c-Fos Expression In Hypothalamus Research Articles

Effects of physical training on hypothalamic neuronal activation and expressions of vasopressin and oxytocin in SHR after running until fatigue.

To assess the influence of physical training on neuronal activation and hypothalamic expression of vasopressin and oxytocin in spontaneously hypertensive rats (SHR), untrained and trained normotensive rats and SHR were submitted to running until fatigue while internal body and tail temperatures were recorded. Hypothalamic c-Fos expression was evaluated in thermoregulatory centers such as the median preoptic nucleus (MnPO), medial preoptic nucleus (mPOA), paraventricular nucleus of the hypothalamus (PVN), and supraoptic nucleus (SON). The PVN and the SON were also investigated for vasopressin and oxytocin expressions. Although exercise training improved the workload performed by the animals, it was reduced in SHR and followed by increased internal body temperature due to tail vasodilation deficit. Physical training enhanced c-Fos expression in the MnPO, mPOA, and PVN of both strains, and these responses were attenuated in SHR. Vasopressin immunoreactivity in the PVN was also increased by physical training to a lesser extent in SHR. The already-reduced oxytocin expression in the PVN of SHR was increased in response to physical training. Within the SON, neuronal activation and the expressions of vasopressin and oxytocin were reduced by hypertension and unaffected by physical training. The data indicate that physical training counterbalances in part the negative effect of hypertension on hypothalamic neuronal activation elicited by exercise, as well as on the expression of vasopressin and oxytocin. These hypertension features seem to negatively influence the workload performed by SHR due to the hyperthermia derived from the inability of physical training to improve heat dissipation through skin vasodilation.

Depleting hypothalamic somatostatinergic neurons recapitulates diabetic phenotypes in mouse brain, bone marrow, adipose and retina.

Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of the metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunological pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation. The present data show that leptin receptor-deficient (db/db) mice exhibit reduced hypothalamic SST neurons, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus delivery of diphtheria toxin subunit A (DTA) driven by an SST-cre system to deplete these neurons in Sstcre/gfp mice (SST-DTA). SST-DTA mice exhibit enhanced hypothalamic c-Fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed haematopoiesis, generating excess granulocyte-monocyte progenitors and increased proinflammatory (C-C chemokine receptor type 2; CCR2hi) monocytes. SST-DTA mice exhibited a 'diabetic retinopathy-like' phenotype: reduced visual function by optokinetic response (0.4 vs 0.25 cycles/degree; SST-DTA vs control mice); delayed electroretinogram oscillatory potentials; and increased percentages of retinal monocytes. Finally, mesenteric visceral adipose tissue from SST-DTA mice was resistant to catecholamine-induced lipolysis, displaying 50% reduction in isoprenaline (isoproterenol)-induced lipolysis compared with control littermates. Importantly, hyperglycaemia was not observed in SST-DTA mice. The isolated reduction in hypothalamic SST neurons was able to recapitulate several hallmark features of type 2 diabetes in disease-relevant tissues.

Metabolic Effects of Light at Night are Time- and Wavelength-Dependent in Rats.

ObjectiveIntrinsically photosensitive retinal ganglion cells are most sensitive to short wavelengths and reach brain regions that modulate biological rhythms and energy metabolism. The increased exposure nowadays to artificial light at night (ALAN), especially short wavelengths, perturbs our synchronization with the 24‐hour solar cycle. Here, the time‐ and wavelength dependence of the metabolic effects of ALAN are investigated.MethodsMale Wistar rats were exposed to white, blue, or green light at different time points during the dark phase. Locomotor activity, energy expenditure, respiratory exchange ratio (RER), and food intake were recorded. Brains, livers, and blood were collected.ResultsAll wavelengths decreased locomotor activity regardless of time of exposure, but changes in energy expenditure were dependent on the time of exposure. Blue and green light reduced RER at Zeitgeber time 16‐18 without changing food intake. Blue light increased period 1 (Per1) gene expression in the liver, while green and white light increased Per2. Blue light decreased plasma glucose and phosphoenolpyruvate carboxykinase (Pepck) expression in the liver. All wavelengths increased c‐Fos activity in the suprachiasmatic nucleus, but blue and green light decreased c‐Fos activity in the paraventricular nucleus.ConclusionsALAN affects locomotor activity, energy expenditure, RER, hypothalamic c‐Fos expression, and expression of clock and metabolic genes in the liver depending on the time of day and wavelength.

