[Severe hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone]. / Severa iponatriemia secondaria a sindrome da inappropriata secrezione di ormone antidiuretico.

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a common and multifactorial cause of hyponatremia that is often overlooked. The common pathophysiological mechanism is the increased production and/or action of antidiuretic hormone within the kidney, resulting in hypotonic hyponatremia. Inadequate correction of hyponatremia may have fatal neurological consequences leading to central pontine myelinolysis. We report the case of a patient with a history of recent head trauma, who came to our observation for acute-onset mental confusion secondary to severe hyponatremia due to SIADH of combined etiology.

Rhythmic cFos expression in the ventral subparaventricular zone influences general activity rhythms in the Nile grass rat, Arvicanthis niloticus.

Circadian rhythms in behavior and physiology are very different in diurnal and nocturnal rodents. A pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus is responsible for generating and maintaining circadian rhythms in mammals, and cellular and molecular rhythms within the SCN of diurnal and nocturnal rodents are very similar. The neural substrates determining whether an animal has a diurnal or nocturnal phase preference are thus likely to reside downstream of the SCN. The ventral subparaventricular zone (vSPVZ), a major target of the SCN that is important for the expression of circadian rhythmicity in nocturnal lab rats (Rattus norvegicus), exhibits different rhythms in cFos expression in diurnal Nile grass rats compared to lab rats. We examined the effects of chemotoxic lesions of the cFos-expressing cells of the vSPVZ on activity rhythms of grass rats to evaluate the hypothesis that these cells support diurnality in this species. Male grass rats housed in a 12:12 light:dark (LD) cycle were given bilateral injections of the neurotoxin n-methyl-D-L-aspartic acid (NMA) or vehicle aimed at the vSPVZ; cells in the SCN are resistant to NMA, which kills neurons in other brain regions, but leaves fibers of passage intact. vSPVZ-damaged grass rats exhibited highly unstable patterns of activity in constant darkness (DD) and in the LD cycle that followed. However, crepuscular bouts of activity could be seen in all animals with vSPVZ lesions. Damage to the vSPVZ reduced cFos expression in this area but not in the SCN. Using correlational analyses, we found that the number of cFos-ir cells in the vSPVZ was unrelated to several parameters of the activity rhythms during the initial post-surgical period, when animals were in LD. However, the number of cells expressing cFos in the vSPVZ was positively correlated with general activity during the subjective day relative to the subjective night when the animals were switched to DD, and this pattern persisted when a LD cycle was reinstated. Also, the number of cFos-ir cells in the vSPVZ was negatively correlated with the strength of rhythmicity in DD and the number of days required to re-entrain to a LD cycle following several weeks in DD. These data suggest that the vSPVZ emits signals important for the expression of stable diurnal activity patterns in grass rats, and that species differences in these signals may contribute to differences in behavioral and physiological rhythms of diurnal and nocturnal mammals. (Author correspondence: mschw009@umaryland.edu ).

Chronic repeated restraint stress increases prolactin-releasing peptide/tyrosine-hydroxylase ratio with gender-related differences in the rat brain.

In this study, we investigated the effect of chronic repeated restraint (RR) on prolactin-releasing peptide (PrRP) expression. In the brainstem, where PrRP colocalize with norepinephrine in neurons of the A1 and A2 catecholaminergic cell groups, the expression of tyrosine hydroxylase (TH) has also been examined. In the brainstem, but not in the hypothalamus, the basal PrRP expression in female rats was higher than that in the males that was abolished by ovariectomy. RR evoked an elevation of PrRP expression in all areas investigated, with smaller reaction in the brainstems of females. There was no gender-related difference in the RR-evoked TH expression. Elevation of PrRP was relatively higher than elevation of TH, causing a shift in PrRP/TH ratio in the brainstem after RR. Estrogen alpha receptors were found in the PrRP neurons of the A1 and A2 cell groups, but not in the hypothalamus. Bilateral lesions of the hypothalamic paraventricular nucleus did not prevent RR-evoked changes. Elevated PrRP production parallel with increased PrRP/TH ratio in A1/A2 neurons indicate that: (i) there is a clear difference in the regulation of TH and PrRP expression after RR, and (ii) among other factors this may also contribute to the changed sensitivity of the hypothalamo-pituitary-adrenal axis during chronic stress.

