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PubMed1997

Fos expression in the rat parabrachial and Kölliker-Fuse nuclei after electrical stimulation of the trigeminal ethmoidal nerve and water stimulation of the nasal mucosa.

The present study examined the location of neurons in the lateral parabrachial nucleus (PBL), Kölliker-Fuse nucleus (KF), nucleus of the solitary tract (NTS), spinal trigeminal nucleus (Sp5C) and upper cervical cord possibly involved in the transmission of autonomic responses (apnea, bradycardia and rise in arterial blood pressure) elicited by nasotrigeminal stimulation in the rat. To identify these neurons we employed immunocytochemical detection of the transcription factor Fos. To induce the expression of Fos protein, two kinds of stimuli and experimental controls were performed in chloralose/urethane-anesthetized animals: (i) electrical stimulation of the trigeminal ethmoidal nerve (EN5) and, as sham controls, dissection of the EN5 without electrical stimulation, (ii) stimulation of the nasal mucosa with water and, as control experiments, no stimulation. Both forms of stimulation lead to a consistent pattern of Fos-positive neurons in the PBL and KF. Differences could be observed rostrally in the PBL and KF, where significantly higher numbers of Fos-positive neurons were present after EN5 versus water stimulation. The EN5-stimulated group had a significantly higher number of Fos-immunoreactive neurons in the KF than the sham controls, especially in the midlevel region. In the PBL significant differences in the numbers of activated cells could be observed between EN5-stimulated versus sham controls. In the water-stimulated rats compared with the anesthesia controls, a significantly higher number of Fos-immunoreactive neurons was always observed at all rostrocaudal levels in the KF and in the midlevel PBL. Electrical EN5 stimulation induced Fos expression in the Sp5C at the level of the area postrema and caudally in the upper cervical cord. In contrast, after water stimulation Fos-positive neurons were exclusively found in the Sp5C. In addition, all forms of stimuli and controls induced strong expression of Fos in the medial and commissural NTS. Linear correlations were found between the numbers of Fos-immunoreactive neurons in the Sp5C versus the KF and the NTS versus the PBL. The activated neurons may belong to two functionally discrete pathways: the nasotrigeminal reflex circuit, which is activated by nasal sensory afferents running through the EN5 via the Sp5C to the KF, and a pathway activated most likely by baro- and chemoreceptor afferents running through the NTS to the PBL. Our results indicate that the PB/KF plays a pivotal role in the mediation and maintenance of the autonomic responses induced by the nasotrigeminal reflex.

Animals↗
PubMed1998

The corticostriatal system mediates the "paradoxical" contraversive rotation but not the striatal hyperexpression of Fos induced by amphetamine early after 6-hydroxydopamine lesion of the nigrostriatal pathway.

In rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway, amphetamine produces ipsiversive rotational behavior and activation of Fos in the intact striatum, but practically no activation of Fos in the denervated striatum. However, a seemingly paradoxical contraversive rotation, accompanied by intense striatal Fos activation in the lesioned striatum, has been observed during the first few days postlesion. In the present work, behavioral tests and immunohistochemistry for Fos protein and tyrosine hydroxylase (TH) were combined to study striatal changes 36 h after 6-OHDA lesion and particularly the possible involvement of glutamatergic corticostriatal afferents. Injection of amphetamine (0.5 mg/kg or 5 mg/kg) induced contraversive rotation and strong and evenly distributed Fos expression in the lesioned striatum; in the contralateral striatum, however, Fos density was lower than in nonlesioned rats. Pretreatment with the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801 (either 0.5 mg/kg or 5 mg/kg) did not significantly affect the hyperexpression of Fos in the lesioned striatum, but suppressed the contraversive rotation. Similarly, rats that were subjected to corticostriatal deafferentation (confirmed by sensory neglect tests) and 6-OHDA lesion (1 week or 3 weeks later) showed no significant reduction in the striatal Fos hyperexpression induced by amphetamine (0.5 mg/kg or 5 mg/kg) and no significant rotational asymmetry. In conclusion, the present results indicate that glutamatergic corticostriatal afferents are essential for the contraversive rotational behavior but not the striatal hyperexpression of Fos observed in response to amphetamine early after 6-OHDA lesion, and suggest that intense dopaminergic stimulation of striatal neurons is sufficient for induction of Fos, but that concurrent glutamatergic stimulation is necessary for the motor response.

