The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Alastair V. Ferguson - One of the best experts on this subject based on the ideXlab platform.
-
the Subfornical Organ and Organum vasculosum of the lamina terminalis critical roles in cardiovascular regulation and the control of fluid balance
Handbook of Clinical Neurology, 2021Co-Authors: Mark W. Fry, Alastair V. FergusonAbstract:Abstract In this chapter, we review the extensive literature describing the roles of the Subfornical Organ (SFO), the Organum vasculosum of the terminalis (OVLT), and the median preoptic nucleus (MnPO), comprising the lamina terminalis, in cardiovascular regulation and the control of fluid balance. We present this information in the context of both historical and technological developments which can effectively be overlaid upon each other. We describe intrinsic anatomy and connectivity and then discuss early work which described how circulating angiotensin II acts at the SFO to stimulate drinking and increase blood pressure. Extensive studies using direct administration and lesion approaches to highlight the roles of all regions of the lamina terminalis are then discussed. At the cellular level we describe c-Fos and electrophysiological work, which has highlighted an extensive group of circulating hormones which appear to influence the activity of specific neurons in the SFO, OVLT, and MnPO. We highlight optogenetic studies that have begun to unravel the complexities of circuitries underlying physiological outcomes, especially those related to different components of drinking. Finally, we describe the somewhat limited human literature supporting conclusions that these structures play similar and potentially important roles in human physiology.
-
The transcriptome of the rat Subfornical Organ is altered in response to early postnatal overnutrition.
IBRO Reports, 2018Co-Authors: Colleen S. Peterson, Shuo Huang, Alastair V. FergusonAbstract:Abstract Early postnatal overnutrition in humans is associated with long-term negative outcomes including obesity, increased risk of type-II diabetes, and cardiovascular disease. Hypothalamic neurons from rodents exposed to early postnatal overnutrition show altered expression of satiety signals and receptors, and exhibit altered responses to many satiety signals, suggesting a hypothalamic link between early overnutrition and development of these sequelae. Importantly, several hypothalamic nuclei receive information regarding circulating hormones (such as insulin, leptin and ghrelin) from the Subfornical Organ (SFO), a forebrain sensory circumventricular Organ which lacks a blood brain barrier. Previous transcriptomic studies indicate that challenges to energy balance and hydration status stimulate changes in gene expression within the SFO, including genes encoding ion channels and receptors. In order to determine if early postnatal overnutrition also causes changes in SFO gene expression which may be associated with homeostatic dysregulation, we performed whole transcriptome sequencing on SFO tissue from rats raised in small (4 pups), or control (large, 12 pups) litters. Illumina RNA sequencing was performed on SFO tissue from rats raised from small and large litters, and read sequences were aligned to the Rat Rnor_6.0 genome. Control data were further compared to previously published microarray data set for validation. We found statistically significant (p
-
brain derived neurotrophic factor acts at neurons of the Subfornical Organ to influence cardiovascular function
Physiological Reports, 2018Co-Authors: Emily A E Black, Pauline M Smith, William Mcisaac, Alastair V. FergusonAbstract:Brain-derived neurotrophic factor (BDNF), a neurotrophin traditionally associated with neural plasticity, has more recently been implicated in fluid balance and cardiovascular regulation. It is abundantly expressed in both the central nervous system (CNS) and peripheral tissue, and is also found in circulation. Studies suggest that circulating BDNF may influence the CNS through actions at the Subfornical Organ (SFO), a circumventricular Organ (CVO) characterized by the lack of a normal blood-brain barrier (BBB). The SFO, well-known for its involvement in cardiovascular regulation, has been shown to express BDNF mRNA and mRNA for the TrkB receptor at which BDNF preferentially binds. This study was undertaken to determine if: (1) BDNF influences the excitability of SFO neurons in vitro; and (2) the cardiovascular consequences of direct administration of BDNF into the SFO of anesthetized rats. Electrophysiological studies revealed that bath application of BDNF (1 nmol/L) influenced the excitability of the majority of neurons (60%, n = 13/22), the majority of which exhibited a membrane depolarization (13.8 ± 2.5 mV, n = 9) with the remaining affected cells exhibiting hyperpolarizations (-11.1 ± 2.3 mV, n = 4). BDNF microinjections into the SFO of anesthetized rats caused a significant decrease in blood pressure (mean [area under the curve] AUC = -364.4 ± 89.0 mmHg × sec, n = 5) with no effects on heart rate (mean AUC = -12.2 ± 3.4, n = 5). Together these observations suggest the SFO to be a CNS site at which circulating BDNF could exert its effects on cardiovascular regulation.