Transforming growth factor-beta in the brain enhances fat oxidation via noradrenergic neurons in the ventromedial and paraventricular hypothalamic nucleus.

We have previously reported that intracisternal administration of TGF-beta induces an increase in fat oxidation and that intracisternal administration of anti-TGF-beta antibody partially inhibits an increase in fat oxidation during treadmill running in rats. These results indicate a regulatory role of that TGF-beta in the brain on fat oxidation during exercise. However, it is not clear how TGF-beta in the brain enhance fat oxidation. We hypothesized that TGF-beta in the brain elicits its regulatory effects on fat oxidation via hypothalamic noradrenergic neurons, because some reports have demonstrated the important role of hypothalamic noradrenergic neurons in the regulation of fat oxidation during and after exercise. To examine this hypothesis, we measured the extracellular noradrenaline (NA) levels in the paraventricular hypothalamic nucleus (PVH), ventromedial hypothalamic nucleus (VMH) and lateral hypothalamic area, which are especially important in the regulation of energy metabolism, after intracisternal administration of TGF-beta by using an in vivo brain microdialysis. Microdialysis study revealed that intracisternal administration of TGF-beta3 caused increases in the NA levels in the PVH and VMH. Then, we investigated the impact of impairment of noradrenergic neurons in the PVH and VMH by neurotoxin 6-hydroxydopamine microinjection (NA-lesion) on the action of intracisternal administration of TGF-beta. The NA lesion completely abolished the regulatory effect of TGF-beta on fat oxidation. These results suggest that TGF-beta in the brain enhances fat oxidation via noradrenergic neurons in the PVH and VMH.

Specificity and generality of the involvement of catecholaminergic afferents in hypothalamic responses to immune insults.

Catecholamine-containing projections from the medulla have been implicated in the mediation of activational responses of the paraventricular nucleus of the hypothalamus (PVH) provoked by moderate doses of interleukin-1 (IL-1). To test the generality of this mechanism, rats bearing unilateral transections of aminergic projections were challenged with intravenous IL-1 (2 microg/kg), bacterial lipopolysaccharide (LPS; 0.1, 2.0, or 100 microg/kg), or saline and perfused 3 hours later; their brains were then prepared for quantitative analysis of Fos induction and relative levels of corticotropin-releasing factor (CRF) mRNA. LPS provoked a robust and dose-related increase in Fos expression within the PVH on the intact side of the brain at all doses tested; the response to IL-1 approximated that to the lowest LPS dose. On the lesioned side, Fos induction was significantly reduced at all dosage levels but was eliminated only at the lowest dosage. The percentage reduction was greatest (75%) in IL-1-challenged rats and was progressively less in animals treated with increasing LPS doses (67, 59, and 46%, respectively). Specificity of aminergic involvement was tested by using intra-PVH administration of the axonally transported catecholamine immunotoxin, antiDBH-saporin. This treatment abolished IL-1-induced elevations of Fos-ir and CRF mRNA in the PVH but left intact comparable responses to restraint stress. These data support a specific involvement of ascending catecholaminergic projections in mediating PVH responses to IL-1 and LPS. Residual Fos induction seen in lesioned animals in response to higher doses of LPS provides a basis for probing additional circuits that may be recruited in a hierarchical manner in response to more strenuous or complex immune insults.

Neural substrate of cold-seeking behavior in endotoxin shock.

