RESUMEN
Rodent studies demonstrated specialized sodium chloride (NaCl) sensing neurons in the circumventricular organs, which mediate changes in sympathetic nerve activity, arginine vasopressin, thirst, and blood pressure. However, the neural pathways involved in NaCl sensing in the human brain are incompletely understood. The purpose of this pilot study was to determine if acute hypernatremia alters the functional connectivity of NaCl-sensing regions of the brain in healthy young adults. Resting-state fMRI scans were acquired in 13 participants at baseline and during a 30 min hypertonic saline infusion (HSI). We used a seed-based approach to analyze the data, focusing on the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) as regions of interest (ROIs). Blood chemistry and perceived thirst were assessed pre- and post-infusion. As expected, serum sodium increased from pre- to post-infusion in the HSI group. The primary finding of this pilot study was that the functional connectivity between the SFO and a cluster within the OVLT increased from baseline to the late-phase of the HSI. Bidirectional connectivity changes were found with cortical regions, with some regions showing increased connectivity with sodium-sensing regions while others showed decreased connectivity. Furthermore, the functional connectivity between the SFO and the posterior cingulate cortex (a control ROI) did not change from baseline to the late-phase of the HSI. This finding indicates a distinct response within the NaCl sensing network in the human brain specifically related to acute hypernatremia that will need to be replicated in large-scale studies.
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Hipernatremia , Imagen por Resonancia Magnética , Humanos , Proyectos Piloto , Hipernatremia/fisiopatología , Masculino , Femenino , Adulto , Adulto Joven , Solución Salina Hipertónica/farmacología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Vías Nerviosas/fisiopatología , Vías Nerviosas/diagnóstico por imagen , Órgano Subfornical/efectos de los fármacos , Órgano Subfornical/fisiología , Organum Vasculosum/fisiología , Organum Vasculosum/fisiopatología , Sed/fisiología , Cloruro de Sodio/administración & dosificación , Cloruro de Sodio/farmacologíaRESUMEN
BACKGROUND: ANG (angiotensin II) elicits dipsogenic and pressor responses via activation of the canonical Gαq (G-protein component of the AT1R [angiotensin type 1 receptor])-mediated AT1R in the subfornical organ. Recently, we demonstrated that ARRB2 (ß-arrestin 2) global knockout mice exhibit a higher preference for salt and exacerbated pressor response to deoxycorticosterone acetate salt. However, whether ARRB2 within selective neuroanatomical nuclei alters physiological responses to ANG is unknown. Therefore, we hypothesized that ARRB2, specifically in the subfornical organ, counterbalances maladaptive dipsogenic and pressor responses to the canonical AT1R signaling. METHODS: Male and female Arrb2FLOX mice received intracerebroventricular injection of either adeno-associated virus (AAV)-Cre-GFP (green fluorescent protein) to induce brain-specific deletion of ARRB2 (Arrb2ICV-Cre). Arrb2FLOX mice receiving ICV-AAV-GFP were used as control (Arrb2ICV-Control). Infection with ICV-AAV-Cre primarily targeted the subfornical organ with few off targets. Fluid intake was evaluated using the 2-bottle choice paradigm with 1 bottle containing water and 1 containing 0.15 mol/L NaCl. RESULTS: Arrb2ICV-Cre mice exhibited a greater pressor response to acute ICV-ANG infusion. At baseline conditions, Arrb2ICV-Cre mice exhibited a significant increase in saline intake compared with controls, resulting in a saline preference. Furthermore, when mice were subjected to water-deprived or sodium-depleted conditions, which would naturally increase endogenous ANG levels, Arrb2ICV-Cre mice exhibited elevated saline intake. CONCLUSIONS: Overall, these data indicate that ARRB2 in selective cardiovascular nuclei in the brain, including the subfornical organ, counterbalances canonical AT1R responses to both exogenous and endogenous ANG. Stimulation of the AT1R/ARRB axis in the brain may represent a novel strategy to treat hypertension.
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Presión Sanguínea , Homeostasis , Órgano Subfornical , Arrestina beta 2 , Animales , Femenino , Masculino , Ratones , Angiotensina II/farmacología , Arrestina beta 2/metabolismo , Arrestina beta 2/genética , Presión Sanguínea/fisiología , Presión Sanguínea/genética , Encéfalo/metabolismo , Homeostasis/fisiología , Ratones Noqueados , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Órgano Subfornical/metabolismoRESUMEN
Neurogenesis continues throughout adulthood in the subventricular zone, hippocampal subgranular zone, and the hypothalamic median eminence (ME) and the adjacent medio-basal hypothalamus. The ME is one of the circumventricular organs (CVO), which are specialized brain areas characterized by an incomplete blood-brain barrier and, thus, are involved in mediating communication between the central nervous system and the periphery. Additional CVOs include the organum vasculosum laminae terminalis (OVLT) and the subfornical organs (SFO). Previous studies have demonstrated that the ME contains neural stem cells (NSCs) capable of generating new neurons and glia in the adult brain. However, it remains unclear whether the OVLT and SFO also contain proliferating cells, the identity of these cells, and their ability to differentiate into mature neurons. Here we show that glial and mural subtypes exhibit NSC characteristics, expressing the endogenous mitotic maker Ki67, and incorporating the exogenous mitotic marker BrdU in the OVLT and SFO of adult rats. Glial cells constitutively proliferating in the SFO comprise NG2 glia, while in the OVLT, both NG2 glia and tanycytes appear to constitute the NSC pool. Furthermore, pericytes, which are mural cells associated with capillaries, also contribute to the pool of cells constitutively proliferating in the OVLT and SFO of adult rats. In addition to these glial and mural cells, a fraction of NSCs containing proliferation markers Ki67 and BrdU also expresses the early postmitotic neuronal marker doublecortin, suggesting that these CVOs comprise newborn neurons. Notably, these neurons can differentiate and express the mature neuronal marker NeuN. These findings establish the sensory CVOs OVLT and SFO as additional neurogenic niches, where the generation of new neurons and glia persists in the adult brain.
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Organum Vasculosum , Órgano Subfornical , Ratas , Animales , Bromodesoxiuridina , Antígeno Ki-67 , Hipotálamo , Neurogénesis/fisiología , Proliferación CelularRESUMEN
BACKGROUND: Sympathoexcitation contributes to myocardial remodeling in heart failure (HF). Increased circulating pro-inflammatory mediators directly act on the Subfornical organ (SFO), the cardiovascular autonomic center, to increase sympathetic outflow. Circulating mitochondria (C-Mito) are the novel discovered mediators for inter-organ communication. Cyclic GMP-AMP synthase (cGAS) is the pro-inflammatory sensor of damaged mitochondria. OBJECTIVES: This study aimed to assess the sympathoexcitation effect of C-Mito in HF mice via promoting endothelial cGAS-derived neuroinflammation in the SFO. METHODS: C-Mito were isolated from HF mice established by isoprenaline (0.0125 mg/kg) infusion via osmotic mini-pumps for 2 weeks. Structural and functional analyses of C-Mito were conducted. Pre-stained C-Mito were intravenously injected every day for 2 weeks. Specific cGAS knockdown (cGAS KD) in the SFO endothelial cells (ECs) was achieved via the administration of AAV9-TIE-shRNA (cGAS) into the SFO. The activation of cGAS in the SFO ECs was assessed. The expression of the mitochondrial redox regulator Dihydroorotate dehydrogenase (DHODH) and its interaction with cGAS were also explored. Neuroinflammation and neuronal activation in the SFO were evaluated. Sympathetic activity, myocardial remodeling, and cardiac systolic dysfunction were measured. RESULTS: C-Mito were successfully isolated, which showed typical structural characteristics of mitochondria with double-membrane and inner crista. Further analysis showed impaired respiratory complexes activities of C-Mito from HF mice (C-MitoHF) accompanied by oxidative damage. C-Mito entered ECs, instead of glial cells and neurons in the SFO of HF mice. C-MitoHF increased the level of ROS and cytosolic free double-strand DNA (dsDNA), and activated cGAS in cultured brain endothelial cells. Furthermore, C-MitoHF highly expressed DHODH, which interacted with cGAS to facilitate endothelial cGAS activation. C-MitoHF aggravated endothelial inflammation, microglial/astroglial activation, and neuronal sensitization in the SFO of HF mice, which could be ameliorated by cGAS KD in the ECs of the SFO. Further analysis showed C-MitoHF failed to exacerbate sympathoexcitation and myocardial sympathetic hyperinnervation in cGAS KD HF mice. C-MitoHF promoted myocardial fibrosis and hypertrophy, and cardiac systolic dysfunction in HF mice, which could be ameliorated by cGAS KD. CONCLUSION: Collectively, we demonstrated that damaged C-MitoHF highly expressed DHODH, which promoted endothelial cGAS activation in the SFO, hence aggravating the sympathoexcitation and myocardial injury in HF mice, suggesting that C-Mito might be the novel therapeutic target for sympathoexcitation in HF.
