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Find video protocols related to scientific articles indexed in Pubmed.
Hydrogen sulfide regulates cardiovascular function by influencing the excitability of subfornical organ neurons.
PLoS ONE
PUBLISHED: 08-21-2014
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Hydrogen sulfide (H2S), a gasotransmitter endogenously found in the central nervous system, has recently been suggested to act as a signalling molecule in the brain having beneficial effects on cardiovascular function. This study was thus undertaken to investigate the effect of NaHS (an H2S donor) in the subfornical organ (SFO), a central nervous system site important to blood pressure regulation. We used male Sprague-Dawley rats for both in vivo and in vitro experiments. We first used RT-PCR to confirm our previous microarray analyses showing that mRNAs for the enzymes required to produce H2S are expressed in the SFO. We then used microinjection techniques to investigate the physiological effects of NaHS in SFO, and found that NaHS microinjection (5 nmol) significantly increased blood pressure (mean AUC?=?853.5±105.7 mmHg*s, n?=?5). Further, we used patch-clamp electrophysiology and found that 97.8% (88 of 90) of neurons depolarized in response to NaHS. This response was found to be concentration dependent with an EC50 of 35.6 µM. Coupled with the depolarized membrane potential, we observed an overall increase in neuronal excitability using an analysis of rheobase and action potential firing patterns. This study has provided the first evidence of NaHS and thus H2S actions and their cellular correlates in SFO, implicating this brain area as a site where H2S may act to control blood pressure.
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AT1 receptor blockade alters nutritional and biometric development in obesity-resistant and obesity-prone rats submitted to a high fat diet.
Front Psychol
PUBLISHED: 07-29-2014
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Obesity is a chronic metabolic condition with important public health implications associated with numerous co-morbidities including cardiovascular disease, insulin resistance, and hypertension. The renin angiotensin system (RAS), best known for its involvement in cardiovascular control and body fluid homeostasis has, more recently, been implicated in regulation of energy balance. Interference with the RAS (genetically or pharmacologically) has been shown to influence body weight gain. In this study we investigated the effects of systemic AT1 receptor blockade using losartan on ingestive behaviors and weight gain in diet induced obese (DIO) rats. Prior to losartan administration (30 mg/kg/day) body weight gain remained constant within the DIO animals (3.6 ± 0.3 g/day, n = 8), diet resistant (DR) animals (2.1 ± 0.6 g/day, n = 8) and in the age-matched chow fed control (CHOW) animals (2.8 ± 0.3 g/day, n = 8), Losartan administration abolished body weight gain in animals fed a high fat diet (DIO: -0.4 ± 0.7 g/day, n = 8; and DR: -0.8 ± 0.3 g/day, n = 8) while chow fed animals continued to gain weight (2.2 ± 0.3 g/day, n = 8) as they had previously to oral administration of losartan. This decrease in daily body weight gain was accompanied by a decrease in food intake in the HFD fed animals. Following the removal of losartan, both the DIO and DR animals again showed daily increases in body weight gain and food intake which were similar to control values. Our data demonstrate that oral losartan administration attenuates body weight gain in animals fed a HFD whether the animal is obese (DIO) or not DR while having no effect on body weight gain in age-matched chow fed animals suggesting a protective effect of losartan against body weight gain while on a HFD.