Systemic inflammation is a leading cause of hospital death. Mild systemic inflammation is accompanied by warmth-seeking behavior (and fever), whereas severe inflammation is associated with cold-seeking behavior (and hypothermia). Both behaviors are adaptive. Which brain structures mediate which behavior is unknown. The involvement of hypothalamic structures, namely, the preoptic area (POA), paraventricular nucleus (PVH), or dorsomedial nucleus (DMH), in thermoregulatory behaviors associated with endotoxin (lipopolysaccharide [LPS])-induced systemic inflammation was studied in rats. The rats were allowed to select their thermal environment by freely moving in a thermogradient apparatus. A low intravenous dose of Escherichia coli LPS (10 microg/kg) caused warmth-seeking behavior, whereas a high, shock-inducing dose (5,000 microg/kg) caused cold-seeking behavior. Bilateral electrocoagulation of the PVH or DMH, but not of the POA, prevented this cold-seeking response. Lesioning the DMH with ibotenic acid, an excitotoxin that destroys neuronal bodies but spares fibers of passage, also prevented LPS-induced cold-seeking behavior; lesioning the PVH with ibotenate did not affect it. Lesion of no structure affected cold-seeking behavior induced by heat exposure or by pharmacological stimulation of the transient receptor potential (TRP) vanilloid-1 channel ("warmth receptor"). Nor did any lesion affect warmth-seeking behavior induced by a low dose of LPS, cold exposure, or pharmacological stimulation of the TRP melastatin-8 ("cold receptor"). We conclude that LPS-induced cold-seeking response is mediated by neuronal bodies located in the DMH and neural fibers passing through the PVH. These are the first two landmarks on the map of the circuitry of cold-seeking behavior associated with endotoxin shock.

Suprachiasmatic control of melatonin synthesis in rats: inhibitory and stimulatory mechanisms.

The suprachiasmatic nucleus (SCN) controls the circadian rhythm of melatonin synthesis in the mammalian pineal gland by a multisynaptic pathway including, successively, preautonomic neurons of the paraventricular nucleus (PVN), sympathetic preganglionic neurons in the spinal cord and noradrenergic neurons of the superior cervical ganglion (SCG). In order to clarify the role of each of these structures in the generation of the melatonin synthesis rhythm, we first investigated the day- and night-time capacity of the rat pineal gland to produce melatonin after bilateral SCN lesions, PVN lesions or SCG removal, by measurements of arylalkylamine N-acetyltransferase (AA-NAT) gene expression and pineal melatonin content. In addition, we followed the endogenous 48 h-pattern of melatonin secretion in SCN-lesioned vs. intact rats, by microdialysis in the pineal gland. Corticosterone content was measured in the same dialysates to assess the SCN lesions effectiveness. All treatments completely eliminated the day/night difference in melatonin synthesis. In PVN-lesioned and ganglionectomised rats, AA-NAT levels and pineal melatonin content were low (i.e. 12% of night-time control levels) for both day- and night-time periods. In SCN-lesioned rats, AA-NAT levels were intermediate (i.e. 30% of night-time control levels) and the 48-h secretion of melatonin presented constant levels not exceeding 20% of night-time control levels. The present results show that ablation of the SCN not only removes an inhibitory input but also a stimulatory input to the melatonin rhythm generating system. Combination of inhibitory and stimulatory SCN outputs could be of a great interest for the mechanism of adaptation to day-length (i.e. adaptation to seasons).

Neuroregulative mechanism of hypothalamic paraventricular nucleus on gastric ischemia-reperfusion injury in rats.

