Role for the subfornical organ in vasopressin release

Mangiapane, Michael L.; Thrasher, T. N.; Keil, L. C.; Simpson, John B.; Ganong, William F.

doi:10.1016/0361-9230(84)90006-6

Cited by 124 publications

(48 citation statements)

References 18 publications

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“…Early studies showed that Ang injection into the SFO induced activation of the hypothalamic neurons and increases in water intake. 49,50 Thus, our result showing that AT 1a inhibition increased water intake is the opposite of what would be predicted based on the effects of Ang stimulation. However, one must consider that peptide injections stimulate all of the Ang receptors, whereas the shRNA approach is receptor specific and produces chronic, rather than acute, changes.…”

Section: Discussioncontrasting

confidence: 76%

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Chen

Hoffmann

et al. 2006

Hypertension

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Abstract-Because of the lack of pharmacological approaches, molecular genetic methods have been required to differentiate between angiotensin type 1(AT 1 ) receptor subtypes AT 1a and AT 1b . RNA interference is a new tool for the study of gene function, producing specific downregulation of protein expression. In this study, we used the small hairpin RNA (shRNA) cassette method to screen target sites for selectively silencing AT 1a or AT 1b receptor subtypes in cultured Neuro-2a cells using real-time RT-PCR. For in vivo functional studies, we used C57BL mice with arterial telemetric probes and computerized licking monitors to test the effect of adenovirus carrying the DNA sequence coding AT 1a shRNA (Ad-AT 1a -shRNA). Ad-AT 1a -shRNA was injected into the lateral ventricle (intracerebroventricular) or the brain stem nucleus tractus solitaries/dorsal vagal nucleus (NTS/DVN) with measurement of water intake, blood pressure (BP), and heart rate (HR) for up to 20 days after injection. Tissue culture studies verified the specificity and the efficiency of the constructs. In animal studies, ␤-galactosidase staining and Ang receptor binding assays showed expression of shRNA and downregulation of Ang AT 1 receptors in the subfornical organ and NTS/DVN by Ͼ70%. Intracerebroventricular injection of Ad-AT 1a -shRNA increased water intake with no effect on BP or HR. In contrast, microinjection of Ad-AT 1a -shRNA into NTS/DVN caused a decrease in BP with no effect on HR or water intake. Results demonstrate the use of the RNA interference method in site-directed silencing of gene expression and provide a method for the in vivo study of Ang AT 1 receptor function. Key Words: blood pressure Ⅲ brain Ⅲ gene regulation Ⅲ renin-angiotensin system B rain angiotensin (Ang) has been implicated in the control of blood pressure (BP), water balance, and hormone secretion. 1-3 Ang type 1 (AT 1 ) receptors are richly expressed in several brain regions, including the subfornical organ (SFO), paraventricular nucleus (PVN), dorsal nucleus vagus (DVN), nucleus tractus solitarii (NTS), and locus coeruleus. 4,5 In rodents, 6 and perhaps in humans, 7,8 there are 2 related AT 1 receptors subtypes, AT 1a and AT 1b . Recent studies by us 4,5 and others 9 demonstrate that AT 1 receptor subtypes AT 1a and AT 1b have similar distribution patterns in the mouse brain. In addition, several lines of reports showed that AT 1a and AT 1b receptor subtypes exhibit individual regulatory functions. 10 -12 Our previous results demonstrated that AT 1a and AT 1b receptors are differentially expressed in response to increased dietary salt and fluid deprivation within mouse brain areas, such as the hypothalamus, anterior pituitary, and brain stem. 4,5,13 However, the precise functional roles of brain AT 1a and AT 1b receptors in specific brain regions remain to be determined.AT 1a and AT 1b receptors share 95% homology in mRNA and amino acid sequences and have similar Ang II binding characteristics. 14 It is difficult to differentiate the subtypes, because there are ...

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Section: Discussioncontrasting

confidence: 76%

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Chen

Hoffmann

et al. 2006

Hypertension

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“…Activation of SFO neurons increases water intake Routtenberg 1973, 1978;Smith et al 1995), plasma vasopressin levels (Ferguson and Kasting 1986), and arterial blood pressure (Gutman et al 1985). Furthermore, lesion or interruption of neurotransmission in the SFO attenuates thirst, vasopressin secretion, and/or changes in sympathetic nerve activity and blood pressure in response to multiple stimuli (Hosutt et al 1981;Mangiapane et al 1984;Osborn et al 2012;Routtenberg 1973, 1978;Sunn et al 2002;Thrasher et al 1982;Thunhorst et al 1999;Tiruneh et al 2013). In addition to water homeostasis, SFO neurons have also been implicated in sodium balance.…”

Section: Subfornical Organ (Sfo) Neurons Play a Pivotal Role In Body mentioning

confidence: 99%

DREADD-induced activation of subfornical organ neurons stimulates thirst and salt appetite

