There is significant prevalence of Low Anterior Resection Syndrome following oncological rectal resection. A low anastomotic height or history of radiotherapy are major risk factors.

Stressful events are known to have a long-term impact on future behavioral stress responses. Previous studies suggested that both glucocorticoid hormones and glutamate acting via glucocorticoid receptors (GRs) and N-methyl D-aspartate (NMDA) receptors, respectively, are of critical importance for the consolidation of these longlasting behavioral responses at the dentate gyrus, the gateway of the hippocampal formation. We found that an acute psychologically stressful event resulted in ERK1/2 phosphorylation (pERK1/2), which within 15 min led to the activation of the nuclear kinases MSK1 and Elk-1 in granule neurons of the dentate gyrus. Next, MSK1 and Elk-1 activation evoked serine-10 phosphorylation and lysine-14 acetylation in histone H3, resulting in the induction of the neuroplasticity-associated immediate-early genes c-Fos and Egr-1 in these neurons. The pERK1/2-mediated activation of MSK1 and Elk-1 required a rapid protein-protein interaction between pERK1/2 and activated GRs. This is a unique nongenomic mechanism of glucocorticoid hormone action in dentate gyrus granule neurons on longlasting behavioral responses to stress involving direct cross-talk of GRs with ERK1/2-MSK1-Elk-1 signaling to the nucleus.corticosterone | chromatin | epigenetics | hippocampus | memory A drenal glucocorticoid hormones play an important role in the behavioral consequences of stress (1). Glucocorticoids secreted during a stressful event facilitate learning of adaptive behavioral responses and the consolidation of memories of the event (1, 2). Aberrant glucocorticoid secretion, as a result of chronic stress, is implicated in stress-related disorders such as major depression and anxiety (3-5).It is still unclear how glucocorticoid hormones affect behavior at the molecular level. Glucocorticoid levels attained after stress influence cellular function by activating glucocorticoid receptors (GRs) (6). These receptors bind to their target sites in gene promoters, thereby changing gene expression (7). Activated GRs can also interact through protein-protein interactions with a broad range of intracellular signaling molecules including transcription factors and enzymes (7). Whether GRs directly interact with intracellular signaling pathways to influence stress-related behavior is unknown.A signaling pathway involved in behavioral adaptation and memory formation is the extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) signaling pathway (8). This pathway is activated through N-methyl D-aspartate receptors (NMDA-Rs) and other membrane receptors and is involved in changes in neuronal structure and function (8). Hippocampal NMDA-R-mediated ERK MAPK signaling is involved in behavioral responses observed in Morris water maze learning, contextual fear conditioning, and the forced swim test (9-11). In vitro experiments suggest that ERK MAPK signaling activates nuclear histone modifying enzymes such as MSK1 (mitogen-and stress-activated kinase 1) (12, 13) and Elk-1 (ETS domain protein-1) (14). These enzymes evoke...

Stressful events evoke long-term changes in behavioral responses; however, the underlying mechanisms in the brain are not well understood. Previous work has shown that epigenetic changes and immediate-early gene (IEG) induction in stress-activated dentate gyrus (DG) granule neurons play a crucial role in these behavioral responses. Here, we show that an acute stressful challenge [i.e., forced swimming (FS)] results in DNA demethylation at specific CpG (5′-cytosine-phosphateguanine-3′) sites close to the c-Fos (FBJ murine osteosarcoma viral oncogene homolog) transcriptional start site and within the gene promoter region of Egr-1 (early growth response protein 1) specifically in the DG. Administration of the (endogenous) methyl donor S-adenosyl methionine (SAM) did not affect CpG methylation and IEG gene expression at baseline. However, administration of SAM before the FS challenge resulted in an enhanced CpG methylation at the IEG loci and suppression of IEG induction specifically in the DG and an impaired behavioral immobility response 24 h later. The stressor also specifically increased the expression of the de novo DNA methyltransferase Dnmt3a [DNA (cytosine-5-)-methyltransferase 3 alpha] in this hippocampus region. Moreover, stress resulted in an increased association of Dnmt3a enzyme with the affected CpG loci within the IEG genes. No effects of SAM were observed on stress-evoked histone modifications, including H3S10p-K14ac (histone H3, phosphorylated serine 10 and acetylated lysine-14), H3K4me3 (histone H3, trimethylated lysine-4), H3K9me3 (histone H3, trimethylated lysine-9), and H3K27me3 (histone H3, trimethylated lysine-27). We conclude that the DNA methylation status of IEGs plays a crucial role in FS-induced IEG induction in DG granule neurons and associated behavioral responses. In addition, the concentration of available methyl donor, possibly in conjunction with Dnmt3a, is critical for the responsiveness of dentate neurons to environmental stimuli in terms of gene expression and behavior.stress | behavior | DNA methylation | immediate-early gene | hippocampus A daptation to stressful challenges is crucial for maintaining health and well-being. These events induce physiological and behavioral responses that enable the individual to cope with the challenge. In the brain, molecular mechanisms are initiated that facilitate learning of adaptive behavioral responses and the consolidation of memories of the event. Inappropriate responses to stress have been linked with psychiatric disorders, such as major depression and anxiety (1-3).Glucocorticoid hormones, secreted in response to a stressful challenge, in conjunction with activated intracellular signaling pathways in neurons of the hippocampus, play a key role in consolidating behavioral responses to stress (4, 5). The hippocampal extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) pathway, activated through N-methyl D-aspartate receptors (NMDA-Rs) and other membrane receptors, is involved in behavioral responses seen in Mo...

Background: An animal model commonly used to investigate pathways and potential therapeutic interventions relevant to abdominal aortic aneurysm (AAA) involves subcutaneous infusion of angiotensin II within the apolipoprotein E deficient mouse. The aim of this study was to investigate genes differentially expressed in aneurysms forming within this mouse model in order to assess the relevance of this model to human AAA.

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