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Circumventricular organs: Targets for integration of circulating fluid and energy balance signals?
PHB-09986; No of Pages 7 Physiology & Behavior xxx (2013) xxx–xxx
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Review
Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Andrea Mimee, Pauline M. Smith, Alastair V. Ferguson ⁎ Queen's University, Department of Biomedical and Molecular Sciences, Kingston, Ontario, Canada K7L 3N6
H I G H L I G H T S • • • •
SFO interfaces with circulating signals that do not cross the blood brain barrier. Circulating indicators of cardiovascular/metabolic status influence SFO neurons. Sensitivity to these circulating signals is modified by physiological state. We suggest integrative roles for SFO neurons in controlling ingestive behavior.
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Article history: Received 13 November 2012 Received in revised form 26 January 2013 Accepted 14 February 2013 Available online xxxx Keywords: Circumventricular organs Subfornical organ Fluid balance Energy balance Angiotensin II Adiponectin Leptin
a b s t r a c t The subfornical organ (SFO), as one of the sensory circumventricular organs (CVOs), is among the only central nervous system structures which interfaces directly with circulating substances that do not cross the blood brain barrier. Here we describe a growing literature showing that circulating indicators of cardiovascular (angiotensin II, osmolarity, calcium, sodium) and metabolic (adiponectin, amylin, glucose, ghrelin, leptin) statuses influence the excitability of single SFO neurons. Single cell electrophysiological studies from our laboratory have demonstrated excitatory effects of angiotensin II on individual SFO neurons, and changes in angiotensin II receptor expression in this CVO in hypertensive states emphasize the dynamic contribution of SFO neurons to the regulation of fluid balance. Furthermore, we have shown both depolarizing and hyperpolarizing effects of the adipokines adiponectin and leptin in SFO cells, and highlight that conditions of fasting in the case of adiponectin, and obesity in the case of leptin, alter the sensitivity of SFO neurons to these circulating factors. The results examined in this review provide evidence for a role of the SFO as a mediator and integrative structure in the maintenance of cardiovascular and metabolic functions. © 2013 Elsevier Inc. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . The subfornical organ . . . . . . . . . . . . Cardiovascular and fluid balance signals . . . 3.1. Angiotensin II . . . . . . . . . . . . 3.2. Additional fluid balance signals . . . . 4. Metabolic and energy balance signals . . . . 4.1. Adiponectin . . . . . . . . . . . . . 4.2. Leptin . . . . . . . . . . . . . . . . 4.3. Additional metabolic and energy balance 5. Conclusions . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . .
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1. Introduction ⁎ Corresponding author. Tel.: +1 613 533 2803; fax: +1 613 533 6880. E-mail address: [email protected] (A.V. Ferguson).
It is now well established that numerous molecules in the peripheral circulation play important roles in signaling both fluid and energy
0031-9384/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.physbeh.2013.02.012
Please cite this article as: Mimee A, et al, Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Physiol Behav (2013), http://dx.doi.org/10.1016/j.physbeh.2013.02.012
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balance status to the central nervous system (CNS). More specifically, osmolarity, concentrations of sodium and calcium in the blood, and circulating levels of regulatory hormones, including angiotensin II, endothelin and vasopressin, play critical roles in signaling fluid balance status to important control centers within the brain. Similarly, homeostatic regulation of energy balance requires that the CNS receive information from the periphery regarding glucose concentrations, as well as levels of circulating adipokines, such as leptin and adiponectin, and regulatory hormones, including amylin, ghrelin, and cholecystokinin (CCK). Intriguingly, many of these circulating signaling molecules influence the brain despite their inability to cross the normal blood brain barrier (BBB). Several potential mechanisms as to how these circulating factors may influence protected neuronal regions have been proposed. For example, the gut hormone CCK has been shown to influence the CNS via vagal afferents to the caudal brainstem [1], while selective transporters for leptin [2] and insulin [3] from blood to brain have been described, though their physiological function remains largely unknown. Transendothelial cell signaling represents another potential mechanism by which circulating factors may influence the brain, as this occurs when molecules act on the luminal side of the cerebral vascular endothelial cell and induce the release of a second, different, signaling molecule (i.e. nitric oxide) on the other side of the barrier [4,5]. Finally, work in our laboratory has focused on the hypothesis that circumventricular organs (CVOs), structures which lack the normal BBB, offer a direct route by which circulating molecules may access the CNS. In this review we will consider the current evidence suggesting important roles for the CVOs, with a specific focus on the subfornical organ (SFO), as relay centers through which peripheral information is collected and transmitted to critical autonomic control centers protected by the BBB. 2. The subfornical organ The SFO, a midline sensory CVO located on the floor of the third ventricle dorsal to the anterior commissure, is primarily known for its well established roles in cardiovascular and neuroendocrine regulation [6,7]. Sensory CVOs are specialized CNS structures characterized firstly by a cerebral vasculature in which fenestrations are found between endothelial cells (similar to the rest of the non-brain systemic vasculature), thus allowing even large, lipophobic, substances, including peptides and proteins, to cross from blood to neural tissue without having to cross the cell membrane [8], and secondly by the presence of exceptionally dense aggregations of a variety of different receptors for peripheral signals. These unique properties make the CVOs, including the SFO, ideally suited to detect and monitor the presence of regulatory molecules in the peripheral circulation. Specifically, the SFO then communicates this information on peripheral signals to numerous hypothalamic autonomic control centers, including the paraventricular nucleus (PVN), supraoptic nucleus (SON), median preoptic nucleus, and the OVLT [9–11]. The SFO also sends more minor projections to the zona incerta, raphe nuclei, infralimbic cortex, rostral and ventral portions of the bed nucleus of the stria terminalis, lateral preoptic area, lateral hypothalamus/dorsal perifornical region and, of significance to fluid and energy homeostasis, the arcuate nucleus [9,12,13]. Anatomical data suggests that SFO neurons have relatively compact dendritic trees and limited neural inputs [14], which, in most cases, originate from the same areas that receive SFO efferents. Specific excitatory projections have been found to vasopressin and oxytocin neurons in the SON and PVN, as well as to parvocellular areas of the PVN that in turn project either to the median eminence, the medulla, or the spinal cord [15]. Roles for the SFO in food intake, anorexia, emaciation and the regulation of energy balance [16], cardiovascular function and hypertension [10,17–26], immune regulation [27], the febrile response (see [28] for review), drinking [29–33], osmoregulation [34], and reproduction [35,36] have all been suggested.
