Tyrosine Phosphorylation of Kir3.1 in Spinal Cord Is Induced by Acute Inflammation, Chronic Neuropathic Pain, and Behavioral Stress

“…Mice subjected to chronic swim stress, for example, exhibit an elevation of kinase activity in brain (29). To determine whether K ir 3.1 phosphorylation occurred in response to stimuli minimally involved in nociception, we exposed mice to a modified Porsolt swim-stress protocol (see "Experimental Procedures") and performed Western immunoblotting (Fig.…”

Repeated Unpredictable Stress and Antidepressants Differentially Regulate Expression of the Bcl-2 Family of Apoptotic Genes in Rat Cortical, Hippocampal, and Limbic Brain Structures

“…The known signaling pathways that mediate the effects of the neurotrophic factors on Bcl-2 and Bcl-xl are the Rsk/MAP pathway, JNK pathway, and the PI-3K/AKT pathway (Manji and Duman, 2001;Bonni et al, 1999;Riccio et al, 1999). Stressors such as forced-swim and restraint stress induce activation of the MKK4-JNK signaling pathway in the hippocampus, amygdala, and hypothalamus (Liu et al, 2004). Although stimulation of this signaling pathway acutely influences the phosphorylation states and membrane translocations of the apoptotic proteins, it is possible that long-term sustained stimulation of this pathway as well as circulating glucocorticoids caused by chronic stress downregulates Bcl-2 and Bcl-xl gene expression as a compensatory response.…”