Role of leptin in the regulation of food intake in fasted mice.

Leptin is well acknowledged as an anorexigenic hormone that plays an important role in feeding control. Hypothalamic GABA system plays a significant role in leptin regulation on feeding and metabolism control. However, the pharmacological relationship of leptin and GABA receptor is still obscure. Therefore, we investigated the effect of leptin or combined with baclofen on the food intake in fasted mice. We detected the changes in hypothalamic c‐Fos expression, hypothalamic TH, POMC and GAD67 expression, plasma insulin, POMC and GABA levels to demonstrate the mechanisms. We found that leptin inhibit fasting‐induced increased food intake and activated hypothalamic neurons. The inhibitory effect on food intake induced by leptin in fasted mice can be reversed by pretreatment with baclofen. Baclofen reversed leptin's inhibition on c‐Fos expression of PAMM in fasted mice. Therefore, these results indicate that leptin might inhibit fasting‐triggered activation of PVN neurons via presynaptic GABA synaptic functions which might be partially blocked by pharmacological activating GABA‐B. Our findings identify the role of leptin in the regulation of food intake.

Decreased food anticipatory activity of obese mice relates to hypothalamic c-Fos expression

During daily Food Restriction (FR), obese Neotomodon alstoni mice present decreased Food Anticipatory Activity (FAA) compared to lean mice. Here, we investigated whether FOS expression in hypothalamic nuclei involved in food synchronization and anticipation parallels decreased FAA during daily FR of obese N. alstoni. Locomotor activity of lean and obese mice in ad libitum feeding conditions was monitored for at least two weeks. Then, a gradual restriction of food access was followed to establish a 5h period of daily food access. FR was maintained during at least two weeks before sacrifice of mice at the starting point of the feeding period. Obese mice subjected to FR displayed an overall reduction of FOS-positive (FOS+) hypothalamic neurons, while lean mice in a similar protocol exhibited an increase in FOS+ neurons within the arcuate and dorsomedial hypothalamic nuclei. These results are consistent with decreased FAA displayed by obese mice in comparison to lean mice. Furthermore, limbic system areas of lean mice, such as the cingulate cortex and the hippocampus, showed an increase in FOS during FR, while no responses were observed in obese mice. The daily food intake of obese mice was severely reduced during FR, compared to the ad libitum condition, whereas food intake in lean mice was not affected by FR. Current data suggests that decreased hypothalamic and limbic neuronal activation may contribute to the reduction of FAA in obese N. alstoni mice.

Gabapentin Differentially Modulate c-Fos Expression in Hypothalamus and Spinal Trigeminal Nucleus in Surgical Molar Extraction.

The study on the efficacy of oral analgesics reported that no single class of drug is effective in post-surgical dental pain. Pain following removal of third molar is most commonly used and widely accepted acute pain model for assessing the analgesic effect of drugs in humans. Reports demonstrated that analgesic efficacy in the human dental model is highly predictive. The high incidence of false-negative findings in analgesic investigations hinders the process of molecular discovery. Molecular mechanism of post-surgical pain is not known. More importantly, the animal model for postoperative dental pain is not well established. In an attempt to discover an effective post-surgical dental pain blocker with acceptable side effects, it is essential to elucidate the molecular mechanism of post-operative dental pain. The present study investigated mandibular molars extraction in rat as an animal model for the post-operative dental pain in central nervous system. Using c-Fos immunohistochemistry, we demonstrated that pre administration of GBP (150 mg/kg. i.p) significantly (p< 0.01) neutralized the surgical molar extraction induced c-Fos expression bilaterally in rat hypothalamus. Present results indicate that pain after surgical molar extraction might follow novel neural pathways therefore difficult to treat with existing anti-nociceptive drugs.

Dietary fat and corticosterone levels are contributing factors to meal anticipation.