-
Subfornical Organ neurons integrate cardiovascular and metabolic signals
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2017Co-Authors: Nicole M Cancelliere, Alastair V. FergusonAbstract:The Subfornical Organ (SFO) is a critical circumventricular Organ involved in the control of cardiovascular and metabolic homeostasis. Despite the plethora of circulating signals continuously sense...
-
physiological roles for the Subfornical Organ a dynamic transcriptome shaped by autonomic state
The Journal of Physiology, 2016Co-Authors: Charles Hindmarch, Alastair V. FergusonAbstract:The Subfornical Organ (SFO) is a circumventricular Organ recognized for its ability to sense and integrate hydromineral and hormonal circulating fluid balance signals, information which is transmitted to central autonomic nuclei to which SFO neurons project. While the role of SFO was once synonymous with physiological responses to osmotic, volumetric and cardiovascular challenge, recent data suggest that SFO neurons also sense and integrate information from circulating signals of metabolic status. Using microarrays, we have confirmed the expression of receptors already described in the SFO, and identified many novel transcripts expressed in this circumventricular Organ including receptors for many of the critical circulating energy balance signals such as adiponectin, apelin, endocannabinoids, leptin, insulin and peptide YY. This transcriptome analysis also identified SFO transcripts, the expressions of which are significantly changed by either 72 h dehydration, or 48 h starvation, compared to fed and euhydrated controls. Expression and potential roles for many of these targets are yet to be confirmed and elucidated. Subsequent validation of data for adiponectin and leptin receptors confirmed that receptors for both are expressed in the SFO, that discrete populations of neurons in this tissue are functionally responsive to these adipokines, and that such responsiveness is regulated by physiological state. Thus, transcriptomic analysis offers great promise for understanding the integrative complexity of these physiological systems, especially with development of technologies allowing description of the entire transcriptome of single, carefully phenotyped, SFO neurons. These data will ultimately elucidate mechanisms through which these uniquely positioned neurons respond to and integrate complex circulating signals.
Robin L Davisson - One of the best experts on this subject based on the ideXlab platform.
-
obesity induced hepatic steatosis is mediated by endoplasmic reticulum stress in the Subfornical Organ of the brain
JCI insight, 2017Co-Authors: Julie A Horwath, Martin D Cassell, Allyn L Mark, Robin L Davisson, Chansol Hurr, Scott D Butler, Mallikarjun Rao Guruju, Colin N YoungAbstract:Nonalcoholic fatty liver disease (NAFLD), characterized by an excess accumulation of hepatic triglycerides, is a growing health epidemic. While ER stress in the liver has been implicated in the development of NAFLD, the role of brain ER stress - which is emerging as a key contributor to a number of chronic diseases including obesity - in NAFLD remains unclear. These studies reveal that chemical induction of ER stress in the brain caused hepatomegaly and hepatic steatosis in mice. Conversely, pharmacological reductions in brain ER stress in diet-induced obese mice rescued NAFLD independent of body weight, food intake, and adiposity. Evaluation of brain regions involved revealed robust activation of ER stress biomarkers and ER ultrastructural abnormalities in the circumventricular Subfornical Organ (SFO), a nucleus situated outside of the blood-brain-barrier, in response to high-fat diet. Targeted reductions in SFO-ER stress in obese mice via SFO-specific supplementation of the ER chaperone 78-kDa glucose-regulated protein ameliorated hepatomegaly and hepatic steatosis without altering body weight, food intake, adiposity, or obesity-induced hypertension. Overall, these findings indicate a novel role for brain ER stress, notably within the SFO, in the pathogenesis of NAFLD.