In the remainder of this review we will focus on data suggesting that single neurons in the SFO play important roles in sensing factors which provide information regarding energy and fluid balance. Specifically, we will describe the literature demonstrating that neurons in the SFO sense levels of circulating angiotensin II, as well as the adipokines adiponectin and leptin. 3. Cardiovascular and fluid balance signals 3.1. Angiotensin II Landmark studies conducted in the late 1970s and early 1980s established the SFO as a critical central site of circulating angiotensin II actions and, as such, provided the background for our understanding of the important roles of the CVOs in sensing circulating signals which regulate both fluid balance and cardiovascular parameters. These microinjection and lesion studies identified the SFO as the primary central nervous system site where angiotensin II acts to induce both drinking [37,38] and increases in blood pressure [25]. Correspondingly, later autoradiographic studies demonstrated the SFO contains the highest density of angiotensin II binding sites in the CNS [39], thus providing anatomical evidence of the critical contribution of the SFO in mediating the central actions of angiotensin II. Importantly, the central effects of angiotensin II on drinking [32,40], blood pressure [25,41], and the secretion of vasopressin [42] and oxytocin [43] are all abolished by lesions of the SFO. Taken together, these in vivo studies indisputably highlight the SFO as an essential central site of angiotensin II effects and thus led to a deeper cellular analysis of the mechanisms through which angiotensin II influences the excitability of SFO neurons to ultimately regulate drinking, cardiovascular function, and neuroendocrine responses. Extracellular recordings [44] and whole cell patch-clamp recordings from dissociated SFO neurons [45] have both demonstrated exclusively excitatory effects of angiotensin II on the majority (>60%) of SFO cells, consistent with the findings of high AT1 receptor density in this CVO. These cellular actions of angiotensin II have been shown to be mediated via the AT1 receptor, as pharmacological pre-treatment of neurons with the AT1 receptor antagonist, losartan, abolished the excitatory effects of angiotensin II on SFO neurons [44]. It is also interesting to note the expression levels of AT1 receptors in the SFO have been reported to be decreased in hypertensive states [46], thus highlighting the dynamic nature of angiotensin II effects on SFO neurons in accordance with the cardiovascular status of the organism. Finally, patch-clamp recordings have revealed that angiotensin II modulates numerous conductances to exert its central effects, namely by inhibiting the transient potassium conductance IA [47], and potentiating both a non-selective cation conductance [48] and voltage-gated calcium channels [49]. 3.2. Additional fluid balance signals Since these studies demonstrating SFO neurons to be critical sensors of circulating angiotensin II, considerable additional evidence has highlighted roles for this CVO in responding to many other circulating signals of importance to cardiovascular regulation and fluid balance. For example, c-Fos studies have indicated that the SFO is activated by changes in circulating osmolarity [50,51]. We have further characterized the osmosensitivity of SFO neurons at the single cell level using patch-clamp techniques, and have shown that SFO cells are excited by increases in extracellular osmolarity [34]. In addition, increases in circulating levels of Ca 2+ [23] or of Na + [52] have been shown to increase the activity of SFO neurons. Finally, numerous other regulatory hormones have been shown to influence the excitability of SFO neurons. More specifically, vasopressin induces both depolarizing and hyperpolarizing effects on these cells [53,54], while atrial natriuretic peptide suppresses the activity of SFO neurons [55,56] and endothelin excites these cells [22,57]. Taken together,
Please cite this article as: Mimee A, et al, Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Physiol Behav (2013), http://dx.doi.org/10.1016/j.physbeh.2013.02.012
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these findings support the conclusion that the SFO processes and integrates information from multiple cardiovascular and fluid balance signals. 4. Metabolic and energy balance signals In addition to the many blood borne factors which regulate fluid balance and cardiovascular function, a remarkable number of different circulating signals play central roles in the regulation of food intake and metabolism, including small molecules such as glucose, peptides produced by the gastrointestinal tract and pancreas, and adipokines produced by adipose tissue. We refer the reader to several recent reviews providing an overview of the important effects of these circulating signals on neurons in regions including the area postrema and the arcuate nucleus of the hypothalamus, and in the present review we highlight the contribution of the SFO as a mediator of ingestive behaviors [58–61]. Recent work from our laboratory has provided evidence for a role of the SFO as a mediator of food intake. Electrical stimulation of the SFO of satiated rats during the light cycle resulted in robust increases in both feeding and drinking, confirming that activation of neurons in this CVO results in ingestive behaviors [62]. Furthermore, we recently undertook a transcriptomic analysis of the SFO using affymetrix gene chips to describe the genes expressed in this CVO under control conditions, as well as conditions of 48 h food restriction or 72 h water restriction [63]. Our analysis identified expression of receptors for a number of novel signaling molecules involved in the regulation of metabolic function within the SFO, thus suggesting roles for these molecules in regulating the excitability of SFO neurons. In the remainder of this review we will highlight studies undertaken to provide both molecular and physiological validation of this transcriptomic analysis, with specific emphasis on actions of adiponectin and leptin within the SFO. 4.1. Adiponectin Adiponectin is an adipokine secreted by adipose tissue which is found in the circulation in concentrations inversely proportional to total body fat mass [64]. Adiponectin has been shown to regulate glucose homeostasis [65,66] and cause centrally mediated decreases in body weight [67] via its two G protein coupled receptors, AdipoR1 and AdipoR2 [68]. Our transcriptomic study revealed high levels of expression of AdipoR1 and AdipoR2 in the SFO of control animals [63], and we subsequently confirmed these microarray findings using polymerase chain reaction (PCR) analysis of whole SFO tissue with primers designed for both receptor isoforms [69]. In light of the strong expression of the adiponectin receptors in the SFO, we examined the effects of this hormone on the excitability of individual dissociated SFO neurons. Whole cell patch-clamp electrophysiological studies demonstrated that over 50% of SFO neurons were influenced by adiponectin and, furthermore, these responses could be almost equally divided into excitatory or inhibitory effects [69] (Fig. 1). These observations suggest the existence of two separate, differentially adiponectin sensitive subpopulations of SFO neurons. Interestingly, our microarray studies also revealed that the expression of 687 transcripts (222 upregulated and 465 downregulated) in the SFO was modified following two days of food deprivation [63]. Among the genes upregulated by food restriction was AdipoR2, an observation which we further confirmed with quantitative real time PCR (Fig. 1) [69]. We next examined whether these changes in receptor expression resulted in altered sensitivity of SFO neurons to adiponectin, and indeed demonstrated that dissociated SFO neurons obtained from food deprived animals with elevated levels of AdipoR2 showed exclusively excitatory responses to bath administration of this adipokine, as illustrated in Fig. 1 [69]. Thus our transcriptomic, PCR, and electrophysiological approaches all suggest an important role for the SFO in mediating the central effects of adiponectin on glucose and energy homeostasis.