Daily restricted access to food leads to the development of food anticipatory activity and metabolism, which depends upon an as yet unidentified food-entrainable oscillator(s). A premeal anticipatory peak in circulating hormones, including corticosterone is also elicited by daily restricted feeding. High-fat feeding is associated with elevated levels of corticosterone with disrupted circadian rhythms and a failure to develop robust meal anticipation. It is not clear whether the disrupted corticosterone rhythm, resulting from high-fat feeding contributes to attenuated meal anticipation in high-fat fed rats. Our aim was to better characterize meal anticipation in rats fed a low- or high-fat diet, and to better understand the role of corticosterone in this process. To this end, we utilized behavioral observations, hypothalamic c-Fos expression, and indirect calorimetry to assess meal entrainment. We also used the glucocorticoid receptor antagonist, RU486, to dissect out the role of corticosterone in meal anticipation in rats given daily access to a meal with different fat content. Restricted access to a low-fat diet led to robust meal anticipation, as well as entrainment of hypothalamic c-Fos expression, metabolism, and circulating corticosterone. These measures were significantly attenuated in response to a high-fat diet, and animals on this diet exhibited a postanticipatory rise in corticosterone. Interestingly, antagonism of glucocorticoid activity using RU486 attenuated meal anticipation in low-fat fed rats, but promoted meal anticipation in high-fat-fed rats. These findings suggest an important role for corticosterone in the regulation of meal anticipation in a manner dependent upon dietary fat content.

Schisandra chinensis and Rhodiola rosea exert an anti-stress effect on the HPA axis and reduce hypothalamic c-Fos expression in rats subjected to repeated stress.

The aim of the present study was to investigate the effects of Schisandra chinensis (S. chinensis) and Rhodiola rosea (R. rosea) on rats subjected to 5 h of stress, induced by water-floating followed by treadmill exercise. Hypothalamus-pituitary-adrenal (HPA) activity and c-Fos and Fos-related antigen 2 (Fra-2) mRNA expression levels in the hypothalamus of the rats were evaluated. Rats were distributed into four groups: S. chinensis (n=12), R. rosea (n=10), stress control (n=10) and quiet control (n=8). Following a training period of 6 consecutive days, the S. chinensis, R. rosea and stress control groups underwent a 3-h water-floating session in the presence of feline predators immediately followed by 2 h treadmill running to induce psychological and physical stress. Following compound stress induction, the serum levels of corticosterone (CORT), adrenocorticotropic hormone and interleukin-1β and the mRNA expression levels of hypothalamic corticotropin-releasing hormone (CRH), neuropeptide-Y, c-Fos and Fra-2 were evaluated using enzyme-linked immunosorbent assay, radioimmunoassay and quantitative polymerase chain reaction, respectively. The results indicated that S. chinensis and R. rosea markedly decreased the stress-induced elevation of CRH and peripheral CORT levels. The mRNA expression levels of c-Fos and Fra-2 in the hypothalamus were significantly increased after 5 h compound stress, and reduced levels of c-Fos expression were detected in rats treated with R. rosea. Thus, S. chinensis and R. rosea exert an anti-stress effect in rats subjected to stress by balancing the HPA axis, and possibly by reducing the expression of c-Fos in the hypothalamus.

Role of 5-HT3 receptor on food intake in fed and fasted mice.

BackgroundMany studies have shown that 5-hydroxytryptamine (5-HT) receptor subtypes are involved in the regulation of feeding behavior. However, the relative contribution of 5-HT3 receptor remains unclear. The present study was aimed to investigate the role of 5-HT3 receptor in control of feeding behavior in fed and fasted mice.Methodology/Principal FindingsFood intake and expression of c-Fos, tyrosine hydroxylase (TH), proopiomelanocortin (POMC) and 5-HT in the brain were examined after acute treatment with 5-HT3 receptor agonist SR-57227 alone or in combination with 5-HT3 receptor antagonist ondansetron. Food intake was significantly inhibited within 3 h after acute treatment with SR 57227 in fasted mice but not fed mice, and this inhibition was blocked by ondansetron. Immunohistochemical study revealed that fasting-induced c-Fos expression was further enhanced by SR 57227 in the brainstem and the hypothalamus, and this enhancement was also blocked by ondansetron. Furthermore, the fasting-induced downregulation of POMC expression in the hypothalamus and the TH expression in the brain stem was blocked by SR 57227 in the fasted mice, and this effect of SR 57227 was also antagonized by ondansetron.Conclusion/SignificanceTaken together, our findings suggest that the effect of SR 57227 on the control of feeding behavior in fasted mice may be, at least partially, related to the c-Fos expression in hypothalamus and brain stem, as well as POMC system in the hypothalamus and the TH system in the brain stem.