Nation

Nicoleau

Kinsman

et al. 2016

Journal of Neurophysiology

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Nation HL, Nicoleau M, Kinsman BJ, Browning KN, Stocker SD. DREADD-induced activation of subfornical organ neurons stimulates thirst and salt appetite. J Neurophysiol 115: 3123-3129, 2016. First published March 30, 2016 doi:10.1152/jn.00149.2016.-The subfornical organ (SFO) plays a pivotal role in body fluid homeostasis through its ability to integrate neurohumoral signals and subsequently alter behavior, neuroendocrine function, and autonomic outflow. The purpose of the present study was to evaluate whether selective activation of SFO neurons using virally mediated expression of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) stimulated thirst and salt appetite. Male C57BL/6 mice (12-15 wk) received an injection of rAAV2-CaMKII-HAhM3D(Gq)-IRES-mCitrine targeted at the SFO. Two weeks later, acute injection of clozapine N-oxide (CNO) produced dose-dependent increases in water intake of mice with DREADD expression in the SFO. CNO also stimulated the ingestion of 0.3 M NaCl. Acute injection of CNO significantly increased the number of Fos-positive nuclei in the SFO of mice with robust DREADD expression. Furthermore, in vivo single-unit recordings demonstrate that CNO significantly increases the discharge frequency of both ANG II-and NaCl-responsive neurons. In vitro current-clamp recordings confirm that bath application of CNO produces a significant membrane depolarization and increase in action potential frequency. In a final set of experiments, chronic administration of CNO approximately doubled 24-h water intake without an effect on salt appetite. These findings demonstrate that DREADD-induced activation of SFO neurons stimulates thirst and that DREADDs are a useful tool to acutely or chronically manipulate neuronal circuits influencing body fluid homeostasis.

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“…Among neurohumoral responses in heart failure that clearly require the involvement of CNS neurons are increased thirst and sodium appetite (82), release of adrenocorticotropic hormone with consequent increase in circulating corticosterone (25), release of AVP (104) with accompanying vasoconstriction (105,134), water retention (23), and hyponatremia (87), and augmented sympathetic nerve activity (91,191) with associated increases in circulating norepinephrine (49). Increased sympathetic drive in heart failure is strongly associated with ventricular remodeling (17,53) and myocardial depression (17), cardiac arrhythmias (159), and vasoconstriction (53), and is an adverse prognostic indicator (49).…”

Section: The Neurohumoral Milieu Of Heart Failurementioning

confidence: 99%

Heart failure and the brain: new perspectives

Felder¹,

Francis²,

Zhang³

et al. 2003

American Journal of Physiology-Regulatory, Integrative and Comp

109

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Heart failure and the brain: new perspectives. Am J Physiol Regul Integr Comp Physiol 284: R259-R276, 2003; 10.1152/ajpregu.00317.2002.-Despite recent therapeutic advances, the prognosis for patients with heart failure remains dismal. Unchecked neurohumoral excitation is a critical element in the progressive clinical deterioration associated with the heart failure syndrome, and its peripheral manifestations have become the principal targets for intervention. The link between peripheral systems activated in heart failure and the central nervous system as a source of neurohumoral drive has therefore come under close scrutiny. In this context, the forebrain and particularly the paraventricular nucleus of the hypothalamus have emerged as sites that sense humoral signals generated peripherally in response to the stresses of heart failure and contribute to the altered volume regulation and augmented sympathetic drive that characterize the heart failure syndrome. This brief review summarizes recent studies from our laboratory supporting the concept that the forebrain plays a critical role in the pathogenesis of ischemiainduced heart failure and suggesting that the forebrain contribution must be considered in designing therapeutic strategies. Forebrain signaling by neuroactive products of the renin-angiotensin system and the immune system are emphasized.angiotensin; aldosterone; cytokines; tumor necrosis factor; immune system; renin; vasopressin; sympathetic; extracellular fluid volume; baroreflex THE IMPORTANCE OF AUTONOMIC dysfunction to the progression of heart failure is firmly established (55,113,120,152). The most effective treatments for heart failure specifically target the peripheral manifestations of neurohumoral activation (86,113). Yet the understanding of the mechanisms leading to neurohumoral excitation in heart failure is still quite limited.Over the last several decades, substantial evidence has been amassed to support the concept that peripheral afferent systems innervating the heart and vascular tree are altered in heart failure. Dysfunction has been described in all components of the reflexes mediated by these cardiovascular afferent systems-the afferent fibers themselves, the central processing of the afferent signals, the efferent innervation of the end organs, and the end organs themselves. In general, the influence of low-and high-pressure baroreceptors (40,42,191) that normally restrain sympathetic drive and vasopressin release is diminished, whereas the excitatory influences of arterial chemoreceptors (161) and cardiac sympathetic afferent fibers (100) are enhanced.Central nervous system (CNS) neurons affecting cardiovascular regulation respond to humoral as well neural signals. Blood-borne neuroactive peptides, too large to readily cross the blood-brain barrier, may influence the brain by activating sensory neurons at specific sites in hindbrain and forebrain that lack a blood-brain barrier (15,18) or by inducing the release of mediators that do penetrate the barrier (135). These neuroactive s...

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Role for the subfornical organ in vasopressin release

Cited by 124 publications

References 18 publications

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

DREADD-induced activation of subfornical organ neurons stimulates thirst and salt appetite

Heart failure and the brain: new perspectives

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Role for the subfornical organ in vasopressin release

Cited by 124 publications

References 18 publications

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT 1a Receptors in Mouse Brain

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT 1a Receptors in Mouse Brain

DREADD-induced activation of subfornical organ neurons stimulates thirst and salt appetite

Heart failure and the brain: new perspectives

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Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain