RESUMEN
In response to dehydration, humans experience thirst. This subjective state is fundamental to survival as it motivates drinking, which subsequently corrects the fluid deficit. To elicit thirst, previous studies have manipulated blood chemistry to produce a physiological thirst stimulus. In the present study, we investigated whether a physiological stimulus is indeed required for thirst to be experienced. Functional MRI (fMRI) was used to scan fully hydrated participants while they imagined a state of intense thirst and while they imagined drinking to satiate thirst. Subjective ratings of thirst were significantly higher for imagining thirst compared with imagining drinking or baseline, revealing a successful dissociation of thirst from underlying physiology. The imagine thirst condition activated brain regions similar to those reported in previous studies of physiologically evoked thirst, including the anterior midcingulate cortex (aMCC), anterior insula, precentral gyrus, inferior frontal gyrus, middle frontal gyrus, and operculum, indicating a similar neural network underlies both imagined thirst and physiologically evoked thirst. Analogous brain regions were also activated during imagined drinking, suggesting the neural representation of thirst contains a drinking-related component. Finally, the aMCC showed an increase in functional connectivity with the insula during imagined thirst relative to imagined drinking, implying functional connectivity between these two regions is needed before thirst can be experienced. As a result of these findings, this study provides important insight into how the neural representation of subjective thirst is generated and how it subsequently motivates drinking behavior.
Asunto(s)
Encéfalo/fisiología , Sed , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Imaginación , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Agua/metabolismoRESUMEN
Much progress has been made during the past 30 years with respect to elucidating the neural and endocrine pathways by which bodily needs for water and energy are brought to conscious awareness through the generation of thirst and hunger. One way that circulating hormones influence thirst and hunger is by acting on neurones within sensory circumventricular organs (CVOs). This is possible because the subfornical organ and organum vasculosum of the lamina terminalis (OVLT), the sensory CVOs in the forebrain, and the area postrema in the hindbrain lack a normal blood-brain barrier such that neurones within them are exposed to blood-borne agents. The neural signals generated by hormonal action in these sensory CVOs are relayed to several sites in the cerebral cortex to stimulate or inhibit thirst or hunger. The subfornical organ and OVLT respond to circulating angiotensin II, relaxin and hypertonicity to drive thirst-related neural pathways, whereas circulating amylin, leptin and possibly glucagon-like peptide-1 act at the area postrema to influence neural pathways inhibiting food intake. As a result of investigations using functional brain imaging techniques, the insula and anterior cingulate cortex, as well as several other cortical sites, have been implicated in the conscious perception of thirst and hunger in humans. Viral tracing techniques show that the anterior cingulate cortex and insula receive neural inputs from thirst-related neurones in the subfornical organ and OVLT, with hunger-related neurones in the area postrema having polysynaptic efferent connections to these cortical regions. For thirst, initially, the median preoptic nucleus and, subsequently, the thalamic paraventricular nucleus and lateral hypothalamus have been identified as likely sites of synaptic links in pathways from the subfornical organ and OVLT to the cortex. The challenge remains to identify the links in the neural pathways that relay signals originating in sensory CVOs to cortical sites subserving either thirst or hunger.
Asunto(s)
Corteza Cerebral/fisiología , Órganos Circunventriculares/fisiología , Hambre/fisiología , Neuronas/fisiología , Sed/fisiología , Animales , Humanos , Vías Nerviosas/fisiologíaRESUMEN
In humans, activity in the anterior midcingulate cortex (aMCC) is associated with both subjective thirst and swallowing. This region is therefore likely to play a prominent role in the regulation of drinking in response to dehydration. Using functional MRI, we investigated this possibility during a period of "drinking behavior" represented by a conjunction of preswallow and swallowing events. These events were examined in the context of a thirsty condition and an "oversated" condition, the latter induced by compliant ingestion of excess fluid. Brain regions associated with swallowing showed increased activity for drinking behavior in the thirsty condition relative to the oversated condition. These regions included the cingulate cortex, premotor areas, primary sensorimotor cortices, the parietal operculum, and the supplementary motor area. Psychophysical interaction analyses revealed increased functional connectivity between the same regions and the aMCC during drinking behavior in the thirsty condition. Functional connectivity during drinking behavior was also greater for the thirsty condition relative to the oversated condition between the aMCC and two subcortical regions, the cerebellum and the rostroventral medulla, the latter containing nuclei responsible for the swallowing reflex. Finally, during drinking behavior in the oversated condition, ratings of swallowing effort showed a negative association with functional connectivity between the aMCC and two cortical regions, the sensorimotor cortex and the supramarginal gyrus. The results of this study provide evidence that the aMCC helps facilitate swallowing during a state of thirst and is therefore likely to contribute to the regulation of drinking after dehydration.
Asunto(s)
Conducta de Ingestión de Líquido/fisiología , Giro del Cíngulo/fisiología , Sed/fisiología , Adulto , Deglución , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
Due to the importance of dietary sodium and its paucity within many inland environments, terrestrial animals have evolved an instinctive sodium appetite that is commensurate with sodium deficiency. Despite a well-established role for central opioid signaling in sodium appetite, the endogenous influence of specific opioid receptor subtypes within distinct brain regions remains to be elucidated. Using selective pharmacological antagonists of opioid receptor subtypes, we reveal that endogenous mu-opioid receptor (MOR) signaling strongly drives sodium appetite in sodium-depleted mice, whereas a role for kappa (KOR) and delta (DOR) opioid receptor signaling was not detected, at least in sodium-depleted mice. Fos immunohistochemistry revealed discrete regions of the mouse brain displaying an increased number of activated neurons during sodium gratification: the rostral portion of the nucleus of the solitary tract (rNTS), the lateral parabrachial nucleus (LPB), and the central amygdala (CeA). The CeA was subsequently targeted with bilateral infusions of the MOR antagonist naloxonazine, which significantly reduced sodium appetite in mice. The CeA is therefore identified as a key node in the circuit that contributes to sodium appetite. Moreover, endogenous opioids, acting via MOR, within the CeA promote this form of appetitive behavior.
Asunto(s)
Apetito/efectos de los fármacos , Núcleo Amigdalino Central/metabolismo , Receptores Opioides mu/genética , Sodio en la Dieta/metabolismo , Analgésicos Opioides/administración & dosificación , Animales , Apetito/genética , Apetito/fisiología , Mapeo Encefálico , Núcleo Amigdalino Central/efectos de los fármacos , Ratones , Naloxona/administración & dosificación , Naloxona/análogos & derivados , Neuronas/metabolismo , Receptores Opioides mu/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacosRESUMEN
In humans, drinking replenishes fluid loss and satiates the sensation of thirst that accompanies dehydration. Typically, the volume of water drunk in response to thirst matches the deficit. Exactly how this accurate metering is achieved is unknown; recent evidence implicates swallowing inhibition as a potential factor. Using fMRI, this study investigated whether swallowing inhibition is present after more water has been drunk than is necessary to restore fluid balance within the body. This proposal was tested using ratings of swallowing effort and measuring regional brain responses as participants prepared to swallow small volumes of liquid while they were thirsty and after they had overdrunk. Effort ratings provided unequivocal support for swallowing inhibition, with a threefold increase in effort after overdrinking, whereas addition of 8% (wt/vol) sucrose to water had minimal effect on effort before or after overdrinking. Regional brain responses when participants prepared to swallow showed increases in the motor cortex, prefrontal cortices, posterior parietal cortex, striatum, and thalamus after overdrinking, relative to thirst. Ratings of swallowing effort were correlated with activity in the right prefrontal cortex and pontine regions in the brainstem; no brain regions showed correlated activity with pleasantness ratings. These findings are all consistent with the presence of swallowing inhibition after excess water has been drunk. We conclude that swallowing inhibition is an important mechanism in the overall regulation of fluid intake in humans.
