Stressful events during adulthood are potent adverse environmental factors that can predispose individuals to psychiatric disorders, including depression; however, many individuals exposed to ...stressful events can adapt and function normally. While stress vulnerability may influence depression, the molecular mechanisms underlying the susceptibility and adaptation to chronic stress within the brain are poorly understood. In this study, two genetically distinct mouse strains that exhibit different behavioral responses to chronic stress were used to demonstrate how the differential epigenetic status of the glial cell-derived neurotrophic factor (
Gdnf) gene in the ventral striatum modulates susceptibility and adaptation to chronic stress. Our results suggest that the histone modifications and DNA methylation of the
Gdnf promoter have crucial roles in the control of behavioral responses to chronic stress. Our data provide insights into these mechanisms, suggesting that epigenetic modifications of
Gdnf, along with genetic and environmental factors, contribute to behavioral responses to stress.
► Stress-induced impairment of GDNF synthesis increases depression-related behaviors ► HDAC2 is required for stress-induced Gdnf repression and behavioral deficits ► DNA methylation is required for stress-susceptible and stress-resilient phenotypes ► MeCP2-HDAC2 complexes contribute to stress-induced Gdnf repression
There is growing evidence suggesting that early life events have long-term effects on the neuroendocrine and behavioral developments of rodents. However, little is known about the involvement of ...early life events in the susceptibility to subsequent stress exposure during adulthood. The present study characterized the effect of maternal separation, an animal model of early life adversity, on the behavioral response to repeated restraint stress in adult rats and investigated the molecular mechanism underlying behavioral vulnerability to chronic stress induced by the maternal separation. Rat pups were separated from the dams for 180 min per day from postnatal day 2 through 14 (HMS180 rats). We found that, as young adults, HMS180 rats showed a greater hypothalamic-pituitary-adrenal axis response to acute restraint stress than nonseparated control rats. In addition, repeatedly restrained HMS180 rats showed increased depression-like behavior and an anhedonic response compared with nonrestrained HMS180 rats. Furthermore, HMS180 rats showed increased expression of REST4, a neuron-specific splicing variant of the transcriptional repressor REST (repressor element-1 silencing transcription factor), and a variety of REST target gene mRNAs and microRNAs in the medial prefrontal cortex (mPFC). Finally, REST4 overexpression in the mPFC of neonatal mice via polyethyleneimine-mediated gene transfer enhanced the expression of its target genes as well as behavioral vulnerability to repeated restraint stress. In contrast, REST4 overexpression in the mPFC of adult mice did not affect depression-like behaviors after repeated stress exposure. These results suggest that the activation of REST4-mediated gene regulation in the mPFC during postnatal development is involved in stress vulnerability.
The introduction of an active Na
+
excretion system from salt-tolerant plants in salt-sensitive crop plants might necessitate enhancement of the robustness of K
+
homeostasis and lead to improved ...plant growth under salt stress. To address this issue, we compared the acquisition and retention of K
+
under excess Na
+
concentrations in the common reed, which possesses excellent Na
+
excretion ability, and low-Na
+
excreting rice. Under excess Na
+
concentrations, common reed maintained constant K
+
content in all plant parts, whereas K
+
content in rice decreased with increasing Na
+
concentration. Preferential uptake of K
+
against high Na
+
/K
+
ratio in nutrient solution was approximately 10 times higher in common reed than in rice. The impact of excess Na
+
on net K
+
absorption rate of common reed was small. On the other hand, the net K
+
absorption rate of rice was decreased by excess Na
+
concentration. However, after the Na
+
concentration in the nutrient solution was decreased from 50 to 1 mM, K
+
absorption in rice recovered immediately. Thus, selectivity of K
+
transporters or channels for K
+
over Na
+
in roots could be involved in the differences in K
+
accumulation in rice and common reed.