-
abstract 086 insulin receptor signaling in the Subfornical Organ protects against the development of metabolic syndrome
Hypertension, 2015Co-Authors: Julie A Horwath, Robin L Davisson, Scott D Butler, A L Mark, Colin N YoungAbstract:Metabolic syndrome encompasses a combination of conditions including obesity, diabetes, dyslipidemia and hypertension. Brain insulin resistance has emerged as a contributor to the development of metabolic syndrome, although the neural regions involved remain unclear. While most studies have focused on hypothalamic areas, recent evidence suggests that the Subfornical Organ (SFO), a circumventricular Organ well-known for cardiovascular control, is also involved in metabolic regulation. We therefore hypothesized that the SFO insulin receptor protects against the development of metabolic syndrome. Male mice (6.5 wks) harboring a conditional allele of the insulin receptor gene ( INSR) underwent SFO-targeted delivery of an adenovirus encoding a control vector (AdLacZ, n=7) or Cre-recombinase (AdCre, n=11) for selective removal of the SFO insulin receptor. Both groups remained on normal chow for 10 wks. Removal of the SFO insulin receptor did not influence food intake, but resulted in an ~40% greater increase in body weight (AdLacZ vs AdCre: Δ2.2±0.3 vs. 3.8±0.4 g; p<0.05). Consistent with the increased body weight, SFO insulin receptor deletion was associated with overall elevations in adiposity (e.g., abdominal fat, AdLacZ vs AdCre: 0.19±0.04 vs. 0.33±0.05 g; p<0.05). Analysis of the liver revealed substantial hepatic triglyceride accumulation in SFO-targeted AdCre mice (AdLacZ vs. AdCre: 62 ± 16 vs. 209 ± 29 mg/dl; p<0.05), with histological examinations (Oil Red O) revealing large lipid droplet accumulation following removal of the SFO insulin receptor. Parallel elevations in circulating triglycerides were also found (AdLacZ vs. AdCre: 1.4 ± 0.2 vs. 3.3 ± 0.6 mg/dl; p=0.05). These data demonstrate that ablation of SFO insulin receptors resulted in an overall deleterious metabolic state including increases in body weight, elevations in adiposity, hepatic steatosis and hypertriglyceridemia. These findings suggest that impairments in insulin signaling within the SFO contribute to the development of metabolic syndrome. Studies are ongoing to investigate the effect of SFO insulin receptor removal on blood pressure.
-
endoplasmic reticulum and oxidant stress mediate nuclear factor κb activation in the Subfornical Organ during angiotensin ii hypertension
American Journal of Physiology-cell Physiology, 2015Co-Authors: Colin N Young, Julie A Horwath, Frederick N Dong, Catharine G Clark, Robin L DavissonAbstract:Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular Subfornical Organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.
-
angiotensin type 1a receptors in the forebrain Subfornical Organ facilitate leptin induced weight loss through brown adipose tissue thermogenesis
Molecular metabolism, 2015Co-Authors: Colin N Young, Donald A Morgan, Allyn L Mark, Scott D Butler, Kamal Rahmouni, Susan B Gurley, Thomas M Coffman, Robin L DavissonAbstract:Objective: Elevations in brain angiotensin-II cause increased energy expenditure and a lean phenotype. Interestingly, the metabolic effects of increased brain angiotensin-II mimic the actions of leptin, suggesting an interaction between the two systems. Here we demonstrate that angiotensin-type 1a receptors (AT1aR) in the Subfornical Organ (SFO), a forebrain structure emerging as an integrative metabolic center, play a key role in the body weight-reducing effects of leptin via brown adipose tissue (BAT) thermogenesis. Methods: Cre/LoxP technology coupled with targeted viral delivery to the SFO in a mouse line bearing a conditional allele of the Agtr1a gene was utilized to determine the interaction between leptin and SFO AT1aR in metabolic regulation. Results: Selective deletion of AT1aR in the SFO attenuated leptin-induced weight loss independent of changes in food intake or locomotor activity. This was associated with diminished leptin-induced increases in core body temperature, blunted upregulation of BAT thermogenic markers, and abolishment of leptin-mediated sympathetic activation to BAT. Conclusions: These data identify a novel interaction between angiotensin-II and leptin in the control of BAT thermogenesis and body weight, and highlight a previously unrecognized role for the forebrain SFO in metabolic regulation.
