The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids

Abstract

Many of the behavioral consequences of stress are mediated by the activation of the glucocorticoid receptor by stress-induced high levels of glucocorticoid hormones. To explore the molecular mechanisms of these effects, we combined in vivo and in vitro approaches. We analyzed mice carrying a brain-specific mutation (GR(NesCre)) in the glucocorticoid receptor gene (GR, also called Nr3c1) and cell lines that either express endogenous glucocorticoid receptor or carry a constitutively active form of the receptor (DeltaGR) that can be transiently induced. In the hippocampus of the wild-type [corrected] mice after stress, as well as in the cell lines, activation of glucocorticoid receptors greatly increased the expression and enzymatic activity of proteins in the MAPK signaling pathway and led to an increase in the levels of both Egr-1 mRNA and protein. In parallel, inhibition of the MAPK pathway within the hippocampus abolished the increase in contextual fear conditioning induced by glucocorticoids. The present results provide a molecular mechanism for the stress-related effects of glucocorticoids on fear memories.

Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons

“…The effects of insulin on learning and memory oppose those of glucocorticoids at multiple levels. Specifically, intrahippocampal insulin 37 or activation of insulin signaling pathways 38 can block the effects of stress on learning and memory. Exposure to elevated corticosterone levels reduces insulin receptor signaling in multiple somatic tissues, including the brain 39 .…”

Glucocorticoids act on glutamatergic pathways to affect memory processes

“…Training in this task increased the amplitude of evoked synaptic transmission in the CA1 region of the hippocampus, similar to that observed during LTP induction. In the fear conditioning task (for which glucocorticoid involvement in consolidation was shown in the amygdala [54] and hippocampus [14,54]), tone conditioning rapidly increases synaptic GluA1 subunit levels in the lateral amygdala, a mechanism that determines the strength of the memory formed [55]. In the hippocampus, this task enhanced AMPAR-mediated synaptic modifications 3 h post-training [56].…”

“…Given that until recently glucocorticoids were thought to act exclusively via genomic mechanisms, research has focused predominantly on changes in gene and protein expression in response to glucocorticoids [13][14][15][16]. Because genomic mechanisms take some time to develop, such a mechanism cannot apply to extremely rapid effects of glucocorticoids reported for some cognitive operations (for example, learning and retrieval when tests are given shortly after the enhancement of glucocorticoid levels).…”

Extracellular Hippocampal Acetylcholine Level Controls Amygdala Function and Promotes Adaptive Conditioned Emotional Response

“…First, previous studies demonstrated that p-ERK1/2 can serve in neural cells, and particularly in hippocampal neurons, as convergence site for several neurotransmitter receptor activation, including acetylcholine receptors (Rosenblum et al, 2000;Berkeley et al, 2001). Second, ERK1/2 activation has been shown to be critically required for learning-dependent plasticity within the hippocampus and the amygdala, in contextual and tone CS fear conditioning, respectively (Atkins et al, 1998;Schafe et al, 2000;Shalin et al, 2004;Revest et al, 2005;Trifilieff et al, 2006). We thus examined ERK1/2 phosphorylation to map and compare the patterns of activation of different hippocampal and amygdalar subregions as a function of the pharmacologically induced manipulation of the hippocampal cholinergic transmission.…”