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The subfornical organ: a novel site of action of cholecystokinin.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
PUBLISHED: 01-15-2014
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The subfornical organ (SFO) is an important sensory circumventricular organ implicated in the regulation of fluid homeostasis and energy balance. We investigated whether the SFO is activated by the hormone cholecystokinin (CCK). CCK? and CCK? receptors were identified in the SFO by RT-PCR. Dissociated SFO neurons that responded to CCK (40/77), were mostly depolarized (9.2 ± 0.9 mV, 30/77), but some were hyperpolarized (-7.3 ± 1.1 mV, 10/77). We next examined the responses of SFO neurons in vivo to CCK (16 ?g/kg ip), in the presence and absence of CCK? or CCK? receptor antagonists (devazepide; 600 ?g/kg and L-365,260; 100 ?g/kg, respectively), using the functional activation markers c-Fos and phosphorylated extracellular signal-related kinase (p-ERK). The nucleus of the solitary tract (NTS) served as a control for CCK-induced activity. There was a significant increase in c-Fos expression in the NTS (259.2 ± 20.8 neurons) compared with vehicle (47.5 ± 2.5). Similarly, in the SFO, c-Fos was expressed in 40.5 ± 10.6 neurons in CCK-treated compared with 6.6 ± 2.7 in vehicle-treated rats (P < 0.01). Devazepide significantly reduced the effects of CCK in the NTS but not in SFO. L-365,260 blocked the effects of CCK in both brain regions. CCK increased the number of p-ERK neurons in NTS (27.0 ± 4.0) as well as SFO (18.0 ± 4.0), compared with vehicle (8.0 ± 2.6 and 4.3 ± 0.6, respectively; P < 0.05). Both devazepide and L-365,260 reduced CCK-induced p-ERK in NTS, but only L-365,260 reduced it in the SFO. In conclusion, the SFO represents a novel brain region at which circulating CCK may act via CCK? receptors to influence central autonomic control.
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Apelin acts in the subfornical organ to influence neuronal excitability and cardiovascular function.
J. Physiol. (Lond.)
PUBLISHED: 04-29-2013
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Apelin is an adipocyte-derived hormone involved in the regulation of water balance, food intake and the cardiovascular system partially through actions in the CNS. The subfornical organ (SFO) is a circumventricular organ with identified roles in body fluid homeostasis, cardiovascular control and energy balance. The SFO lacks a normal blood-brain barrier, and is thus able to detect circulating signalling molecules such as angiotensin II and leptin. In this study, we investigated actions of apelin-13, the predominant apelin isoform in brain and circulatory system, on the excitability of dissociated SFO neurons using electrophysiological approaches, and determined the cardiovascular consequences of direct administration into the SFO of anaesthetized rats. Whole cell current clamp recording revealed that bath-applied 100 nm apelin-13 directly influences the excitability of the majority of SFO neurons by eliciting either depolarizing (31.8%, mean 7.0 ± 0.8 mV) or hyperpolarizing (28.6%, mean -10.4 ± 1.8 mV) responses. Using voltage-clamp techniques, we also identified modulatory actions of apelin-13 on specific ion channels, demonstrating that apelin-13 activates a non-selective cationic conductance to depolarize SFO neurons while activation of the delayed rectifier potassium conductance underlies hyperpolarizing effects. In anaesthetized rats, microinjection of apelin into SFO decreased both blood pressure (BP) (mean area under the curve -1492.3 ± 357.1 mmHg.s, n = 5) and heart rate (HR) (-32.4 ± 10.39 beats, n = 5). Our data suggest that circulating apelin can directly affect BP and HR as a consequence of the ability of this peptide to modulate the excitability of SFO neurons.
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Cellular actions of nesfatin-1 on hypothalamic and medullary neurons.
Curr. Pharm. Des.
PUBLISHED: 02-01-2013
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The present review summarizes the current understanding of the neuronal activation patterns induced by nesfatin-1 in both the hypothalamus and the brainstem, as well as the physiological outcomes caused by the activation of these neuronal populations. Studies using cFos measurements, Ca(2+) imaging techniques, electrophysiological recordings, and microinjections have led to the identification of the paraventricular nucleus, arcuate nucleus, lateral and ventromedial hypothalamic areas, as well as medullary centers such as the nucleus of the solitary tract and dorsal motor nucleus of the vagus as targets of central nesfatin-1 actions on food intake, cardiovascular function, stress responses, and glucose homeostasis.
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Circumventricular organs: targets for integration of circulating fluid and energy balance signals?
Physiol. Behav.
PUBLISHED: 01-26-2013
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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.
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Depolarizing actions of hydrogen sulfide on hypothalamic paraventricular nucleus neurons.