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Insuficiencia Cardíaca , Órgano Subfornical , Ratones , Animales , Células Endoteliales/metabolismo , Enfermedades Neuroinflamatorias , Dihidroorotato Deshidrogenasa , Nucleotidiltransferasas/metabolismo , Mitocondrias/metabolismoRESUMEN
In addition to being recognised for involvement in cardiovascular control and hydromineral balance, the renin-angiotensin system (RAS) has also been associated with the neuroendocrine control of energy balance. One of the main brain sites for angiotensin II (ANG II)/type 1 receptor (AT1 R) signalling is the subfornical organ (SFO), a circumventricular organ related to the control of autonomic functions, motivated behaviours and energy metabolism. Thus, we hypothesised that circulating ANG II may act on the SFO AT1 R receptors to integrate metabolic and hydromineral balance. We evaluated whether food deprivation can modulate systemic RAS activity and Agrt1a brain expression, and if ANG II/AT1 R signalling influences the hypothalamic expression of mRNAs encoding neuropeptides and food and water ingestion in fed and fasted Wistar rats. We found a significant increase in both ANG I and ANG II plasma levels after 24 and 48 h of fasting. Expression of Agrt1a mRNA in the SFO and paraventricular nucleus (PVN) also increased after food deprivation for 48 h. Treatment of fasted rats with low doses of losartan in drinking water attenuated the decrease in glycemia and meal-associated water intake without changing the expression in PVN or arcuate nucleus of mRNAs encoding selected neuropeptides related to energy homeostasis control. These findings point to a possible role of peripheral ANG II/SFO-AT1 R signalling in the control of refeeding-induced thirst. On the other hand, intracerebroventricular losartan treatment decreased food and water intake over dark time in fed but not in fasted rats.
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Ayuno , Órgano Subfornical , Animales , Masculino , Ratas , Angiotensina II/farmacología , Encéfalo/metabolismo , Ayuno/metabolismo , Losartán/farmacología , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas Wistar , Receptor de Angiotensina Tipo 1/metabolismo , Órgano Subfornical/metabolismoRESUMEN
Parathyroid hormone (PTH) is one of the most important hormones for bone turnover and calcium homeostasis. It is unclear how the central nervous system regulates PTH. The subfornical organ (SFO) lies above the third ventricle and modulates body fluid homeostasis. Through retrograde tracing, electrophysiology, and in vivo calcium imaging, we identified the SFO as an important brain nucleus that responds to serum PTH changes in mice. Chemogenetic stimulation of GABAergic neurons in SFO induces decreased serum PTH followed by a decrease in trabecular bone mass. Conversely, stimulation of glutamatergic neurons in the SFO promoted serum PTH and bone mass. Moreover, we found that the blockage of different PTH receptors in the SFO affects peripheral PTH levels and the PTH's response to calcium stimulation. Furthermore, we identified a GABAergic projection from the SFO to the paraventricular nucleus, which modulates PTH and bone mass. These findings advance our understanding of the central neural regulation of PTH at cellular and circuit level.
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Líquidos Corporales , Órgano Subfornical , Animales , Ratones , Hormona Paratiroidea/farmacología , Calcio , Neuronas GABAérgicasRESUMEN
The study demonstrates the astroglial and gliovascular structures of the area postrema (AP) in three planes, and compares them to our former findings on the subfornical organ (SFO) and the organon vasculosum laminae terminalis (OVLT). The results revealed long glial processes interconnecting the AP with deeper areas of brain stem. The laminin and ß-dystroglycan immunolabeling altered along the vessels indicating alterations of the gliovascular relations. These and the distributions of glial markers displayed similarities to the SFO and OVLT. In every organ, there was a central area with vimentin- and nestin-immunopositive glia, whereas GFAP and the water-channel aquaporin 4 were found at the periphery. This separation supports different functions of the two regions. The presence of nestin may indicate stem cell capabilities, whereas aquaporin 4 has been suggested by other studies to be a possible participant of osmoperception. Numerous S100-immunopositive glial cells were found approximately evenly distributed in both parts of the AP. Frequency of glutamine synthetase-immunoreactive cells was similar in the surrounding brain tissue in contrast to that found in the OVLT and SFO. Our findings on the three sensory circumventricular organs (AP, OVLT, and SFO) are compared in parallel.