Asunto(s)
Deglución/fisiología , Deshidratación/diagnóstico por imagen , Ingestión de Líquidos/fisiología , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Deshidratación/fisiopatología , Femenino , Humanos , Masculino , Concentración Osmolar , Sed/fisiología , Agua/metabolismo , Equilibrio Hidroelectrolítico/fisiologíaRESUMEN
NEW FINDINGS: What is the central question of this study? Sodium appetite is controlled by conserved neuronal transmitter-receptor systems. Here, we tested the contribution made by relaxin family peptide 3 receptor (RXFP3), the cognate G-protein-coupled receptor for the neuropeptide relaxin-3. What is the main finding and its importance? Intracerebroventricular infusion of an RXFP3 antagonist reduced in a dose-dependent manner the volume of 0.3 m NaCl consumed by sodium-depleted C57Bl/6J (wild-type) mice. This effect was absent in sodium-depleted Rxfp3 knockout mice, and RXFP3 antagonist infusion did not alter water consumption in wild-type mice subjected to multiple thirst tests, indicating both the pharmacological and the physiological specificity of observed effects. Our findings identify endogenous relaxin-3-RXFP3 signalling as a modulator of sodium appetite. Overconsumption of highly salted foods is common in Western diets and contributes significantly to metabolic disorders such as hypertension, renal dysfunction and diabetes. Sodium appetite, or the desire of terrestrial animals to seek and consume sodium-containing salts, is a behaviour mediated by a set of evolutionarily conserved neuronal systems. In these studies, we tested whether this instinctive behavioural drive is influenced by the G-protein-coupled relaxin family peptide 3 receptor (RXFP3), the cognate receptor for the neuropeptide relaxin-3, because relaxin-3-RXFP3 signalling can modulate arousal, motivation and ingestive behaviours. Intracerebroventricular (i.c.v.) infusion of the selective RXFP3 antagonist, R3(B1-22)R, reduced in a dose-dependent manner the volume of 0.3 m NaCl solution consumed when offered to sodium-depleted C57Bl/6J wild-type mice, relative to vehicle-treated control animals. Notably, i.c.v. R3(B1-22)R infusion did not alter 0.3 m NaCl consumption relative to vehicle in sodium-depleted Rxfp3 knockout mice, confirming the pharmacological specificity of this effect. Furthermore, i.c.v. R3(B1-22)R did not alter the volume of water consumed by wild-type mice in three tests where water drinking was the normal physiological response, suggesting that the ability of R3(B1-22)R to reduce activated salt appetite is specific and not due to a generalized reduction in drinking behaviour. These findings identify, for the first time, that endogenous relaxin-3-RXFP3 signalling is a powerful mediator of salt appetite in mice and further elucidate the functional role of the relaxin-3-RXFP3 system in the integrative control of motivated behaviours.
Asunto(s)
Apetito/fisiología , Relaxina/metabolismo , Cloruro de Sodio Dietético/metabolismo , Sodio/metabolismo , Animales , Nivel de Alerta/fisiología , Conducta de Ingestión de Líquido/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuropéptidos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/fisiologíaRESUMEN
The instinct of thirst was a cardinal element in the successful colonization by vertebrates of the dry land of the planet, which began in the Ordovician period about 400 million y ago. It is a commonplace experience in humans that drinking water in response to thirst following fluid loss is a pleasant experience. However, continuing to drink water once thirst has been satiated becomes unpleasant and, eventually, quite aversive. Functional MRI experiments reported here show pleasantness of drinking is associated with activation in the anterior cingulate cortex (Brodmann area 32) and the orbitofrontal cortex. The unpleasantness and aversion of overdrinking is associated with activation in the midcingulate cortex, insula, amygdala, and periaqueductal gray. Drinking activations in the putamen and cerebellum also correlated with the unpleasantness of water, and the motor cortex showed increased activation during overdrinking compared with drinking during thirst. These activations in motor regions may possibly reflect volitional effort to conduct compliant drinking in the face of regulatory mechanisms inhibiting intake. The results suggestive of a specific inhibitory system in the control of drinking are unique.
Asunto(s)
Encéfalo/fisiología , Agua Potable , Sed , Adulto , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Sodium appetite is an instinct that involves avid specific intention. It is elicited by sodium deficiency, stress-evoked adrenocorticotropic hormone (ACTH), and reproduction. Genome-wide microarrays in sodium-deficient mice or after ACTH infusion showed up-regulation of hypothalamic genes, including dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP-32), dopamine receptors-1 and -2, α-2C- adrenoceptor, and striatally enriched protein tyrosine phosphatase (STEP). Both DARPP-32 and neural plasticity regulator activity-regulated cytoskeleton associated protein (ARC) were up-regulated in lateral hypothalamic orexinergic neurons by sodium deficiency. Administration of dopamine D1 (SCH23390) and D2 receptor (raclopride) antagonists reduced gratification of sodium appetite triggered by sodium deficiency. SCH23390 was specific, having no effect on osmotic-induced water drinking, whereas raclopride also reduced water intake. D1 receptor KO mice had normal sodium appetite, indicating compensatory regulation. Appetite was insensitive to SCH23390, confirming the absence of off-target effects. Bilateral microinjection of SCH23390 (100 nM in 200 nL) into rats' lateral hypothalamus greatly reduced sodium appetite. Gene set enrichment analysis in hypothalami of mice with sodium appetite showed significant enrichment of gene sets previously linked to addiction (opiates and cocaine). This finding of concerted gene regulation was attenuated on gratification with perplexingly rapid kinetics of only 10 min, anteceding significant absorption of salt from the gut. Salt appetite and hedonic liking of salt taste have evolved over >100 million y (e.g., being present in Metatheria). Drugs causing pleasure and addiction are comparatively recent and likely reflect usurping of evolutionary ancient systems with high survival value by the gratification of contemporary hedonic indulgences. Our findings outline a molecular logic for instinctive behavior encoded by the brain with possible important translational-medical implications.
Asunto(s)
Apetito/genética , Conducta Adictiva/genética , Hipotálamo/fisiología , Sodio en la Dieta/administración & dosificación , Hormona Adrenocorticotrópica/administración & dosificación , Hormona Adrenocorticotrópica/fisiología , Animales , Apetito/efectos de los fármacos , Apetito/fisiología , Conducta Adictiva/fisiopatología , Evolución Biológica , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Líquidos/genética , Ingestión de Líquidos/fisiología , Femenino , Estudio de Asociación del Genoma Completo , Hipotálamo/efectos de los fármacos , Instinto , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Psicológicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , Ratas Sprague-Dawley , RecompensaRESUMEN
This study used arterial spin labeling (ASL) fMRI to measure brain perfusion in a group of healthy men under conditions that closely resembled customary sexual behavior. Serial perfusion measures for 30 min during two self-limited periods of partnered penis stimulation, and during post-stimulatory periods, revealed novel sexual activity-related cerebral blood flow (rCBF) changes, mainly in subcortical parts of the brain. Ventral pallidum rCBF was highest during the onset of penile erection, and lowest after the termination of penis stimulation. The perceived level of sexual arousal showed the strongest positive association with rCBF in the right basal forebrain. In addition, our results demonstrate that distinct subregions of the hypothalamus and cingulate cortex subserve opposite functions during human male sexual behavior. The lateral hypothalamus and anterior part of the middle cingulate cortex showed increased rCBF correlated with penile erection. By contrast, the anteroventral hypothalamus and subgenual anterior cingulate cortex exhibited rCBF changes correlated with penile detumescence after penile stimulation. Continuous rapid and high-resolution brain perfusion imaging during normal sexual activity has provided novel insights into the central mechanisms that control male sexual arousal.
