Changes In c-Fos Expression Research Articles

Long-term changes of c-Fos expression in the rat spinal cord following chronic constriction injury

The expression of c-Fos protein has been used as a relative marker of nociceptive neuronal activity in the spinal cord following various noxious stimuli. Experiments were conducted to examine c-Fos expression in lumbar spinal cord (L3–L6) following chronic constriction injury (CCI) in relation to nociceptive behavior over longer survival period up to 28 days. Development of mechanical allodynia was observed in the ipsilateral hind paw of CCI rats at day 3 and lasted up to 28 days. In contrast, the spinal c-Fos expression in CCI rats appeared in a biphasic manner. The highest number of c-Fos positive neurons occurred during the first week, followed by a decline at 7 and 14 days and reappearance at day 28 following injury. The early increase of c-Fos expression correlated with allodynia development, however, at longer survival period (28 days) c-Fos positivity become comparable in both CCI and sham groups despite their obvious behavior differences. Our results suggest that, at least in the CCI model, the c-Fos protein expression should not be considered as a reliable index of pain sensation disorders.

Single footshock attenuates c-Fos expression induced by 5-HT 2A receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride in rat brain

Administration of 3 mg/kg 5-hydroxytryptamine 2A/2C (5-HT 2A/2C) receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) induced c-Fos expression in all areas of the rat neocortex. The single footshock 24 h before DOI administration significantly attenuated DOI-induced c-Fos expression in layer IV of the primary somatosensory cortex. These changes in c-Fos expression suggest an adaptational change in the somatosensory cortex by acute stress.

약침이 반복적인 코카인 투여로 인한 행동적 민감화 현상에 미치는 효과

Substantial evidence suggests that behavioral and reinforcing effects of cocaine can be mediated by the mesolimbic dopaminergic system. It has been shown that repeated injections of cocaine produce increase in locomotor activity, expression of the immediate-early gene, c-fos in the nucleus accumbens (NAc), which was one of the main dopaminergic terminal areas. Herbal-acupuncture as a therapeutic intervention has been widely used for the treatment of many functional disorders such as drug abuse. Coptidis Rhizoma (CR) and its main component, berberine (BER) were selected as herbal medicine of herbal-acupuncture. Both medicines have been known to have the therapeutic effect on the central nervous system. In order to investigate the effects of CR and BER herbalacupuncture at shenmen (HT7) point (CR/H and BER/H) on the cocaine-induced behavioral sensitization, the influence of CR/H and BER/H on repeated cocaine-induced locomotor activity, the change of c-Fos expression in the brain by immunohistochemistry were examined. Male SD rats were given CR/H (0.4mg/kg) and BER/H (0.1mg/kg) 30 min before daily injections of cocaine hydrochloride (15mg/kg. i.p.) 10 days. After 3 days withdrawal, rats received a challenge injection of cocaine (15mg/kg, i.p.). Systemic challenge with cocaine produced much larger increased locomotor activity, accumbal Fos-like immunoreactivity in the NAc. Pretreatment with CR/H and BER/H significantly inhibited cocaine-induced locomotor activity, the change of c-Fos expression in the rats. Our data demonstrated that the inhibitory effects of cocaine-induced behavioral sensitization by CR/H and BER/H were closely associated with the reduction of presynaptic dopamine release in the NAc. These results suggest that CR/H and BER/H can be effectively applied to cocaine addiction.

Heme oxygenase-1 in cholecystokinin-octapeptipe attenuated injury of pulmonary artery smooth muscle cells induced by lipopolysaccharide and its signal transduction mechanism.