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Área Postrema , Órgano Subfornical , Ratas , Humanos , Animales , Área Postrema/metabolismo , Nestina/metabolismo , Células Ependimogliales/metabolismo , Acuaporina 4 , Astrocitos/metabolismo , Órgano Subfornical/irrigación sanguínea , Órgano Subfornical/metabolismoRESUMEN
OBJECTIVES: Subfornical organ (SFO) is vital in chronic kidney disease (CKD) progression caused by high salt levels. The current study investigated the effects of high salt on phosphoproteomic changes in SFO in CKD rats. METHODS: 5/6 nephrectomized rats were fed a normal-salt diet (0.4%) (NC group) or a high-salt diet (4%) (HC group) for three weeks, while sham-operated rats were fed a normal-salt diet (0.4%) (NS group). For phosphoproteomic analysis of SFO in different groups, TiO2 enrichment, isobaric tags for relative and absolute quantification (iTRAQ) labeling, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used. RESULTS: There were 6808 distinct phosphopeptides found, which corresponded to 2661 phosphoproteins. NC group had 168 upregulated and 250 downregulated phosphopeptides compared to NS group. Comparison to NC group, HC group had 154 upregulated and 124 downregulated phosphopeptides. Growth associated protein 43 (GAP43) and heat shock protein 27 (Hsp27) were significantly upregulated phosphoproteins and may protect against high-salt damage. Differential phosphoproteins with tight functional connection were synapse proteins and microtubule-associated proteins, implying that high-salt diet disrupted brain's structure and function. Furthermore, differential phosphoproteins in HC/NC comparison group were annotated to participate in GABAergic synapse signaling pathway and aldosterone synthesis and secretion, which attenuated inhibitory neurotransmitter effects and increased sympathetic nerve activity (SNA). DISCUSSION: This large scale phosphoproteomic profiling of SFO sheds light on how salt aggravates CKD via the central nervous system.
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Insuficiencia Renal Crónica , Órgano Subfornical , Ratas , Animales , Ratas Sprague-Dawley , Cromatografía Liquida , Órgano Subfornical/fisiología , Fosfopéptidos/farmacología , Espectrometría de Masas en Tándem , Cloruro de Sodio Dietético/farmacología , Fosfoproteínas/metabolismo , Fosfoproteínas/farmacologíaRESUMEN
In mammals, thirst is strongly influenced by the subfornical organ (SFO), a forebrain structure that integrates circulating signals including osmotic pressure and sodium contents. Secretin (SCT), a classical gastrointestinal hormone, has been implicated as a humoral factor regulating body-fluid homeostasis. However, the neural mechanism of secretin in the central nervous system in managing thirst remains unclear. In this study, we report that the local ablation of SCT receptor (SCTR) in the SFO reduces water but not salt intake in dehydrated mice and this effect could not be rescued by exogenous SCT administration. Electrophysiology with single-cell RT-PCR indicates that SCT elicits inward currents in the SFO neuronal nitric oxide synthase (SFOnNOS) neurons via SCTR in the presence of glutamate receptor antagonists. We further show that the SCTR in the SFO permits the activation of SFOnNOS neurons under distinct thirst types. Projection-specific gene deletion of SCTR in SFO to the median preoptic nucleus (MnPO) pathway also reduces water intake in dehydrated animals. SCT signaling thus plays an indispensable role in driving thirst. These data not only expand the functional boundaries of SCTR but also provide insights into the central mechanisms of homeostatic regulation.
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Órgano Subfornical , Animales , Ratones , Órgano Subfornical/metabolismo , Secretina/metabolismo , Secretina/farmacología , Deshidratación/metabolismo , Neuronas/fisiología , MamíferosRESUMEN
The brain renin-angiotensin system plays important roles in blood pressure and cardiovascular regulation. There are two isoforms of prorenin in the brain: the classic secreted form (prorenin/sREN) encoded by renin-a, and an intracellular form (icREN) encoded by renin-b. Emerging evidence indicates the importance of renin-b in cardiovascular and metabolic regulation. However, the role of endogenous brain prorenin in the development of salt-sensitive hypertension remains undefined. In this study, we test the hypothesis that renin-a produced locally in the brain contributes to the pathogenesis of hypertension. Using RNAscope, we report for the first time that renin mRNA is expressed in several regions of the brain, including the subfornical organ (SFO), the paraventricular nucleus of the hypothalamus (PVN), and the brainstem, where it is found in glutamatergic, GABAergic, cholinergic, and tyrosine hydroxylase-positive neurons. Notably, we found that renin mRNA was significantly elevated in the SFO and PVN in a mouse model of DOCA-salt-induced hypertension. To examine the functional importance of renin-a in the SFO, we selectively ablated renin-a in the SFO in renin-a-floxed mice using a Cre-lox strategy. Importantly, renin-a ablation in the SFO attenuated the maintenance of DOCA-salt-induced hypertension and improved autonomic function without affecting fluid or sodium intake. Molecularly, ablation of renin-a prevented the DOCA-salt-induced elevation in NADPH oxidase 2 (NOX2) in the SFO without affecting NOX4 or angiotensin II type 1 and 2 receptors. Collectively, our findings demonstrate that endogenous renin-a within the SFO is important for the pathogenesis of salt-sensitive hypertension.