Asunto(s)
Encéfalo/irrigación sanguínea , Encéfalo/fisiología , Circulación Cerebrovascular , Conducta Sexual/fisiología , Adulto , Mapeo Encefálico , Estudios de Cohortes , Heterosexualidad , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Erección Peniana/fisiología , Pene/fisiología , Imagen de Perfusión/métodos , Factores de Tiempo , Población Blanca , Adulto JovenRESUMEN
In heart failure (HF), sympathetic nerve activity is increased. Measurements in HF patients of cardiac norepinephrine spillover, reflecting cardiac sympathetic nerve activity (CSNA), indicate that it is increased earlier and to a greater extent than sympathetic activity to other organs. This has important consequences because it worsens prognosis, provoking arrhythmias and sudden death. To elucidate the mechanisms responsible for the activation of CSNA in HF, we made simultaneous direct neural recordings of CSNA and renal SNA (RSNA) in two groups of conscious sheep: normal animals and animals in HF induced by chronic, rapid ventricular pacing. In normal animals, the level of activity, measured as burst incidence (bursts of pulse related activity/100 heart beats), was significantly lower for CSNA (30 +/- 5%) than for RSNA (94 +/- 2%). Furthermore, the resting level of CSNA, relative to its maximum achieved while baroreceptors were unloaded by reducing arterial pressure, was set at a much lower percentage than RSNA. In HF, burst incidence of CSNA increased from 30 to 91%, whereas burst incidence of RSNA remained unaltered at 95%. The sensitivity of the control of both CSNA and RSNA by the arterial baroreflex remained unchanged in HF. These data show that, in the normal state, the resting level of CSNA is set at a lower level than RSNA, but in HF, the resting levels of SNA to both organs are close to their maxima. This finding provides an explanation for the preferential increase in cardiac norepinephrine spillover observed in HF.
Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Corazón/inervación , Sistema Nervioso Simpático/fisiopatología , Animales , Barorreflejo , Femenino , Riñón/inervación , Ovinos , Volumen SistólicoRESUMEN
In addition to its role in the storage of fat, adipose tissue acts as an endocrine organ, and it contains a functional renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) plays a key role in the RAS by converting angiotensin I to the bioactive peptide angiotensin II (Ang II). In the present study, the effect of targeting the RAS in body energy homeostasis and glucose tolerance was determined in homozygous mice in which the gene for ACE had been deleted (ACE(-/-)) and compared with wild-type littermates. Compared with wild-type littermates, ACE(-/-) mice had lower body weight and a lower proportion of body fat, especially in the abdomen. ACE(-/-) mice had greater fed-state total energy expenditure (TEE) and resting energy expenditure (REE) than wild-type littermates. There were pronounced increases in gene expression of enzymes related to lipolysis and fatty acid oxidation (lipoprotein lipase, carnitine palmitoyl transferase, long-chain acetyl CoA dehydrogenase) in the liver of ACE(-/-) mice and also lower plasma leptin. In contrast, no differences were detected in daily food intake, activity, fed-state plasma lipids, or proportion of fat excreted in fecal matter. In conclusion, the reduction in ACE activity is associated with a decreased accumulation of body fat, especially in abdominal fat depots. The decreased body fat in ACE(-/-) mice is independent of food intake and appears to be due to a high energy expenditure related to increased metabolism of fatty acids in the liver, with the additional effect of increased glucose tolerance.
Asunto(s)
Tejido Adiposo/anatomía & histología , Metabolismo Energético , Glucosa/metabolismo , Peptidil-Dipeptidasa A/deficiencia , Tejido Adiposo/enzimología , Animales , Composición Corporal , Peso Corporal , Calorimetría , Ingestión de Líquidos , Heces/química , Conducta Alimentaria , Regulación de la Expresión Génica , Prueba de Tolerancia a la Glucosa , Hormonas/sangre , Metabolismo de los Lípidos/genética , Hígado/enzimología , Ratones , Modelos Biológicos , Actividad Motora , Tamaño de los Órganos , Condicionamiento Físico AnimalRESUMEN
Water intakes in response to hypertonic, hypovolemic, and dehydrational stimuli were investigated in mice lacking angiotensin II as a result of deletion of the angiotensinogen gene (Agt-/- mice), and in C57BL6 wild-type (WT) mice. Baseline daily water intake in Agt-/- mice was approximately threefold that of WT mice because of a renal developmental disorder of the urinary concentrating mechanisms in Agt-/- mice. Intraperitoneal injection of hypertonic saline (0.4 and 0.8 mol/l NaCl) caused a similar dose-dependent increase in water intake in both Agt-/- and WT mice during the hour following injection. As well, Agt-/- mice drank appropriate volumes of water following water deprivation for 7 h. However, Agt-/- mice did not increase water or 0.3 mol/l NaCl intake in the 8 h following administration of a hypovolemic stimulus (30% polyethylene glycol sc), whereas WT mice increased intakes of both solutions during this time. Osmoregulatory regions of the brain [hypothalamic paraventricular and supraoptic nuclei, median preoptic nucleus, organum vasculosum of the lamina terminalis (OVLT), and subfornical organ] showed an increased number of neurons exhibiting Fos-immunoreactivity in response to intraperitoneal hypertonic NaCl in both Agt-/- mice and WT mice. Polyethylene glycol treatment increased Fos-immunoreactivity in the subfornical organ, OVLT, and supraoptic nuclei in WT mice but only increased Fos-immunoreactivity in the supraoptic nucleus in Agt-/- mice. These data show that brain angiotensin is not essential for the adequate functioning of neural pathways mediating osmoregulatory thirst. However, angiotensin II of either peripheral or central origin is probably necessary for thirst and salt appetite that results from hypovolemia.
Asunto(s)
Angiotensina II/fisiología , Ingestión de Líquidos/fisiología , Hipovolemia/fisiopatología , Sed/fisiología , Equilibrio Hidroelectrolítico/fisiología , Angiotensina II/genética , Animales , Química Encefálica/fisiología , Coloides/administración & dosificación , Coloides/farmacología , Ingestión de Alimentos/fisiología , Genes fos , Inmunohistoquímica , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacología , Solución Salina Hipertónica/farmacología , Privación de Agua/fisiologíaRESUMEN
BACKGROUND: Addition of up to 15.0 g/d salt to the diet of chimpanzees caused large rises in blood pressure, which reversed when the added salt was removed. Effects of more modest alterations to sodium intakes in chimpanzees, akin to current efforts to lower sodium intakes in the human population, are unknown. METHODS AND RESULTS: Sodium intakes were altered among 17 chimpanzees in Franceville, Gabon, and 110 chimpanzees in Bastrop, Tex. In Gabon, chimpanzees had a biscuit diet of constant nutrient composition except that the sodium content was changed episodically over 3 years from 75 to 35 to 120 mmol/d. In Bastrop, animals were divided into 2 groups; 1 group continued on the standard diet of 250 mmol/d sodium for 2 years, and sodium intake was halved for the other group. Lower sodium intake was associated with lower systolic, diastolic, and mean arterial blood pressures in Gabon (2-tailed P<0.001, unadjusted and adjusted for age, sex, and baseline weight) and Bastrop (P<0.01, unadjusted; P=0.08 to 0.10, adjusted), with no threshold down to 35 mmol/d sodium. For systolic pressure, estimates were -12.7 mm Hg (95% confidence interval, -16.9 to -8.5, adjusted) per 100 mmol/d lower sodium in Gabon and -10.9 mm Hg (95% confidence interval, -18.9 to -2.9, unadjusted) and -5.7 mm Hg (95% confidence interval, -12.2 to 0.7, adjusted) for sodium intake lower by 122 mmol/d in Bastrop. Baseline systolic pressures higher by 10 mm Hg were associated with larger falls in systolic pressure by 4.3/2.9 mm Hg in Gabon/Bastrop per 100 mmol/d lower sodium. CONCLUSIONS: These findings from an essentially single-variable experiment in the species closest to Homo sapiens with high intakes of calcium and potassium support intensified public health efforts to lower sodium intake in the human population.