PLoS ONE
PUBLISHED: 01-01-2013
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Hydrogen sulfide (H2S) is a novel neurotransmitter that has been shown to influence cardiovascular functions as well and corticotrophin hormone (CRH) secretion. Since the paraventricular nucleus of the hypothalamus (PVN) is a central relay center for autonomic and endocrine functions, we sought to investigate the effects of H2S on the neuronal population of the PVN. Whole cell current clamp recordings were acquired from the PVN neurons and sodium hydrosulfide hydrate (NaHS) was bath applied at various concentrations (0.1, 1, 10, and 50 mM). NaHS (1, 10, and 50 mM) elicited a concentration-response relationship from the majority of recorded neurons, with almost exclusively depolarizing effects following administration. Cells responded and recovered from NaHS administration quickly and the effects were repeatable. Input differences from baseline and during the NaHS-induced depolarization uncovered a biphasic response, implicating both a potassium and non-selective cation conductance. The results from the neuronal population of the PVN shed light on the possible physiological role that H2S has in autonomic and endocrine function.
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Switching control of sympathetic activity from forebrain to hindbrain in chronic dehydration.
J. Physiol. (Lond.)
PUBLISHED: 06-27-2011
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We investigated the mechanisms responsible for increased blood pressure and sympathetic nerve activity (SNA) caused by 2-3 days dehydration (DH) both in vivo and in situ preparations. In euhydrated (EH) rats, systemic application of the AT(1) receptor antagonist Losartan and subsequent pre-collicular transection (to remove the hypothalamus) significantly reduced thoracic (t)SNA. In contrast, in DH rats, Losartan, followed by pre-collicular and pontine transections, failed to reduce tSNA, whereas transection at the medulla-spinal cord junction massively reduced tSNA. In DH but not EH rats, selective inhibition of the commissural nucleus tractus solitarii (cNTS) significantly reduced tSNA. Comparable data were obtained in both in situ and in vivo (anaesthetized/conscious) rats and suggest that following chronic dehydration, the control of tSNA transfers from supra-brainstem structures (e.g. hypothalamus) to the medulla oblongata, particularly the cNTS. As microarray analysis revealed up-regulation of AP1 transcription factor JunD in the dehydrated cNTS, we tested the hypothesis that AP1 transcription factor activity is responsible for dehydration-induced functional plasticity. When AP1 activity was blocked in the cNTS using a viral vector expressing a dominant negative FosB, cNTS inactivation was ineffective. However, tSNA was decreased after pre-collicular transection, a response similar to that seen in EH rats. Thus, the dehydration-induced switch in control of tSNA from hypothalamus to cNTS seems to be mediated via activation of AP1 transcription factors in the cNTS. If AP1 activity is blocked in the cNTS during dehydration, sympathetic activity control reverts back to forebrain regions. This unique reciprocating neural structure-switching plasticity between brain centres emphasizes the multiple mechanisms available for the adaptive response to dehydration.
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The transcriptome of the medullary area postrema: the thirsty rat, the hungry rat and the hypertensive rat.
Exp. Physiol.
PUBLISHED: 02-11-2011
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The area postrema (AP) is a sensory circumventricular organ characterized by extensive fenestrated vasculature and neurons which are capable of detecting circulating signals of osmotic, cardiovascular, immune and metabolic status. The AP can communicate these messages via efferent projections to brainstem and hypothalamic structures that are able to orchestrate an appropriate response. We have used microarrays to profile the transcriptome of the AP in the Sprague-Dawley (SD) and Wistar-Kyoto rat and present here a comprehensive catalogue of gene expression, focusing specifically on the population of ion channels, receptors and G protein-coupled receptors expressed in this sensory tissue; of the G protein-coupled receptors expressed in the rat AP, we identified ?36% that are orphans, having no established ligand. We have also looked at the ways in which the AP transcriptome responds to the physiological stressors of 72 h dehydration (DSD) and 48 h fasting (FSD) and have performed microarrays in these conditions. Comparison between the DSD and SD or between FSD and SD revealed only a modest number of AP genes that are regulated by these homeostatic challenges. The expression levels of a much larger number of genes are altered in the spontaneously hypertensive rat AP compared with the normotensive Wistar-Kyoto control rat, however. Finally, analysis of these hypertension-related elements revealed genes that are involved in the regulation of both blood pressure and immune function and as such are excellent targets for further study.