To study the effect of cholecystokinin-octapeptide (CCK-8) on lipopolysaccharide (LPS) -induced pulmonary artery smooth muscle cell (PASMCs) injury and the role of heme oxygenase-1 (HO-1), and to explore the regulation mechanism of c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1) signal transduction pathway in inducing HO-1 expression further. Cultured PASMCs were randomly divided into 4 or 6 groups: normal culture group, LPS (10 mg/L), CCK-8 (10(-6) mol/L) plus LPS (10 mg/L) group, CCK-8 (10(-6) mol/L) group, zinc protoporphyrin 9 (ZnPPIX) (10(-6) mol/L) plus LPS (10 mg/L) group, CCK-8 (10(-6) mol/L) plus ZnPPIX and LPS (10 mg/L) group. Seven hours after LPS administration, ultrastructural changes and content of malondialdehyde (MDA) of PASMCs in each group were investigated by electron microscopy and biochemical assay respectively. HO-1 mRNA and protein of PASMCs in the former 4 groups were examined by reverse transcriptase polymerase chain reaction (RT-PCR) and immunocytochemistry staining. Changes of c-fos expression and activation of JNK of PASMCs in the former 4 groups were detected with immunocytochemistry staining and Western blot 30 min after LPS administration. The injuries of PASMCs and the increases of MDA content induced by LPS were alleviated and significantly reduced by CCK-8 (P<0.05). The specific HO-1 inhibitor- ZnPPIX could worsen LPS-induced injuries and weaken the protective effect of CCK-8. The expressions of c-fos, p-JNK protein and HO-1 mRNA and protein were all slightly increased in LPS group, and significantly enhanced by CCK-8 further (P<0.05). HO-1 may be a key factor in CCK-8 attenuated injuries of PASMCs induced by LPS, and HO-1 expression may be related to the activation of JNK and activator protein (AP-1).

C-FOS changes following an aggressive encounter in female California mice: A synthesis of behavior, hormone changes and neural activity

Although there has been growing interest in the neuroanatomical and physiological mechanisms underlying aggressive behavior, little work has focused on possible mechanisms controlling natural plasticity in aggression. In the current study, we used naturally occurring changes in aggression level displayed by female Peromyscus californicus across the estrous cycle and parallel changes in c-fos expression to examine possible brain regions involved in mediating this plasticity. We found that c-fos expression was increased in females exposed to a conspecific female intruder compared with control females in numerous brain regions thought to be involved in the control of aggression. More importantly, we found that c-fos increased in the bed nucleus of the stria terminalis (BNST) and ventral lateral septum (LSv) only in the more aggressive, diestrous females, and not in the less aggressive, proestrous and estrous females. Conversely, c-fos increased in the medial amygdala (MeA) across all stages of estrus compared with controls, suggesting the MeA is not involved in mediating changes in individual levels of aggression. Moreover, we found correlations between several measures of aggression and c-fos expression in the BNST and LSv but not the MeA, again suggesting a role in mediating aggression plasticity for the former two but not the latter brain region. We further hypothesize that the BNST and the LSv may be involved more generally in mediating natural changes in aggression, such as increases often observed after individuals win aggressive interactions against conspecifics.

Involvement of the anterior pretectal nucleus in the control of persistent pain: a behavioral and c-Fos expression study in the rat

The anterior pretectal nucleus (APtN) participates in nociceptive processing and in the activation of central descending mechanisms of pain control. In this study we used behavioral tests (incisional pain and carrageenan-induced inflammatory pain) and c-Fos expression changes to examine the involvement of the APtN in the control of persistent pain in rats. A 1cm longitudinal incision through the skin and fascia of the plantar region (large incision), or a 0.5cm longitudinal incision through the skin only (small incision) was used, and the postoperative incisional allodynia was evaluated with von Frey filaments. The hyperalgesia produced by the intraplantar administration of carrageenan (25 or 50μg/100μl) into a hind paw was evaluated by a modified paw pressure test. The electrolytic lesion of the contralateral, but not ipsilateral, APtN significantly intensified the allodynia produced by a large incision of the hind paw. The incisional allodynia and the carrageenan-induced hyperalgesia were intensified by the microinjection of 2% lidocaine into the contralateral, but not ipsilateral APtN, the effect being significantly stronger when a large incision or a higher carrageenan concentration was utilized. A significant increase in the number of c-Fos positive cells was found in the ipsilateral, and mainly in the contralateral APtN of rats submitted to a large incision. The number of positive cells in the superficial or deep laminae of the contralateral spinal cord of control and incised rats was not significantly different. Positive cells in the superficial or deep laminae of the ipsilateral spinal cord were significantly more numerous than in control, the effect being significantly more intense in rats with large incision. The microinjection of 0.5% bupivacaine into the APtN contralateral to the incised hind paw reduced the number of positive cells bilaterally in the APtN, but the effect was significant in the contralateral nucleus only. The number of positive cells in the superficial and deep laminae of the contralateral spinal cord of incised and non-incised animals was not significantly changed by the neural block of the contralateral APtN. In the ipsilateral spinal cord, the incision-induced increase in the number of positive cells was significantly reduced in the superficial lamina and significantly increased in the deep lamina of animals previously treated with bupivacaine in the contralateral APtN. In conclusion, the integrity of the APtN is necessary to reduce the severity of the responses to persistent injury. The results also are in agreement with the current notion that persistent noxious inputs to the APtN tonically activate a descending mechanism that excites superficial cells and inhibits deep cells in the spinal dorsal horn.

