Expression Of Immediate Early Gene C-fos Research Articles

Whole-brain mapping of neuronal activity evoked by maternal separation in neonatal mice: An association with ultrasound vocalization.

Neonatal mice emit ultrasonic vocalizations (USVs) when separated from their mothers. Since the USVs attract their mothers' attention and trigger maternal retrieval, they are considered to serve as social signals for communication. We have modeled paternal aging effects on the vocal communication of offspring in mice. However, little is known about the neural basis underlying neonatal USV production. To identify responsible brain regions driving the vocal behavior, we comprehensively mapped the neuronal activity associated with USV production in the entire brain of mice at postnatal day 6 (P6). Using an expression of immediate-early gene c-Fos as a neuronal activity marker, correlations between the numbers of USVs and c-Fos positive neurons were analyzed. We identified 23 candidate brain regions associated with USV production in the mice at P6. Our study would be a first step toward comprehensively understanding the neuronal mechanisms that regulate and develop vocal behaviors in neonatal mice.

Neuroprotective effects of exercise in rodent models of memory deficit and Alzheimer's.

Alzheimer's disease (AD) is a fastest growing neurodegenerative condition with no standard treatment. There are growing evidence about the beneficial effects of exercise in brain health promotion and slowing the cognitive decline. The aim of this study was to review the protective mechanisms of treadmill exercise in different models of rodent memory deficits. Online literature database, including PubMed-Medline, Scopus, Google scholar were searched from 2003 till 2017. Original article with English language were chosen according to following key words in the title: (exercise OR physical activity) AND (memory OR learning). Ninety studies were finally included in the qualitative synthesis. The results of these studies showed the protective effects of exercise on AD induced neurodegerative and neuroinflammatory process. Neuroperotective effects of exercise on the hippocampus seem to be increasing in immediate-early gene c-Fos expression in dentate gyrus; enhancing the Wnt3 expression and inhibiting glycogen synthase kinase-3β expression; increasing the 5-bro-mo-2'-deoxyridine-positive and doublecortin-positive cells (dentate gyrus); increasing the level of astrocytes glial fibrillary acidic protein and decrease in S100B protein, increasing in blood brain barrier integrity; prevention of oxidative stress injury, inducing morphological changes in astrocytes in the stratum radiatum of cornu ammonis 1(CA1) area; increase in cell proliferation and suppress apoptosis in dentate gyrus; increase in brain-derived neurotrophic factor and tropomyosin receptor kinase B expressions; enhancing the glycogen levels and normalizing the monocarboxylate transporter 2 expression.

Inverse Regulation of Plasticity-related Immediate Early Genes by Calcineurin in Hippocampal Neurons

In the mammalian hippocampus, changes in the expression of immediate early genes (IEGs) is thought to contribute to long term plastic changes in neurons brought about by learning tasks and high frequency stimulation of synapses. The phosphatase calcineurin has emerged as an important negative regulator of hippocampus-dependent learning and long term potentiation. Here we investigated the possibility that the constraining action of calcineurin on hippocampal plasticity is mediated in part by regulation of gene expression through negative control of transcription factors, such as cAMP-response element (CRE)-binding protein (CREB). We assessed the effect of calcineurin inhibitors on CREB activation by neuronal activity and show that calcineurin activity is in fact required for CREB-mediated gene expression. However, inhibition of calcineurin had disparate effects on the transcriptional induction of CREB-dependent IEGs. We find that the IEG c-fos is unaffected by suppression of calcineurin activity, the plasticity-related genes Egr1/Zif268 and Egr2/Krox-20 are up-regulated, and genes encoding the orphan nuclear hormone receptors Nor1 and Nur77 are down-regulated. We further show that the up-regulation of particular IEGs is probably due to the presence of serum response elements (SREs) in their promoters, because SRE-mediated gene expression is enhanced by calcineurin blockers. Moreover, expression of the c-fos gene, which is unaffected by calcineurin inhibitors, could be down-regulated by mutating the SRE. Conversely, SRE-mediated c-fos induction in the absence of a functional CRE was enhanced by calcineurin inhibitors. Our experiments thus implicate calcineurin as a negative regulator of SRE-dependent neuronal genes.

Enhancement of antibody production and expression of c-Fos in the insular cortex in response to a conditioned stimulus after a single-trial learning paradigm

Immune responses can be modulated by Pavlovian conditioning techniques. In this study, to evaluate the conditionability of antibody response via a single-trial conditioning paradigm, we used a protein antigen ovalbumin as an unconditioned stimulus (UCS) that was paired with a novel taste of saccharin in a single-trial learning protocol. A significant enhancement of anti-ovalbumin antibody production was observed in the conditioned rats at Days 15, 20 and 25 after re-exposure to the conditioned stimulus. The pattern of conditioned antibody response is similar to that of antigen-induced antibody response. Furthermore, to identify the involvement of a limbic brain structure in the expression of conditioned antibody response, immediate-early gene c-fos expression was used as a marker of neuronal activation to detect the functional activation in the insular cortex (IC) in response to the conditioned stimulus. The re-exposure of conditioned rats to the conditioned stimulus resulted in a significant increase of c-Fos immunoreactivity in all three areas of the IC including the agranular, dysgranular, and granular areas, suggesting that IC is involved in the neural mechanism of expression of conditioned immune response.