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Effects of albumin-conjugated PYY on food intake: the respective roles of the circumventricular organs and vagus nerve.
Eur. J. Neurosci.
PUBLISHED: 07-16-2010
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The mechanism and routes through which peptide tyrosine-tyrosine (PYY) exerts its anorectic effects are still largely unknown. In the present study, we investigated the roles of the area postrema (AP), subfornical organ (SFO) and vagus nerve in mediating the anorectic effect of PYY using PYY(3-36) conjugated to human serum albumin (PYY(3-36)-HSA) in rats. PYY(3-36)-HSA is a large molecule that does not penetrate the blood-brain barrier, and thus provides a useful tool to discriminate between the central (brain) and peripheral actions of this peptide. PYY(3-36)-HSA induced significant reductions in food and body weight gain up to 24 h after administration. The anorectic effect of PYY(3-36)-HSA was delayed for 2 h in rats in which both AP and SFO were ablated, while lesion of either of these circumventricular organs in isolation did not influence the feeding responses to PYY(3-36)-HSA. The PYY(3-36)-HSA-induced anorectic effect was also reduced during the 3- to 6-h period following subdiaphragmatic vagotomy. Lesions of AP, SFO and AP/SFO as well as subdiaphragmatic vagotomy blunted PYY(3-36)-HSA-induced expression of c-fos mRNA in specific brain structures including the bed nucleus of stria terminalis, central amygdala, lateral-external parabrachial nucleus and medial nucleus of the solitary tract. In addition, subdiaphragmatic vagotomy inhibited the neuronal activation induced by PYY(3-36)-HSA in AP and SFO. These findings suggest that the anorectic effect and brain neuronal activation induced by PYY(3-36)-HSA are dependent on integrity of AP, SFO and subdiaphragmatic vagus nerve.
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Circulating signals as critical regulators of autonomic state--central roles for the subfornical organ.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
PUBLISHED: 05-12-2010
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To maintain homeostasis autonomic control centers in the hypothalamus and medulla must respond appropriately to both external and internal stimuli. Although protected behind the blood-brain barrier, neurons in these autonomic control centers are known to be influenced by changing levels of important signaling molecules in the systemic circulation (e.g., osmolarity, glucose concentrations, and regulatory peptides). The subfornical organ belongs to a group of specialized central nervous system structures, the circumventricular organs, which are characterized by the lack of the normal blood-brain barrier, such that circulating lipophobic substances may act on neurons within this region and via well-documented efferent neural projections to hypothalamic autonomic control centers, influence autonomic function. This review focuses on the role of the subfornical organ in sensing peripheral signals and transmitting this information to autonomic control centers in the hypothalamus.
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Adiponectin modulates excitability of rat paraventricular nucleus neurons by differential modulation of potassium currents.
Endocrinology
PUBLISHED: 05-05-2010
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The adipocyte-derived hormone adiponectin acts at two seven-transmembrane domain receptors, adiponectin receptor 1 and adiponectin receptor 2, present in the paraventricular nucleus of the hypothalamus to regulate neuronal excitability and endocrine function. Adiponectin depolarizes rat parvocellular preautonomic neurons that secrete either thyrotropin releasing hormone or oxytocin and parvocellular neuroendocrine corticotropin releasing hormone neurons, leading to an increase in plasma adrenocorticotropin hormone concentrations while also hyperpolarizing a subgroup of neurons. In the present study, we investigate the ionic mechanisms responsible for these changes in excitability in parvocellular paraventricular nucleus neurons. Patch clamp recordings of currents elicited from slow voltage ramps and voltage steps indicate that adiponectin inhibits noninactivating delayed rectifier potassium current (I(K)) in a majority of neurons. This inhibition produced a broadening of the action potential in cells that depolarized in the presence of adiponectin. The depolarizing effects of adiponectin were abolished in cells pretreated with tetraethyl ammonium (0/15 cells depolarize). Slow voltage ramps performed during adiponectin-induced hyperpolarization indicate the activation of voltage-independent potassium current. These hyperpolarizing responses were abolished in the presence of glibenclamide [an ATP-sensitive potassium (K(ATP)) channel blocker] (0/12 cells hyperpolarize). The results presented in this study suggest that adiponectin controls neuronal excitability through the modulation of different potassium conductances, effects which contribute to changes in excitability and action potential profiles responsible for peptidergic release into the circulation.
