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PubMed1999

Elevated Fos-like immunoreactivity in the brains of postpartum female prairie voles, Microtus ochrogaster.

This study investigated the expression of the protein product of the immediate early gene c-fos in the brains of female prairie voles (Microtus ochrogaster) in association with pregnancy and postparturient activities including maternal behavior, lactation and postpartum estrus. Fos expression was assessed in female voles that were late in pregnancy, nonpregnant or at one of three different times postpartum (0-8, 12-24, and 24-48 h, respectively). A significant increase in the number of cells displaying Fos immunoreactivity (Fos-ir) was observed during the 0-8 h and 12-24 h postpartum time periods in the accessory olfactory bulbs, medial preoptic area, hypothalamus (specifically, the supraoptic nucleus, ventro-medial hypothalamus, and paraventricular nucleus), lateral septum, bed nucleus of the stria terminalis, and primary somatosensory area of the brain. The number of Fos-ir cells decreased after 24 h postpartum. There were no significant changes in Fos-ir cell numbers in the primary olfactory bulbs, hippocampus, or caudate putamen. The neural activation of the medial preoptic area, accessory olfactory bulbs, hypothalamus, and bed nucleus is consistent with reports in rats of Fos induction associated with the onset of maternal behavior. In voles postpartum estrous behavior begins and ends 0-12 h after parturition. Maternal behavior, including lactation, is initiated at the same time but persists for several weeks. The highest Fos-ir cell numbers reported here coincide with the timing of postpartum estrous behavior in this species.

Animals↗
PubMed1990

Heat shock induces the transcriptional activation of c-fos protooncogene.

Treatment of murine 3T3 fibroblasts with mild elevated temperature (43 degrees C for 45 minutes) followed by recovery at 37 degrees C induced high levels of c-fos mRNA. The maximal c-fos induction was found after recovery at 37 degrees C for 15 minutes. Sodium arsenite induced both hsp 70 and c-fos transcripts. Induction of hsp 70 and c-fos by heat shock did not require intact protein synthesis. c-fos mRNA induced by heat shock was more stable (T1/2 greater than 90 minutes) than that induced by phorbol esters (t1/2 approximately 30 minutes). Northern blot analysis in the presence of actinomycin D and nuclear run off experiments demonstrated that heat shock augmented the transcription rate of c-fos protooncogene. Human growth hormone under the control of a murine genomic c-fos fragment spanning 770 bp 5' from the start of transcription is induced in transfected cells in response to heat shock. These data indicate that heat shock induces c-fos protooncogene acting at both transcriptional and post-transcriptional (i.e. via stabilization of transcripts) levels.

Animals↗
PubMed1990

Effects of hypoxia-ischemia and seizures on neuronal and glial-like c-fos protein levels in the infant rat.

Unilateral carotid ligation in immature rats, followed by 2 h of hypoxia led to ischemic cell change from 2 h after the insult, on the ligated side of the brain. There was a time-dependent induction of immunoreactive c-fos protein in neurones but not glia or ependyma on the non-ligated side of the brain. Induction only occurred in rats that had seizures post hypoxia-ischemia. In the ligated hemisphere c-fos protein was induced in glial-like cells in the corpus callosum, fornix/fimbria and internal capsule and in ependymal cells lining the lateral ventricle starting from 2 h after hypoxia but subsiding by 3 days. No neuronal c-fos induction was seen in areas showing neuronal damage. MK-801 or carbamazepine, which prevented hypoxia-ischemia-induced seizures, also prevented c-fos induction in the non-ligated hemisphere while MK-801 was associated with increased c-fos induction in hippocampal neurones from the ligated side, as well as in glial-like and ependymal cells. These results suggest several processes are involved following the hypoxic-ischemic insult. Firstly, severe hypoxia-ischemia is associated with a reduction in neuronal c-fos protein levels, probably as a result of neuronal failure and death. Secondly, post hypoxic seizures cause c-fos induction in surviving neurones. Thirdly, glial-like from regions in which there is neural loss also exhibit induction of c-fos, which may be important for their subsequent proliferation or for the production of growth factors.

Animals↗
PubMed1991

Effects of early experience on c-fos gene expression in the chick forebrain.

The expression of c-fos mRNA was studied by blot and in situ hybridisation in the forebrains of young chicks subjected to different types of experience-dependent stimulation. Exposure to one hour of activity in a rich visual environment produced a significant increase in forebrain c-fos mRNA in 1-day or 2-day-old chicks; this increase was most marked in cerebellum and medial forebrain--especially intermediate medial hyperstriatum ventrale (IMHV) regions. Levels of c-fos mRNA were not elevated in birds which had been accommodated to the enriched environment for 2 days, suggesting that the novelty of presented stimuli play a critical role in the c-fos induction. Training chicks on a one-trial passive avoidance task was followed by 2- to 2.5-fold increases in c-fos mRNA in both left and right IMHV and lobus parolfactorius (LPO) 30 min after the learning experience. Occlusion of one eye during training resulted in an asymmetrical expression of c-fos in the hemisphere contralateral to the open eye. Therefore c-fos is induced in the chick forebrain during learning and its activation cannot be attributed to 'stress', arousal or intensity of sensory stimulation alone. These observations support the hypothesis that c-fos expression in the brain is related to the acquisition of new experience.

Animals↗
PubMed1992

Immunohistochemical studies of noradrenergic-induced expression of c-fos in the rat CNS.

Previous studies have shown that stimulation of adrenergic receptors in the rat brain causes increased levels of mRNA of the immediate early gene, c-fos. The present studies were undertaken to determine if this stimulation also induces increased levels of c-fos immunoreactivity in the central nervous system (CNS). Rats were treated with the alpha-2 adrenoceptor blockers, yohimbine or atipamezole, or with restraint stress to activate central noradrenergic activity and were perfused 2 h later for immunohistochemical analysis of the cerebral cortex. Yohimbine, atipamezole and restraint stress each was found to cause increases in c-fos-like immunoreactivity (c-fos-li). Western blot analysis revealed increased c-fos protein in the cortex after yohimbine treatment. The c-fos-li response to yohimbine was blocked by prior administration of the beta receptor antagonist, dl-propranolol, and to a lesser degree by the alpha-1 antagonist, prazosin. It is concluded that adrenergic receptor stimulation in the cortex causes increased production of c-fos or fos related antigens and that this (these) immediate early gene product(s) may play a role in noradrenergic function in the CNS.

Adrenergic alpha-Antagonists↗
PubMed1993

c-Fos expression by dorsal horn neurons chronically deafferented by peripheral nerve section in response to spared, somatotopically inappropriate nociceptive primary input.

Subcutaneous formalin injection into the hindpaw of rats induces c-Fos expression in neurons in the ipsilateral spinal cord dorsal horn. In laminae I and II of the dorsal horn at the junction of 4th and 5th segments of the lumbar spinal cord, neurons exhibiting c-Fos protein-like immunoreactivity (Fos-LI) are concentrated in the medial 3/4 that correspond to the terminal field of primary neurons innervating the sciatic nerve. Subacute tibial nerve section 24 h before formalin stimulation caused almost complete elimination of neurons with the formalin-induced Fos-LI in the medial 1/2 (tibial territory) of the above sciatic territory of the dorsal horn. Following a longer survival period (chronic tibial nerve section of 21 days standing), neurons with the formalin-induced Fos-LI re-appeared in the tibial territory. In addition, the number of neurons with the formalin-induced Fos-LI increased in the medial part of the peroneal territory (the lateral 1/2 of the sciatic territory). The results indicate that the activation of c-Fos expression in that part of dorsal horn that has been chronically deafferented by the tibial nerve section is taken over by the spared, but somatotopically inappropriate primary nociceptors. Furthermore, dorsal horn neurons outside but near the deafferented tibial nerve's territory exhibit hypersensitivity to c-Fos expression evoked by intact, somatotopically appropriate primary nociceptive input.

Animals↗
PubMed1993

Light induces expression of fos-related proteins within gastrin-releasing peptide neurons in the rat suprachiasmatic nucleus.

The present study was conducted to determine whether the photic induction of c-fos expression in the rat suprachiasmatic nucleus (SCN) occurs within neurons containing gastrin-releasing peptide (GRP) and/or vasoactive intestinal polypeptide (VIP) because these peptidergic cells are closely associated with retinal projections to the ventrolateral subfield. Using dual immunostaining and thin sectioning techniques, the ventrolateral SCN of light-exposed rats was examined for evidence of individual neurons coexpressing nuclear immunostaining for c-fos proteins (Fos) with cytoplasmic immunoreactivity for GRP or VIP. In all animals, the photic induction of Fos expression in the SCN was mainly confined to cells segregated within the ventrolateral subfield and was evident in approximately 40% of the SCN neurons with cytoplasmic immunoreactivity for GRP. However, neurons coexpressing Fos and GRP comprised only a small fraction of the total number of cells within the ventrolateral SCN exhibiting light-induced Fos immunoreactivity. No sign of Fos expression was detected within VIP-immunoreactive perikarya in the ventrolateral SCN of light-treated rats. These results demonstrate that light induces Fos expression in a number of GRP-containing neurons within the SCN, suggesting that these peptidergic cells may process photic information mediating circadian entrainment.

Amino Acid Sequence↗
PubMed1993

Peripheral and central contributions to the persistent expression of spinal cord fos-like immunoreactivity produced by sciatic nerve transection in the rat.

Previous studies have demonstrated that noxious stimuli, intense enough to produce tissue injury, evoke a transient expression of the Fos protein product of the c-fos proto-oncogene in neurons, in regions of the spinal cord that contribute to the transmission of nociceptive messages in the rat. Since there is evidence that increases in fos-like immunoreactivity reflect increases in neuronal activity, it has thus been possible to identify populations of neurons that are activated in response to tissue injury. In this study we used immunocytochemical localization of fos-like immunoreactive (FLI) neurons to map the patterns of neuronal activity in the spinal cord at different times after peripheral nerve injury in the rat. Sciatic nerve transection induced a persistent (at least 1 month) elevation in the number of FLI neurons, predominantly in laminae 1, 2, 5, 6 and 7 of the ipsilateral lumbar enlargement of the spinal cord. In the L5 segment, the expression of fos-like immunoreactivity in the superficial dorsal horn (laminae 1 and 2) fluctuated, with peaks of Fos expression at 2 h, 2 days and 2 weeks after nerve transection. Furthermore, by 2 weeks after nerve injury, the distribution of labelled neurons in the superficial laminae of the dorsal horn shifted, with the most densely labelled cells now located in the central portion of the superficial dorsal horn. In contrast, the pattern of labelled neurons in laminae 5, 6 and 7 was relatively constant over the 4-week study period. Local anesthetic block of the sciatic nerve significantly decreased the number of FLI neurons when it was administered at either 2 days or 2 weeks post nerve injury. At 2 days, injection of the local anesthetic subcutaneously in the dorsum of neck, to control for a systemic action, also reduced expression of FLI in laminae 1 and 2; at 2 weeks, the systemic injection of the local anesthetic reduced expression of FLI throughout the gray matter of the spinal cord. These results demonstrate that peripheral nerve injury, in contrast to tissue injury, induces a prolonged increase in Fos expression in neurons predominantly in those regions of the spinal cord that are associated with the transmission of nociceptive messages. This pattern of fos-like immunoreactivity is probably the result of persistent neuronal activity in the spinal cord. The increased 'activity' in the spinal cord appears to be maintained both by abnormal activity in the injured peripheral nerve as well as by reorganization of circuits within the spinal cord secondary to the nerve injury.

Anesthetics, Local↗
PubMed1994

Elevated neuronal c-Fos-like immunoreactivity and messenger ribonucleic acid (mRNA) in genetically obese (ob/ob) mice.

Adult genetically obese (ob/ob) mice display a number of metabolic alterations, the primary cause of which may be a defect in their central nervous system (CNS). The protein encoded by the protooncogene c-fos, c-Fos, functions as a nuclear transcription factor, and also serves as a marker of neuronal activity. The specific objectives of this study were (1) to use c-Fos immunohistochemistry to identify regions with altered neuronal activity in 6-7 week old male lean and ob/ob mice; (2) to examine c-fos relative mRNA abundance by northern blot analysis in brains of these mice and compare it with that of neuropeptide Y (NPY), a peptide well known to alter feeding and (3) determine changes in c-Fos immunoreactivity and mRNA caused by food deprivation. Fos-like immunoreactivity (FLI) tended to be higher in ad libitum fed ob/ob mice than in lean controls in most brain regions examined. The most prominent and consistent differences were in the paraventricular nuclei (PVN) where the numbers of Fos-positive nuclei were approximately 3 fold higher in ob/ob mice. Food deprivation for 24 h increased FLI in the PVN in lean mice but did not further augment FLI in the PVN of ob/ob mice. Arcuate nuclei of lean and ob/ob mice showed minimal FLI staining under ad libitum fed conditions. Food deprivation however, induced FLI in arcuate nuclei of both lean and ob/ob mice. The abundance of c-fos mRNA in whole brain of ob/ob mice averaged several fold higher than in leans under both fed and fasted conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

c-fos expression in specific rat brain nuclei after intestinal anaphylaxis: involvement of 5-HT3 receptors and vagal afferent fibers.

The c-fos immediate-early gene is acutely induced in brain after various stimuli from the digestive tract. 5-HT3 receptors and vagal afferents have been found involved in intestinal motor disturbances induced by intestinal anaphylaxis. Our aim was to determine whether intestinal anaphylaxis activates brain structures, using c-fos expression, and to evaluate the modulation of c-fos induction by 5-HT3 receptors and vagal afferents. The effects of antigen challenge on intestinal motility were evaluated in ovalbumin-sensitized Hooded Lister rats chronically fitted with NiCr electrodes in the jejunal wall. Intestinal motility was assessed in conscious rats pretreated or not by perivagal capsaicin or a 5-HT3 antagonist (ondansetron). In sensitized rats, ovalbumin disrupted for 62.4 +/- 9.5 min the jejunal migrating motor complexes (MMC) and an important c-fos expression was detected in the nucleus tractus solitarius (NTS), lateral parabrachial nucleus (LPB) and paraventricular nucleus of the hypothalamus (PVN). Intraperitoneal administration of ondansetron or perivagal capsaicin treatment significantly reduced the duration of MMC disruption and attenuated markedly c-fos staining in the 3 brain sites. In contrast, intracerebroventricular administration of ondansetron significantly reduced jejunal motor alterations but did not diminish the c-fos expression, suggesting a role of central 5-HT3 receptors in the efferent control of the intestinal disturbances. Blockade of both c-fos expression and MMC disruption by systemic ondansetron and by perivagal capsaicin indicates that some brainstem nuclei are involved in digestive disturbances after intestinal anaphylaxis, and reflects an involvement of peripheral 5-HT3 receptors on vagal afferents. The reduction of c-fos staining in NTS as well as in LPB and PVN after perivagal capsaicin suggests that the NTS is the primary relay in the activation of the central nervous system during intestinal allergic challenge.

Afferent Pathways↗
PubMed1996

The effect of adrenalectomy on stress-induced c-fos mRNA expression in the rat brain.

Previously, we determined the pattern of stress-induced c-fos mRNA expression throughout the brain in order to gain further insight into the identification of the neural circuits mediating stress-induced regulation of the hypothalamic-pituitary-adrenal axis. In the present study, we determined if rapid effects of increased glucocorticoid levels after stress contribute to changes in c-fos mRNA expression. To this end, stress-induced c-fos expression was characterized in adrenalectomized (ADX) or adrenalectomized and corticosterone replaced (ADX/B) male rats. Animals were sacrificed 30 min post-onset of a 10 min swim stress, and in situ hybridization histochemistry was used to detect c-fos mRNA throughout the brain. The pattern of c-fos induction in the ADX and ADX/B animals was similar to that observed in the sham operated animals. Additionally, densitometric measurements were made to quantify the c-fos response in the paraventricular nucleus of the hypothalamus and the CA1/2 region of the hippocampus. We found that ADX did not alter the magnitude of the c-fos response to stress in these areas, but there was a slight dampening of the response in ADX/B animals. In sum, these results suggest that the pattern of c-fos expression observed 30 min post-stress is independent of stress-induced increases in circulating glucocorticoid concentrations.

Acute Disease↗
PubMed1996

Neuroanatomical characterization of Fos induction in rat behavioral models of anxiety.

Immunohistochemical staining for Fos-like immunoreactivity (Fos-LI) was used to map functional activation in discrete brain regions of rats processed in three empirical models of anxiety: foot shock avoidance responding in a shuttle box, the elevated plus maze, and an air puff-induced ultrasonic vocalization test. The avoidance test and elevated plus maze induced prominent Fos-LI in select brain regions, including the medial prefrontal, cingulate, and ventrolateral orbital cortices, taenia tecta, nucleus accumbens, paraventricular nucleus of the hypothalamus, medial nucleus of the amygdala and lateral septum. Air puff stimuli that produced ultrasonic vocalizations induced Fos-LI to a more limited extent compared to the plus maze and avoidance test, with only the medial prefrontal cortex, medial nucleus of the amygdala, and lateral septum being significantly affected by air-puff. Even though the sensory stimuli and environmental conditions associated with the three anxiety models were markedly different, specific common forebrain regions were affected, i.e. the medial prefrontal cortex, medial amygdala, and lateral septum. It is hypothesized that these regions are components of a circuit in the rat brain related to anxiety or distress. To determine the potential relationship between generalized arousal and the observed induction of Fos-LI in the anxiety models, rats were tested in a non-aversive situation involving marked behavioral activation. Accordingly, after vigorous bar pressing behavior for reinforcement with sweetened condensed milk, induction of Fos-LI was minimal and comparable to that in unhandled control rats. These latter data indicate that the distinctive neuroanatomical patterns of Fos-LI observed in the paradigms related to anxiety were not simply due to generalized behavioral activation. In summary, select common brain regions were identified that express Fos-LI in empirical models of anxiety. These data provide a functional framework to explore neuroanatomical sites of action of psychotherapeutic drugs that influence behavioral responses in these tasks.

Animals↗
PubMed1996

Ureteral ligation induces Fos expression in the dorsal horn.

To describe a sympathetic afferent circuit, the left ureter was ligated in anesthetized rats for 1.5-2 h followed by immunocytochemical processing to localize expression of either the immediate early gene (IEG) c-fos or Krox-24 in the spinal cord or dorsal root ganglia (DRG). No IEG expression was detected in DRG. Both Fos and Krox-24 expression was found in the dorsal horn. More Fos immunocytochemically stained cells were found in the dorsal horn both ipsi- and and contralateral to the ligated ureter at spinal segments T10-T13 after ureteral than after either sham ligation or anesthesia control procedures. More Fos stained cells were in the dorsal horn ipsilateral to the ligated ureter than on the contralateral side. The Fos staining patterns in the dorsal horn of ligated and sham-ligated animals were similar with most labeled cells in dorsomedial portions of laminae I and II. In contrast, the Fos staining pattern in the dorsal horn in anesthetized animals (unoperated controls) was noticeably different from operated animals with the most Fos cells in the ventrolateral part of laminae I-II. These results indicate that (1) Fos Immunocytochemistry may be useful for tracing sympathetic afferent pathways, (2) the sensory pathway activated by ureteral ligation enters the spinal cord at lower thoracic levels, where renal and upper ureteral afferents are terminating, and (3) some of this sympathetic afferent pathway is located contralateral to the stimulated kidney. Neurons activated by ureteral ligation in the contralateral dorsal horn may mediate reno-renal reflexes.

Afferent Pathways↗
PubMed1996

Alterations in c-fos expression after different experimental procedures of sleep deprivation in the cat.