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Acetato de Desoxicorticosterona , Hipertensión , Sodio en la Dieta , Órgano Subfornical , Angiotensina II , Animales , Colinérgicos , Hipertensión/genética , Hipertensión/metabolismo , Ratones , NADPH Oxidasa 2 , ARN Mensajero/metabolismo , Renina/genética , Cloruro de Sodio , Sodio en la Dieta/efectos adversos , Órgano Subfornical/metabolismo , Tirosina 3-MonooxigenasaRESUMEN
An important role of pH homeostasis has been suggested in the physiology of panic disorder, with acidosis as an interoceptive trigger leading to fear and panic. Identification of novel mechanisms that can translate acidosis into fear will promote a better understanding of panic physiology. The current study explores a role of the subfornical organ (SFO), a blood-brain barrier compromised brain area, in translating acidosis to fear-relevant behaviors. We performed SFO-targeted acidification in male, wild-type mice and mice lacking microglial acid-sensing G protein-coupled receptor-T-cell death-associated gene 8 (TDAG8). Localized SFO acidification evoked significant freezing and reduced exploration that was dependent on the presence of acid-sensor TDAG8. Acidosis promoted the activation of SFO microglia and neurons that were absent in TDAG8-deficient mice. The assessment of regional neuronal activation in wild-type and TDAG8-deficient mice following SFO acidification revealed significant acidosis and genotype-dependent alterations in the hypothalamus, amygdala, prefrontal cortex, and periaqueductal gray nuclei. Furthermore, mapping of interregional co-activation patterns revealed that SFO acidosis promoted positive hypothalamic-cortex associations and desynchronized SFO-cortex and amygdala-cortex associations, suggesting an interplay of homeostatic and fear regulatory areas. Importantly, these alterations were not evident in TDAG8-deficient mice. Overall, our data support a regulatory role of subfornical organ microglial acid sensing in acidosis-evoked fear, highlighting a centralized role of blood-brain barrier compromised nodes in interoceptive sensing and behavioral regulation. Identification of pathways by which humoral information can modulate fear behavior is relevant to panic disorder, where aberrant interoceptive signaling has been reported.
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Acidosis , Órgano Subfornical , Acidosis/metabolismo , Animales , Miedo , Masculino , Ratones , Microglía/metabolismo , Prosencéfalo , Órgano Subfornical/metabolismoRESUMEN
OBJECTIVE: We recently reported cases of adipsic hypernatremia caused by autoantibodies against the subfornical organ in patients with hypothalamic-pituitary lesions. This study aimed to clarify the clinical features of newly identified patients with adipsic hypernatremia whose sera displayed immunoreactivity to the mouse subfornical organ. DESIGN: Observational cohort study of patients diagnosed with adipsic hypernatremia in Japan, United States, and Europe. METHODS: The study included 22 patients with adipsic hypernatremia but without overt structural changes in the hypothalamic-pituitary region and congenital disease. Antibody response to the mouse subfornical organ was determined using immunohistochemistry. The clinical characteristics were compared between the patients with positive and negative antibody responses. RESULTS: Antibody response to the mouse subfornical organ was detected in the sera of 16 patients (72.7%, female/male ratio, 1:1, 12 pediatric and 4 adult patients). The prolactin levels at the time of diagnosis were significantly higher in patients with positive subfornical organ (SFO) immunoreactivity than in those with negative SFO immunoreactivity (58.9 ± 33.5 vs. 22.9 ± 13.9 ng/ml, p < .05). Hypothalamic disorders were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia. Plasma renin activity levels were significantly higher in patients with serum immunoreactivity to the Nax channel. CONCLUSIONS: The patients with serum immunoreactivity to the SFO had higher prolactin levels and hypothalamic disorders compared to those without the immunoreactivity. The clinical characteristics of patients with serum immunoreactivity to the subfornical organ included higher prolactin levels and hypothalamic disorders, which were frequently associated with central hypothyroidism and the presence of retroperitoneal tumors.