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Actions of adiponectin on the excitability of subfornical organ neurons are altered by food deprivation.
Brain Res.
PUBLISHED: 02-22-2010
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Adiponectin (ADP) is a peptide produced by adipose tissue, which acts as an insulin sensitizing hormone. Recent studies have shown that adiponectin receptors (AdipoR1 and AdipoR2) are present in the CNS, and although adiponectin does appear in both circulation and the cerebrospinal fluid there is still some debate as to whether or not ADP crosses the blood brain barrier (BBB). Circumventricular organs (CVO) are CNS sites which lack normal BBB, and thus represent sites at which circulating adiponectin may act to directly influence the CNS. The subfornical organ (SFO) is a CVO that has been implicated in the regulation of energy balance as a consequence of the ability of SFO neurons to respond to a number of different circulating satiety signals including amylin, CCK, PYY and ghrelin. Our recent microarray analysis suggested the presence of adiponectin receptors in the SFO. We report here that the SFO shows a high density of mRNA for both adiponectin receptors (AdipoR1 and AdipoR2), and that ADP influences the excitability of dissociated SFO neurons. Separate subpopulations of SFO neurons were either depolarized (8.9+/-0.9 mV, 21 of 97 cells), or hyperpolarized (-8.0+/-0.5 mV, 34 of 97 cells), by bath application of 10nM ADP, effects which were concentration dependent and reversible. Our microarray analysis also suggested that 48 h of food deprivation resulted in specific increases in AdipoR2 mRNA expression (no effect on AdipoR1 mRNA), observations which we confirm here using real-time PCR techniques. The effects of food deprivation also resulted in a change in the responsiveness of SFO neurons to adiponectin with 77% (8/11) of cells tested responding to adiponectin with depolarization, while no hyperpolarizations were observed. These observations support the concept that the SFO may be a key player in sensing circulating ADP and transmitting such information to critical CNS sites involved in the regulation of energy balance.
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Ghrelin: central nervous system sites of action in regulation of energy balance.
Int J Pept
PUBLISHED: 02-15-2010
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Ghrelin, a peptide hormone secreted by the stomach, has been shown to regulate energy homeostasis by modulating electrical activity of neurons in the central nervous system (CNS). Like many circulating satiety signals, ghrelin is a peptide hormone and is unable to cross the blood-brain barrier without a transport mechanism. In this review, we address the notion that the arcuate nucleus of the hypothalamus is the only site in the CNS that detects circulating ghrelin to trigger orexigenic responses. We consider the roles of a specialized group of CNS structures called the sensory circumventricular organs (CVOs), which are not protected by the blood-brain barrier. These areas include the subfornical organ and the area postrema and are already well known to be key areas for detection of other circulating hormones such as angiotensin II, cholecystokinin, and amylin. A growing body of evidence indicates a key role for the sensory CVOs in the regulation of energy homeostasis.
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Lesions of area postrema and subfornical organ alter exendin-4-induced brain activation without preventing the hypophagic effect of the GLP-1 receptor agonist.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
PUBLISHED: 01-27-2010
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The mechanism and route whereby glucagon-like peptide 1 (GLP-1) receptor agonists, such as GLP-1 and exendin-4 (Ex-4), access the central nervous system (CNS) to exert their metabolic effects have yet to be clarified. The primary objective of the present study was to investigate the potential role of two circumventricular organs (CVOs), the area postrema (AP) and the subfornical organ (SFO), in mediating the metabolic and CNS-stimulating effects of Ex-4. We demonstrated that electrolytic ablation of the AP, SFO, or AP + SFO does not acutely prevent the anorectic effects of Ex-4. AP + SFO lesion chronically decreased food intake and body weight and also modulated the effect of Ex-4 on the neuronal activation of brain structures involved in the hypothalamic-pituitary-adrenal axis and glucose metabolism. The results of the study also showed that CVO lesions blunted Ex-4-induced expression of c-fos mRNA (a widely used neuronal activity marker) in 1) limbic structures (bed nucleus of the stria terminalis and central amygdala), 2) hypothalamus (paraventricular hypothalamic nucleus, supraoptic nucleus, and arcuate nucleus), and 3) hindbrain (lateral and lateral-external parabrachial nucleus, medial nucleus of the solitary tract, and ventrolateral medulla). In conclusion, although the present results do not support a role for the CVOs in the anorectic effect induced by a single injection of Ex-4, they suggest that the CVOs play important roles in mediating the actions of Ex-4 in the activation of CNS structures involved in homeostatic control.