Afferent Pathways↗
PubMed1993

Autonomic areas of rat brain exhibit increased Fos-like immunoreactivity during opiate withdrawal in rats.

We sought to identify the brain areas that might contribute to the increased autonomic activity seen during morphine withdrawal by mapping neuronal expression of c-fos protein (Fos) and Fos-related antigens. Rats were implanted with morphine pellets or placebo pellets over a 5 day regimen and injected on day 6 with either saline or naltrexone (100 mg/kg). After a standard PAP immunocytochemical protocol, Fos-like immunoreactivity (Fos-LIR) was observed in medullary nuclei including the NTS (nucleus of the solitary tract), caudal (CVL) and rostral ventrolateral medulla (RVL). Although some Fos-LIR was seen in these areas in control rats (either morphine-implanted, saline injected, or placebo-implanted, saline or naltrexone injected), a significantly higher number of Fos-LIR-positive cells in NTS, CVL and RVL were seen after morphine withdrawal. Large numbers of Fos-like immunoreactive cells were also seen in the A5 area, the parabrachial nuclei of the pons and the locus coeruleus. Increased Fos-LIR was also detected in the paraventricular nucleus of the hypothalamus and the amygdala of morphine withdrawn rats. The Fos-LIR was co-localized with tyrosine hydroxylase immunoreactivity in many of the cells in caudal and rostral ventrolateral medulla, A5 and locus coeruleus. These data support the conclusion that autonomic areas in brain and noradrenergic/adrenergic cells in these areas are activated during morphine withdrawal and may contribute to the autonomic symptoms of opiate withdrawal.

Animals↗
PubMed1994

2-Mercaptoacetate and 2-deoxy-D-glucose induce Fos-like immunoreactivity in rat brain.

2-Deoxy-D-glucose (2-DG) and 2-mercaptoacetate (MA) are antimetabolic drugs that selectively antagonize glucose and fatty acid utilization, respectively, and stimulate feeding. Fos immunohistochemistry was employed to identify brain neurons activated by these drugs and to assess the role of the vagus nerve in the drug effects. Remote intravenous infusions of both MA and 2-DG induced Fos-like immunoreactivity (Fos-li) in specific brain sites, but the pattern was different for the two drugs. Mercaptoacetate induced Fos-li in the nucleus of the solitary tract (NTS), the central subnucleus of the lateral parabrachial nucleus (1PBN), the central nucleus of the amygdala (CNA, lateral part) and the dorsal motor nucleus of the vagus (DMV). Induction of Fos-li in the brain by MA was totally abolished by vagotomy. 2-Deoxy-D-glucose also induced Fos-li in the NTS, CNA (lateral part) and DMV, as well as in the external 1PBN subnucleus, locus coeruleus, paraventricular and supraoptic hypothalamic nuclei, and in scattered cells throughout the diencephalon. Induction of Fos-li by 2-DG was not blocked by vagotomy. Results suggest that 2-DG's effects on Fos-li are mediated by a direct central action, whereas MA's effects are mediated by peripheral sensory neurons. Thus, availability of glucose and fatty acids influences the activity of specific brain sites by different neural mechanisms. The correlation of Fos-immunoreactive sites with sites where lesions have been shown to cause deficits in MA- and 2-DG-induced feeding indicates that c-fos expression defines in part the central pathways involved in the metabolic control of feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Prolonged induction of c-fos in neuropeptide Y- and somatostatin-immunoreactive neurons of the rat dentate gyrus after electroconvulsive stimulation.

Induction of c-fos mRNA and Fos was studied in the hilus and granular layer of the dentate gyrus at various times up to 24 h after single electroconvulsive stimulation (ECS) using in situ hybridization and immunocytochemistry. In both areas of the dentate gyrus, a prominent induction of c-fos mRNA and Fos was observed. Compared to the granular layer, however, c-fos mRNA and Fos in hilar cells reached maximum later and remained elevated considerably longer. Several neurochemically distinct populations of hilar neurons have been described, some of which contain neuropeptide Y (NPY) and/or somatostatin (SS). Using double-labelling immunocytochemistry, we examined to what extent Fos was induced in these hilar neurons after ECS. Although a minor population of non-NPY non-SS cells displayed Fos induction early after ECS, prolonged induction of Fos almost exclusively occurred in NPY or SS neurons. The Fos-immunoreactive NPY or SS neurons only amounted to about 50% of the total hilar population of NPY or SS neurons. The present observations suggest that a subpopulation of hilar NPY and SS neurons may be central to the actions of electroconvulsive seizures in the dentate gyrus.

Animals↗
PubMed1996

Effect of chronic dexfenfluramine on Fos in rat brain.

The acute appetite suppressant effect of dexfenfluramine (DF) in rats, which may depend upon its action to release serotonin (5-HT) in the brain, often declines with repeated dosing (tolerance). The mechanisms of this tolerance remain unclear. Previously, we used Fos-like immunoreactivity (Fos-IR) to map potential brain sites activated by single injections of DF in rats. A dose of 5 mg DF/kg activated the central amygdala (CeA), bed nucleus of the stria terminalis (BST), caudate-putamen (CPu), lateral parabrachial nucleus (LPB), nucleus tractus solitarius (NST), frontal cerebral cortex and the parvocellular paraventricular hypothalamic nucleus (PVN). We now report studies using Fos-IR in an attempt to understand which regions might underlie tolerance to the action of DF. Pretreatment of rats with an escalating dosage regimen of DF (0.5-4 mg/kg, i.p.) was associated with complete loss of Fos-IR to a probe dose (5 mg DF/kg) in the cortex, CPu, PVN and NTS, and partial loss of Fos-IR in the BST, CeA and LPB. Second, repeated treatment with DF (2 mg/kg), which has been shown to produce tolerance the anorexia caused by DF but not cholecystokinin (CCK), likewise reduced Fos-IR induced in the above brain regions, but had no effect on Fos-IR induced by either CCK or the 5-HT agonist, 5-carboxamidotryptamine. Third, repeated treatment with 5-HT (2 mg/kg, s.c.) had no effect on Fos-IR induced by a probe dose of DF. These data show that regionally heterogeneous hyporesponsiveness to the induction of Fos by DF develops after repeated low doses of DF; however, the Fos response to other putative anorectics or weight reducing agents is not affected. This may be related to behavioral tolerance.

Animals↗
PubMed1994

Effects of opioids and non-opioids on c-Fos-like immunoreactivity induced in rat lumbar spinal cord neurons by noxious heat stimulation.

This study evaluated Fos-like immunoreactivity in rat lumbar spinal cord neurons following peripheral noxious heat stimulation and the modifications induced by pharmacological agents. Under urethane anaesthesia, the hindpaw was stimulated by dipping it in a regulated temperature bath at various temperatures (44-65 degrees C) and for various durations (5 s to 2 min). There was no Fos-like immunoreactivity in lumbar spinal cord neurons when the paw was stimulated at 44 degrees C for 15 s. From 46 to 52 degrees C, the number of Fos-like immunoreactivity neurons increased with increasing stimulation temperature, but was decreased at 65 degrees C as compared to 52 degrees C. At 52 degrees C, the number of Fos-like immunoreactivity neurons increased with the duration of stimulation. Fos-like immunoreactive neurons in the L4 segment were almost exclusively located in laminae I-II. On the basis of the results of the latter experiments, we chose a stimulation of 52 degrees C for 15 s to perform pharmacological investigations. The number of Fos-like immunoreactive neurons induced by the heat stimulation was significantly decreased by pretreatment with morphine (42, 64 and 75% decrease as compared to control values after 2.5, 5 and 7.5 mg/kg i.v. respectively), and these effects were blocked by naloxone. When various stimulation intensities (46-52 degrees C) were used, the effects of morphine (5 mg/kg i.v.) were most marked when the temperature was highest. In morphine-tolerant rats, morphine (5 mg/kg i.v.) was half as potent in decreasing Fos-like immunoreactivity induced by the heat stimulation than in non-tolerant rats. RB 101, a systemically active mixed inhibitor of enkephalin-metabolising enzymes, significantly decreased Fos-like immunoreactivity induced by heat stimulation (19, 29 and 48% decreases as compared to control values at 10, 20 and 40 mg/kg i.v. respectively) and these effects were blocked by naloxone. Aspirin (150 mg/kg i.v.), proacetaminophen (300 mg/kg i.v.) and tizanidine, a centrally acting myorelaxant (0.25-1 mg/kg i.v.), had no effect on the number of Fos-like immunoreactivity neurons induced by heat stimulation. The use of immunochemistry of the c-Fos protein as a pharmacological test in order to gauge antinociceptive effects at the dorsal horn level is discussed.