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Hipernatremia , Enfermedades Hipotalámicas , Órgano Subfornical , Animales , Niño , Femenino , Humanos , Hipotálamo , Inmunidad , Masculino , Ratones , Prolactina , Órgano Subfornical/fisiologíaRESUMEN
Impaired threat responding and fear regulation is a hallmark of psychiatric conditions such as post-traumatic stress disorder (PTSD) and Panic Disorder (PD). Most studies have focused on external psychogenic threats to study fear, however, accumulating evidence suggests a primary role of homeostatic perturbations and interoception in regulating emotional behaviors. Heightened reactivity to interoceptive threat carbon dioxide (CO2) inhalation associates with increased risk for developing PD and PTSD, however, contributory mechanisms and molecular targets are not well understood. Previous studies from our group suggested a potential role of interleukin 1 receptor (IL-1R1) signaling within BBB-devoid sensory circumventricular organ, the subfornical organ (SFO) in CO2-evoked fear. However, the necessity of SFO-IL-1R1 in regulating CO2-associated spontaneous fear as well as, long-term fear potentiation relevant to PD/PTSD has not been investigated. The current study tested male mice with SFO-targeted microinfusion of the IL-1R1 antagonist (IL-1RA) or vehicle in a recently developed CO2-startle-fear conditioning-extinction paradigm. Consistent with our hypothesis, SFO IL-1RA treatment elicited significant attenuation of freezing and increased rearing during CO2 inhalation suggesting SFO-IL1R1 regulation of spontaneous fear to CO2. Intriguingly, SFO IL-1RA treatment normalized CO2-associated potentiation of conditioned fear and impaired extinction a week later suggesting modulation of long-term fear by SFO-IL-1R1 signaling. Post behavior FosB mapping revealed recruitment of prefrontal cortex-amygdala-periaqueductal gray (PAG) areas in SFO-IL-1RA mediated effects. Additionally, we localized cellular IL-1R1 expression within the SFO to blood vessel endothelial cells and observed CO2-induced alterations in IL-1ß/IL-1R1 expression in peripheral mononuclear cells and SFO. Lastly, CO2-evoked microglial activation was attenuated in SFO-IL-1RA treated mice. These observations suggest a peripheral monocyte-endothelial-microglia interplay in SFO-IL-1R1 modulation of CO2-associated spontaneous fear and delayed fear memory. Collectively, our data highlight a novel, "bottom-up" neuroimmune mechanism that integrates interoceptive and exteroceptive threat processing of relevance to fear-related pathologies.
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Receptores de Interleucina-1 , Órgano Subfornical , Animales , Dióxido de Carbono/metabolismo , Dióxido de Carbono/farmacología , Células Endoteliales/metabolismo , Miedo/fisiología , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Masculino , Ratones , Receptores de Interleucina-1/metabolismo , Receptores Tipo I de Interleucina-1 , Órgano Subfornical/metabolismoRESUMEN
Patients with adipsic hypernatremia present with chronic hypernatremia because of defects in thirst sensation and dysregulated salt appetite, without demonstrable hypothalamic structural lesions. The involvement of autoantibodies directed against the sodium channel, Nax in the subfornical organ (SFO) has recently been reported. However, the pathophysiology of water and electrolyte imbalance underlying the disease has yet to be elucidated. We describe the case of a 5-year-old boy who complained of headaches and vomiting that gradually worsened. Brain magnetic resonance imaging detected no abnormal lesions. Blood laboratory testing revealed a serum sodium (Na) concentration of 152 mmol/L and a serum osmolarity of 312 mOsm/L. His body weight had slightly decreased, and his thirst sensation was absent. His plasma vasopressin concentration was 0.9 pg/mL, despite the high serum osmolarity. He was encouraged to drink water, and oral 1-deamino-8-D-arginine-vasopressin was administered. When serum sodium concentrations were normalized, plasma vasopressin concentrations were apparently normal and ranged from 0.8 to 2.0 pg/mL. He did not present with polyuria at any time. Immunohistochemical study using mouse brain sections and the patient's serum revealed the deposition of human immunoglobulin G (IgG) antibody in the mouse SFO. In conclusion, our observations suggested that water and electrolyte imbalance in adipsic hypernatremia is characterized by a certain amount of vasopressin release regardless of serum sodium concentrations with no response to hyperosmolarity.