A rat model of gastric ischemia-reperfusion injury (GI-RI) was established by clamping the celiac artery for 30 min and allowing reperfusion for 1 h, on which the regulatory effect of the paraventricular nucleus (PVN) and its neural mechanisms were investigated. The results were: 1. Electrical stimulation of the PVN obviously attenuated the GI-RI. Microinjection of L-glutamic acid into PVN produced an effect similar to that of PVN stimulation. 2. Electrolytic ablation of the PVN aggravated the GI-RI. 3. Nucleus tractus solitarius (NTS) ablation could eliminate the protective effect of electrical stimulation of PVN on GI-RI. 4. Hypophysectomy did not alter the effect of electrical stimulation of PVN. 5. Vagotomy or sympathectomy both could increase the effect of PVN stimulation on GI-RI. These results indicate that the PVN participates in the development of GI-RI as a specific area in the CNS, exerting protective effects on the GI-RI. The NTS and vagus and sympathetic nerve may be involved in the regulative mechanism of PVN on GI-RI, but the PVN mechanism here is independent of the PVN-hypophyseal pathway.

Paraventricular-subparaventricular hypothalamic lesions selectively affect circadian function.

The circadian timing system has three principal components: (i) entrainment pathways, (ii) pacemakers, and (iii) efferent pathways from the pacemakers that convey the circadian signal to effector systems. The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal mammalian circadian pacemaker and, although we understand the organization of entrainment pathways to the SCN and the pacemaker itself, we know much less about the functional organization of SCN projections mediating control of effector systems. It is unclear, for example, whether specific subsets of SCN projections control specific effector systems. In this study, we analyzed the effects of lesions ablating the paraventricular hypothalamic nucleus (PVH), with variable extension into the subparaventricular zone (SPVZ) and adjacent structures, on nocturnal pineal melatonin production and rhythms in core body temperature (Tb) and rest-activity (R-A). In accordance with prior work, ablation of the PVH abolishes the nocturnal rise in pineal melatonin. Lesions restricted to the PVH do not affect rhythms in Tb and R-A but lesions extending caudally and ventrally into the SPVZ disrupt the R-A rhythm proportionate to the interruption of caudal SCN projections without affecting the rhythm in Tb. We conclude that pacemaker regulation of the circadian rhythms analyzed in this study is mediated by discrete sets of SCN projections: (i) dorsal projections to the PVH control pineal melatonin production; (ii) rostral projections to the anterior hypothalamic/preoptic areas mediate the Tb rhythm; and (iii) caudal projections to the SPVZ and hypothalamic arousal systems located in the posterior and lateral hypothalamic areas control the rhythm in R-A.

Obesity-inducing lesions of the central nervous system alter leptin uptake by the blood-brain barrier.

Leptin regulates body adiposity by decreasing feeding and increasing thermogenesis. Obese humans and some obese rodents are resistant to peripherally administered leptin, suggesting a defect in the transport of leptin across the blood-brain barrier (BBB). Defective transport of exogenous leptin occurs in some models of obesity, but in other models transport is normal. This shows that factors other than obesity are associated with impairment of leptin transport across the BBB. In order to further investigate these factors, we determined leptin transport in rats made obese by lesioning of the ventromedial hypothalamus (VMH), paraventricular nucleus (PVN), or posterodorsal amygdala (PDA). These regions all contain leptin receptors and lesions there induce obesity and hyperleptinemia and alter the levels of many feeding hormones which might participate in leptin transporter regulation. We measured the uptake of radioactively labeled leptin by the BBB by multiple-time regression analysis which divides uptake into a reversible phase (Vi, e.g., receptor/transporter binding to the brain endothelial cell) and an irreversible phase (Ki, complete transport across the BBB). Leptin uptake was not affected in rats with VMH lesions. No significant change occurred in the entry rate (Ki) for any group, although Ki declined by over 35% in rats with PVN lesions. Decreased uptake was observed in rats with PVN lesions and with PDA lesions. This was primarily due to a reduced Vi (about 21% for the PDA). This decreased uptake is most likely explained by decreased binding of leptin to the brain endothelial cell, which could be because of decreased binding by either receptors or transporters. This suggests that some of the feeding hormones controlled by the PVN and PDA may participate in regulating leptin uptake by the BBB.