Analgesia↗
PubMed1996

Effects of cellular aging on the induction of c-fos by antioxidant treatments.

The proto-oncogene c-fos (the cellular homolog of v-fos, Finkel-Biskis-Jenkins (FBJ) murine osteogenic sarcoma virus) encodes a major component of the activator protein-1 (AP-1) transcription factor. Serum stimulation as well as oxidizing treatments induce transitory increases in c-fos mRNA abundance. The induction of c-fos by serum stimulation is also known to decline during proliferative senesence. In this study, we examined the effects of two classes of antioxidants on the induction of c-fos in early and late passage human fetal lung fibroblasts (WI-38). N-acetyl cysteine (NAC) induces c-fos transcription in both early and late passage cells, while nordihydroguaiaretic acid (NGA) induced c-fos transcription in early passage cells but fails to stimulate it in late passage cells. Since we had previously observed an age-related decline in protein kinase C (PKC) translocation from the cytosol to the membrane, following its activation, and because PKC activation appears to be involved in the NGA induction of c-fos we examined the relative protein abundances of several PKC isoforms in early and late passage cells. Additionally, we examined the protein abundance of several members of the MAP kinase pathway which could play a role in c-fos induction by the PKC-dependent pathway. We were unable to detect PKC-beta or theta in early or late passage cells. Late passage cells contained a slightly greater abundance of PKC alpha, gamma and epsilon than cells at an early passage. No other differences in PKC isoforms or in members of the MAP kinase family were observed in early or late passage cells. These results clearly demonstrate that at least some pathways leading to c-fos induction remain intact in late passage cells. While we were unable to detect any decreases in PKC isoforms or MAP kinase proteins we cannot exclude the possibility that functional decrements accumulate in these proteins during senesence.

Aging↗
PubMed1996

Expression of Fos protein in various rat brain areas following acute nicotine and diazepam.

We studied the effects of an acute dose of (-)-nicotine (1 mg/kg) on Fos-like immunostaining (IS) in rat brain areas. Nicotine increased Fos IS significantly in the medial terminal nucleus of accessory optic tract (MT), and tended to increase it in the interpeduncular nucleus (i.p.), as well as in the stress-related areas, the paraventricular hypothalamic nucleus (PVN) and the supraoptic nucleus (SON). Previously nicotine was reported to increase Fos IS also in another stress-related area, the central nucleus of amygdala (ACe). This led us to study the interaction of nicotine with diazepam (10 mg/kg). Diazepam alone increased Fos IS in PVN and in SON as well as in ACe. In diazepam- and nicotine-treated rats Fos IS was increased in PVN and SON as well as in MT and i.p.. In MT and i.p. of diazepam and nicotine-treated rats Fos IS was similar to that induced by nicotine alone, and in PVN and SON of these rats Fos IS in ACe. Taken together, diazepam induced Fos IS in all stress-related areas studied (PVN, SON, ACe), but not in central visual structures, where nicotine induces Fos IS (MT, i.p.). No significant interactions on Fos expression were found between acute effects of diazepam and nicotine suggesting that these drugs activate different sets of neurons within the stress-related brain areas.

Amino Acid Sequence↗
PubMed1993

Diurnal expression of c-fos in the mouse retina.

The diurnal levels of c-fos mRNA were studied in the mouse retinas by means of RNA blot analysis. Mice were kept on a 12/12 h dark/light cycle and gene expression was studied at various time points during the day and night periods. The highest levels of c-fos mRNA were measured during the first half of the night period. The high levels persisted for about 4-5 h. The c-fos mRNA levels declined during the second half of the night period and remained low during the day period. Continuous illumination of mice during the first hours of the night period prevented the increase in c-fos mRNA. If mice were kept in the dark during the day period, they failed to show an increase in c-fos mRNA levels in the subsequent night period. Hence, following activation of c-fos during the night period, a refractory period exists at which illumination is required before c-fos can be induced again by dark. Although light appears to suppress the activation of c-fos in the night period, a short lived burst in c-fos expression of 30-60 min in duration was observed when dark-adapted animals were illuminated, either at the transition between the dark and light period or during the dark period. Thus, it appears that c-fos is activated in at least two different cell types in the retina which respond differently to light and dark stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Time course of phosphorylated CREB and Fos-like immunoreactivity in the hypothalamic supraoptic nucleus after salt loading.

Phosphorylation of the cAMP response element binding protein (CREB) precedes the induction of immediate early gene expression. Using antibodies that distinguish CREB from phosphorylated CREB (PCREB), we studied the appearance of PCREB-like immunoreactivity (PCREB-LI) and Fos-LI in the hypothalamic supraoptic nucleus (SON) of rats treated with hypertonic or normal saline and uninjected controls. Fifteen minutes after injection, increased numbers of PCREB-LI cells were seen in both normal and hypertonic saline-treated rats as compared with uninjected controls. Forty-five minutes after injection, levels of c-fos mRNA in the SON were elevated in hypertonic saline-treated rats as compared with normal saline-treated rats, and were minimally detectable in uninjected rats. At this time period, the hypertonic saline-treated rats showed increased number of Fos-LI cells in the SON, whereas normal saline-treated rats showed little or no Fos-LI cells. The discrepancy between levels of PCREB-LI and c-fos mRNA suggests that injection of hypertonic saline may activate additional transcriptional factors besides CREB. The lack of Fos-LI in the presence of modest increases in c-fos mRNA in normal saline-treated rats implies that levels of c-fos mRNA must exceed a threshold before increases in Fos-LI cells are detectable by immunostaining of the SON. Such a threshold might permit neuronal cells to activate diverse genes, through phosphorylation of CREB, without inducing the constellation of Fos-responsive genes.

Animals↗
PubMed1995

Dopaminergic control of gene transcription during striatal ontogeny: c-fos induction by D1 receptor activation in the developing striosomes.

During striatal development, dopamine afferents initially reach the striosomal compartment, and this early dopamine innervation is thought to influence, through the D1 receptors first expressed in the developing patches, the phenotype of target striatal cells. Dopaminergic control of gene expression during ontogeny could be mediated by transcription factors such as c-fos, whose expression is regulated by synaptic signals. However, in the striatum of intact adult animals, D1 dopamine agonists fail to induce c-fos expression. The c-fos response to D1 receptor activation in adults requires a previous sensitization of dopaminergic receptors by chronic treatment with reserpine or by lesion of the nigro-striatal pathway. In this work, we investigated through in situ hybridization the ability of striatal cells to express c-fos messenger RNA (mRNA) in response to the D1 agonist SKF 38393 (4 to 8 mg/kg) in developing mice. During a transient postnatal period, c-fos expression in a patchy distribution was induced by D1 receptor activation: only a faint response was detected on postnatal day 1, but islands of strong hybridization signals for c-fos mRNA in response to the D1 agonist were observed at postnatal day 3, with a progressive decrease in intensity from day 6 to day 15. The distribution of this transient c-fos response corresponded to the early striosomal compartment since it matched with the regions of intense mu-opioid and dopamine-D1 receptor binding, as assessed by autoradiography performed on adjacent sections. By day 21, as in adult animals, no more c-fos response to D1 agonists was observed, except in the most caudal division of the striatum. Strong expression, which persisted into adulthood, was detected in this region from the third postnatal day. This induction of striatal c-fos expression by D1 agonists during early postnatal development is indicative of an enhanced sensitivity of D1 receptors or of D1-associated transduction pathways compared to the adult pattern, and suggests a possible role for dopamine-controlled c-fos gene expression in the development of target striatal neurons during this critical period.

Animals↗
PubMed1993

Effects of morphine and naloxone on basal and evoked Fos-like immunoreactivity in lumbar spinal cord neurons of arthritic rats.

We have previously shown, on the one hand, that the number of Fos-like immunoreactive (Fos-LI) neurons in the lumbar spinal cord observed during the development of adjuvant-induced arthritis in the rat correlates with the clinical and behavioral scores and, on the other hand, that the number of Fos-LI neurons induced by repeated mechanical pressure to the ankle was greater in arthritic animals than in healthy ones. In non-stimulated arthritic rats, Fos-LI neurons were mainly present in the neck of the dorsal horn and in the ventral horn of L3-L5, whereas following stimulation they were numerous in the superficial laminae. The aim of this study was to evaluate Fos-LI following morphine injection (1) in arthritic animals in the absence of any stimulation, (2) in arthritic rats after ankle stimulation pretreated with morphine or by the combination of morphine and naloxone, and (3) following naloxone treatment in non-stimulated and stimulated polyarthritic rats. In non-stimulated arthritic rats, a single morphine injection (1-9 mg/kg, i.v.) or a single naloxone injection (1-3 mg/kg, i.v.) induced no change in the basal Fos-LI present in lumbar spinal neurons. In contrast, Fos-LI evoked by noxious pressure was strongly depressed by morphine. In the superficial laminae pretreatment with a single morphine injection of either 0.5 or 1 mg/kg, i.v., reduced by more than 50% the number of Fos-LI neurons and at 3 mg/kg completely abolished the labeling evoked by the stimulation. Similar effects were obtained in the neck of the dorsal horn. These effects were reversed by naloxone (morphine 3 mg/kg and naloxone 0.3 mg/kg). Pretreatment with naloxone (1 mg/kg) did not change Fos labeling. This study which is based on mechanical stimulation in arthritic rats confirms and extends previous investigations and demonstrates that the use of Fos-LI is a suitable method to reveal the efficacy of opioid analgesic. However, the lack of effects of opioids on basal labeling suggests that long-term drug treatment should be used to study the effects of various putative analgesics on chronic pain models.

Animals↗
PubMed1996

Enhanced effects of co-administered dexamethasone and diclofenac on inflammatory pain processing and associated spinal c-Fos expression in the rat.

This study determines the effects of dexamethasone versus co-administered dexamethasone and diclofenac, on carrageenan-evoked spinal c-Fos expression and peripheral oedema in the freely moving rat. Drugs were administered intravenously 25 min before intraplantar injection of carrageenan (6 mg/150 microliters of saline). Three hours later the number of spinal c-Fos-LI neurones and peripheral oedema were assessed. The total number of control carrageenan-evoked c-Fos-LI neurones in the lumbar spinal cord was 121 +/- 5 labelled neurones per section, segments L4-L5, which were predominantly located in the superficial and deep laminae (41 +/- 3% and 40 +/- 2% of the total number of c-Fos-LI neurones per section, respectively) of the dorsal horn of the spinal cord. Pre-administered dexamethasone (0.05, 0.10 and 0.50 mg/kg i.v.) dose-dependently reduced the total number of c-Fos-LI neurones (30 +/- 4%, 52 +/- 3% and 58 +/- 2% reduction, respectively), with effects of the higher doses being strongest on the deep laminae c-Fos-LI neurones. The effects of dexamethasone on the total number of c-Fos-LI neurones and the peripheral oedema were positively correlated. Co-administration of low doses of dexamethasone and diclofenac (0.025 + 1.5 mg/kg i.v. respectively), which had negligible effects when administered separately, greatly reduced both the total number of carrageenan-evoked c-Fos-LI neurones (61 +/- 5% reduction as compared to control value) and the peripheral oedema (80 +/- 8% and 60 +/- 5% reduction for ankle and paw oedema, respectively). The attenuation by co-administered dexamethasone and diclofenac, of both c-Fos expression and the peripheral oedema, was significantly greater than the effect of dexamethasone alone (P < 0.001 for both) and diclofenac alone (P < 0.001 for both). Our study illustrates enhanced attenuating effects of co-administered dexamethasone and diclofenac on both inflammatory oedema and the associated spinal expression of c-Fos, an indicator of nociceptive transmission at the spinal level. The apparent interactions between the mechanisms of action of NSAIDs and steroids suggest that co-therapy may produce beneficial inflammatory and pain relief in the absence of excessive side effects.

Animals↗
PubMed1992

Increased expression of c-fos in the medial preoptic area after mating in male rats: role of afferent inputs from the medial amygdala and midbrain central tegmental field.