In the present study, we sought to examine the expression of the c-fos proto-oncogene in the cat brain after two different procedures of 24 h sleep deprivation. A first group of cats was gently sleep-deprived; they were awoken by a gentle touch of the hand (n = 5). A second group was sleep-deprived by the water tank technique which is a stressful deprivation (n = 4). A third group was placed 2 h on the water tank and was therefore stressed but not sleep-deprived (n = 2). A fourth group (control group of basal and unspecific Fos expression) was not sleep-deprived (n = 5). These four groups allowed us to separate Fos expression due to stress from Fos expression due to sleep deprivation. On the one hand, compared with controls cats, an important increase in Fos expression, detected by immunohistochemistry, was observed in the preoptic area of sleep-deprived cats by both gentle and stressful methods. On the other hand, there was a significant increase in Fos expression in the lateral hypothalamus of gently deprived cats as compared with control cats. These data indicate that c-fos expression can be employed as a marker of some putative homeostatic mechanism regulating sleep. The only sites in which there was a significant increased number of c-fos expressing neurons were located in the preoptic area which is known to be involved in sleep and in the lateral hypothalamic area.

Animals↗
PubMed1991

Presence of an estradiol response region in the mouse c-fos oncogene.

We have previously shown that the intracellular content of c-fos mRNA is rapidly induced (within 1 to 3 hours) in ovariectomized rat or mouse uteri following administration of estradiol. This induction is sensitive to actinomycin D but not to protein synthesis inhibitor puromycin, indicating an effect of estradiol at the transcriptional level, possibly mediated by the estrogen receptor. We have used transient transfection assays with defined regions of the mouse c-fos gene ligated to a reporter plasmid expressing chloramphenicol acetyl transferase to study regulation of this gene by estrogens. These recombinants were transfected in two different estrogen-responsive cell lines, GH4 and MCF-7, and stimulated with estradiol. A two- to five-fold induction of chloramphenicol acetyl transferase activity was observed with a construct containing the intact c-fos promoter and 351 bases of 5'-flanking sequence (-351/+44). A similar induction by estrogen is observed with the endogenous c-fos gene in the two cell lines as determined by RNA blot analysis. Estrogen induction is lost when a construct containing -135/+44 region of the c-fos gene is transfected. Plasmid containing the consensus estrogen response element GGTCAnnnTGACC derived from vitellogenin gene is induced 10- to 50-fold in both estrogen-responsive cell lines. Under identical conditions, the oligonucleotide containing the perfect palindrome GGTCTnnnAGACC, present around the -209 region of the c-fos gene, is completely silent when transfected under the control of thymidine kinase promoter. Additional transfection analysis with a number of c-fos promoter constructs has narrowed the estrogen response region to within the -278 to -135 region upstream of the c-fos promoter.

Animals↗
PubMed1994

Role of protein kinase C in ras-mediated fos-expression.

HC-11 mouse mammary epithelial cells stably transfected with a glucocorticoid-inducible Ha-ras construct encoding a transforming (val12) p21Ha-ras were cotransfected with a c-fos-CAT construct containing the human c-fos promoter up to position -711 and the CAT reporter gene. Expression of Ha-ras by dexamethasone leads to a transcriptional activation of the fos-CAT construct which was found to be sensitive to the PKC inhibitor ilmofosine (BM41440) and abrogated by PKC depletion following long-term exposure to TPA. The responsiveness to Ha-ras is retained if only the portion of the fos promoter covering the serum response element (SRE) and the adjacent fos AP-1 (FAP) site are put in front of a CAT gene linked to a thymidine kinase (TK) promoter. Further depletion of the FAP-site does not affect the inducibility by Ha-ras. Transcriptional activation of the SRE-FAP-TK-CAT as well as the SRE-TK-CAT constructs by Ha-ras is sensitive to the PKC-inhibitor ilmofosine (BM41440) and blocked by long-term exposure to TPA. Long-term exposure to TPA depletes cells of PKC alpha and significantly reduces the PKC epsilon levels. Long-term exposure in bryostatin 1 selectively depletes PKC alpha. Depletion of PKC alpha by bryostatin 1 does not reduce the transcriptional activation of the SRE-FAP-TK-CAT-construct by Ha-ras. It is concluded that (i) transforming Ha-ras induces c-fos in HC-11 cells via PKC (presumably epsilon), (ii) the signal is mediated to the serum response element (SRE) of the fos promoter and (iii) the fos AP-1 (FAP) site is not required for this mechanism.

