The origins of the circumventricular organs.

The circumventricular organs (CVOs) are specialised neuroepithelial structures found in the midline of the brain, grouped around the third and fourth ventricles. They mediate the communication between the brain and the periphery by performing sensory and secretory roles, facilitated by increased vascularisation and the absence of a blood-brain barrier. Surprisingly little is known about the origins of the CVOs (both developmental and evolutionary), but their functional and organisational similarities raise the question of the extent of their relationship. Here, I review our current knowledge of the embryonic development of the seven major CVOs (area postrema, median eminence, neurohypophysis, organum vasculosum of the lamina terminalis, pineal organ, subcommissural organ, subfornical organ) in embryos of different vertebrate species. Although there are conspicuous similarities between subsets of CVOs, no unifying feature characteristic of their development has been identified. Cross-species comparisons suggest that CVOs also display a high degree of evolutionary flexibility. Thus, the term 'CVO' is merely a functional definition, and features shared by multiple CVOs may be the result of homoplasy rather than ontogenetic or phylogenetic relationships.

Chemotherapy-Induced Pica in Rats Reduced by Electroacupuncture.

OBJECTIVES: Acupuncture or electroacupuncture (EA) has been applied for treating chemotherapy-induced emesis with limited success. The aims of this study were to investigate the anti-emetic effect of EA and to explore underlying anti-emetic mechanisms. MATERIALS AND METHODS: Rats were chronically implanted with a pair of stainless steel leads at acupoint pericardium 6 (PC6). Effects of EA with different parameters on cisplatin-induced nausea were assessed by pica (intake of kaolin, a surrogate of nausea in species without vomiting reflex). C-fos expressions in the area postrema (AP) and nucleus tractus solitarii (NTS) were analyzed. Subdiaphragmatic vagotomy was used to study involvement of the vagal pathway. RESULTS: 1) EA at 20 Hz/0.6 msec reduced kaolin intake in the first and second days after cisplatin injection compared with the sham-EA group (first day: 1.0 ± 0.2 vs. 1.9 ± 0.3 g, p = 0.017; second day: 0.4 ± 0.2 vs.1.1 ± 0.3 g, p = 0.010). However, EA at 10 Hz/1.2 msec was ineffective on both days. 2) Subdiaphragmatic vagotomy significantly reduced cisplatin-induced kaolin intake (1.1 ± 0.3 vs. 2.2 ± 0.3 g, p = 0.014) and also blocked the inhibitory effect of EA on kaolin intake in the first day. 3) Cisplatin significantly increased the expression of c-fos in the NTS and AP. Vagotomy greatly reduced c-fos expression in both NTS and AP. EA reduced the cisplatin-induced c-fos expression in the AP but not the NTS. CONCLUSIONS: EA at PC6 with appropriate parameters has an inhibitory effect on cisplatin-induced nausea. The anti-emetic effect of the EA is centrally medicated involving the AP via the vagal pathway as well as the potential effect on AP by reducing the release of hormones.

Role of the area postrema in the hypophagic effects of oleoylethanolamide.

The satiety-promoting action of oleoylethanolamide (OEA) has been associated to the indirect activation of selected brain areas, such as the nucleus of the solitary tract (NST) in the brainstem and the tuberomammillary (TMN) and paraventricular (PVN) nuclei in the hypothalamus, where noradrenergic, histaminergic and oxytocinergic neurons play a necessary role. Visceral ascending fibers were hypothesized to mediate such effects. However, our previous findings demonstrated that the hypophagic action of peripherally administered OEA does not require intact vagal afferents and is associated to a strong activation of the area postrema (AP). Therefore, we hypothesized that OEA may exert its central effects through the direct activation of this circumventricular organ. To test this hypothesis, we subjected rats to the surgical ablation of the AP (APX rats) and evaluated the effects of OEA (10mgkg-1 i.p.) on food intake, Fos expression, hypothalamic oxytocin (OXY) immunoreactivity and on the expression of dopamine beta hydroxylase (DBH) in the brainstem and hypothalamus. We found that the AP lesion completely prevented OEA's behavioral and neurochemical effects in the brainstem and the hypothalamus. Moreover OEA increased DBH expression in AP and NST neurons of SHAM rats while the effect in the NST was absent in APX rats, thus suggesting the possible involvement of noradrenergic AP neurons. These results support the hypothesis of a necessary role of the AP in mediating OEA's central effects that sustain its pro-satiety action.