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Hipernatremia , Órgano Subfornical , Animales , Humanos , Hipernatremia/complicaciones , Hipernatremia/etiología , Masculino , Ratones , Sodio , Vasopresinas , AguaRESUMEN
AIMS: Hypertension is a prevalent yet poorly understood feature of polycystic kidney disease. Previously, we demonstrated that increased glutamatergic neurotransmission within the hypothalamic paraventricular nucleus produces hypertension in the Lewis Polycystic Kidney (LPK) rat model of polycystic kidney disease. Here, we tested the hypothesis that augmented glutamatergic drive to the paraventricular nucleus in Lewis polycystic kidney rats originates from the forebrain lamina terminalis, a sensory structure that relays blood-borne information throughout the brain. METHODS AND RESULTS: Anatomical experiments revealed that 38% of paraventricular nucleus-projecting neurons in the subfornical organ of the lamina terminalis expressed Fos/Fra, an activation marker, in LPK rats while <1% of neurons were Fos/Fra+ in Lewis control rats (P = 0.01, n = 8). In anaesthetized rats, subfornical organ neuronal inhibition using isoguvacine produced a greater reduction in systolic blood pressure in LPK vs. Lewis rats (-21±4 vs. -7±2 mmHg, P < 0.01; n = 10), which could be prevented by prior blockade of paraventricular nucleus ionotropic glutamate receptors using kynurenic acid. Blockade of ionotropic glutamate receptors in the paraventricular nucleus produced an exaggerated depressor response in LPK relative to Lewis rats (-23±4 vs. -2±3 mmHg, P < 0.001; n = 13), which was corrected by prior inhibition of the subfornical organ with muscimol but unaffected by chronic systemic angiotensin II type I receptor antagonism or lowering of plasma hyperosmolality through high-water intake (P > 0.05); treatments that both nevertheless lowered blood pressure in LPK rats (P < 0.0001). CONCLUSION: Our data reveal multiple independent mechanisms contribute to hypertension in polycystic kidney disease, and identify high plasma osmolality, angiotensin II type I receptor activation and, importantly, a hyperactive subfornical organ to paraventricular nucleus glutamatergic pathway as potential therapeutic targets.
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Hipertensión , Enfermedades Renales Poliquísticas , Órgano Subfornical , Angiotensina II/metabolismo , Animales , Núcleo Hipotalámico Paraventricular/metabolismo , Enfermedades Renales Poliquísticas/metabolismo , Ratas , Ratas Endogámicas Lew , Receptores Ionotrópicos de Glutamato/metabolismo , Órgano Subfornical/metabolismoRESUMEN
In the laboratory, animals' motivation to work tends to be positively correlated with reward magnitude. But in nature, rewards earned by work are essential to survival (e.g., working to find water), and the payoff of that work can vary on long timescales (e.g., seasonally). Under these constraints, the strategy of working less when rewards are small could be fatal. We found that instead, rats in a closed economy did more work for water rewards when the rewards were stably smaller, a phenomenon also observed in human labor supply curves. Like human consumers, rats showed elasticity of demand, consuming far more water per day when its price in effort was lower. The neural mechanisms underlying such "rational" market behaviors remain largely unexplored. We propose a dynamic utility maximization model that can account for the dependence of rat labor supply (trials/day) on the wage rate (milliliter/trial) and also predict the temporal dynamics of when rats work. Based on data from mice, we hypothesize that glutamatergic neurons in the subfornical organ in lamina terminalis continuously compute the instantaneous marginal utility of voluntary work for water reward and causally determine the amount and timing of work.
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Encéfalo/fisiología , Neuronas/fisiología , Órgano Subfornical/fisiología , Sed/fisiología , Agua/química , Animales , Conducta Animal , Femenino , Modelos Neurológicos , Modelos Teóricos , Motivación , Ratas , Ratas Long-Evans , RecompensaRESUMEN
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.