Control of hypothalamic–pituitary–adrenal stress axis activity by the intermediate conductance calcium‐activated potassium channel, SK4

The anterior pituitary corticotroph is a major control point for the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the neuroendocrine response to stress. Although corticotrophs are known to be electrically excitable, ion channels controlling the electrical properties of corticotrophs are poorly understood. Here, we exploited a lentiviral transduction system to allow the unequivocal identification of live murine corticotrophs in culture. We demonstrate that corticotrophs display highly heterogeneous spontaneous action-potential firing patterns and their resting membrane potential is modulated by a background sodium conductance. Physiological concentrations of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) cause a depolarization of corticotrophs, leading to a sustained increase in action potential firing. A major component of the outward potassium conductance was mediated via intermediate conductance calcium-activated (SK4) potassium channels. Inhibition of SK4 channels with TRAM-34 resulted in an increase in corticotroph excitability and exaggerated CRH/AVP-stimulated ACTH secretion in vitro. In accordance with a physiological role for SK4 channels in vivo, restraint stress-induced plasma ACTH and corticosterone concentrations were significantly enhanced in gene-targeted mice lacking SK4 channels (Kcnn4(-/-)). In addition, Kcnn4(-/-) mutant mice displayed enhanced hypothalamic c-fos and nur77 mRNA expression following restraint, suggesting increased neuronal activation. Thus, stress hyperresponsiveness observed in Kcnn4(-/-) mice results from enhanced secretagogue-induced ACTH output from anterior pituitary corticotrophs and may also involve increased hypothalamic drive, thereby suggesting an important role for SK4 channels in HPA axis function.

Accumbens shell-hypothalamus interactions mediate extinction of alcohol seeking.

The nucleus accumbens shell (AcbSh) is required to inhibit drug seeking after extinction training. Conversely, the lateral hypothalamus (LH), which receives projections from AcbSh, mediates reinstatement of previously extinguished drug seeking. We hypothesized that reversible inactivation of AcbSh using GABA agonists (baclofen/muscimol) would reinstate extinguished alcohol seeking and increase neuronal activation in LH. Rats underwent self-administration training for 4% (v/v) alcoholic beer followed by extinction. AcbSh inactivation reinstated extinguished alcohol seeking when infusions were made after, but not before, extinction training. We then used immunohistochemical detection of c-Fos as a marker of neuronal activity, combined with immunohistochemical detection of the orexin and cocaine- and amphetamine-related transcript (CART) peptides, to study the profile and phenotype of neural activation during reinstatement produced by AcbSh inactivation. AcbSh inactivation increased c-Fos expression in hypothalamus, as well as in paraventricular thalamus and amygdala. Within hypothalamus, there was an increase in the number of orexin and CART cells expressing c-Fos. Finally, we hypothesized that concurrent inactivation of LH would prevent reinstatement produced by inactivation of AcbSh alone. Our results confirmed this. Together, these findings suggest that AcbSh mediates extinction of reward seeking by inhibiting hypothalamic neuropeptide neurons. Reversible inactivation of the AcbSh removes this influence, thereby releasing hypothalamus from AcbSh inhibition and enabling reinstatement of reward seeking. These ventral striatal-hypothalamic circuits for extinction overlap with those that mediate satiety, and we suggest that extinction training inhibits drug seeking because it co-opts neural circuits originally selected to produce satiety.