Estradiol selectively reduces central neural activation induced by hypertonic NaCl infusion in ovariectomized rats.

We recently reported that the latency to begin drinking water during slow, intravenous infusion of a concentrated NaCl solution was shorter in estradiol-treated ovariectomized rats compared to oil vehicle-treated rats, despite comparably elevated plasma osmolality. To test the hypothesis that the decreased latency to begin drinking is attributable to enhanced detection of increased plasma osmolality by osmoreceptors located in the CNS, the present study used immunocytochemical methods to label fos, a marker of neural activation. Increased plasma osmolality did not activate the subfornical organ (SFO), organum vasculosum of the lamina terminalis (OVLT), or the nucleus of the solitary tract (NTS) in either oil vehicle-treated rats or estradiol-treated rats. In contrast, hyperosmolality increased fos labeling in the area postrema (AP), the paraventricular nucleus of the hypothalamus (PVN) and the rostral ventrolateral medulla (RVLM) in both groups; however, the increase was blunted in estradiol-treated rats. These results suggest that estradiol has selective effects on the sensitivity of a population of osmo-/Na(+)-receptors located in the AP, which, in turn, alters activity in other central areas associated with responses to increased osmolality. In conjunction with previous reports that hyperosmolality increases blood pressure and that elevated blood pressure inhibits drinking, the current findings of reduced activation in AP, PVN, and RVLM-areas involved in sympathetic nerve activity-raise the possibility that estradiol blunts HS-induced blood pressure changes. Thus, estradiol may eliminate or reduce the initial inhibition of water intake that occurs during increased osmolality, and facilitate a more rapid behavioral response, as we observed in our recent study.

Sensory circumventricular organs in health and disease.

Circumventricular organs (CVOs) are specialized brain structures located around the third and fourth ventricles. They differ from the rest of the brain parenchyma in that they are highly vascularised areas that lack a blood-brain barrier. These neurohaemal organs are classified as "sensory", when they contain neurons that can receive chemical inputs from the bloodstream. This review focuses on the sensory CVOs to describe their unique structure, and their functional roles in the maintenance of body fluid homeostasis and cardiovascular regulation, and in the generation of central acute immune and febrile responses. In doing so, the main neural connections to visceral regulatory centres such as the hypothalamus, the medulla oblongata and the endocrine hypothalamic-pituitary axis, as well as some of the relevant chemical substances involved, are described. The CVOs are vulnerable to circulating pathogens and can be portals for their entry in the brain. This review highlights recent investigations that show that the CVOs and related structures are involved in pathological conditions such as sepsis, stress, trypanosomiasis, autoimmune encephalitis, systemic amyloidosis and prion infections, while detailed information on their role in other neurodegenerative diseases such as Alzheimer's disease or multiple sclerosis is lacking. It is concluded that studies of the CVOs and related structures may help in the early diagnosis and treatment of such disorders.

The role of hypothalamic ingestive behavior controllers in generating dehydration anorexia: a Fos mapping study.

Giving rats 2.5% saline to drink for 3-5 days simply and reliably generates anorexia. Despite having the neurochemical and hormonal markers of negative energy balance, dehydrated anorexic rats show a marked suppression of spontaneous food intake, as well as the feeding that is usually stimulated by overnight starvation or a 2-deoxy-d-glucose (2DG) challenge. These observations are consistent with a dehydration-dependent inhibition of the core circuitry that controls feeding. We hypothesize that this inhibition is directed at those neurons in the paraventricular nucleus and lateral hypothalamic area that constitute the hypothalamic "behavior controller" for feeding rather than their afferent inputs from the arcuate nucleus or hindbrain that convey critical feeding-related sensory information. To test this hypothesis, we mapped and quantified the Fos-immunoreactive response to 2DG in control and dehydrated rats drinking 2.5% saline. Our rationale was that regions showing an attenuated Fos response to 2DG in dehydrated animals would be strong candidates as the targets of dehydration-induced suppression of 2DG feeding. We found that the Fos response to combined dehydration and 2DG was attenuated only in the lateral hypothalamic area, with dehydration alone increasing Fos in the lateral part of the paraventricular nucleus. In the arcuate nucleus and those regions of the hindbrain that provide afferent inputs critical for the feeding response to 2DG, the Fos response to 2DG was unaffected by dehydration. Therefore, dehydration appears to target the lateral hypothalamic area and possibly the lateral part of the paraventricular nucleus to suppress the feeding response to 2DG.