Immunocytochemical methods were used to localize the protein product of the immediate-early gene, c-fos, in male rats after exposure to, or direct physical interaction with, oestrous females. Increasing amounts of physical contact with a female, with resultant olfactory-vomeronasal and/or genital-somatosensory inputs, caused corresponding increments in c-fos expression in the medial preoptic area, the caudal part of the bed nucleus of the stria terminalis, the medial amygdala, and the midbrain central tegmental field. Males bearing unilateral electrothermal lesions of the olfactory peduncle showed a significant reduction in c-fos expression in the ipsilateral medial amygdala, but not in other structures, provided their coital interaction with oestrous females was restricted to mount-thrust and occasional intromissive patterns due to repeated application of lidocaine anaesthetic to the penis. No such lateralization of c-fos expression occurred in other males with unilateral olfactory lesions which were allowed to intromit and ejaculate with a female. These results suggest that olfactory inputs, possibly of vomeronasal origin, contribute to the activation of c-fos in the medial amygdala. However, lesion-induced deficits in this type of afferent input to the nervous system appear to be readily compensated for by the genital somatosensory input derived from repeated intromissions. Unilateral excitotoxic lesions of the medial preoptic area, made by infusing quinolinic acid, failed to reduce c-fos expression in the ipsilateral or contralateral medial amygdala or central tegmental field following ejaculation. By contrast, combined, unilateral excitotoxic lesions of the medial amygdala and the central tegmental field significantly reduced c-fos expression in the ipsilateral bed nucleus of the stria terminalis and medial preoptic area after mating; no such asymmetry in c-fos expression occurred when lesions were restricted to either the medial amygdala or central tegmental field. This suggests that afferent inputs from the central tegmental field (probably of genital-somatosensory origin) and from the medial amygdala (probably of olfactory-vomeronasal origin) interact to promote cellular activity, and the resultant induction of c-fos, in the ipsilateral bed nucleus of the stria terminalis and medial preoptic area. The monitoring of neuronal c-fos expression provides an effective means of studying the role of sensory factors in governing the activity of integrated neural structures which control the expression of a complex social behaviour.

Amygdala↗
PubMed1995

Acute injection of adrenal steroids reduces cornea-evoked expression of c-fos within the spinal trigeminal nucleus of adrenalectomized rats.

The influence of transient increases in adrenal steroid hormones on the number of Fos-positive neurons after nociceptor activation was assessed in adrenalectomized rats. Fos protein, the product of the immediate early gene, c-fos, was detected immunocytochemically within the spinal trigeminal nucleus 2 h after noxious thermal stimulation of the cornea. Adrenalectomized rats displayed an enhanced number of Fos-positive neurons within the caudal-most portions of trigeminal subnucleus caudalis compared to that seen in adrenal-intact animals, an effect reversed by a single acute injection of corticosterone (1 mg/kg, i.p.) given 5 min prior to stimulation. Acute injection of the selective mineralocorticoid receptor agonist, aldosterone, or the selective glucocorticoid receptor agonist, RU28362, also reduced the number of Fos-positive neurons. Aldosterone and RU28362 had an additive effect on Fos when given concurrently. In contrast, adrenal status or acute injections of adrenal steroid receptor agonists had no effect on the number of Fos-positive neurons after corneal stimulation located within the ventrolateral pole of the spinal trigeminal nucleus at the level of the subnucleus interpolaris/caudalis junction. Acute administration of adrenal steroids to adrenalectomized rats greatly attenuated the number of Fos-positive neurons seen after corneal stimulation within select portions of trigeminal subnucleus caudalis. The contribution of both glucocorticoid and mineralocorticoid receptor subtypes in reducing Fos suggested a central site of action rather than an anti-inflammatory effect on peripheral tissue. These results are consistent with the hypothesis that transient increases in adrenal steroids, such as occur after injury, are sufficient to modify the production of Fos protein in central neurons that process nociceptive information.

Adrenal Cortex Hormones↗
PubMed1994

Increase of c-fos and ras oncoproteins in the denervated neuropil of the rat dentate gyrus.