-
relief of endoplasmic reticulum stress in the brain Subfornical Organ rescues high fat diet induced non alcoholic fatty liver disease 1126 16
The FASEB Journal, 2014Co-Authors: Julie A Horwath, Colin N Young, Allyn L Mark, Scott D Butler, Robin L DavissonAbstract:NAFLD is a hallmark of metabolic syndrome and endoplasmic reticulum (ER) stress has been suggested as an underlying mechanism. However, the role of the brain in mediating NAFLD remains unclear. Importantly, brain ER stress has emerged as the basis of a number of chronic diseases, and we have recently demonstrated robust ER stress in the Subfornical Organ (SFO) of high fat diet (HFD)-fed mice. Therefore, we tested the hypothesis that ER stress in the SFO mediates HFD-induced NAFLD. Male C57Bl/6 mice were fed HFD (60% fat, n=13) for 20 weeks. SFO-targeted microinjections of an adenovirus encoding the ER chaperone GRP78 (AdGRP78) to reduce ER stress, or control vector (AdLacZ), were then performed. Selective reductions in SFO-ER stress resulted in a significant decrease in HFD-induced hepatomegaly (2.25±0.06 vs 1.71±0.12 g, HFD AdLacZ vs HFD AdGRP78, p 0.05), food intake or adiposity. SFO-targeted AdGRP78 also reduced HFD-med...
Curt D Sigmund - One of the best experts on this subject based on the ideXlab platform.
-
mechanisms of brain renin angiotensin system induced drinking and blood pressure importance of the Subfornical Organ
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2015Co-Authors: Jeffrey P Coble, Justin L Grobe, Alan Kim Johnson, Curt D SigmundAbstract:It is critical for cells to maintain a homeostatic balance of water and electrolytes because disturbances can disrupt cellular function, which can lead to profound effects on the physiology of an Organism. Dehydration can be classified as either intra- or extracellular, and different mechanisms have developed to restore homeostasis in response to each. Whereas the renin-angiotensin system (RAS) is important for restoring homeostasis after dehydration, the pathways mediating the responses to intra- and extracellular dehydration may differ. Thirst responses mediated through the angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptors (AT2R) respond to extracellular dehydration and intracellular dehydration, respectively. Intracellular signaling factors, such as protein kinase C (PKC), reactive oxygen species (ROS), and the mitogen-activated protein (MAP) kinase pathway, mediate the effects of central angiotensin II (ANG II). Experimental evidence also demonstrates the importance of the Subfornical Organ (SFO) in mediating some of the fluid intake effects of central ANG II. The purpose of this review is to highlight the importance of the SFO in mediating fluid intake responses to dehydration and ANG II.
-
activation of the renin angiotensin system specifically in the Subfornical Organ is sufficient to induce fluid intake
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2014Co-Authors: Jeffrey P Coble, Martin D Cassell, Deborah R Davis, Justin L Grobe, Curt D SigmundAbstract:Increased activity of the renin-angiotensin system within the brain elevates fluid intake, blood pressure, and resting metabolic rate. Renin and angiotensinogen are coexpressed within the same cells of the Subfornical Organ, and the production and action of ANG II through the ANG II type 1 receptor in the Subfornical Organ (SFO) are necessary for fluid intake due to increased activity of the brain renin-angiotensin system. We generated an inducible model of ANG II production by breeding transgenic mice expressing human renin in neurons controlled by the synapsin promoter with transgenic mice containing a Cre-recombinase-inducible human angiotensinogen construct. Adenoviral delivery of Cre-recombinase causes SFO-selective induction of human angiotensinogen expression. Selective production of ANG II in the SFO results in increased water intake but did not change blood pressure or resting metabolic rate. The increase in water intake was ANG II type 1 receptor-dependent. When given a choice between water and 0.15 M NaCl, these mice increased total fluid and sodium, but not water, because of an increased preference for NaCl. When provided a choice between water and 0.3 M NaCl, the mice exhibited increased fluid, water, and sodium intake, but no change in preference for NaCl. The increase in fluid intake was blocked by an inhibitor of PKC, but not ERK, and was correlated with increased phosphorylated cyclic AMP response element binding protein in the Subfornical Organ. Thus, increased production and action of ANG II specifically in the Subfornical Organ are sufficient on their own to mediate an increase in drinking through PKC.