Immunotoxic destruction of distinct catecholamine subgroups produces selective impairment of glucoregulatory responses and neuronal activation.

The toxin-antibody complex anti-d(beta)h-saporin (DSAP) selectively destroys d(beta)h-containing catecholamine neurons. To test the role of specific catecholamine neurons in glucoregulatory feeding and adrenal medullary secretion, we injected DSAP, unconjugated saporin (SAP), or saline bilaterally into the paraventricular nucleus of the hypothalamus (PVH) or spinal cord (T2-T4) and subsequently tested rats for 2-deoxy-D-glucose (2DG)-induced feeding and blood glucose responses. Injections of DSAP into the PVH abolished 2DG-induced feeding, but not hyperglycemia. 2DG-induced Fos expression was profoundly reduced or abolished in the PVH, but not in the adrenal medulla. The PVH DSAP injections caused a nearly complete loss of tyrosine hydroxylase immunoreactive (TH-ir) neurons in the area of A1/C1 overlap and severe reduction of A2, C2, C3 (primarily the periventricular portion), and A6 cell groups. Spinal cord DSAP blocked 2DG-induced hyperglycemia but not feeding. 2DG-induced Fos-ir was abolished in the adrenal medulla but not in the PVH. Spinal cord DSAP caused a nearly complete loss of TH-ir in cell groups A5, A7, subcoeruleus, and retrofacial C1 and a partial destruction of C3 (primarily the ventral portion) and A6. Saline and SAP control injections did not cause deficits in 2DG-induced feeding, hyperglycemia, or Fos expression and did not damage catecholamine neurons. DSAP eliminated d(beta)h immunoreactivity but did not cause significant nonspecific damage at injection sites. The results demonstrate that hindbrain catecholamine neurons are essential components of the circuitry for glucoprivic control of feeding and adrenal medullary secretion and indicate that these responses are mediated by different subpopulations of catecholamine neurons.

Impaired sexual response after lesions of the paraventricular nucleus of the hypothalamus in male rats.

N-methyl-D-aspartic acid (NMDA) or radiofrequency (RF) lesions were made in the paraventricular nucleus of the hypothalamus (PVH) of male rats. The rats were tested for copulation, noncontact erection (NCE) evoked by remote cues from estrous females, and (after RF lesions) reflexive erection. NMDA, which destroyed parvocellular but spared magnocellular neurons, caused no deficits in copulation but caused longer NCE latencies and fewer NCEs. Rats with RF lesions had parvo- and magnocellular neuron damage; these males copulated to ejaculation, but they had lower intromission ratios and longer ejaculatory latencies. RF-lesioned rats also had longer NCE latencies, and a smaller proportion of males displayed reflexive erection. Results indicate that the PVH participates in mediating erectile function in copula and ex copula, and that the parvo- and magnocellular PVH neurons may have different roles in mediating erection.

Effect of paraventricular nucleus lesion and cold restraint stress on gastric emptying of a liquid meal in rats.

The effects of cold restraint stress on gastric emptying (GE) and the involvement of the hypothalamic paraventricular nucleus (PVN) were investigated in male Wistar rats (200-250 g body weight). Electrolytic lesions were produced stereotaxically in the nucleus by passing a 2.0-mA current for 10 s through stainless steel electrodes. GE was measured by means of a liquid test meal of 5% (w/v) glucose solution plus phenol red (6 mg/dl) dye as marker, given by orogastric infusion. Cold restraint stress induces a significant increase (43.7%, N = 11) in gastric retention of a 5% glucose solution in rats, i.e., a delay in GE of this solution. However, restraint stress alone does not produce any change. Both truncal vagotomy and electrolytic lesion of the PVN completely block the cold restraint-induced delay in GE. However, PVN lesion per se results in a decrease of GE (30.6%, N = 10) when compared to nonoperated controls. In addition, PVN-lesioned rats exposed to cold restraint present a slightly faster GE (14.7%, N = 11) than controls, demonstrating an opposite response to that initially observed without lesion. These data suggest an important role for PVN efferents, probably influencing medullary vagal preganglionic neurons, in the development of this gastric motor impairment under stress conditions.