Effects of previous noxious stimulus applied to remote areas on noxious stimulus-evoked c-Fos expression in the rat trigeminal nucleus caudalis.

Noxious stimulus-evoked c-Fos expression in the spinal dorsal horn is modulated by noxious stimuli applied previously to remote areas of the body. To confirm the existence of such modulation in c-Fos expression in the trigeminal system, changes in c-Fos expression in the trigeminal nucleus caudalis induced by formalin injection into the rat whisker pad were examined by previously injecting formalin into different areas (contralateral whisker pad, ipsilateral or contralateral forepaw) of the body. Formalin injection-evoked c-Fos expression in this nucleus was significantly reduced by previous formalin injection into the contralateral whisker pad or ipsilateral forepaw but not into the contralateral forepaw. The interval between the two injections of formalin that produced a maximal reduction of formalin injection-evoked c-Fos expression was 1 h, and the reduction of c-Fos expression was less when the interval of the two noxious stimuli was longer or shorter than 1 h. These results suggested that noxious stimulus-evoked c-Fos expression in the trigeminal nucleus caudalis is reduced by noxious stimulus applied previously to remote areas, and the reduction is dependent on the area of previous noxious stimulation and interval between the two noxious stimuli.

Synergistic induction of matrix metalloproteinase 1 by interleukin-1alpha and oncostatin M in human chondrocytes involves signal transducer and activator of transcription and activator protein 1 transcription factors via a novel mechanism.

To investigate the mechanism of interleukin-1alpha (IL-1alpha) and oncostatin M (OSM) synergistic regulation of matrix metalloproteinase 1 (MMP-1) in human chondrocytes. Using an immortalized human chondrocyte cell line (T/C28a4), we investigated regulation of the MMP-1 gene. Northern blotting and flow cytometric analysis were used to assess changes in receptor, MMP-1, and c-fos expression. Transient transfections using MMP-1 promoter/luciferase constructs, electrophoretic mobility shift assay, and site-directed mutagenesis were used to investigate MMP-1 promoter activation. We found no alteration in the expression of receptors used by these cytokines after stimulation with IL-1alpha/OSM. Using MMP-1 promoter/luciferase reporter constructs, we found that the proximal (-517/+63) region of the MMP-1 promoter was sufficient to support a synergistic activation. A role for activated signal transducers and activators of transcription (STAT-3) was demonstrated, although no binding of STAT-3 to the MMP-1 promoter was found. However, constitutive binding of activator protein 1 (AP-1) was detected, and changes in c-fos expression could modulate promoter activity. Since no changes in receptor expression were observed, receptor modulation cannot account for the IL-1alpha/OSM synergy observed. Instead, the interplay of various intracellular signaling pathways is a more likely explanation. STAT activation is required, but STAT proteins do not interact directly with the MMP-1 promoter. We propose that activated STATs stimulate c-fos expression, and changes in expression of the AP-1 components regulate MMP-1 expression. We highlight a new mechanism for MMP-1 regulation in human chondrocytes that could provide potential new therapeutic targets.