Gut and hormones and obesity.

Following the discovery of secretin in 1902, a host of further peptide hormones that are synthesised and released from the gastrointestinal tract have been identified. While their roles in the regulation of gastrointestinal function have been known for some time, it is now evident that many of these hormones also physiologically regulate energy balance. Our understanding of how gut hormones signal to the brain has advanced significantly in recent years. Several hormones, including peptide YY, pancreatic polypeptide, oxyntomodulin, glucagon-like peptide 1 and cholecystokinin function as satiety signals. In contrast, only ghrelin, produced by the stomach, has emerged as a putative hunger signal, appearing to act both as a meal initiator and a long-term body weight regulator. Recent research suggests that gut hormones can be manipulated to regulate energy balance in man and that obese subjects retain sensitivity to the actions of gut hormones. The worldwide obesity pandemic continues unabated, despite public health initiatives and current best therapy. Future gut hormone-based therapies may provide an effective and well-tolerated treatment for obesity.

Diet-derived nutrients modulate the effects of amylin on c-Fos expression in the area postrema and on food intake.

The pancreatic hormone amylin decreases food intake via activation of area postrema (AP) neurons. We investigated whether amylin's potency to reduce food intake and to induce c-Fos expression in the AP/nucleus of the solitary tract region is affected by the feeding conditions and specifically by the macronutrient composition of the diet. Whereas a low dose of amylin (5 microg/kg s.c.) induced very little c-Fos expression in ad libitum chow fed rats, it caused a strong c-Fos expression in 24-hour food-deprived rats and in rats that received a nutrient-deficient non-caloric mash (NCM; vanilla-flavoured cellulose) 24 h before injection. To reveal the contribution of single nutrients to the low c-Fos expression after chow feeding, amylin-induced c-Fos was analyzed after feeding NCM that was selectively supplemented with glucose, fat (lard), or protein (casein), matching the intake of these nutrients of chow-fed rats. While the rats fed NCM supplemented with glucose or fat displayed an equally strong amylin-induced activation as fasted rats or rats fed plain NCM, a significantly lower c-Fos expression was observed in rats fed a protein-supplemented NCM or a NCM containing all three nutrients. In line with this lower activation, the same dose of amylin failed to reduce food intake in NCM/protein-fed rats, while amylin caused a reduction in feeding when animals received NCM, NCM/glucose, or NCM/fat. Interestingly, amylin effectively reduced food intake in ad libitum chow fed rats despite the low level of amylin-induced c-Fos expression in the AP under these conditions. We conclude that the anorectic potential of amylin may be attenuated by diet-derived proteins, whereas this effect appears to be overridden when the amount of carbohydrates/fat is high relative to the protein content, such as, e.g., in standard chow.

The circumventricular organs: an atlas of comparative anatomy and vascularization.

The circumventricular organs are small sized structures lining the cavity of the third ventricle (neurohypophysis, vascular organ of the lamina terminalis, subfornical organ, pineal gland and subcommissural organ) and of the fourth ventricle (area postrema). Their particular location in relation to the ventricular cavities is to be noted: the subfornical organ, the subcommissural organ and the area postrema are situated at the confluence between ventricles while the neurohypophysis, the vascular organ of the lamina terminalis and the pineal gland line ventricular recesses. The main object of this work is to study the specific characteristics of the vascular architecture of these organs: their capillaries have a wall devoid of blood-brain barrier, as opposed to central capillaries. This particular arrangement allows direct exchange between the blood and the nervous tissue of these organs. This work is based on a unique set of histological preparations from 12 species of mammals and 5 species of birds, and is taking the form of an atlas.