In the present study, we established and characterized an animal model of vulnerability to repeated stress. We found that control Sprague–Dawley (SD) rats showed a gradual decrease in the HPA axis ...response following 14 days of repeated restraint stress, whereas Fischer 344 (F344) rats did not show such HPA axis habituation. Similar habituation was observed in the expression of c‐fos mRNA, corticotropin‐releasing hormone hnRNA, and phospho‐CREB and phospho‐ERK proteins in the hypothalamic paraventricular nucleus (PVN) of SD rats, but not in the F344 rats. In addition, repeatedly restrained F344 rats exhibited decreased cell proliferation in the dentate gyrus of the hippocampus and increased anxiety‐related behaviours, while repeatedly restrained SD rats exhibited a selective enhancement of hippocampal cell proliferation in the ventral area. Moreover, we found a lower expression of glucocorticoid receptor (GR) protein, but not mRNA, in the PVN of F344 rats compared to SD rats. We also identified that microRNA (miR)‐18a inhibited translation of GR mRNA in cultured neuronal cells and that increased expression of miR‐18a in the PVN was observed in F344 rats compared with SD rats. These strain differences in GR protein levels were not found in the hippocampus and prefrontal cortex, and the expression of miR‐18a was much lower in these brain regions than in the PVN. Our results suggest that F344 rats could be a useful animal model for studying vulnerability to repeated stress, and that miR‐18a‐mediated down‐regulation of GR translation may be an important factor to be considered in susceptibility to stress‐related disorders.
Memory is formed by synapse-to-nucleus communication that leads to regulation of gene transcription, but the identity and organizational logic of signaling pathways involved in this communication ...remain unclear. Here we find that the transcription cofactor CRTC1 is a critical determinant of sustained gene transcription and memory strength in the hippocampus. Following associative learning, synaptically localized CRTC1 is translocated to the nucleus and regulates Fgf1b transcription in an activity-dependent manner. After both weak and strong training, the HDAC3-N-CoR corepressor complex leaves the Fgf1b promoter and a complex involving the translocated CRTC1, phosphorylated CREB, and histone acetyltransferase CBP induces transient transcription. Strong training later substitutes KAT5 for CBP, a process that is dependent on CRTC1, but not on CREB phosphorylation. This in turn leads to long-lasting Fgf1b transcription and memory enhancement. Thus, memory strength relies on activity-dependent changes in chromatin and temporal regulation of gene transcription on specific CREB/CRTC1 gene targets.
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•Neuronal stimulation and learning induce Fgf1b in the mouse hippocampus•FGF1 is essential for enduring long-term potentiation and memory enhancement•Learning-induced nuclear transport of CRTC1 activates Fgf1b transcription•CRTC1-mediated substitution of KAT5 for CBP on the Fgf1b promoter enhances memory
Uchida et al. link CRTC1 synapse-to-nucleus shuttling in memory. Weak and strong training induce CRTC1 nuclear transport and transient Fgf1b transcription by a complex including CRTC1, CREB, and histone acetyltransferase CBP, whereas strong training alone maintains Fgf1b transcription through CRTC1-dependent substitution of KAT5 for CBP, leading to memory enhancement.
Most proteins produced in the endoplasmic reticulum (ER) of eukaryotic cells fold via disulfide formation (oxidative folding). Oxidative folding is catalyzed by protein disulfide isomerase (PDI) and ...PDI-related ER protein thiol disulfide oxidoreductases (ER oxidoreductases). In yeast and mammals, ER oxidoreductin-1s (Ero1s) supply oxidizing equivalent to the active centers of PDI. In this study, we expressed recombinant soybean Ero1 (GmERO1a) and found that GmERO1a oxidized multiple soybean ER oxidoreductases, in contrast to mammalian Ero1s having a high specificity for PDI. One of these ER oxidoreductases, GmPDIM, associated in vivo and in vitro with GmPDIL-2, was unable to be oxidized by GmERO1a. We therefore pursued the possible cooperative oxidative folding by GmPDIM, GmERO1a, and GmPDIL-2 in vitro and found that GmPDIL-2 synergistically accelerated oxidative refolding. In this process, GmERO1a preferentially oxidized the active center in the aʹ domain among the a, aʹ, and b domains of GmPDIM. A disulfide bond introduced into the active center of the aʹ domain of GmPDIM was shown to be transferred to the active center of the a domain of GmPDIM and the a domain of GmPDIM directly oxidized the active centers of both the a or aʹ domain of GmPDIL-2. Therefore, we propose that the relay of an oxidizing equivalent from one ER oxidoreductase to another may play an essential role in cooperative oxidative folding by multiple ER oxidoreductases in plants.