Animals↗
PubMed1996

Interactions between D1 and muscarinic receptors in the induction of striatal c-fos in rats depleted of dopamine as neonates.

The contributions of striatal D1 receptors to the expression of sensorimotor behavior are qualitatively different in rats depleted of dopamine (DA) as neonates vs. as adults. In an effort to reveal neuronal mechanisms underlying these behavioral difference we determined the effects of the partial D1 agonist SKF 38393, the muscarinic antagonist scopolamine, and the combination of the two drugs on the induction of c-fos in the striatum and its projection sites, the globus pallidus and substantia nigra. Adult rats, given intracerebroventricular injections of 6-hydroxydopamine (6-OHDA, 50 micrograms/5 microliters/hemisphere) or its vehicle on postnatal day 3, were treated with SKF 38393 (1.5 mg/kg, i.p.), scopolamine (5.0 mg/kg, i.p.) or the combination of the two drugs. There was no significant induction of c-fos in vehicle-treated controls, regardless of drug administration. In DA-depleted rats, scopolamine also did not induce c-fos whereas SKF 38393 produced a significant increases in the number of FOS-positive cells in the dorsal, but not ventral, striatum. The combined administration of scopolamine and SKF 38393 resulted in a potent synergism in the number of FOS-positive cells in DA-depleted rats. These interactions between lesion condition and drugs on c-fos induction were not secondary to differences in drug-induced behavioral activity. Activity levels were no different in vehicle vs. DA-depleted rats following the combined administration of scopolamine + SKF 38393, yet the two groups of rats exhibited marked differences in the density of FOS-positive striatal neurons. The effects of scopolamine and SKF 38393 on c-fos induction in striatum are qualitatively similar to those reported in rats DA-depleted as adults and suggest that, at this single-label level of analysis, the ability of D1 and muscarinic receptors to influence striatal activity does not contribute to the marked age-related differences in the behavioral effects of DA depletions.

Animals↗
PubMed1992

Protein kinase C-independent activation of c-jun and c-fos transcription by epidermal growth factor.

Phorbol esters, epidermal growth factor (EGF) and serum induce the transient expression of the c-jun and c-fos proto-oncogenes in quiescent fibroblasts. While phorbol esters such as phorbol 12-myristate 13-acetate (PMA) are thought to induce the transcription of these genes by activating protein kinase C (PKC), the signal transduction pathway(s) mediating the effects of EGF and serum are still unclear. We have investigated whether PKC and/or calcium play a role in mediating EGF-stimulated c-jun and c-fos RNA and protein expression in quiescent NIH 3T3 fibroblasts. PMA, EGF or serum stimulated a rapid, transient increase in c-jun and c-fos expression and cJun protein synthesis in quiescent NIH 3T3 cells. Depletion of whole cell PKC activity by pretreatment with PMA abolished any subsequent response to PMA, but had no effect on the ability of EGF or serum to induce c-jun and c-fos RNA and cJun protein expression. Nuclear run-on analysis indicated that EGF-induced gene expression was due to an increase in the rate of transcription of c-jun and c-fos in both naive and PKC-depleted cells. The role of calcium in the EGF-induced expression of c-jun and c-fos was also investigated using an NIH 3T3 cell line (HER-14) overexpressing the wild type human EGF receptor. Removal of extracellular calcium by chelation with excess EGTA or use of the non-specific calcium channel blocker lanthanide, both of which abolish the EGF-induced calcium transient in HER-14 cells, had no effect on the PMA or EGF induced c-jun or c-fos response. These findings suggest that EGF induces c-jun and c-fos transcription and cJun protein synthesis in a manner independent of an increase in intracellular calcium or activation of PKC in quiescent NIH 3T3 cells.

3T3 Cells↗