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Acute electrical stimulation of the subfornical organ induces feeding in satiated rats.
Physiol. Behav.
PUBLISHED: 01-07-2010
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The SFO, a circumventricular organ (CVO) that lacks the normal blood-brain barrier, is an important site in central autonomic regulation. A role for the SFO in sensing circulating satiety signals has been suggested by electrophysiological studies demonstrating that the anorexigenic satiety signals, leptin and amylin, as well as the orexigenic satiety signal, ghrelin, influence the excitability of separate populations of SFO neurons. The present study examined whether acute, short duration, electrical stimulation of the SFO influenced feeding in satiated rats. Electrical stimulation (200 microA) of satiated animals with subfornical organ (SFO) electrode placement (n=6) elicited feeding in all animals tested with a mean latency to eat of 8.0+/-4.0 min after termination of SFO stimulation (mean food consumption: 0.6+/-0.12 g/100g bw). These same rats undergoing a sham stimulation did not eat (mean food consumption: 0.0+/-0.0 g, n=6) nor did animals receiving stimulation with non-SFO electrode placements (mean food consumption: 0.0+/-0.0 g, n=6). SFO stimulation at this intensity elicited drinking in 5/6 animals with a mean latency to drink of 15.2+/-2.6 min. Feeding effects were specific to higher stimulation intensities as lower intensity stimulation (100 microA, n=6) elicited drinking (mean latency to drink: 6.2+/-2.6 min) but did not cause any animal to eat. The results of the present study show that acute, short duration, SFO stimulation induces feeding in satiated rats, lending support for a role for the SFO as an integrator of circulating peptides that control feeding.
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Prokineticin 2 modulates the excitability of area postrema neurons in vitro in the rat.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
PUBLISHED: 01-06-2010
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Despite recent evidence describing prokineticin 2 (PK2)-producing neurons and receptors in the dorsomedial medulla, little is known regarding the potential mechanisms by which this circadian neuropeptide acts in the medulla to influence autonomic function. Using whole cell electrophysiology, we have investigated a potential role for PK2 in the regulation of excitability in neurons of the area postrema (AP), a medullary structure known to influence autonomic processes in the central nervous system. In current-clamp recordings, focal application of 1 microM PK2 reversibly influenced the excitability of the majority of dissociated AP cells tested, producing depolarizations (38%) and hyperpolarizations (28%) in a concentration-dependent manner. Slow voltage ramps and ion-substitution experiments revealed that a PK2-induced Cl(-) current was responsible for membrane depolarization, whereas hyperpolarizations were the result of inhibition of a nonselective cation current. In contrast to these differential effects on membrane potential, nearly all neurons that displayed spontaneous activity responded to PK2 with a decrease in spike frequency. These observations are in accordance with voltage-clamp experiments showing that PK2 caused a leftward shift in Na(+) channel activation and inactivation gating. Lastly, using post hoc single-cell RT-PCR technology, we have shown that 7 of 10 enkephalin-expressing AP neurons were depolarized by PK2 indicating that PK2 may have specific inhibitory actions on this population of neurons in the AP to reduce their sensitivity to homeostatic signals. These data suggest that the level of AP neuronal excitability may be regulated by PK2, ultimately affecting AP autonomic control.
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Angiotensinergic regulation of autonomic and neuroendocrine outputs: critical roles for the subfornical organ and paraventricular nucleus.