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4.2. Leptin A second intriguing new target identified in our transcriptomic analysis was the leptin receptor (LepR) [63]. Subsequent immunohistochemical and reverse transcriptase PCR (RT-PCR) analyses confirmed the presence of the signaling form of the leptin receptor [70–72], ObRb, within the SFO. Once again, we utilized patch-clamp recording techniques to examine the sensitivity of dissociated SFO neurons to bath applied leptin, and demonstrated that, much like adiponectin, approximately 30% of SFO neurons were inhibited and a further 30% excited by bath application of leptin [73]. Interestingly, we also found that SFO neurons activated by leptin were similarly activated by amylin [73], another signaling molecule known to inhibit food intake, suggesting that multiple circulating factors can act on individual SFO neurons to regulate energy and fluid homeostasis. Given the well documented role of the SFO in cardiovascular regulation, and our data showing ObRb expression and leptin actions in the SFO, we examined whether the SFO may represent a target for circulating leptin influences on cardiovascular function. Numerous previous studies examining the effects of central administration of leptin on blood pressure have demonstrated hypertensive effects of this adipokine [74–80]. However, microinjection of picomolar doses of leptin into the SFO of anesthetized animals caused rapid, site specific decreases in blood pressure without influencing heart rate (Fig. 2) [81]. These results suggested that circulating leptin, rather than being hypertensive, may play a positive role in cardiovascular regulation by providing a tonic inhibitory effect on sympathetic tone through actions at the SFO. We reasoned that the concept of selective leptin resistance might explain our apparently contradictory findings. Leptin resistance describes the phenomenon in which obese animals are resistant to the effects of systemic and central leptin on weight reduction, but remain sensitive to its effects on renal sympathetic output [82–84], which in turn may contribute to obesity related hypertension (for review see [85,86]). We thus speculated that in obese, leptin-resistant animals, leptin acting at the SFO would no longer be effective in maintaining an inhibitory control over blood pressure, and blood pressure would increase. To validate our hypothesis, we examined the effects of microinjection of leptin into the SFO of rats rendered obese via a high fat diet (diet induced obese (DIO) animals) and of rats resistant to weight gain caused by a high fat diet (diet resistant (DR) animals). While leptin microinjections into the SFO of DR animals resulted in the depressor effects we observed in control animals, these microinjections failed to alter blood pressure or heart rate in DIO animals, as illustrated in Fig. 2. Our findings suggest the development of resistance to the cardiovascular effects of leptin in the SFO under obese conditions which ultimately results in obesity related hypertension, and support the hypothesis that leptin acting in the SFO exerts a depressor effect in normal physiological states. While further experiments will be required to identify the mechanisms responsible for this SFO leptin resistance, we did not observe significantly altered expression levels of leptin receptors in the SFO in our transcriptomic studies, and thus, unlike adiponectin, it is unlikely that changes in receptor mRNA can account for altered leptin sensitivity in SFO neurons. 4.3. Additional metabolic and energy balance signals In addition to adiponectin and leptin, the SFO has also been suggested to play a role in sensing a number of other circulating signals which provide critical information regarding metabolic status to the CNS. Work from other laboratories has clearly established a role for the anorexigenic peptide amylin in influencing the excitability of SFO neurons [87,88], and our own recent work also demonstrated that the orexigenic hormone ghrelin exerts excitatory effects on a separate subpopulation of SFO neurons [89]. These observations suggest the possibility of an intriguing functional division of SFO neurons into groups which exert opposite effects on food intake. Single cell
Please cite this article as: Mimee A, et al, Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Physiol Behav (2013), http://dx.doi.org/10.1016/j.physbeh.2013.02.012
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Microarray
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Fig. 1. Two day food deprivation in the rat alters the expression of the adiponectin 2 receptor and the responsiveness of SFO neurons to adiponectin. A) Bar graphs illustrating relative expression levels of adiponectin 1 and adiponectin 2 receptors (AdipoR1 and AdipoR2) in the rat SFO as measured by transcriptomic and quantitative real time polymerase chain reaction analysis of whole SFO. Two day food restriction resulted in significantly increased expression of AdipoR2 relative to control fed animals (* indicates p b 0.05, ***p b 0.0001). No change in AdipoR1 expression was observed. B) Whole cell current clamp recordings obtained from three individual dissociated rat SFO neurons. Panel i) shows an SFO neuron from a control fed animal exhibiting a hyperpolarizing response to bath applied 10 nM adiponectin (red horizontal bar — left trace), and a different SFO neuron showing a depolarizing response to 10 nM adiponectin (right trace). Panel ii) shows an SFO neuron from a fasted animal with increased levels of AdipoR2 exhibiting a depolarizing response to adiponectin. Note that only depolarizing responses were observed in fasted animals, in contrast to control fed animals. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Please cite this article as: Mimee A, et al, Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Physiol Behav (2013), http://dx.doi.org/10.1016/j.physbeh.2013.02.012
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A) 5 pmol leptin microinjection into SFO
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DIO (n=4) DIO
▲ Control (n=4) B) (4) (4)
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Fig. 2. Diet induced obesity abolishes the cardiovascular effects of leptin in the SFO. A) Normalized mean blood pressure (BP) traces showing the response to 5 pmol leptin microinjection (black arrow) into the SFO of young control animals (blue trace, n = 4) or leptin resistant, diet induced obese (DIO) animals (red trace, n = 4). DIO animals were no longer responsive to the depressor effects of leptin in the SFO. B) Summary bar graph showing the mean area under the curve for BP in response to leptin microinjection into the SFO of young control animals (blue bar), animals resistant to the weight gain typically caused by a high fat diet (DR — black bar), or DIO animals (red bar). Note that DR animals remained responsive to the cardiovascular effects of leptin in the SFO, while DIO animals were resistant to these effects of leptin (**p b 0.01).