Enhancement of antibody production and expression of c-Fos in the insular cortex in response to a conditioned stimulus after a single-trial learning paradigm

Immune responses can be modulated by Pavlovian conditioning techniques. In this study, to evaluate the conditionability of antibody response via a single-trial conditioning paradigm, we used a protein antigen ovalbumin as an unconditioned stimulus (UCS) that was paired with a novel taste of saccharin in a single-trial learning protocol. A significant enhancement of anti-ovalbumin antibody production was observed in the conditioned rats at Days 15, 20 and 25 after re-exposure to the conditioned stimulus. The pattern of conditioned antibody response is similar to that of antigen-induced antibody response. Furthermore, to identify the involvement of a limbic brain structure in the expression of conditioned antibody response, immediate-early gene c-fos expression was used as a marker of neuronal activation to detect the functional activation in the insular cortex (IC) in response to the conditioned stimulus. The re-exposure of conditioned rats to the conditioned stimulus resulted in a significant increase of c-Fos immunoreactivity in all three areas of the IC including the agranular, dysgranular, and granular areas, suggesting that IC is involved in the neural mechanism of expression of conditioned immune response.

Macrophage migration inhibitory factor is upregulated in an endotoxin-induced model of bladder inflammation in rats.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine found in epithelial cells as preformed stores, such that MIF release can activate innate immune responses. Our identification of MIF stores in the urothelium suggests that MIF may function in the bladder's initial response to infectious stimuli, such as lipopolysaccharide (LPS). To test this hypothesis, we observed changes in MIF, cyclooxygenase-2 (COX-2) and c-fos in the bladder, L6-S1 spinal cord, dorsal root ganglion (DRG), and major pelvic ganglion (MPG) and MIF changes in the prostate following intravesical LPS. Intravesical LPS induced bladder edema and leukocyte infiltration, as well as increased MIF protein and mRNA in the bladder and lumbosacral spinal cord. Expression of immediate-early gene c-fos, a transcription factor used as a marker of neuronal activation, increased in the L6-S1 spinal cord and L6-S1 DRG of rats that received LPS. We conclude that significant increases in bladder MIF expression and protein in response to intravesical LPS may represent part of this organ's initial innate immune response. In addition, MIF upregulation may represent a neural response to visceral inflammation. Finally, changes in prostate MIF content after intravesical LPS suggest that MIF may be involved in viscerovisceral interactions associated with chronic pelvic pain syndromes.

Involvement of nitric oxide in morphine-induced c-Fos expression in the rat striatum

Induction of expression of immediate-early gene c-Fos in the striatum is a common effect of many drugs of abuse, including morphine. Previous studies have shown that the morphine-mediated c-Fos response is attenuated by antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Other evidence suggests that the NDMA receptor may be coupled to the enzyme neuronal nitric oxide synthase (nNOS). NMDA receptor-mediated increases in intracellular calcium can activate nNOS, which catalyzes the formation of the signaling molecule nitric oxide. Because activation of NMDA receptors mediates morphine-induced c-Fos expression, we tested the hypothesis that activation of nNOS is involved in this cascade. Male rats were injected with the nNOS-selective inhibitor 7-nitroindazole (7-NI) or vehicle 30 min prior to injection of morphine sulfate or vehicle. Two hours later they were perfused with fixative and the brains removed for immunocytochemical analysis for c-Fos. Morphine induced c-Fos expression in the striatum, cerebral cortex, and midline/intralaminar nuclei of thalamus. Expression in the striatum, but not thalamus or cortex, was significantly blocked by 7-NI. Double-label immunocytochemistry revealed no co-localization of c-Fos and nNOS in any brain region. These results support a role for nNOS in the neural circuits activated by morphine.