Effect of paraventricular nucleus lesion and cold restraint stress on gastric emptying of a liquid meal in rats

The effects of cold restraint stress on gastric emptying (GE) and the involvement of the hypothalamic paraventricular nucleus (PVN) were investigated in male Wistar rats (200-250 g body weight). Electrolytic lesions were produced stereotaxically in the nucleus by passing a 2.0-mA current for 10 s through stainless steel electrodes. GE was measured by means of a liquid test meal of 5 per cent (w/v) glucose solution plus phenol red (6 mg/dl) dye as marker, given by orogastric infusion. Cold restraint stress induces a significant increase (43.7 per cent , N = 11) in gastric retention of a 5 per cent glucose solution in rats, i.e., a delay in GE of this solution. However, restraint stress alone does not produce any change. Both truncal vagotomy and electrolytic lesion of the PVN completely block the cold restraint-induced delay in GE. However, PVN lesion per se results in a decrease of GE (30.6 per cent , N = 10) when compared to nonoperated controls. In addition, PVN-lesioned rats exposed to cold restraint present a slightly faster GE (14.7 per cent , N = 11) than controls, demonstrating an opposite response to that initially observed without lesion. These data suggest an important role for PVN efferents, probably influencing medullary vagal preganglionic neurons, in the development of this gastric motor impairment under stress conditions

Corticotropin-releasing hormone-containing neurons in the hypothalamo-hypophyseal system in rats six weeks after bilateral lesions of the paraventricular nucleus.

Corticotropin-releasing factor-like immunoreactive nerve fibers and varicosities are present in the pituitary stalk and median eminence 6 weeks after bilateral lesioning of the hypothalamic paraventricular nucleus. The total immunoreactivity may reach 10% of the control density. The origin of these fibers was investigated 3 days after hypothalamic transections in paraventricular-lesioned (6 weeks postoperatively) rats. Accumulations of corticotropin-releasing factor immunostaining were observed in the proximal portions of the transected axons and in neuronal perikarya. Fibers with retrograde labeling were seen lateral and dorsolateral from the sagittally oriented knife cuts which transected the retrochiasmatic area and cells were found in the supraoptic nucleus and in the perifornical nucleus (dorsal-dorsolateral to the fornix), ipsilateral to the lesion. No corticotropin-releasing factor immunostained cells were seen in other hypothalamic or preoptic nuclei which project to the median eminence or the posterior pituitary. Corticotropin-releasing factor containing cells in the supraoptic and perifornical nuclei may have an importance in stress response in rats with long-term paraventricular lesions.

[Effect of fasting on the function of the islands of Langerhans in rats with hypothalamic obesity]. / Vliianie golodaniia na funktsional'noe sostoianie pankreaticheskikh ostrovkov pri gipotalamicheskom ozhirenii u krys.

Experiments were conducted on albino rats with hypothalamic adiposity caused by electrolyte damage of the area of the ventro-medial nuclei of the hypothalamus; it was shown that the character of food regimen had a significant effect on the function of the islar apparatus of the pancreas and glucose tolerance. There was a marked increase in functional activity of the beta-cells of the pancreatic islands and disturbed carbohydrate tolerance in the animals kept on food rich in carbohydrates. Prolonged starvation in rats with hypothalamic adiposity decreased the morphometric indices of overstrain in the insulinogenic tissue, and normalized the glycemic curves.

Male-like sexual behaviour of female rats with unilateral lesions in the hypothalamic ventromedial nuclear region.

In castrated female rats treated with androgen or oestrogen a significant decrease of female sexual behaviour assocated with a significant increase of male sexual behaviour was induced by unilateral lesions of the hypothalamic ventromedial nucleus.