Making sense of it: roles of the sensory circumventricular organs in feeding and regulation of energy homeostasis.

Obesity is associated with significant health risks including stroke and heart disease. The prevalence of obesity has dramatically increased over the past 20 years. Although the development of obesity is clearly related to changing lifestyles, the central nervous system plays a key role in regulation of energy balance. To develop effective strategies for treating obesity, we must gain a clearer understanding of the neuro-circuitry and signaling mechanisms involved. Toward this end, recent progress has been made in the understanding of the roles played by the sensory circumventricular organs (CVOs) of the brain. These areas lack the normal blood-brain barrier and thus act as transducers of signals between the blood, other centers in the brain, and the cerebrospinal fluid. This review focuses on the roles played by the sensory CVOs in detecting and responding to a number of signals that carry information regarding nutritional status, including cholecystokinin, amylin, ghrelin, peptide YY, pancreatic polypeptide, leptin, adiponectin, and glucose.

Subfornical organ disconnection alters Fos expression in the lamina terminalis, supraoptic nucleus, and area postrema after intragastric hypertonic NaCl.

The lamina terminalis was severed by a horizontal knife cut through the anterior commissure to determine the effects of a disconnection of the subfornical organ (SFO) on drinking and Fos-like immunoreactivity (Fos-ir) in the rat brain in response to an intragastric load of hypertonic saline (5 ml/kg of 1.5 M NaCl by gavage). After an initial load, knife-cut rats drank significantly less water than sham-cut rats, thus confirming a role for the SFO in osmotic drinking. After a second load at least 1 wk later, the rats were not allowed to drink after the gavage and were perfused for analysis of Fos-ir at 90 min. Compared with sham-cut rats, the knife-cut rats displayed significantly elevated Fos-ir in the main body of the SFO, in the dorsal cap of the organum vasculosum laminae terminalis, and in the ventral median preoptic nucleus after the hypertonic load. The knife cut significantly decreased Fos-ir in the supraoptic nucleus. Fos-ir was expressed mainly in the midcoronal and caudal parts of the area postrema of sham-cut rats, and this expression was greatly reduced in knife-cut rats. These findings strengthen the case for the presence of independently functioning osmoreceptors within the SFO and suggest that the structures of the lamina terminalis provide mutual inhibition during hypernatremia. They also demonstrate that the Fos-ir in the area postrema after intragastric osmotic loading is heavily dependent on the intact connectivity of the SFO.

Regional differences in the expression of Fos-like immunoreactivity after central salt loading in conscious rats: modulation by endogenous vasopressin and role of the area postrema.

In this study, we examined the quantitative relationship between centrally administered hypertonic saline (HS) concentrations and the expression of Fos-like immunoreactivity (FLI) in brain regions involved in the homeostasis of body fluids. The regions examined were the organum vasculosum laminae terminalis (OVLT), the median preoptic nucleus (MnPO), the subfornical organ (SFO), the paraventricular nucleus (PVN), the supraoptic nucleus of the hypothalamus, the nucleus of the solitary tract (NTS), and the area postrema (AP). The experiments were performed in conscious rats with attention to the actual changes in central [Na(+)]. Hypertonic saline (0.3, 0.67, or 1.0 M) was delivered at 1 microl/min for 20 min. The changes in cerebrospinal fluid [Na(+)] during i.c.v. administration of 0.3 M hypertonic saline were compatible with those expected for thermal dehydration. FLI increased in a dose-dependent manner in the dorsomedial cap of the PVN and NTS. Although the pressor responses during central salt loading were not significantly affected by pretreatment with the peripheral vasopressin V(1) receptor antagonist OPC-21268, FLI expression in the PVN was significantly augmented. In addition, in AP-lesioned rats, FLI expression in the lateral magnocellular part of the PVN and NTS was significantly enhanced after central salt loading. These results suggest that the peripheral vasopressin system participates in negative feedback to modulate neuronal activities in the PVN, probably through the AP or direct action at the PVN in response to central osmotic and/or Na(+) stimulation.