Asunto(s)
Organum Vasculosum , Órgano Subfornical , Humanos , Hipotálamo , Área Preóptica , Equilibrio HidroelectrolíticoRESUMEN
Neurons in the subfornical organ (SFO) sense both neurotransmitters and circulating humoral factors such as angiotensin II (AII) and atrial natriuretic peptide (ANP), and regulate multiple physiological functions including drinking behavior. We recently reported that AII at nanomolar concentrations induced a persistent [Ca2+]i increase in acutely dissociated SFO neurons and that this effect of AII was reversibly inhibited by GABA. In the present study, we studied the inhibitory mechanism of GABA using Ca2+ imaging and patch-clamp electrophysiology. The AII-induced persistent [Ca2+]i increase was inhibited by GABA in more than 90% of AII-responsive neurons and by other two SFO inhibitory ligands, ANP and galanin, in about 60 and 30% of neurons respectively. The inhibition by GABA was mimicked by the GABAA and GABAB receptor agonists muscimol and baclofen. The involvement of both GABA receptor subtypes was confirmed by reversal of the GABA-mediated inhibition only when the GABAA and GABAB receptors antagonists bicuculline methiodide and CGP55845 were both present. The GABAB agonist baclofen rapidly and reversibly inhibited voltage-gated Ca2+ channel (VGCC) currents recorded in response to depolarizing pulses in voltage-clamp electrophysiology using Ba2+ as a charge carrier (IBa). Baclofen inhibition of IBa was antagonized by CGP55845, confirming GABAB receptor involvement; was reduced by N-ethylmaleimide, suggesting downstream Gi-mediated actions; and was partially removed by a large prepulse, indicating voltage-dependency. The magnitude of IBa inhibition by baclofen was reduced by the application of selective blockers for N-, P/Q-, and L-type VGCCs (ω-conotoxin GVIA, ω-agatoxin IVA, and nifedipine respectively). Overall, our study indicates that GABA inhibition of the AII-induced [Ca2+]i increase is mediated by both GABAA and GABAB receptors, and that GABAB receptors associated with Gi proteins suppress Ca2+ entry through VGCCs in SFO neurons.
Asunto(s)
Angiotensina II/metabolismo , Bicuculina/análogos & derivados , Calcio/metabolismo , Agonistas de Receptores de GABA-A/farmacología , Agonistas de Receptores GABA-B/farmacología , Órgano Subfornical/efectos de los fármacos , Animales , Baclofeno/metabolismo , Bicuculina/farmacología , Canales de Calcio/metabolismo , Etilaminas/farmacología , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Wistar , Receptores de GABA-B/metabolismo , Órgano Subfornical/metabolismoRESUMEN
Multiple neurological problems have been reported in coronavirus disease-2019 (COVID-19) patients because severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) likely spreads to the central nervous system (CNS) via olfactory nerves or through the subarachnoid space along olfactory nerves into the brain's cerebrospinal fluid and then into the brain's interstitial space. We hypothesize that SARS-CoV-2 enters the subfornical organ (SFO) through the above routes and the circulating blood since circumventricular organs (CVOs) such as the SFO lack the blood-brain barrier, and infection of the SFO causes dysfunction of the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON), leading to hydroelectrolytic disorder. SARS-CoV-2 can readily enter SFO-PVN-SON neurons because these neurons express angiotensin-converting enzyme-2 receptors and proteolytic viral activators, which likely leads to neurodegeneration or neuroinflammation in these regions. Considering the pivotal role of SFO-PVN-SON circuitry in modulating hydroelectrolyte balance, SARS-CoV-2 infection in these regions could disrupt the neuroendocrine control of hydromineral homeostasis. This review proposes mechanisms by which SARS-CoV-2 infection of the SFO-PVN-SON pathway leads to hydroelectrolytic disorder in COVID-19 patients.
Asunto(s)
COVID-19/complicaciones , Núcleo Hipotalámico Paraventricular/patología , Órgano Subfornical/patología , Desequilibrio Hidroelectrolítico/etiología , Animales , COVID-19/patología , Humanos , Núcleo Hipotalámico Paraventricular/virología , Centrales Eléctricas , Órgano Subfornical/virología , Desequilibrio Hidroelectrolítico/virologíaRESUMEN
Thirst is a highly potent drive that motivates organisms to seek out and consume balance-restoring stimuli. The detection of dehydration is well understood and involves signals of peripheral origin and the sampling of internal milieu by first order homeostatic neurons within the lamina terminalis-particularly glutamatergic neurons of the subfornical organ expressing CaMKIIa (SFOCaMKIIa). However, it remains unknown whether mesolimbic dopamine pathways that are critical for motivation and reinforcement integrate information from these "early" dehydration signals. We used in vivo fiber photometry in the ventral tegmental area and measured phasic dopamine responses to a water-predictive cue. Thirst, but not hunger, potentiated the phasic dopamine response to the water cue. In euvolemic rats, the dipsogenic hormone angiotensin II, but not the orexigenic hormone ghrelin, potentiated the dopamine response similarly to that observed in water-deprived rats. Chemogenetic manipulations of SFOCaMKIIa revealed bidirectional control of phasic dopamine signaling during cued water reward. Taking advantage of within-subject designs, we found predictive relationships between changes in cue-evoked dopamine response and changes in behavioral responses-supporting a role for dopamine in motivation induced by homeostatic need. Collectively, we reveal a putative mechanism for the invigoration of goal-directed behavior: internal milieu communicates to first order, need state-selective circuits to potentiate the mesolimbic dopamine system's response to cues predictive of restorative stimuli.