Long-Lasting Effect of Changes in Incubation Temperature on Heat Stress Induced Neuronal Hypothalamic c-Fos Expression in Chickens

In birds, during prenatal 'critical periods' the thermoregulatory system can be life-long imprinted by the actual incubation temperature. The aim of the present study is to elucidate long-term effects of prenatal temperature experiences, applied at the end of incubation, on central thermoregulatory mechanisms by detection of neuronal hypothalamic c-Fos expression as a consequence of acute heat stress in growing and adult chickens using immunohistochemistry. From day 18 of incubation chicken embryos were incubated in three temperature groups: 37.5°C (regular incubated), 34.5°C (cold incubated) or 38.5°C (warm incubated). C-Fos expression was detected in 29 4-weeks old and 61 8-weeks old chickens after acute heat stress (42°C for 90 min). The results show, that prenatal temperature experiences can induce long-lasting changes in the heat induced neuronal hypothalamic c-Fos expression. But significant alterations could be only found in 8 weeks old chickens and these changes were in opposite as expected. It means that after acute heat stress cold incubated chickens have a significantly lower neuronal c-Fos expression compared with the warm incubated ones. This effect could be caused by cross adaptation to the actual ambient temperature during the growing period. Further, the developmental pattern of the hypothalamic neuronal network in different incubated birds, which is demonstrated by neuronal c-Fos expression in the actual study, is similar to the pattern, which we found after recordings of single neurons activity, to a higher extent. Correlations between both parameters, which are involved in neuronal plasticity, can be accepted.

Abrupt rather than gradual hormonal changes induce postpartum blues-like behavior in rats

Aims Postpartum blues is thought to be related to hormonal events accompanying delivery. We investigated whether blues-like symptoms depend on the rate of the decline of hormones, by comparing the behavioral consequences of an abrupt versus a gradual decline of gonadal hormones in an animal model. Methods Female rats were treated with estrogen and progesterone for 23 days, administered either by injections or by subcutaneously implanted tubes filled with hormones. A gradual hormone decline was achieved by discontinuation of the injections; and rapid decline by removal of the tubes. Control groups received either a continued treatment or no hormones. In the period following the decline the stress-reactivity was tested with an acoustic startle test on 3 consecutive days, and anxiety behavior with an open-field test on the 2nd day. The Hypothalamus-, Pituitary-, Adrenal-axis (HPA-axis) response to stress was measured by assessing the corticosterone levels and hypothalamic c-fos expression stress-response at the 4th day. Key findings The rapid decline of hormones induced an increased startle response lasting for two days, and increased anxiety-like behavior in the open field. This was not found in the gradual-decline and control groups. The HPA-axis response to stress was decreased in all hormone-treated animals. Significance This animal study suggests that: 1) abrupt rather than gradual hormonal changes induce increased stress-reactivity and anxiety-like behavior; 2) postpartum blues may result from differences in the capacity to adapt to the changes of gonadal hormones; 3) Recovery of pregnancy-induced diminished HPA-axis response is independent of the postpartum hormone kinetics.

Ingestion of non-caloric liquid diet is sufficient to restore plasma corticosterone level, but not to induce the hypothalamic c-Fos expression in food-deprived rats

Male Sprague-Dawley rats were subjected to four different conditions; free fed control (FC), 48 h of food deprivation (FD), 1 h of refeeding with chow (RF/CW) or with a non-caloric liquid diet following FD (RF/NC) and then sacrificed for c-Fos immunohistochemistry in the hypothalamic paraventricular nucleus (PVN) and the nucleus tractus of solitarius (NTS). Plasma corticosterone level and the postmortem weight of gastric contents were measured. Plasma level of corticosterone significantly increased during FD, and then decreased within 1 h after ad libitum access to chow or non-caloric liquid diet. c-Fos-ir in the brain regions was not changed by FD; however, significantly increased by chow refeeding, but not by non-caloric diet. Chow, but not the non-caloric, refeeding significantly increased gastric contents. Results suggest that caloric load and/or gastric distension may require for the postprandial activation of neurons in the PVN and NTS, but ingestion of non-caloric palatable mixture may be sufficient to normalize the fasting-induced increase of plasma corticosterone. In conclusion, feeding-related changes in the HPA axis activity may not be related with meal-induced c-Fos expression in the PVN and NTS.