Expression of immediate-early genes c-fos and c-jun in small intestinal transplantation

Expression of immediate-early genes c-fos and c-jun in small intestinal transplantation

Novelty-induced increased expression of immediate-early genes c-fos and arg 3.1 in the mouse brain

The detection of novel stimuli is a memory-dependent process. The presented stimulus has to be compared with memory contents to judge its novelty. In addition, the novelty of stimuli activates attention-related processes that facilitate memory formation. To determine the involvement of limbic and neocortical brain structures in novelty detection, we exposed mice to a novel gustatory stimulus (0.5% saccharin) added to their drinking fluid. We then compared the novelty-induced expression of the two immediate-early genes (IEGs) c-fos and arg 3.1, with their expression in mice familiarized with the same stimulus or mice not exposed to that stimulus. Exposure to taste novelty increased expression of c-fos and arg 3.1 mRNA in the cingulate cortex and deep layers of the parietal cortex. In addition, c-fos mRNA expression was increased in the amygdala and arg 3.1 mRNA was increased in the dentate gyrus. Expression of c-fos and arg 3.1 was elevated 30 min after the exposure to novelty. For arg 3.1, a second peak of expression was found 4.5 h after presentation of the novel stimulus. Our results indicate that the amygdala, the dentate gyrus, and the cingulate and parietal cortices may be involved in novelty detection and associated cognitive events, and suggest that c-fos and arg 3.1 play distinct roles in these processes.

Effect of immobilization stress on transcriptional activity of inducible immediate-early genes, corticotropin-releasing factor, its type 1 receptor, and enkephalin in the hypothalamus of borderline hypertensive rats.

The effects of immobilization on the expression of immediate-early gene c-fos and nerve growth factor-inducible (NGFI)-B mRNAs, corticotropin-releasing factor (CRF) mRNA, CRF heteronuclear RNA (hnRNA), CRF receptor types 1 and 2alpha mRNA, and enkephalin hn/mRNA were investigated in the hypothalamic paraventricular nucleus of Wistar-Kyoto (WKY) rats and borderline hypertensive rats (BHRs). Rats were deeply anesthetized 0, 30, 60, and 180 min after the beginning of the immobilization session (60 min maximum). BHR paraventricular nuclei displayed slight differences in their resting levels of NGFI-B mRNA and CRF hnRNA, both being significantly elevated compared with those of WKY rats. Conversely, basal levels of enkephalin primary transcript were significantly lower in BHRs. Immobilization, however, induced transient variations in the hybridization signals for all evaluated genes within the paraventricular nucleus (except for CRF 2alpha receptor). Immediate-early gene mRNA levels were higher and more prolonged in BHRs than in WKY rats. This heightened neuronal activation in the BHRs was associated with a more rapid increase in CRF mRNA expression (30 min) compared with that in WKY rats (60 min). It is interesting that a transient rise in CRF hnRNA levels was detected in stressed WKY rats, whereas the BHR group displayed a progressive decline in this transcript, being significantly below resting levels 180 min after the immobilization session. The stress-induced expression of CRF type 1 receptor mRNA was similar in both strains. Moreover, no significant differences were observed for enkephalin hn/mRNA in either strain during the immobilization session. Therefore, the hypothalamic paraventricular nucleus appears to be involved in the functional hyperreactivity of the hypothalamic-pituitary-adrenal and autonomic axes to stress observed in BHRs, which may lead ultimately to a stress-induced hypertensive state.

Peroxisome Proliferators Activate Extracellular Signal-regulated Kinases in Immortalized Mouse Liver Cells

Peroxisome proliferators (PPs) are a class of nongenotoxic carcinogens in the rodent liver. The induction of immediate-early gene expression in immortalized mouse liver cells by the PPs Wy-14, 643, monoethylhexyl phthalate, ciprofibrate ethyl ester, and clofibrate suggested that they may be activating growth-regulatory signal transduction pathways. We report that incubation of quiescent ML457 cells with Wy-14,643 resulted in the appearance of two tyrosine-phosphorylated bands of approximately 44 and 42 kDa with maximal phosphorylation at 20 min. These two proteins were identified as extracellular signal-regulated kinases (ERKs) ERK1 and ERK2 (also known as mitogen-activated protein kinases, or MAPKs). Stimulation of quiescent ML457 cells with monoethylhexyl phthalate, ciprofibrate ethyl ester, and clofibrate also resulted in tyrosine phosphorylation of ERK1 and ERK2; however, the steroid PP dehydroepiandrosterone sulfate, which does not induce immediate-early gene expression, did not induce phosphorylation of ERK1 and ERK2. Kinase activity of ERK1 and ERK2 was stimulated by the PPs, consistent with their phosphorylation. The PPs also induced phosphorylation of the upstream regulator MAPK/ERK kinase (MEK). Preincubation of quiescent cells with MEK inhibitor PD98059 blocked activation of ERK1 and ERK2 by the PPs, implicating MEK activation as a requirement for PP-induced ERK activation. In addition, pretreatment with PD98059 greatly reduced the PP-induced expression of immediate-early genes c-fos, egr-1, and to a lesser extent junB. Induction of ERK phosphorylation and junB expression by Wy-14,643 was also seen in rat hepatocytes. These results attribute many of the effects of PPs on immediate-early gene expression to the activation of the MEK/ERK signal transduction pathway and add the PPs to the growing number of tumor promoters that modulate signaling proteins.