Enhancement of the acoustic startle response by dopamine agonists after 6-hydroxydopamine lesions of the substantia nigra pars compacta: corresponding changes in c-Fos expression in the caudate–putamen

Rats with 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway show enhanced locomotor and stereotyped behaviors when challenged with direct and indirect dopamine (DA) agonists due to the development of postsynaptic supersensitivity. To determine if this phenomenon generalizes to other motor behaviors, we have used this rat model of Parkinson’s disease to examine the effects of the direct dopamine D 1 receptor agonist SKF 82958 and the indirect DA agonist l-3,4-dihydroxyphenylalanine ( l-DOPA) on the acoustic startle response. In addition, we used the expression of c-Fos protein as a marker of neuronal activity to assess any corresponding drug-induced changes in the caudate–putamen (CPu) after l-DOPA administration. Male Sprague–Dawley rats received bilateral injections of 6-OHDA into the substantia nigra pars compacta and 1 week later were tested for startle after systemic administration of SKF 82958 (0.05 mg/kg) or l-DOPA (1, 5, 10 mg/kg). SKF 82958 produced a marked enhancement of startle with a rapid onset in 6-OHDA-lesioned but not SHAM animals. l-DOPA produced a dose- and time-dependent enhancement of startle in 6-OHDA-lesioned rats that had no effect in SHAM animals even at the highest dose (10 mg/kg). Furthermore, l-DOPA produced a dramatic induction of c-Fos in the CPu in 6-OHDA-lesioned animals. Consistent with other literature, these data suggest that neurons in the CPu become supersensitive to the effects of DA agonists after 6-OHDA-induced denervation of the nigrostriatal pathway and that supersensitive dopamine D 1 receptors may mediate the enhancement of startle seen in the present study.

Synergistic enhancement of the acoustic startle reflex by dopamine D1 and 5-HT1A agonists and corresponding changes in c-Fos expression in the dorsal raphe of rats.

Several studies have reported an increase in dopamine (DA)-stimulated behavioral responses after manipulations that reduce brain serotonin (5-hydroxytryptamine, 5-HT) levels. Because others have shown that systemic administration of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) reduces 5-HT levels throughout the brain, we tested the effects of 8-OH-DPAT on the enhancement of the acoustic startle reflex by the dopamine D1 receptor agonist SKF 82958. In addition, we used the expression of the c-Fos protein as a marker of neuronal activity to assess any corresponding drug-induced changes within the dorsal raphe (DR). Male Sprague-Dawley rats pretreated (10 min) with 8-OH-DPAT (0.5 mg/kg) showed a marked potentiation of the enhancement of startle by SKF 82958 (0.1 mg/kg). Furthermore, SKF 82958 produced a dramatic induction of c-Fos in the DR, an effect that was blocked by 8-OH-DPAT. Double-labeling immunohistochemistry for c-Fos and 5-HT showed that SKF 82958-induced expression of c-Fos, and its blockade by 8-OH-DPAT, occurred in a percentage of 5-HT-containing cells of the DR. These data suggest the possibility that inhibition of the DR by 8-OH-DPAT mediates the potentiation of startle by SKF 82958, perhaps through a reduction in 5-HT release in the striatum. Such an interpretation is consistent with the hypothesis of an inhibitory role of the 5-HT system on DA-mediated behaviors.

Behavioral and c-fos expression changes induced by nitric oxide donors microinjected into the dorsal periaqueductal gray