recordings from our laboratory have also shown that SFO neurons are sensitive to circulating glucose concentrations, with separate subpopulations of cells demonstrating all of the sensory abilities associated with the classification of glucose excited (GE), or glucose inhibited (GI) neurons in other regions of the CNS [90]. Finally, our genomic analysis of the SFO identified receptors whose roles in this CVO have yet to be explored, including apelin, cannabinoid CB1, and neuropeptide Y (NPY) Y1 receptors, as well as the peptide apelin, cocaine and amphetamine related transcript (CART), CCK, orexin, NPY, oxytocin, pro-melanin concentrating hormone (PMCH), and vasopressin [63]. Thus, despite the numerous metabolic factors presently shown to be expressed in the SFO and to influence the excitability of individual SFO neurons, the physiological effects of these molecules have yet to be examined, and, in turn, the total contribution of this CVO as an ultimate mediator of energy balance has not yet been fully elucidated. 5. Conclusions In this review, we have highlighted information demonstrating that the SFO, a sensory CVO, is among the only CNS structures which interface
directly with circulating substances that do not cross the BBB. We have also described a portion of the extensive and growing literature showing that circulating indicators of cardiovascular status, such as angiotensin II, osmolarity, calcium, sodium, and metabolic function, including adiponectin and leptin, influence the excitability of single SFO neurons. Interestingly, the ability of SFO neurons to sense these circulating signals can be modified by physiological state, as in the cases of angiotensin II (normotensive versus hypertensive), adiponectin (fasted versus fed), and leptin (obese versus lean), indicating a dynamic and highly responsive contribution of SFO cells in the maintenance of cardiovascular and metabolic functions. Such observations suggest integrative roles for SFO neurons in regulating ingestive behavior, through its ability to constantly monitor multiple circulating signals which, once integrated, provide the essential information regarding central autonomic responses necessary for the appropriate maintenance of the physiologically healthy “milieu interieur”. The next critical steps in understanding such roles for SFO will require a detailed analysis of how SFO neurons and their integrated connections with autonomic control centers of the hypothalamus actually regulate autonomic outputs. We do not know how this will turn out, and hopefully new technologies will help us to understand
Please cite this article as: Mimee A, et al, Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Physiol Behav (2013), http://dx.doi.org/10.1016/j.physbeh.2013.02.012
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the potentially integrated importance of separate subpopulations of neurons responding differently to the same signaling molecule. However, the current evidence does highlight the potential role of the SFO as a critical gateway for multiple factors involved in the control of fluid balance and energy homeostasis, and suggests that this CVO, through its local actions and projections to other neuronal centers, is an important component of the total neuronal network which coordinates the control of ingestive behaviors. Acknowledgments This article is based on a presentation during the 2012 Annual Meeting of the Society for the Study of Ingestive Behavior, Zurich, Switzerland, July 10–14, 2012, made possible in part by a generous donations from Research Diets, Inc., Sanofi, Inc., and TSE, Inc. 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Lesions of the subfornical organ block angiotensin-induced drinking in the dog. Neuroendocrinology 1982;35:68–72. [33] Smith PM, Beninger RJ, Ferguson AV. Subfornical organ stimulation elicits drinking. Brain Res Bull 1995;38:209–13. [34] Anderson JW, Washburn DL, Ferguson AV. Intrinsic osmosensitivity of subfornical organ neurons. Neuroscience 2000;100:539–47. [35] Summy-Long JY, Kadekaro M. Role of circumventricular organs (CVO) in neuroendocrine responses: interactions of CVO and the magnocellular neuroendocrine system in different reproductive states. Clin Exp Pharmacol Physiol 2001;28:590–601. [36] Hornsby DJ, Wilson BC, Summerlee AJ. Relaxin and drinking in pregnant rats. Prog Brain Res 2001;133:229–40. [37] Simpson JB, Routtenberg A. Subfornical organ lesions reduce intravenous angiotensin-induced drinking. Brain Res 1975;88:154–61. [38] Simpson JB, Epstein AN, Camardo Jr JS. Localization of receptors for the dipsogenic action of angiotensin II in the subfornical organ of rat. 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[45] Ferguson AV, Bicknell RJ, Carew MA, Mason WT. Dissociated adult rat subfornical organ neurons maintain membrane properties and angiotensin responsiveness for up to 6 days. Neuroendocrinology 1997;66:409–15. [46] Nunes FC, Braga VA. Chronic angiotensin II infusion modulates angiotensin II type I receptor expression in the subfornical organ and the rostral ventrolateral medulla in hypertensive rats. J Renin Angiotensin Aldosterone Syst 2011;12:440–5. [47] Ferguson AV, Li Z. Whole cell patch recordings from forebrain slices demonstrate angiotensin II inhibits potassium currents in subfornical organ neurons. Regul Pept 1996;66:55–8. [48] Ono K, Honda E, Inenaga K. Angiotensin II induces inward currents in subfornical organ neurones of rats. J Neuroendocrinol 2001;13:517–23. [49] Washburn DL, Ferguson AV. Selective potentiation of N-type calcium channels by angiotensin II in rat subfornical organ neurones. J Physiol 2001;536:667–75. [50] Giovannelli L, Bloom FE. c-Fos protein expression in the rat subfornical organ following osmotic stimulation. Neurosci Lett 1992;139:1–6. [51] Smith DW, Day TA. Hypovolaemic and osmotic stimuli induce distinct patterns of c-Fos expression in the rat subfornical organ. Brain Res 1995;698:232–6. [52] Gutman MB, Ciriello J, Mogenson GJ. Effects of plasma angiotensin II and hypernatremia on subfornical organ neurons. Am J Physiol 1988;254:R746–54. [53] Anthes N, Schmid HA, Hashimoto M, Riediger T, Simon E. Heterogeneous actions of vasopressin on ANG II-sensitive neurons in the subfornical organ of rats. Am J Physiol 1997;273:R2105–11. [54] Smith PM, Ferguson AV. Vasopressin acts in the subfornical organ to decrease blood pressure. Neuroendocrinology 1997;66:130–5. [55] Yamashita H, Inenaga K, Okuya S, Hattori Y, Yamamoto S. Effect of brain-gut peptides upon neurons in centrally regulating sites for drinking. Arch Histol Cytol 1989;52:121–7 [Suppl.]