-
activity of protein kinase c α within the Subfornical Organ is necessary for fluid intake in response to brain angiotensin
Hypertension, 2014Co-Authors: Jeffrey P Coble, Martin D Cassell, Justin L Grobe, Ralph F Johnson, Alan Kim Johnson, Curt D SigmundAbstract:Angiotensin-II production in the Subfornical Organ acting through angiotensin-II type-1 receptors is necessary for polydipsia, resulting from elevated renin–angiotensin system activity. Protein kinase C and mitogen-activated protein kinase pathways have been shown to mediate effects of angiotensin-II in the brain. We investigated mechanisms that mediate brain angiotensin-II–induced polydipsia. We used double-transgenic sRA mice, consisting of human renin controlled by the neuron-specific synapsin promoter crossed with human angiotensinogen controlled by its endogenous promoter, which results in brain-specific overexpression of angiotensin-II, particularly in the Subfornical Organ. We also used the deoxycorticosterone acetate-salt model of hypertension, which exhibits polydipsia. Inhibition of protein kinase C, but not extracellular signal–regulated kinases, protein kinase A, or vasopressin V 1A and V 2 receptors, corrected the elevated water intake of sRA mice. Using an isoform selective inhibitor and an adenovirus expressing dominant negative protein kinase C-α revealed that protein kinase C-α in the Subfornical Organ was necessary to mediate elevated fluid and sodium intake in sRA mice. Inhibition of protein kinase C activity also attenuated polydipsia in the deoxycorticosterone acetate-salt model. We provide evidence that inducing protein kinase C activity centrally is sufficient to induce water intake in water-replete wild-type mice, and that cell surface localization of protein kinase C-α can be induced in cultured cells from the Subfornical Organ. These experimental findings demonstrate a role for central protein kinase C activity in fluid balance, and further mechanistically demonstrate the importance of protein kinase C-α signaling in the Subfornical Organ in fluid intake stimulated by angiotensin-II in the brain.
-
angiotensin type 1a receptors in the Subfornical Organ are required for deoxycorticosterone acetate salt hypertension
Hypertension, 2013Co-Authors: Aline M Hilzendeger, Martin D Cassell, Deborah R Davis, Justin L Grobe, Allyn L Mark, Harald M Stauss, Curt D SigmundAbstract:Although elevated renin–angiotensin system activity and angiotensinergic signaling within the brain are required for hypertension, polydipsia, and increased metabolic rate induced by deoxycorticosterone acetate (DOCA)-salt, the contribution of specific receptor subtypes and brain nuclei mediating these responses remains poorly defined. We hypothesized that angiotensin type 1a receptors (AT1aR) within the Subfornical Organ (SFO) mediate these responses. Transgenic mice carrying a conditional allele of the endogenous AT1aR (AT1aRflox) were administered an adenovirus encoding Cre-recombinase and enhanced green fluorescent protein (eGFP) or adenovirus encoding eGFP alone into the lateral cerebral ventricle. Adenovirus encoding Cre-recombinase reduced AT1aR mRNA and induced recombination in AT1aRflox genomic DNA specifically in the SFO, without significant effect in the paraventricular or arcuate nuclei, and also induced SFO-specific recombination in ROSATdTomato reporter mice. The effect of SFO-targeted ablation of endogenous AT1aR was evaluated in AT1aRflox mice at 3 time points: (1) baseline, (2) 1 week after virus injection but before DOCA-salt, and (3) after 3 weeks of DOCA-salt. DOCA-salt–treated mice with deletion of AT1aR in SFO exhibited a blunted increase in arterial pressure. Increased sympathetic cardiac modulation and urine copeptin, a marker of vasopressin release, were both significantly reduced in DOCA-salt mice when AT1aR was deleted in the SFO. Additionally, deletion of AT1aR in the SFO significantly attenuated the polydipsia, polyuria, and sodium intake in response to DOCA-salt. Together, these data highlight the contribution of AT1aR in the SFO to arterial pressure regulation potentially through changes on sympathetic cardiac modulation, vasopressin release, and hydromineral balance in the DOCA-salt model of hypertension.
