Abstract
Stressful events evoke molecular adaptations of neural circuits through chromatin remodeling and regulation of gene expression. However, the identity of the molecular pathways activated by stress in experimental models of depression is not fully understood. We investigated the effect of acute forced swimming (FS) on the phosphorylation of the extracellular signal-regulated kinase (ERK)1/2 (pERK) and histone H3 (pH3) in limbic brain areas of genetic models of vulnerability (RLA, Roman low-avoidance rats) and resistance (RHA, Roman high-avoidance rats) to stress-induced depression-like behavior. We demonstrate that FS markedly increased the density of pERK-positive neurons in the infralimbic (ILCx) and the prelimbic area (PrLCx) of the prefrontal cortex (PFCx), the nucleus accumbens, and the dorsal blade of the hippocampal dentate gyrus to the same extent in RLA and RHA rats. In addition, FS induced a significant increase in the intensity of pERK immunoreactivity (IR) in neurons of the PFCx in both rat lines. However, RHA rats showed stronger pERK-IR than RLA rats in the ILCx both under basal and stressed conditions. Moreover, the density of pH3-positive neurons was equally increased by FS in the PFCx of both rat lines. Interestingly, pH3-IR was higher in RHA than RLA rats in PrLCx and ILCx, either under basal conditions or upon FS. Finally, colocalization analysis showed that in the PFCx of both rat lines, almost all pERK-positive cells express pH3, whereas only 50% of the pH3-positive neurons is also pERK-positive. Moreover, FS increased the percentage of neurons that express exclusively pH3, but reduced the percentage of cells expressing exclusively pERK. These results suggest that (i) the distinctive patterns of FS-induced ERK and H3 phosphorylation in the PFCx of RHA and RLA rats may represent molecular signatures of the behavioural traits that distinguish the two lines and (ii) FS-induced H3 phosphorylation is, at least in part, ERK-independent.
Highlights
The extracellular signal-regulated kinase (ERK) 1/2 is a member of the mitogen-activated protein kinase (MAPK) intracellular signaling cascade that is highly expressed throughout the brain in mature, postmitotic neurons [1]
We initially focused our analysis on the prefrontal cortex (PFCx) in view of our previous finding that mild stressors induce a significant increase in dopamine release in the PFCx of Roman high-avoidance (RHA), but not RLA rats [20]
A two-way analysis of variance (ANOVA) analysis revealed a significant increment in the density of pERK-positive cells after forced swimming (FS) in the PFCx of both rat lines
Summary
The extracellular signal-regulated kinase (ERK) 1/2 is a member of the mitogen-activated protein kinase (MAPK) intracellular signaling cascade that is highly expressed throughout the brain in mature, postmitotic neurons [1]. In addition to cytoplasmic substrates (e.g., protein kinases, ion channels, cytoskeletal and synaptic vesicle trafficking proteins), ERK 1/2 can directly or indirectly modify transcription factors and histones [2,6] These processes lead in turn to the encoding of environmental stimuli by a rapid and long-term regulation of immediate early genes (IEGs), a mechanism that plays a key role in the adaptive responses to stressors, addictive drugs and their associated learning processes [2,5]. It is unclear whether such epigenetic mechanisms are differentially regulated in genetic animal models showing divergent responses to stress and vulnerability to depression One of these models is represented by the Roman high-avoidance (RHA) and low-avoidance (RLA) rats, two outbred lines psychogenetically selected from a Wistar stock for respectively rapid vs extremely poor acquisition of active avoidance in a shuttle-box [11,12,13,14]. The depression-like behavior of RLA rats in the above test is normalized by subacute and chronic treatment with antidepressant drugs [18,19]
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