. [56] Ehrlich KJ, Fitts DA. Atrial natriuretic peptide in the subfornical organ reduces drinking induced by angiotensin or in response to water deprivation. Behav Neurosci 1990;104:365–72. [57] Wall KM, Ferguson AV. Endothelin acts at the subfornical organ to influence the activity of putative vasopressin and oxytocin-secreting neurons. Brain Res 1992;586:111–6. [58] Smith PM, Ferguson AV. Neurophysiology of hunger and satiety. Dev Disabil Res Rev 2008;14:96–104. [59] Blouet C, Schwartz GJ. Hypothalamic nutrient sensing in the control of energy homeostasis. Behav Brain Res 2010;209:1–12. [60] Schwartz GJ. Brainstem integrative function in the central nervous system control of food intake. Forum Nutr 2010;63:141–51. [61] Sanchez-Lasheras C, Konner AC, Bruning JC. Integrative neurobiology of energy homeostasis-neurocircuits, signals and mediators. Front Neuroendocrinol 2010;31: 4–15. [62] Smith PM, Rozanski G, Ferguson AV. Acute electrical stimulation of the subfornical organ induces feeding in satiated rats. 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A. Mimee et al. / Physiology & Behavior xxx (2013) xxx–xxx [63] Hindmarch C, Fry M, Yao S, Smith PM, Murphy D, Ferguson AV. Microarray analysis of the transcriptome of the subfornical organ in the rat: regulation by fluid and food deprivation. Am J Physiol Regul Integr Comp Physiol 2008;295(6): R1914–20. [64] Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 1996;271:10697–703. [65] Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 2002;277:25863–6. [66] Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002;8:731–7. [67] Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB, et al. Adiponectin acts in the brain to decrease body weight. Nat Med 2004;10:524–9. [68] Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003;423:762–9. [69] Alim I, Fry WM, Walsh MH, Ferguson AV. Actions of adiponectin on the excitability of subfornical organ neurons are altered by food deprivation. Brain Res 2010;1330:72–82. [70] Bjorbaek C, Uotani S, da SB, Flier JS. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem 1997;272:32686–95. [71] Banks AS, Davis SM, Bates SH, Myers Jr MG. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 2000;275:14563–72. [72] Kloek C, Haq AK, Dunn SL, Lavery HJ, Banks AS, Myers Jr MG. Regulation of Jak kinases by intracellular leptin receptor sequences. J Biol Chem 2002;277:41547–55. [73] Smith PM, Chambers AP, Price CJ, Ho W, Hopf C, Sharkey KA, et al. The subfornical organ: a central nervous system site for actions of circulating leptin. Am J Physiol Regul Integr Comp Physiol 2009;296:R512–20. [74] Dunbar JC, Hu Y, Lu H. Intracerebroventricular leptin increases lumbar and renal sympathetic nerve activity and blood pressure in normal rats. Diabetes 1997;46: 2040–3. [75] Rahmouni K, Morgan DA. Hypothalamic arcuate nucleus mediates the sympathetic and arterial pressure responses to leptin. Hypertension 2007;49:647–52. [76] Casto RM, VanNess JM, Overton JM. Effects of central leptin administration on blood pressure in normotensive rats. Neurosci Lett 1998;246:29–32.
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Review
Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Andrea Mimee, Pauline M. Smith, Alastair V. Ferguson ⁎ Queen's University, Department of Biomedical and Molecular Sciences, Kingston, Ontario, Canada K7L 3N6
H I G H L I G H T S • • • •
SFO interfaces with circulating signals that do not cross the blood brain barrier. Circulating indicators of cardiovascular/metabolic status influence SFO neurons. Sensitivity to these circulating signals is modified by physiological state. We suggest integrative roles for SFO neurons in controlling ingestive behavior.
a r t i c l e
i n f o
Article history: Received 13 November 2012 Received in revised form 26 January 2013 Accepted 14 February 2013 Available online xxxx Keywords: Circumventricular organs Subfornical organ Fluid balance Energy balance Angiotensin II Adiponectin Leptin
a b s t r a c t The subfornical organ (SFO), as one of the sensory circumventricular organs (CVOs), is among the only central nervous system structures which interfaces directly with circulating substances that do not cross the blood brain barrier. Here we describe a growing literature showing that circulating indicators of cardiovascular (angiotensin II, osmolarity, calcium, sodium) and metabolic (adiponectin, amylin, glucose, ghrelin, leptin) statuses influence the excitability of single SFO neurons. Single cell electrophysiological studies from our laboratory have demonstrated excitatory effects of angiotensin II on individual SFO neurons, and changes in angiotensin II receptor expression in this CVO in hypertensive states emphasize the dynamic contribution of SFO neurons to the regulation of fluid balance. Furthermore, we have shown both depolarizing and hyperpolarizing effects of the adipokines adiponectin and leptin in SFO cells, and highlight that conditions of fasting in the case of adiponectin, and obesity in the case of leptin, alter the sensitivity of SFO neurons to these circulating factors. The results examined in this review provide evidence for a role of the SFO as a mediator and integrative structure in the maintenance of cardiovascular and metabolic functions. © 2013 Elsevier Inc. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . The subfornical organ . . . . . . . . . . . . Cardiovascular and fluid balance signals . . . 3.1. Angiotensin II . . . . . . . . . . . . 3.2. Additional fluid balance signals . . . . 4. Metabolic and energy balance signals . . . . 4.1. Adiponectin . . . . . . . . . . . . . 4.2. Leptin . . . . . . . . . . . . . . . . 4.3. Additional metabolic and energy balance 5. Conclusions . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . .
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1. Introduction ⁎ Corresponding author. Tel.: +1 613 533 2803; fax: +1 613 533 6880. E-mail address: [email protected] (A.V. Ferguson).