The dorsolateral periaqueductal gray matter (DLPAG) is a key structure in behavioral and autonomic expression of defensive reactions. Inhibitors of nitric oxide (NO) synthase microinjected into the DLPAG are anxiolytic. The purpose of the present study was to evaluate the behavioral effects produced by administration of two NO donors, SIN-1 or DEA/NO, into the DLPAG. We also employed the detection of Fos-like immunoreactivity (FLI) to reveal brain areas activated by SIN-1 administration. Male Wistar rats ( n = 7–11/group) received intra-DLPAG injection of SIN-1 (150 or 300 nmol), DEA/NO (150, 300, or 600 nmol), or saline (0.5 μl), and their behavior was observed in an open arena during 15 min. For the FLI assay, the animals ( n = 3–5/group) were sacrificed 2.25 h after the drug. In a second experiment, rats ( n = 5–7/group) received a first intra-DLPAG injection of saline or methylene blue (MB, 30 nmol), an NO antagonist, followed by saline or SIN-1 (300 nmol). SIN-1 (300 nmol) induced a flight response characterized by coordinated running and oriented jumps with escape attempts. Similar but short-lasting changes were seen after the administration of DEA/NO. FLI was dose-dependently induced by SIN-1 in several regions related to defensive reactions, including the periaqueductal gray, hypothalamic nuclei, medial amygdala, and cingulate cortex (analysis of variance, p < 0.05). A greater number of neurons showing FLI was found ipsilateral to the microinjection site. The drug effect was greater at this side in the bed nucleus of the stria terminalis, paraventricular and lateral hypothalamus, cingulate cortex, septohipoccampal nucleus, and horizontal limb of the diagonal band. The increase in SIN-1-induced FLI was attenuated by MB pretreatment in most regions. These results suggest that NO may participate in the modulation of defensive responses in the DLPAG.

C-Fos expression in the cholinergic basal forebrain after enforced wakefulness and recovery sleep

The present study used c-Fos expression to examine cellular activity in cholinergic regions in the basal forebrain (BF) following enforced waking and recovery sleep. Cholinergic cells within the vertical and horizontal limbs of the diagonal band of Broca (VDB and HDB, respectively) showed significantly higher c-Fos immunoreactivity after prolonged waking than after recovery sleep. Cholinergic cells within the medial septal nucleus (MS), however, showed no change in c-Fos expression under these conditions. Consistent with our previous findings, c-Fos immunoreactivity in the ventral lateral preoptic area (VLPO) was increased after 1-2h of recovery sleep compared with enforced waking. These results indicate state-specific effects on transcription and subsequent protein expression in cell populations associated with behavioral state and further show that the HDB, VDB and VLPO are good candidates for the further study of intracellular events associated with sleep and wakefulness.

Estradiol induces a phasic Fos response in the hippocampal CA1 and CA3 regions of adult female rats.

Previous studies have shown that estradiol induces structural and functional changes in hippocampal CA1 pyramidal cells of the adult female rat. Estradiol increases the density of dendritic spines and axospinous synapses on CA1 pyramidal cells, and increases these cells' sensitivity to NMDA receptor-mediated synaptic input. Curiously, while estradiol effects are observed in CA1 pyramidal cells, the majority of the evidence indicates that these cells lack genomic estradiol receptors. In contrast, genomic estradiol receptors are expressed in at least some hippocampal interneurons in CA1. The goal of the present study was to determine which hippocampal neuronal populations are activated by estradiol, as determined by induction of c-Fos immunoreactivity, as well as the time-course of this activation. We quantified c-Fos expression in each of the major subdivisions of the hippocampus in adult female rats at various time points during the same estradiol treatment regimen known to regulate dendritic spines and synapses on CA1 pyramidal cells. Our results show a phasic estradiol-induced c-Fos response in the pyramidal cell layers of both CA1 and CA3. c-Fos was induced within 2 h of treatment, decreased at 6 and 12 h, and subsequently increased again at 24 h after treatment with estradiol. Double labeling for c-Fos and GAD 65 or GAD 67 suggests that c-Fos is induced primarily in principal cells, though a small proportion of GABAergic cells is also labeled. These estradiol-induced changes in c-Fos expression may reflect phasic neuronal activation and coupling to gene expression, which could be involved in estradiol's effects on excitatory synaptic connectivity in the hippocampus.

Is there tonic activity in the endogenous opioid systems? A c-Fos study in the rat central nervous system after intravenous injection of naloxone or naloxone-methiodide.

This study examined the possibility that a tonic activity in the endogenous opioid systems (EO systems) exists in animals under normal conditions. In a first set of experiments, concurrent changes in behavioral responses and in the numbers of c-Fos-like immunoreactive (Fos-LI) neurons in 58 structures of the brain and lumbosacral spinal cord were analyzed in rats after systemic administration of the opioid antagonist naloxone (NAL; 2 mg/kg). Possible roles of the EO systems were inferred from changes in the numbers of Fos-LI neurons between normal rats that received either NAL or the same volume of saline. Free-floating sections were processed immunohistochemically for c-Fos protein using standard avidin-biotin complex methods. After NAL, the numbers of Fos-LI neurons were significantly increased in the area postrema; in the caudal, intermediate, and rostral parts of the nucleus tractus solitarii; in the rostral ventrolateral medulla; in the Kölliker-Fuse nucleus; in the supramammillary nucleus; and in the central nucleus of the amygdala. In a second set of experiments examining changes in c-Fos expression in the latter structures, similar increases were found after NAL but not after an equimolar dose of NAL-methiodide, a preferential, peripherally acting opioid receptor antagonist. Therefore, Fos-LI was likely triggered after blockade of central opioid receptors, but not peripheral opioid receptors, releasing neurons from EO system-mediated inhibition. The results of this study suggest the existence of a tonic activity of the EO systems exerted on a restricted number of brain regions in normal rats. This tonic activity of the EO systems may control part of the neural networks involved in cardiorespiratory functions and in emotional and learning processes.

Selective c-fos induction and decreased dopamine release in the central nucleus of amygdala in rats displaying a mecamylamine-precipitated nicotine withdrawal syndrome.

In the present study the neuronal expression of Fos, the protein product of c-fos, was used to study changes in neuronal activity in nerve terminal regions of the ascending dopaminergic system during nicotine withdrawal. Rats were infused for 14 days with nicotine (9 mg/kg/day nicotine hydrogen tartrate) via minipumps, whereas control animals carried empty pumps. Withdrawal was induced by the nicotinic receptor (nAChR) antagonist mecamylamine (1 mg/kg, s.c.). The behavior of each animal was observed after mecamylamine injection and subsequently its brain was processed for Fos-like immunoreactivity. Following mecamylamine, the score of abstinence signs increased in the nicotine-treated rats as compared to controls. The number of Fos-positive nuclei was substantially increased in the central nucleus of amygdala (CNA) in animals undergoing mecamylamine-precipitated withdrawal, whereas no significant changes in c-fos expression were observed in the basolateral amygdaloid nucleus, the core and the shell of the nucleus accumbens, the dorsolateral striatum, or the medial prefrontal cortex. Since there are indications of involvement of amygdaloid dopaminergic neurotransmission in anxiety-a core symptom of withdrawal from dependence-producing drugs-in a second experiment utilizing microdialysis we examined whether nicotine withdrawal affects dopaminergic neurotransmission in the CNA. Following mecamylamine injection, dopamine (DA) significantly decreased in nicotine-treated animals compared with controls. These results indicate that the mecamylamine-precipitated nicotine withdrawal reaction is accompanied by a selective induction of c-fos and a concurrent decrease in DA release in the CNA, which may have a bearing on symptoms such as anxiety and distress, which frequently are associated with the nicotine abstinence reaction in humans.

Regional differences in desensitization of c-Fos expression following repeated self-stimulation of the medial forebrain bundle in the rat