Neuroendocrinology
PUBLISHED: 04-03-2009
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Considerable recent work has focused on identifying the mechanisms through which circulating angiotensin II acts in the central nervous system (CNS) to control a variety of different autonomic and neuroendocrine effectors. The following review will focus on work identifying the subfornical organ (SFO), and its efferent projections to the paraventricular nucleus of the hypothalamus (PVN), as a critical component of the CNS circuitry activated by circulating angiotensin II. It will also summarize the current knowledge describing cellular mechanisms through which this peptide controls the excitability of both SFO and PVN neurons.
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Adiponectin acts in the nucleus of the solitary tract to decrease blood pressure by modulating the excitability of neuropeptide Y neurons.
Brain Res.
PUBLISHED: 03-17-2009
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Adiponectin is an adipocyte derived hormone which acts in the CNS to control autonomic function, energy and cardiovascular homeostasis. Two 7-transmembrane domain receptors, AdipoR1 and AdipoR2, expressed in the hypothalamus and brainstem mediate the actions of adiponectin. The medullas nucleus of the solitary tract (NTS) is the primary viscerosensory integration site and an important nucleus in the regulation of cardiovascular function. Here we show the localization of both AdipoR1 and AdipoR2 mRNA in the NTS. We have investigated the consequences of receptor activation in response to exogenous application of adiponectin on cardiovascular (blood pressure and heart rate monitoring in vivo), and single neuron (whole cell current-clamp recordings in vitro) function. Microinjection of adiponectin in the medial NTS (mNTS) at the level of the area postrema resulted in a decrease in BP (mean AUC= -2055+/-648.1, n=5, mean maximum effect: -11.7+/-3.6 mm Hg) while similar commissural NTS (cNTS) microinjections were without effect. Patch clamp recordings from NTS neurons in a medullary slice preparation showed rapid (within 200 s of application) reversible (usually within 1000 s following washout) effects of adiponectin on the membrane potential of 62% of mNTS neurons tested (38/61). In 34% (n=21) of mNTS neurons adiponectin induced a depolarization of membrane potential (6.8+/-0.9 mV), while the remainder of mNTS cells influenced by adiponectin (n=17) hyperpolarized in response to this adipokine (-5.4+/-0.7 mV). Post-hoc single cell RT-PCR (ssRT-PCR) analysis of neurons showed that the majority of NPY mRNA positive mNTS neurons were depolarized by adiponectin (7/11), while 4 of these depolarized cells were also GAD67 positive. The results presented in this study suggest adiponectin acts in the NTS to control BP and suggest that such effects may occur as a direct result of the ability of this adipokine to modulate the excitability of discrete groups of neurons in the NTS. These studies identify the mNTS as a new CNS site which adiponectin may act to influence central autonomic processing.
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Adiponectin depolarizes parvocellular paraventricular nucleus neurons controlling neuroendocrine and autonomic function.
Endocrinology
PUBLISHED: 02-21-2009
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Adiponectin plays important roles in the control of energy homeostasis and autonomic function through peripheral and central nervous system actions. The paraventricular nucleus (PVN) of the hypothalamus is a primary site of neuroendocrine (NE) and autonomic integration, and, thus, a potential target for adiponectin actions. Here, we investigate actions of adiponectin on parvocellular PVN neurons. Adiponectin influenced the majority (65%) of parvocellular PVN neurons, depolarizing 47%, whereas hyperpolarizing 18% of neurons tested. Post hoc identification (single-cell RT-PCR) after recordings revealed that adiponectin depolarizes NE-CRH neurons, whereas intracerebroventricular injections of adiponectin in vivo caused increased plasma ACTH concentrations. Adiponectin also depolarized the majority of TRH neurons, however, NE-TRH neurons were unaffected, in accordance with in vivo experiments showing that intracerebroventricular adiponectin was without effect on plasma TSH. In addition, bath administration of adiponectin also depolarized both preautonomic TRH and oxytocin neurons. These results show that adiponectin acts in the central nervous system to coordinate NE and autonomic function through actions on specific functional groups of PVN neurons.