When the entorhinal cortical input to the rat dentate gyrus is destroyed, the process of sprouting and synaptogenesis begins within the denervated dendritic laminae. The present study used immunohistochemical methods to determine whether there was an increase in the oncoproteins c-fos and ras within the denervated neuropil of the dentate gyrus during this period of terminal growth and synapse formation. Animals were prepared for immunolabeling one, three, six and 30 days after unilateral lesion of the entorhinal cortex. Rats were perfused with paraformaldehyde fixative and brain sections were incubated with antibodies to either c-fos or ras oncoprotein. Qualitative light microscopic analysis showed a marked increase in both c-fos and ras proteins over the denervated zone at three days postlesion when compared to both the intact contralateral control and the naive control. At one- and six-day postlesion intervals there was also an increase in labeling over the denervated neuropil with each oncoprotein; however, the intensity of label was reduced relative to that of the three-day time interval. No increase in labeling over the denervated zone was visible for either antibody at 30 days postlesion. The high level of both c-fos and ras labeling in the denervated molecular layer was confirmed with Western blot analysis of dissected molecular layers from lesioned and contralateral control hippocampi. Controls for antibody and method specificity showed that the labeling was specific for c-fos and ras proteins. The high level of c-fos labeling over the denervated molecular layer was uniform with scattered punctate sites of reaction product interspersed in the neuropil. Glial cell bodies in the neuropil contained the highest levels of c-fos oncoprotein. The granule cell nuclei showed an apparent reduction in the level of c-fos labeling at one, three and six days postlesion when compared with the nuclear staining of naive control cases. At 30 days postlesion, high levels of labeling over the denervated zone were not visible and c-fos localization had returned to the typical predominant nuclear sites seen in controls. Ras oncoprotein localization was diffuse in the cell processes of the molecular layer, with intermittent glial labeling within the denervated zone. No cell nuclei labeling was observed with antibodies to ras protein. These results show that both c-fos and ras oncoproteins are increased within the denervated neuropil of the dentate gyrus during sprouting and synapse formation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

D1 dopamine receptor agonist-induced Fos-like immunoreactivity occurs in basal forebrain and mesopontine tegmentum cholinergic neurons and striatal neurons immunoreactive for neuropeptide Y.

The present study sought to determine whether the D1 dopamine receptor agonist CY 208-243 increases Fos-like immunoreactivity in neurochemically distinct populations of interneurons in the 6-hydroxydopamine-denervated striatum. In vivo microdialysis studies indicate that cholinergic interneurons in the striatum are excited by the administration of CY 208-243 and that this effect is potentiated by dopaminergic deafferentation. Since Fos is considered to be a marker of neuronal activity, we examined the overlap between CY-208-243-induced Fos-like immunoreactivity and striatal cholinergic interneurons labelled with the cholinergic marker enzyme choline acetyltransferase. Unexpectedly, cholinergic interneurons in the striatum were not found to express Fos-like immunoreactivity. However, D1 agonist-induced Fos-like immunoreactivity was found in neurons immunoreactive for neuropeptide Y. Consequently, the failure of cholinergic neurons in the striatum to express D1 agonist-induced Fos-like immunoreactivity does not appear to be a general property of striatal interneurons. Indeed, CY 208-243 increased Fos-like immunoreactivity in choline-acetyltransferase-positive neurons in the basal forebrain and lateral dorsal tegmental nucleus. In the case of cholinergic basal forebrain neurons, administration of CY 208-243 has been shown to enhance the release of acetylcholine from their terminals located in the frontal cortex. Thus, unlike cholinergic interneurons in the striatum, the expression of Fos-like immunoreactivity in cholinergic basal forebrain neurons is correlated with an increase in transmitter release. Choline acetyltransferase immunoreactivity was markedly reduced in cholinergic basal forebrain neurons ipsilateral to the 6-hydroxydopamine lesion. This decrease in choline acetyltransferase immunoreactivity was confined to a pocket of cortically projecting neurons located in the posterior part of the horizontal limb of the diagonal band which included the medial preoptic nucleus. Interestingly, D1 agonist-induced Fos-like immunoreactivity was located predominantly in those cholinergic neurons which displayed depressed choline acetyltransferase immunoreactivity. Since Fos is often induced as a consequence of increased activity, it is tempting to speculate that those neurons which stained weakly for choline acetyltransferase had been excited by the D1 agonist administration. Accordingly, the destruction of mesencephalic dopaminergic neurons with 6-hydroxydopamine may have deprived these cholinergic neurons of an excitatory D1 receptor-mediated drive, resulting in a reduction of choline acetyltransferase immunoreactivity. These results suggest that the degeneration of nigrostriatal dopamine neurons may contribute to the loss of cholinergic basal forebrain function in Parkinson's disease.

Acetylcholine↗