The acute self-stimulation of the medial forebrain bundle was reported to induce the expression of c-Fos, the protein product of c-fos, an immediate early gene, in the central nervous system. In the present study, we examined regional changes in c-Fos expression in several reward-related areas of rat brain in response to short- and long-term exposure to self-stimulation of the medial forebrain bundle. Short-term one-hour stimulation of the medial forebrain bundle for one day after training, which evoked steady self-stimulation behavior, significantly increased the number of c-Fos-positive neurons bilaterally in all of 15 brain structures assayed, as compared to the non-stimulation control. Among them, structures showing a larger number of the stained neurons on the stimulated side were the anterior olfactory nucleus, amygdala, medial caudate–putamen complex, lateral septum, bed nucleus of the stria terminals, ventral pallidum, substantia innominata, lateral preoptic area, medial preoptic area, lateral hypothalamus rostral to the stimulating electrodes, and substantia nigra. Long-term stimulation of the medial forebrain bundle once daily for five successive days, which maintained consistently stable self-stimulation behavior, also increased the number of c-Fos-positive neurons in the aforementioned structures, as compared to the control. However, the long-term rewarding stimulation diminished the increased number of labeled neurons, as compared to the short-term rewarding stimulation. Seven areas, medial caudate–putamen complex, ventral pallidum, substantia innominata, lateral preoptic area, medial preoptic area, rostral lateral hypothalamus and substantia nigra, showed asymmetrical, ipsilateral predominance after the short- and long-term stimulation. However, the stained neuron count in those areas after the long-term stimulation was reduced to less than 50% of that found after the short-term stimulation with the exception of lateral preoptic area and rostral lateral hypothalamus. The results suggest that the development of desensitization of c-Fos response may differ among the reward-relevant brain regions as a consequence of repeated self-stimulation. They also indicate that a larger portion of neurons in the lateral preoptic area and rostral lateral hypothalamus may be implicated in both short- and long-term self-stimulations of the medial forebrain bundle.

Compartmental changes in expression of c-Fos and FosB proteins in intact and dopamine-depleted striatum after chronic apomorphine treatment

Chronic administration of dopaminergic agonists to rats with unilateral 6-OH-dopamine (6-OHDA) lesions of nigrostriatal pathway produces behavioral sensitization to subsequent agonist challenges and may serve as a model for DOPA-induced dyskinesias. In order to understand striatal mechanisms behind this long-term behavioral change we examined striatal c-Fos and FosB immunoreactivity induced by apomorphine challenge (5 mg/kg, s.c.) after 3 days of withdrawal following a 2-week administration (5 mg/kg, b.i.d., s.c.) both in intact and 6-OHDA-lesioned animals. In intact rats, c-Fos induction by acute apomorphine exposure showed a striosomal pattern, whereas FosB immunopositivity was diffusely distributed. Following chronic administration, FosB induction turned to a clear striosome dominant pattern similar to c-Fos expression. In denervated striatum, expression of both proteins was profoundly augmented in a homogeneous pattern after a single dose of apomorphine. A distinct striosomal patterning appeared after chronic apomorphine administration in ventromedial part of the denervated striatum with a down-regulation in the matrix and relative enhancement in striosomes. These results suggest that compartmental reorganization of striatal neuronal activity may play a role in long-term behavioral changes induced by chronic dopaminergic treatments both under normal and dopamine-depleted conditions.

Changes in c-Fos expression induced by noxious stimulation in the trigeminal spinal nucleus caudalis and C1 spinal neurons of rats after hyperbaric exposure.

The present study aims to test the hypothesis that hyperbaric exposure inhibits nociceptive processing in the trigeminal spinal nucleus caudalis and C1 spinal neurons. We investigated the c-Fos-like immunoreactivity of the brainstem and upper cervical spinal cord (C1 region) following an injection of mustard oil (15 microliters of 20%) into the nasal mucosa of pentobarbital anesthetized rats after exposure to hyperbaric (2-atmospheres, 1 h) and normobaric pressures. After the hyperbaric exposure, the mean number of Fos-immunoreactive neurons in the ipsilateral laminae I-II and III-IV of the trigeminal spinal nucleus caudalis were significantly lower than those in the normobaric condition. Similarly, the mean number of c-Fos positive neurons in the superficial layer (I-II) of the ipsilateral C1 segment were significantly reduced as compared with that in the normobaric condition. When treated with the vehicle alone, no significant difference was detected in the numbers of c-Fos positive neurons in the trigeminal spinal nucleus caudalis and C1 regions between hyperbaric and normobaric conditions. These results suggest that hyperbaric exposure may attenuate nociceptive signals from the area innervated by the trigeminal nerves at the level of both the trigeminal spinal nucleus caudalis and C1 dorsal horn.