Hindbrain Noradrenergic Lesions Attenuate Anorexia and Alter Central cFos Expression in Rats after Gastric Viscerosensory Stimulation

Behavioral, autonomic, and endocrine outputs of the CNS are subject to important feedback modulation by viscerosensory signals that are conveyed initially to the hindbrain nucleus of the solitary tract (NST). In the present study, noradrenergic (NA) neurons [i.e., those that express the NA synthetic enzyme dopamine beta hydroxylase (DbH)] in the caudal NST were lesioned to determine their role in mediating anorexic responses to gastric stimulation and in conveying gastric sensory signals to the hypothalamus and amygdala. For this purpose, saporin toxin conjugated to an antibody against DbH was microinjected bilaterally into the caudal NST in adult rats. Control rats received similar microinjections of vehicle. Several weeks later, rats were tested for the ability of systemic cholecystokinin octapeptide (CCK) (0 or 10 microg/kg) to inhibit food intake. CCK-induced anorexia was significantly attenuated in toxin-treated rats. Rats subsequently were used in a terminal cFos study to determine central neural activation patterns after systemic CCK or vehicle and to evaluate lesion extent. Toxin-induced loss of DbH-positive NST neurons was positively correlated with loss of CCK-induced anorexia. Hypothalamic cFos expression was markedly attenuated in lesioned rats after CCK treatment, whereas CCK-induced neural activation in the parabrachial nucleus and amygdala appeared normal. These findings suggest that hindbrain NA neurons are an integral component of brainstem circuits that mediate CCK-induced anorexia and also are necessary for hypothalamic but not parabrachial or amygdala responses to gastric sensory stimulation.

Effect of NOS inhibition on central response to atrial distension during pregnancy.

Atrial distension increases c-fos expression in the paraventricular nucleus of virgin, but not pregnant, rats. We proposed that nitric oxide (NO), biosynthesis of which increases during pregnancy, blunts this reflex and that blocking NO biosynthesis would restore the response. Female rats were implanted with indwelling intracardiac balloons. On day 14 of pregnancy, osmotic minipumps containing either D- or N(G)-nitro-L-arginine methyl ester (L-NAME) (120 mg/2 ml at 10 microg/min) were implanted. On day 20, the rats were infused with saline (3 ml/h) with or without atrial balloon inflation (1 h). The brains were then processed for quantitation of c-fos expression. In the virgin rats, and in the pregnant rats treated with L-NAME, atrial distension significantly increased hypothalamic c-fos expression. In the pregnant animals treated with D-NAME, the response was greatly attenuated. NO had no effect on the increase in atrial receptor afferent discharge (single-fiber recordings) elicited by atrial distension. We conclude that, during pregnancy, NO attenuates central processing of the reflex response to atrial distension but does not alter the transducer properties of the volume receptors.

C-Fos gene expression pattern in the hypothalamus and the preoptic area of defeminized rats

The object of the present study was to determine the c-fos gene expression pattern in the hypothalamus (HYP) and the preoptic area (POA) after estradiol and testosterone priming during the critical period of sexual differentiation of the rat brain. Three-day-old female rats were injected s.c. with a single dose of 17β-estradiol (200 μg), testosterone enantate (200 μg) or vehicle (corn oil). HYP and POA were dissected 2 h, 24 h and 14 days after treatments and on the day of vaginal opening (VO). Other animals, previously treated as above, were acutely injected with 17β-estradiol (5 μg) on the day of VO; HYP and POA were obtained 3 h later. Total RNA was extracted and processed for semiquantitative RT-PCR. We observed that c-fos gene expression was markedly increased in POA of the animals treated with estradiol or testosterone 2 h after treatments, while a non-significant increase in c-fos gene expression was observed in the HYP of these animals. We found a significant increase in c-fos expression in HYP and POA on the day of VO in both estradiol and testosterone defeminized rats. Interestingly, the acute estradiol administration on the day of VO did not induce c-fos gene expression in either HYP or POA of defeminized animals, instead a diminution in its expression was observed in animals treated with testosterone in POA. The overall results suggest that estradiol and testosterone imprinting during critical postnatal period of sexual differentiation of the brain permanently modifies the regulation of c-fos gene expression.

Heatstroke induces c-fos expression in the rat hypothalamus

We induced heat stress in urethane-anesthetized rats (the animals were exposed to an ambient temperature at 42°C), and monitored their colon temperature, mean arterial pressure and local cerebral blood flow. Rats 0, 20, 40 or 80 min after heat stress were sacrificed for determination of c-fos mRNA and protein expression in the paraventricular nucleus (PVN), supraoptic nucleus (SON) and preoptic nucleus (PON). The heatstroke, which appears as profound decreases in both mean arterial pressure and local cerebral blood flow and increases in colon temperature, is produced 80 min after heat stress. We show the c-fos mRNA and protein is strongly induced in all these nuclei of rat hypothalamus after the onset of heatstroke. We conclude that c-fos expression in the hypothalamus during rat heatstroke is associated with hyperthermia, arterial hypotension and cerebral ischemia.

Neonatal hypothalamic c-fos expression in an excitotoxicity-induced model of precocious puberty

We have used immunocytochemical detection of c-fos expression (FOS-like immunoreactivity, FLI) to establish the site of action of monosodium glutamate (MSG) in neonatal rats in a model of lesion-induced precocious puberty. The primary target appears to be the hypothalamic arcuate nucleus (ARC) but other circumventricular organs (CVO) are also affected (e.g. subfornical organ). Single injections of MSG (1–4 mg/g single dose, postnatal day 2 (P2)) which result in precocious puberty induce an area of edema, surrounded by a ring of FLI in the basal hypothalamus. In contrast, a maximal sub-lethal dose of NMDA ( N-methyl- d-aspartate; 3 mg/kg) which produces a different pattern of ARC FLI, without edema, has no effect on puberty. Multiple doses of MSG (4 mg/g P2, P4, P6, P8), consistent with severe ARC damage and resultant sterility, markedly attenuates the FLI response by P8, with no visible edematous reaction following the final injection. In efforts to block the effect of MSG, pretreatment with the NMDA receptor-specific antagonist MK-801 (dizocilpine maleate) prevented the appearance of edema, as well as the onset of precocious puberty. However, MK-801 did not completely eliminate the FLI, but transformed the pattern of staining so that the original edematous area now contained many FOS-positive cells. This remaining MSG-induced FLI could not be eliminated by higher doses of MK-801 or by the non-NMDA antagonist DNQX (6,7-dinitroquinoxaline-2,3-dione). The combination of MK-801 and DNQX was also ineffective. MK-801 or DNQX had no effect on FLI when injected alone (i.e., without MSG) or in combination. The receptor which mediates MSG-induced c-fos expression, in the presence of MK-801 or DNQX, needs to be identified. We conclude, in conjunction with our previous work, that MSG induces precocious sexual maturation via an MK-801-sensitive mechanism associated with an edematous response of the basal hypothalamus. Whether the appearance of edema is indicative of an excitotoxic action of MSG, resulting in the removal of neurons inhibitory to sexual maturation, remains to be established.

Interrelated adrenocortical and neurohypophysial responses associated with fever in endotoxin-treated pigs.

Low intravenous doses of endotoxin [lipopolysaccharide (LPS), 0.7 microgram/kg] induce monophasic fever, increase anterior and posterior pituitary hormone release, and enhance hypothalamic c-Fos expression in pigs, all of which can be prevented by indomethacin (Ind). The present study shows that the synthetic corticosteroid dexamethasone (Dex, 5 mg/kg) has a similar action to Ind and, when given alone, lowers core temperature. In addition, the corticosteroid synthesis inhibitor metyrapone (Met, 3.3 mg/kg, every one-half hour) reduces LPS fever and amplifies the effect of LPS on vasopressin, but not on oxytocin, release. The similar actions of Dex and Ind suggest that phospholipase A2 pathways controlling prostaglandin synthesis mediate the responses of prepubertal pigs to immunological challenge with LPS. The increased vasopressin release induced when animals receiving Met are also given LPS supports findings in other nonrodent species indicating an inverse relationship between cortisol and vasopressin. The attenuation of LPS fever by Met is suggestive of an endogenous antipyretic mechanism associated with enhanced neurohypophysial vasopressin secretion.