-
local production of angiotensin ii in the Subfornical Organ causes elevated drinking
Journal of Clinical Investigation, 2007Co-Authors: Koji Sakai, Martin D Cassell, Robin L Davisson, Khristofor Agassandian, Satoshi Morimoto, Puspha Sinnayah, Curt D SigmundAbstract:The mechanism controlling cell-specific Ang II production in the brain remains unclear despite evidence supporting neuron-specific renin and glial- and neuronal-specific angiotensinogen (AGT) expression. We generated double-transgenic mice expressing human renin (hREN) from a neuron-specific promoter and human AGT (hAGT) from its own promoter (SRA mice) to emulate this expression. SRA mice exhibited an increase in water and salt intake and urinary volume, which were significantly reduced after chronic intracerebroventricular delivery of losartan. Ang II–like immunoreactivity was markedly increased in the Subfornical Organ (SFO). To further evaluate the physiological importance of de novo Ang II production specifically in the SFO, we utilized a transgenic mouse model expressing a floxed version of hAGT (hAGTflox), so that deletions could be induced with Cre recombinase. We targeted SFO-specific ablation of hAGTflox by microinjection of an adenovirus encoding Cre recombinase (AdCre). SRAflox mice exhibited a marked increase in drinking at baseline and a significant decrease in water intake after administration of AdCre/adenovirus encoding enhanced GFP (AdCre/AdEGFP), but not after administration of AdEGFP alone. This decrease only occurred when Cre recombinase correctly targeted the SFO and correlated with a loss of hAGT and angiotensin peptide immunostaining in the SFO. These data provide strong genetic evidence implicating de novo synthesis of Ang II in the SFO as an integral player in fluid homeostasis.
John P Collister - One of the best experts on this subject based on the ideXlab platform.
-
the role of the Subfornical Organ in angiotensin ii salt hypertension in the rat
Experimental Physiology, 2012Co-Authors: John W Osborn, Michael D Hendel, John P Collister, Pilar Arizaguzman, Gregory D FinkAbstract:Hypertension caused by chronic infusion of angiotensin II (Ang II) in experimental animals is dependent, in part, on increased activity of the sympathetic nervous system. This chronic sympathoexcitatory response is amplified by a high-salt diet, suggesting an interaction of circulating Ang II and dietary salt on sympathetic regulatory pathways in the brain. The present study tested the hypothesis that the Subfornical Organ (SFO), a forebrain circumventricular Organ known to be activated by circulating Ang II, is crucial to the pathogenesis of hypertension induced by chronic Ang II administration in rats on a high-salt diet (Ang II-salt model). Rats were randomly selected to undergo either Subfornical Organ lesion (SFOx) or sham surgery (Sham) and then placed on a high-salt (2% NaCl) diet. One week later, rats were instrumented for radiotelemetric measurement of mean arterial pressure (MAP) and heart rate (HR) and placed in metabolic cages to measure sodium and water balance. Baseline MAP was slightly (but not statistically) lower in SFOx compared with Sham rats during the 5 day control period. During the subsequent 10 days of Ang II administration, MAP was statistically lower in SFOx rats. However, when MAP responses to Ang II were analysed by comparing the change from the 5 day baseline period, only on the fifth day of Ang II was MAP significantly different between groups. There were no differences between groups for water or sodium balance throughout the protocol. We conclude that, although the SFO is required for the complete expression of Ang II-salt hypertension in the rat, other brain sites are also involved.
-
lesion of the Subfornical Organ attenuates neuronal activation of the paraventricular nucleus in response to angiotensin ii in normal rats
Open Journal of Neuroscience, 2011Co-Authors: Jessica L Meehan, John P CollisterAbstract:Introduction/Hypothesis: The Subfornical Organ, one of the central circumventricular Organs, has been shown to mediate many of the effects of circulating angiotensin II (AngII). Where these signals are processed downstream is not fully understood. The SFO does indeed project to prominent cardiovascular regulatory centers such as the paraventricular nucleus (PVN), of whose neurons are activated by central AngII. We reasoned that AngII sensed at the SFO would cause neuronal activation at downstream hypothalamic areas such as the median preoptic nucleus and paraventricular nucleus, and as such would be diminished in animals with lesions of the SFO. Materials and Methods: To test this hypothesis, groups of rats underwent either SFO lesion (SFOx) or sham operation. Five days later rats were instrumented with radiotelemetry transducers for monitoring of mean arterial pressure (MAP) and venous catheters for infusions. MAP and heart rate were measured continuously. After a 4 day control period, infusion of AngII (0.575 µg/kg/min) was begun for a period of 2 hours. Rats were then sacrificed and brains were processed for neuronal Fos expression. Results: AngII produced Fos expression in the SFO, MnPO and PVN of sham rats. Fos expression was greatly attenuated in the PVN of SFOx rats. Conclusion: These results support our hypothesis, suggesting that AngII sensitive neurons of the SFO can mediate neuronal activation in the PVN.