Aberrant transcriptional regulation in the brain is thought to be one of the key components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Heat shock factors (HSFs) modulate ...cellular homeostasis through the control of gene expression. However, the roles of HSFs in brain function have yet to be elucidated fully. In the present study, we attempted to clarify the role of HSF1-mediated gene regulation in neuronal and behavioral development using HSF1-deficient (HSF1⁻/⁻) mice. We found granule neurons of aberrant morphology and impaired neurogenesis in the dentate gyrus of HSF1⁻/⁻ mice. In addition, HSF1⁻/⁻ mice showed aberrant affective behavior, including reduced anxiety and sociability but increased depression-like behavior and aggression. Furthermore, HSF1 deficiency enhanced behavioral vulnerability to repeated exposure to restraint stress. Importantly, rescuing the HSF1 deficiency in the neonatal but not the adult hippocampus reversed the aberrant anxiety and depression-like behaviors. These results indicate a crucial role for hippocampal HSF1 in neuronal and behavioral development. Analysis of the molecular mechanisms revealed that HSF1 directly modulates the expression of polysialyltransferase genes, which then modulate polysialic acid-neural cell adhesion molecule (PSA-NCAM) levels in the hippocampus. Enzymatic removal of PSA from the neonatal hippocampus resulted in aberrant behavior during adulthood, similar to that observed in HSF1⁻/⁻ mice. Thus, these results suggest that one role of HSF1 is to control hippocampal PSA-NCAM levels through the transcriptional regulation of polysialyltransferases, a process that might be involved in neuronal and behavioral development in mice.
Although depression is the leading cause of disability worldwide, its pathophysiology is poorly understood. Recent evidence has suggested that sirtuins (SIRTs) play a key role in cognition and ...synaptic plasticity, yet their role in mood regulation remains controversial. Here, we aimed to investigate whether SIRT function is associated with chronic stress-elicited depression-like behaviors and neuronal atrophy.
We measured SIRT expression and activity in a mouse model of depression. We injected mice with a SIRT1 activator or inhibitor and measured their depression-like behaviors and dendritic spine morphology. To assess the role of SIRT1 directly, we used a viral-mediated gene transfer to overexpress the wild-type SIRT1 or dominant negative SIRT1 and evaluated their depression-like behaviors. Finally, we examined the role of extracellular signal-regulated protein kinases 1 and 2, a potential downstream target of SIRT1, in depression-like behavior.
We found that chronic stress reduced SIRT1 activity in the dentate gyrus of the hippocampus. Pharmacologic and genetic inhibition of hippocampal SIRT1 function led to an increase in depression-like behaviors. Conversely, SIRT1 activation blocked both the development of depression-related phenotypes and aberrant dendritic structures elicited by chronic stress exposure. Furthermore, hippocampal SIRT1 activation increased the phosphorylation level of extracellular signal-regulated protein kinases 1 and 2 in the stressed condition, and viral-mediated activation and inhibition of hippocampal extracellular signal-regulated protein kinase 2 led to antidepressive and prodepressive behaviors, respectively.
Our results suggest that the hippocampal SIRT1 pathway contributes to the chronic stress-elicited depression-related phenotype and aberrant dendritic atrophy.
Abstract Early environmental factors can modulate the development of the hypothalamic–pituitary–adrenal (HPA) axis response to stress, together with subsequent brain functions and emotional ...behaviors. Two rat strains, Sprague–Dawley (SD) and Fischer 344 (F344), are known to exhibit differences in HPA axis reactivity and anxiety behavior in response to restraint stress in adulthood. To investigate the contribution of maternal influences in determining HPA axis and behavioral responses to stress, a cross-fostering study was performed using stress-resilient (SD) or stress-susceptible (F344) strains. We found that SD rats adopted by either an SD (in-fostered) or an F344 (cross-fostered) dam and F344 rats adopted by an SD dam (cross-fostered) showed a suppression of the HPA axis response following 14 days of repeated restraint stress. In contrast, F344 rats adopted by an F344 dam (in-fostered) did not show such HPA axis habituation. We also found that F344 rats adopted by an F344 dam showed increased anxiety-related behaviors in social interaction and novelty-suppressed feeding tests as a result of the 14 days of restraint stress, while SD rats adopted by either an SD or an F344 dam and F344 rats adopted by an SD dam showed normal anxiety-related behaviors under the same experimental conditions. These results suggest that while genetic differences between SD and F344 strains account for some of the variations in stress vulnerability, maternal factors also contribute.
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