It is now well established that numerous molecules in the peripheral circulation play important roles in signaling both fluid and energy
0031-9384/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.physbeh.2013.02.012
Please cite this article as: Mimee A, et al, Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Physiol Behav (2013), http://dx.doi.org/10.1016/j.physbeh.2013.02.012
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balance status to the central nervous system (CNS). More specifically, osmolarity, concentrations of sodium and calcium in the blood, and circulating levels of regulatory hormones, including angiotensin II, endothelin and vasopressin, play critical roles in signaling fluid balance status to important control centers within the brain. Similarly, homeostatic regulation of energy balance requires that the CNS receive information from the periphery regarding glucose concentrations, as well as levels of circulating adipokines, such as leptin and adiponectin, and regulatory hormones, including amylin, ghrelin, and cholecystokinin (CCK). Intriguingly, many of these circulating signaling molecules influence the brain despite their inability to cross the normal blood brain barrier (BBB). Several potential mechanisms as to how these circulating factors may influence protected neuronal regions have been proposed. For example, the gut hormone CCK has been shown to influence the CNS via vagal afferents to the caudal brainstem [1], while selective transporters for leptin [2] and insulin [3] from blood to brain have been described, though their physiological function remains largely unknown. Transendothelial cell signaling represents another potential mechanism by which circulating factors may influence the brain, as this occurs when molecules act on the luminal side of the cerebral vascular endothelial cell and induce the release of a second, different, signaling molecule (i.e. nitric oxide) on the other side of the barrier [4,5]. Finally, work in our laboratory has focused on the hypothesis that circumventricular organs (CVOs), structures which lack the normal BBB, offer a direct route by which circulating molecules may access the CNS. In this review we will consider the current evidence suggesting important roles for the CVOs, with a specific focus on the subfornical organ (SFO), as relay centers through which peripheral information is collected and transmitted to critical autonomic control centers protected by the BBB. 2. The subfornical organ The SFO, a midline sensory CVO located on the floor of the third ventricle dorsal to the anterior commissure, is primarily known for its well established roles in cardiovascular and neuroendocrine regulation [6,7]. Sensory CVOs are specialized CNS structures characterized firstly by a cerebral vasculature in which fenestrations are found between endothelial cells (similar to the rest of the non-brain systemic vasculature), thus allowing even large, lipophobic, substances, including peptides and proteins, to cross from blood to neural tissue without having to cross the cell membrane [8], and secondly by the presence of exceptionally dense aggregations of a variety of different receptors for peripheral signals. These unique properties make the CVOs, including the SFO, ideally suited to detect and monitor the presence of regulatory molecules in the peripheral circulation. Specifically, the SFO then communicates this information on peripheral signals to numerous hypothalamic autonomic control centers, including the paraventricular nucleus (PVN), supraoptic nucleus (SON), median preoptic nucleus, and the OVLT [9–11]. The SFO also sends more minor projections to the zona incerta, raphe nuclei, infralimbic cortex, rostral and ventral portions of the bed nucleus of the stria terminalis, lateral preoptic area, lateral hypothalamus/dorsal perifornical region and, of significance to fluid and energy homeostasis, the arcuate nucleus [9,12,13]. Anatomical data suggests that SFO neurons have relatively compact dendritic trees and limited neural inputs [14], which, in most cases, originate from the same areas that receive SFO efferents. Specific excitatory projections have been found to vasopressin and oxytocin neurons in the SON and PVN, as well as to parvocellular areas of the PVN that in turn project either to the median eminence, the medulla, or the spinal cord [15]. Roles for the SFO in food intake, anorexia, emaciation and the regulation of energy balance [16], cardiovascular function and hypertension [10,17–26], immune regulation [27], the febrile response (see [28] for review), drinking [29–33], osmoregulation [34], and reproduction [35,36] have all been suggested.
In the remainder of this review we will focus on data suggesting that single neurons in the SFO play important roles in sensing factors which provide information regarding energy and fluid balance. Specifically, we will describe the literature demonstrating that neurons in the SFO sense levels of circulating angiotensin II, as well as the adipokines adiponectin and leptin. 3. Cardiovascular and fluid balance signals 3.1. Angiotensin II Landmark studies conducted in the late 1970s and early 1980s established the SFO as a critical central site of circulating angiotensin II actions and, as such, provided the background for our understanding of the important roles of the CVOs in sensing circulating signals which regulate both fluid balance and cardiovascular parameters. These microinjection and lesion studies identified the SFO as the primary central nervous system site where angiotensin II acts to induce both drinking [37,38] and increases in blood pressure [25]. Correspondingly, later autoradiographic studies demonstrated the SFO contains the highest density of angiotensin II binding sites in the CNS [39], thus providing anatomical evidence of the critical contribution of the SFO in mediating the central actions of angiotensin II. Importantly, the central effects of angiotensin II on drinking [32,40], blood pressure [25,41], and the secretion of vasopressin [42] and oxytocin [43] are all abolished by lesions of the SFO. Taken together, these in vivo studies indisputably highlight the SFO as an essential central site of angiotensin II effects and thus led to a deeper cellular analysis of the mechanisms through which angiotensin II influences the excitability of SFO neurons to ultimately regulate drinking, cardiovascular function, and neuroendocrine responses. Extracellular recordings [44] and whole cell patch-clamp recordings from dissociated SFO neurons [45] have both demonstrated exclusively excitatory effects of angiotensin II on the majority (>60%) of SFO cells, consistent with the findings of high AT1 receptor density in this CVO. These cellular actions of angiotensin II have been shown to be mediated via the AT1 receptor, as pharmacological pre-treatment of neurons with the AT1 receptor antagonist, losartan, abolished the excitatory effects of angiotensin II on SFO neurons [44]. It is also interesting to note the expression levels of AT1 receptors in the SFO have been reported to be decreased in hypertensive states [46], thus highlighting the dynamic nature of angiotensin II effects on SFO neurons in accordance with the cardiovascular status of the organism. Finally, patch-clamp recordings have revealed that angiotensin II modulates numerous conductances to exert its central effects, namely by inhibiting the transient potassium conductance IA [47], and potentiating both a non-selective cation conductance [48] and voltage-gated calcium channels [49]. 3.2. Additional fluid balance signals Since these studies demonstrating SFO neurons to be critical sensors of circulating angiotensin II, considerable additional evidence has highlighted roles for this CVO in responding to many other circulating signals of importance to cardiovascular regulation and fluid balance. For example, c-Fos studies have indicated that the SFO is activated by changes in circulating osmolarity [50,51]. We have further characterized the osmosensitivity of SFO neurons at the single cell level using patch-clamp techniques, and have shown that SFO cells are excited by increases in extracellular osmolarity [34]. In addition, increases in circulating levels of Ca 2+ [23] or of Na + [52] have been shown to increase the activity of SFO neurons. Finally, numerous other regulatory hormones have been shown to influence the excitability of SFO neurons. More specifically, vasopressin induces both depolarizing and hyperpolarizing effects on these cells [53,54], while atrial natriuretic peptide suppresses the activity of SFO neurons [55,56] and endothelin excites these cells [22,57]. Taken together,
Please cite this article as: Mimee A, et al, Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Physiol Behav (2013), http://dx.doi.org/10.1016/j.physbeh.2013.02.012
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these findings support the conclusion that the SFO processes and integrates information from multiple cardiovascular and fluid balance signals. 4. Metabolic and energy balance signals In addition to the many blood borne factors which regulate fluid balance and cardiovascular function, a remarkable number of different circulating signals play central roles in the regulation of food intake and metabolism, including small molecules such as glucose, peptides produced by the gastrointestinal tract and pancreas, and adipokines produced by adipose tissue. We refer the reader to several recent reviews providing an overview of the important effects of these circulating signals on neurons in regions including the area postrema and the arcuate nucleus of the hypothalamus, and in the present review we highlight the contribution of the SFO as a mediator of ingestive behaviors [58–61]. Recent work from our laboratory has provided evidence for a role of the SFO as a mediator of food intake. Electrical stimulation of the SFO of satiated rats during the light cycle resulted in robust increases in both feeding and drinking, confirming that activation of neurons in this CVO results in ingestive behaviors [62]. Furthermore, we recently undertook a transcriptomic analysis of the SFO using affymetrix gene chips to describe the genes expressed in this CVO under control conditions, as well as conditions of 48 h food restriction or 72 h water restriction [63]. Our analysis identified expression of receptors for a number of novel signaling molecules involved in the regulation of metabolic function within the SFO, thus suggesting roles for these molecules in regulating the excitability of SFO neurons. In the remainder of this review we will highlight studies undertaken to provide both molecular and physiological validation of this transcriptomic analysis, with specific emphasis on actions of adiponectin and leptin within the SFO. 4.1. Adiponectin Adiponectin is an adipokine secreted by adipose tissue which is found in the circulation in concentrations inversely proportional to total body fat mass [64]. Adiponectin has been shown to regulate glucose homeostasis [65,66] and cause centrally mediated decreases in body weight [67] via its two G protein coupled receptors, AdipoR1 and AdipoR2 [68]. Our transcriptomic study revealed high levels of expression of AdipoR1 and AdipoR2 in the SFO of control animals [63], and we subsequently confirmed these microarray findings using polymerase chain reaction (PCR) analysis of whole SFO tissue with primers designed for both receptor isoforms [69]. In light of the strong expression of the adiponectin receptors in the SFO, we examined the effects of this hormone on the excitability of individual dissociated SFO neurons. Whole cell patch-clamp electrophysiological studies demonstrated that over 50% of SFO neurons were influenced by adiponectin and, furthermore, these responses could be almost equally divided into excitatory or inhibitory effects [69] (Fig. 1). These observations suggest the existence of two separate, differentially adiponectin sensitive subpopulations of SFO neurons. Interestingly, our microarray studies also revealed that the expression of 687 transcripts (222 upregulated and 465 downregulated) in the SFO was modified following two days of food deprivation [63]. Among the genes upregulated by food restriction was AdipoR2, an observation which we further confirmed with quantitative real time PCR (Fig. 1) [69]. We next examined whether these changes in receptor expression resulted in altered sensitivity of SFO neurons to adiponectin, and indeed demonstrated that dissociated SFO neurons obtained from food deprived animals with elevated levels of AdipoR2 showed exclusively excitatory responses to bath administration of this adipokine, as illustrated in Fig. 1 [69]. Thus our transcriptomic, PCR, and electrophysiological approaches all suggest an important role for the SFO in mediating the central effects of adiponectin on glucose and energy homeostasis.
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4.2. Leptin A second intriguing new target identified in our transcriptomic analysis was the leptin receptor (LepR) [63]. Subsequent immunohistochemical and reverse transcriptase PCR (RT-PCR) analyses confirmed the presence of the signaling form of the leptin receptor [70–72], ObRb, within the SFO. Once again, we utilized patch-clamp recording techniques to examine the sensitivity of dissociated SFO neurons to bath applied leptin, and demonstrated that, much like adiponectin, approximately 30% of SFO neurons were inhibited and a further 30% excited by bath application of leptin [73]. Interestingly, we also found that SFO neurons activated by leptin were similarly activated by amylin [73], another signaling molecule known to inhibit food intake, suggesting that multiple circulating factors can act on individual SFO neurons to regulate energy and fluid homeostasis. Given the well documented role of the SFO in cardiovascular regulation, and our data showing ObRb expression and leptin actions in the SFO, we examined whether the SFO may represent a target for circulating leptin influences on cardiovascular function. Numerous previous studies examining the effects of central administration of leptin on blood pressure have demonstrated hypertensive effects of this adipokine [74–80]. However, microinjection of picomolar doses of leptin into the SFO of anesthetized animals caused rapid, site specific decreases in blood pressure without influencing heart rate (Fig. 2) [81]. These results suggested that circulating leptin, rather than being hypertensive, may play a positive role in cardiovascular regulation by providing a tonic inhibitory effect on sympathetic tone through actions at the SFO. We reasoned that the concept of selective leptin resistance might explain our apparently contradictory findings. Leptin resistance describes the phenomenon in which obese animals are resistant to the effects of systemic and central leptin on weight reduction, but remain sensitive to its effects on renal sympathetic output [82–84], which in turn may contribute to obesity related hypertension (for review see [85,86]). We thus speculated that in obese, leptin-resistant animals, leptin acting at the SFO would no longer be effective in maintaining an inhibitory control over blood pressure, and blood pressure would increase. To validate our hypothesis, we examined the effects of microinjection of leptin into the SFO of rats rendered obese via a high fat diet (diet induced obese (DIO) animals) and of rats resistant to weight gain caused by a high fat diet (diet resistant (DR) animals). While leptin microinjections into the SFO of DR animals resulted in the depressor effects we observed in control animals, these microinjections failed to alter blood pressure or heart rate in DIO animals, as illustrated in Fig. 2. Our findings suggest the development of resistance to the cardiovascular effects of leptin in the SFO under obese conditions which ultimately results in obesity related hypertension, and support the hypothesis that leptin acting in the SFO exerts a depressor effect in normal physiological states. While further experiments will be required to identify the mechanisms responsible for this SFO leptin resistance, we did not observe significantly altered expression levels of leptin receptors in the SFO in our transcriptomic studies, and thus, unlike adiponectin, it is unlikely that changes in receptor mRNA can account for altered leptin sensitivity in SFO neurons. 4.3. Additional metabolic and energy balance signals In addition to adiponectin and leptin, the SFO has also been suggested to play a role in sensing a number of other circulating signals which provide critical information regarding metabolic status to the CNS. Work from other laboratories has clearly established a role for the anorexigenic peptide amylin in influencing the excitability of SFO neurons [87,88], and our own recent work also demonstrated that the orexigenic hormone ghrelin exerts excitatory effects on a separate subpopulation of SFO neurons [89]. These observations suggest the possibility of an intriguing functional division of SFO neurons into groups which exert opposite effects on food intake. Single cell
Please cite this article as: Mimee A, et al, Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Physiol Behav (2013), http://dx.doi.org/10.1016/j.physbeh.2013.02.012
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Microarray
AdipoR1
AdipoR2
Expression Level
***
A)
Control
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Quantitative RT-PCR
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Expression Level
*
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B) i) Control Adiponectin
Adiponectin
-58 mV
-67mV 10 mV 50s
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ii) Fasted Adiponectin
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10 mV 25 s
Fig. 1. Two day food deprivation in the rat alters the expression of the adiponectin 2 receptor and the responsiveness of SFO neurons to adiponectin. A) Bar graphs illustrating relative expression levels of adiponectin 1 and adiponectin 2 receptors (AdipoR1 and AdipoR2) in the rat SFO as measured by transcriptomic and quantitative real time polymerase chain reaction analysis of whole SFO. Two day food restriction resulted in significantly increased expression of AdipoR2 relative to control fed animals (* indicates p b 0.05, ***p b 0.0001). No change in AdipoR1 expression was observed. B) Whole cell current clamp recordings obtained from three individual dissociated rat SFO neurons. Panel i) shows an SFO neuron from a control fed animal exhibiting a hyperpolarizing response to bath applied 10 nM adiponectin (red horizontal bar — left trace), and a different SFO neuron showing a depolarizing response to 10 nM adiponectin (right trace). Panel ii) shows an SFO neuron from a fasted animal with increased levels of AdipoR2 exhibiting a depolarizing response to adiponectin. Note that only depolarizing responses were observed in fasted animals, in contrast to control fed animals. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Please cite this article as: Mimee A, et al, Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Physiol Behav (2013), http://dx.doi.org/10.1016/j.physbeh.2013.02.012
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A) 5 pmol leptin microinjection into SFO
-
DIO (n=4) DIO
▲ Control (n=4) B) (4) (4)
(10)
Fig. 2. Diet induced obesity abolishes the cardiovascular effects of leptin in the SFO. A) Normalized mean blood pressure (BP) traces showing the response to 5 pmol leptin microinjection (black arrow) into the SFO of young control animals (blue trace, n = 4) or leptin resistant, diet induced obese (DIO) animals (red trace, n = 4). DIO animals were no longer responsive to the depressor effects of leptin in the SFO. B) Summary bar graph showing the mean area under the curve for BP in response to leptin microinjection into the SFO of young control animals (blue bar), animals resistant to the weight gain typically caused by a high fat diet (DR — black bar), or DIO animals (red bar). Note that DR animals remained responsive to the cardiovascular effects of leptin in the SFO, while DIO animals were resistant to these effects of leptin (**p b 0.01).
recordings from our laboratory have also shown that SFO neurons are sensitive to circulating glucose concentrations, with separate subpopulations of cells demonstrating all of the sensory abilities associated with the classification of glucose excited (GE), or glucose inhibited (GI) neurons in other regions of the CNS [90]. Finally, our genomic analysis of the SFO identified receptors whose roles in this CVO have yet to be explored, including apelin, cannabinoid CB1, and neuropeptide Y (NPY) Y1 receptors, as well as the peptide apelin, cocaine and amphetamine related transcript (CART), CCK, orexin, NPY, oxytocin, pro-melanin concentrating hormone (PMCH), and vasopressin [63]. Thus, despite the numerous metabolic factors presently shown to be expressed in the SFO and to influence the excitability of individual SFO neurons, the physiological effects of these molecules have yet to be examined, and, in turn, the total contribution of this CVO as an ultimate mediator of energy balance has not yet been fully elucidated. 5. Conclusions In this review, we have highlighted information demonstrating that the SFO, a sensory CVO, is among the only CNS structures which interface
directly with circulating substances that do not cross the BBB. We have also described a portion of the extensive and growing literature showing that circulating indicators of cardiovascular status, such as angiotensin II, osmolarity, calcium, sodium, and metabolic function, including adiponectin and leptin, influence the excitability of single SFO neurons. Interestingly, the ability of SFO neurons to sense these circulating signals can be modified by physiological state, as in the cases of angiotensin II (normotensive versus hypertensive), adiponectin (fasted versus fed), and leptin (obese versus lean), indicating a dynamic and highly responsive contribution of SFO cells in the maintenance of cardiovascular and metabolic functions. Such observations suggest integrative roles for SFO neurons in regulating ingestive behavior, through its ability to constantly monitor multiple circulating signals which, once integrated, provide the essential information regarding central autonomic responses necessary for the appropriate maintenance of the physiologically healthy “milieu interieur”. The next critical steps in understanding such roles for SFO will require a detailed analysis of how SFO neurons and their integrated connections with autonomic control centers of the hypothalamus actually regulate autonomic outputs. We do not know how this will turn out, and hopefully new technologies will help us to understand
Please cite this article as: Mimee A, et al, Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Physiol Behav (2013), http://dx.doi.org/10.1016/j.physbeh.2013.02.012
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the potentially integrated importance of separate subpopulations of neurons responding differently to the same signaling molecule. However, the current evidence does highlight the potential role of the SFO as a critical gateway for multiple factors involved in the control of fluid balance and energy homeostasis, and suggests that this CVO, through its local actions and projections to other neuronal centers, is an important component of the total neuronal network which coordinates the control of ingestive behaviors. Acknowledgments This article is based on a presentation during the 2012 Annual Meeting of the Society for the Study of Ingestive Behavior, Zurich, Switzerland, July 10–14, 2012, made possible in part by a generous donations from Research Diets, Inc., Sanofi, Inc., and TSE, Inc. 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Please cite this article as: Mimee A, et al, Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Physiol Behav (2013), http://dx.doi.org/10.1016/j.physbeh.2013.02.012