-
effect of Subfornical Organ lesion on the development of mineralocorticoid salt hypertension
Brain Research, 2006Co-Authors: John W Osborn, Michael D Hendel, John P Collister, Frederic Jacob, Leah A Clark, Pilar GuzmanAbstract:Abstract Accumulating evidence suggests that structures within the lamina terminalis; the Organum vasculosm of the lamina terminalis (OVLT), the median preoptic nucleus (MnPO) and/or the Subfornical Organ (SFO); are required for the development of DOCA-salt hypertension. Lesion of the anteroventral tissue lining the third ventricle (AV3V), which destroys cell bodies in the OVLT and MnPO, as well as efferent projections from the SFO to the OVLT and MnPO, abolishes DOCA-salt hypertension in the rat. However, the individual contribution of these structures to DOCA-salt hypertension is unknown. The present study was designed to determine whether an intact SFO is required for hypertension development in the DOCA-salt model. In uninephrectomized SFO lesioned (SFOx; n = 6) and SHAM (n = 8) Sprague-Dawley rats, 24-h mean arterial pressure (MAP) and heart rate (HR) were continuously recorded telemetrically 4 days before and 36 days after DOCA implantation (100 mg/rat; s.c.); 24-h sodium and water balances were measured throughout the protocol. No differences in control MAP, HR, sodium and water balances were observed between groups. Following DOCA implantation, the magnitude of the elevation of MAP was similar between groups (∼ 40 mm Hg) so that by Day 40, MAP was 148 ± 5 mm Hg in SFOx and 145 ± 4 mm Hg in SHAM rats. The magnitude of decrease in HR from control values was similar in both groups. Differences in sodium and water balances were not observed between groups. We conclude that the SFO alone does not play a significant role in the development of mineralocorticoid-salt hypertension.
-
chronic effects of angiotensin ii and at1 receptor antagonists in Subfornical Organ lesioned rats
Clinical and Experimental Pharmacology and Physiology, 2005Co-Authors: John P Collister, Michael D HendelAbstract:SUMMARY 1. Angiotensin (Ang) II is known to exert some of its effects centrally via circumventricular Organs. These unique central nervous system areas lack the normal blood–brain barrier and, therefore, allow peptide hormones access to the brain. Of these, the Subfornical Organ (SFO) has been shown to be involved in many of the acute dipsogenic and pressor effects of AngII, but much less is known about the role of the SFO in the chronic effects of AngII. We hypothesized that the SFO is a central site involved in the chronic hypotensive effects of endogenous AT1 receptor blockade, as well as the chronic hypertensive effects of exogenously administered AngII. 2. In order to test these hypotheses, SFO-lesioned (SFOx) or sham Sprague-Dawley rats were instrumented with venous catheters and radiotelemetric pressure transducers for intravenous administration of losartan or AngII and continuous measurement of blood pressure and heart rate. Rats were given 3 days of saline control infusion (7 mL/day of 0.9% NaCl) and were then infused with either losartan (10 mg/kg per day) or AngII (10 ng/kg per min) for 10 days. 3. By day 4 of losartan treatment, arterial pressure had decreased 24 ± 2 and 18 ± 2 mmHg in sham (n = 9) and SFOx (n = 10) rats, respectively. Furthermore, by day 5 of AngII infusion, arterial pressure had increased 12 ± 3 mmHg in sham rats (n = 9), but only by 4 ± 1 mmHg in SFOx rats (n = 9). In each treatment group, these attenuated pressure responses in SFOx rats continued through day 10 of treatment. 4. These results support the hypotheses that the SFO plays a role in both the hypotensive effects of chronic AT1 receptor blockade and the chronic hypertensive phase of exogenously administered AngII.
-
contribution of the Subfornical Organ to angiotensin ii induced hypertension
American Journal of Physiology-heart and Circulatory Physiology, 2005Co-Authors: Michael D Hendel, John P CollisterAbstract:Previous studies clearly demonstrated acute actions of angiotensin II (ANG II) at one of the central circumventricular Organs, the Subfornical Organ (SFO), but studies demonstrating a role for the ...