Involvement of the spinoparabrachial pathway in inflammatory nociceptive processes: a c-Fos protein study in the awake rat.

The effect of graded inflammatory stimuli (intraplantar-carrageenan, 0.2, 1, and 6 mg/150 microl) on paw edema and c-Fos protein expression at two levels of the spinoparabrachial pathway, the spinal cord and parabrachial area (PB), were studied. The present study, in awake rats, is an extension of previous study (Bester et al. [1997] J. Comp. Neurol. 383:439-458) which evaluated, in anesthetized rats, the effect of graded cutaneous heat stimulation on c-Fos-expression at the same levels. At the spinal level, the c-Fos-protein-like-immunoreactive (c-Fos-LI) neurons were located primarily in superficial laminae ipsilateral to intraplantar carrageenan. The number of c-Fos-LI neurons increased dose dependently (r = 0.973, n = 24) for carrageenan, from a number close to zero for the saline injection. At the PB level, c-Fos was predominantly expressed contralateral to intraplantar carrageenan. c-Fos-LI neurons were located primarily around the pontomesencephalic junction in (i) a restricted pontine area, centered in the lateral crescent, and including an adjacent part of the outer portion of the external lateral subnucleus, and (ii) the mesencephalic superior lateral subnuclei. The number of c-Fos-LI neurons in the PB area was correlated with that in the superficial laminae (r = 0.935, n = 24) and with the paw edema (r = 0.931, n = 24). No significant changes in c-Fos expression were observed in the nucleus of the solitary tract and ventrolateral medulla. The close correlation between c-Fos expression at both the spinal and PB levels and inflammatory edema provides further evidence for the involvement of spinoparabrachial pathway in inflammatory nociceptive processes. The present results are congruent with the existence of electrophysiologically demonstrated spinoparabrachio-amygdaloid and -hypothalamic nociceptive pathways.

Modulated expression of c‐Fos in the spinal cord following noxious thermal stimulation of monoarthritic rats

Peripheral noxious stimulation evokes functional and biochemical changes in the spinal cord which results in central sensitization and hyperalgesia, but at the same time also induces the activation of inhibitory control systems. The purpose of the present study was to investigate whether the adaptive changes induced by ongoing peripheral inflammation influence the spinal cord expression of c-Fos (a commonly used marker of neuronal activity) following an additional acute noxious stimulus. Therefore, the spinal expression of c-Fos was immunohistochemically investigated following noxious thermal stimulation of a rat monoarthritic hindpaw at various time points (1, 4, 8, 21 days) after induction of monoarthritis. Compared to normal rats, c-Fos expression following ipsilateral noxious thermal stimulation of monoarthritic rats was strongly modified in the deep laminae of the dorsal horn depending on the time course of inflammation. At 1 day of monoarthritis, an enhanced ipsilateral expression (135% and 208% of normal rats in laminae III–VI and VII, respectively) and at 3 weeks a reduced expression (38% and 23% of normal rats in laminae III–VI and VII, respectively) was detected. The amount of c-Fos-positive neurons in the ipsilateral superficial laminae I and II was unchanged at all time points investigated. To assess excitability changes on the contralateral side at an early stage of inflammation, a group of monoarthritic rats received a contralateral noxious stimulus at day 1 of monoarthritis. This resulted in a potentiated expression of c-Fos ipsilateral to the acute noxious stimulus (i.e., contralateral to the monoarthritic hindpaw) restricted to lamina II (137% of normal rats) of the dorsal horn. The data showed that changes in c-Fos expression depended on the time point of noxious heat stimulation (NHS) of monoarthritic rats, and differed in the ipsi- and contralateral side of the spinal cord. In addition to a possible habituation of c-Fos expression, it may be speculated that the time course-dependent changes reflect laminae-specific modulations of excitatory and inhibitory mechanisms during monoarthritis. Further studies are necessary in order to provide more insights into the contribution of these mechanisms on noxious stimulus-evoked c-Fos expression. J. Neurosci. Res. 53:203–213, 1998. © 1998 Wiley-Liss, Inc.