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Ghrelin modulates electrical activity of area postrema neurons.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
PUBLISHED: 01-02-2009
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Ghrelin, a peptide hormone secreted from the stomach, is known to have a potent appetite-stimulating activity. Recently, it has been shown that area postrema (AP), a caudal brain stem center that lacks a blood-brain barrier, is a key site of activity for ghrelin in stimulating appetite and regulating pancreatic protein secretion. In this study, we have examined the ability of ghrelin to regulate the electrical activity of area postrema neurons using patch-clamp electrophysiology. Using current-clamp configuration, we found that at a concentration of 10 nM, ghrelin caused inhibition in 19% of neurons tested, while a further 19% were excited by similar application of ghrelin. The remaining 62% of AP neurons were insensitive to ghrelin. These effects were concentration dependent, with an apparent EC(50) of 1.9 nM. Voltage-clamp recordings revealed that ghrelin caused a potentiation of voltage-gated K(+) currents in neurons that exhibited a hyperpolarization and a potentiation of a depolarizing nonspecific cation current (NSCC) in those neurons that exhibited a depolarization of membrane potential. These are the first data showing that ghrelin exerts a direct effect on electrical activity of AP neurons and supports the notion that ghrelin can act via the AP to regulate energy homeostasis.
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Nesfatin-1 influences the excitability of neurons in the nucleus of the solitary tract and regulates cardiovascular function.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
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Nesfatin-1 has been identified as one of the most potent centrally acting anorexigenic peptides, and it has also been shown to play important roles in the control of cardiovascular function. In situ hybridization and immunohistochemical studies have revealed the expression of nesfatin-1 throughout the brain and, in particular, in the medullary autonomic gateway known as the nucleus of the solitary tract (NTS). The present study was thus undertaken to explore the cellular correlates and functional roles of nesfatin-1 actions in the medial NTS (mNTS). Using current-clamp electrophysiology recordings from mNTS neurons in slice preparation, we show that bath-applied nesfatin-1 directly influences the excitability of the majority of mNTS neurons by eliciting either depolarizing (42%, mean: 7.8 ± 0.8 mV) or hyperpolarizing (21%, mean: -8. 2 ± 1.0 mV) responses. These responses were observed in all electrophysiologically defined cell types in the NTS and were site specific and concentration dependent. Furthermore, post hoc single cell reverse transcriptase polymerase reaction revealed a depolarizing action of nesfatin-1 on NPY and nucleobindin-2-expressing mNTS neurons. We have also correlated these actions of nesfatin-1 on neuronal membrane potential with physiological outcomes, using in vivo microinjection techniques to demonstrate that nesfatin-1 microinjected into the mNTS induces significant increases in both blood pressure (mean AUC = 3354.1 ± 750.7 mmHg·s, n = 6) and heart rate (mean AUC = 164.8 ± 78.5 beats, n = 6) in rats. Our results provide critical insight into the circuitry and physiology involved in the profound effects of nesfatin-1 and highlight the NTS as a key structure mediating these autonomic actions.
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Metabolic Signaling to the Central Nervous System: Routes Across the Blood Brain Barrier.
Curr. Pharm. Des.
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In order to maintain an ideal body weight, an organism must balance energy intake with energy expenditure. It is well known that metabolic signals derived in the periphery act in well-defined hypothalamic and brainstem neuronal circuits to control energy homeostasis. As such, peripheral signals that convey information regarding nutritional and metabolic status of the individual must be able to access and control these neuronal circuits in order to direct both food intake and energy expenditure. Within the hypothalamus, the arcuate nucleus of the hypothalamus has become recognized as a critical center in this integrated circuitry. Although there is considerable anatomical evidence indicating that the arcuate is protected by the blood brain barrier, neurons in this region have been repeatedly suggested to directly sense many circulating signals which do not readily diffuse across this barrier. In this review we will describe the hypothalamic circuitry involved in the regulation of energy homeostasis and will discuss data indicating that the arcuate nucleus is, in fact, protected by the blood brain barrier. We will then consider alternative mechanisms through which one specific circulating adipokine, leptin, can gain access to and influence central nervous sites involved in the regulation of energy homeostasis without the requirement for direct access from the peripheral circulation to arcuate neurons.
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