Douglas A Fitts - One of the best experts on this subject based on the ideXlab platform.
-
Subfornical Organ disconnection alters fos expression in the lamina terminalis supraoptic nucleus and area postrema after intragastric hypertonic nacl
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2005Co-Authors: Julia A Freece, Julie E Van Bebber, Dannielle Zierath, Douglas A FittsAbstract: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.
-
Subfornical Organ disconnection and fos like immunoreactivity in hypothalamic nuclei after intragastric hypertonic saline
Brain Research, 2002Co-Authors: Elizabeth M Starbuck, Douglas A FittsAbstract:The Subfornical Organ (SFO) may act as a sodium- or osmoreceptor that drives hypothalamic and other nuclei to secrete vasopressin and to elicit drinking. However, in response to mild doses of hypertonic saline, Fos-like immunoreactivity (Fos-ir) is absent in the SFO whereas it is well expressed in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei. This suggests that the hypothalamus may be activated in advance of the SFO. In this study, the fibers connecting the SFO and hypothalamus were disconnected by a wire knife cut so that Fos-ir could be examined in both the SFO and hypothalamus after an intragastric (ig) load of 0.5% of body weight of 0.6 M NaCl. Compared with Fos-ir in isotonic-loaded rats, Fos-ir after the hypertonic load was not significantly elevated in the SFO or median preoptic nucleus in sham-cut or knife-cut rats and was only slightly elevated in the OVLT in sham-cut rats. However, the hypertonic load in sham-cut rats greatly elevated Fos-ir in the SON and in the entire PVN, but this expression was reduced significantly by 30-50% in knife-cut rats. Thus, the connectivity between SFO and the hypothalamus is critical for the full expression of Fos-ir in the hypothalamus during moderate ig hypertonic saline loading even when the SFO itself does not yet express Fos-ir.
-
interaction of hydration and Subfornical Organ lesions in sodium depletion induced salt appetite
Behavioral Neuroscience, 1997Co-Authors: Elizabeth M Starbuck, Jeannine R Lane, Douglas A FittsAbstract:The authors tested whether the level of hydration after furosemide diuresis and 22 hr of sodium depletion affects the amount of water or 0.3 M NaCl solution consumed by rats with intact brains or with lesions of the Subfornical Organ (SFO). Rats received 2 (underhydrated) or 10 (euhydrated) ml/kg water by gavage as the only fluid input 2, 4, and 20 hr after 10 mg/kg furosemide. These hydration treatments had little or no effect on the amount of saline consumed in 2 hr by intact rats. SFO lesions reduced water intake regardless of hydration condition. Euhydrated, SFO-lesioned rats drank a normal amount of saline, but underhydrated, lesioned rats drank less saline than any other group. Thus, euhydration may facilitate salt appetite in SFO-lesioned rats, and the deficits in salt appetite noted in SFO-lesioned rats may result from deficits in water ingestion rather than from a destruction of angiotensin II receptor sites that directly provoke salt appetite.
-
effects of lesions of the ventral ventral median preoptic nucleus or Subfornical Organ on drinking and salt appetite after deoxycorticosterone acetate or yohimbine
Behavioral Neuroscience, 1991Co-Authors: Douglas A FittsAbstract:Lesions of the ventral ventral median preoptic nucleus (VVMnPO) enhanced daily salt appetite induced by subcutaneous (sc) injections of deoxycorticosterone acetate (DOCA) but did not affect acute salt appetite or water intake after sc injections of 5 mg/kg of the alpha-2-adrenoreceptor blocker yohimbine. Lesions of the Subfornical Organ (SFO) or its rostral fiber pathways had no effect on fluid intakes during DOCA treatments but significantly reduced water intake after yohimbine. These findings extend those of a previous report (Fitts, Tjepkes, & Bright, 1990) of enhanced DOCA-induced saline intake in VVMnPO-lesioned rats and demonstrate that the effect is specific to lesions of the VVMnPO. The mechanism of the thirst and salt intake elicited by yohimbine is still unclear, but the SFO and its fiber pathways appear to be important for the expression of the water drinking component. Neither lesion reliably affected yohimbine-induced salt appetite.