Asunto(s)
Modelos Animales de Enfermedad , Hipertensión/dietoterapia , Hipertensión/etiología , Pan troglodytes , Cloruro de Sodio Dietético/farmacología , Animales , Presión Sanguínea , Dieta Hiposódica , Femenino , Humanos , Masculino , Especificidad de la EspecieRESUMEN
Thirst and resultant water drinking can arise in response to deficits in both the intracellular and extracellular fluid compartments. Inhibitory influences mediating the satiation of thirst also are necessary to prevent overhydration. The brain regions that underpin the generation or inhibition of thirst in these circumstances can be categorized as sensory, integrative, or cortical effector sites. The anterior cingulate cortex and insula are activated in thirsty human beings as shown by functional brain-imaging techniques. It is postulated that these sites may be cortical effector regions for thirst. A major sensory site for generating thirst is the lamina terminalis in the forebrain. Osmoreceptors within the organum vasculosum of the lamina terminalis and subfornical organ detect systemic hypertonicity. The subfornical organ mediates the dipsogenic actions of circulating angiotensin II and relaxin. Major integrative sites are the nucleus of the tractus solitarius, the lateral parabrachial nucleus, the midbrain raphé nuclei, the median preoptic nucleus, and the septum. Despite these advances, most of the neural pathways and neurochemical mechanisms subserving the genesis of thirst remain to be elucidated.
Asunto(s)
Ingestión de Líquidos/fisiología , Vías Nerviosas/fisiología , Sed/fisiología , Animales , Estado de Conciencia , Humanos , Equilibrio HidroelectrolíticoRESUMEN
This study used positron-emission tomography to establish the patterns of brain activity involved in the isolated and concurrent experiences of thirst and pain. Ten subjects were scanned while experiencing pain evoked with noxious pressure, while experiencing thirst after the infusion of hypertonic saline, and while experiencing pain when thirsty. After the onset of thirst, noxious pressure evoked more intense sensations of pain. Noxious pressure did not change subjective ratings of thirst. Thirst caused activation in the anterior cingulate (Brodmann area 32) and the insula. Enhanced pain responses were associated with increased activity in cortical regions that are known to correlate with pain intensity, and also with unique activity in the pregenual anterior cingulate and ventral orbitofrontal cortex. These findings suggest a role for limbic and prefrontal cortices in the modulation of pain during the experience of thirst.
Asunto(s)
Corteza Cerebral/fisiología , Dolor/fisiopatología , Sed/fisiología , Adulto , Conducta/fisiología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiopatología , Humanos , Sistema Límbico/diagnóstico por imagen , Sistema Límbico/fisiología , Sistema Límbico/fisiopatología , Masculino , Dolor/diagnóstico por imagen , Tomografía de Emisión de Positrones , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiología , Corteza Prefrontal/fisiopatología , Solución Salina Hipertónica/administración & dosificaciónRESUMEN
A fall in skin temperature precipitates a repertoire of thermoregulatory responses that reduce the likelihood of a decrease in core temperature. Studies in animals suggest that medullary raphé neurons are essential for cold-defense, mediating both the cutaneous vasoconstrictor and thermogenic responses to ambient cooling; however, the involvement of raphé neurons in human thermoregulation has not been investigated. This study used functional MRI with an anatomically guided region of interest (ROI) approach to characterize changes in the blood oxygen level-dependent (BOLD) signal within the human medulla of nine normal subjects during non-noxious cooling and rewarming of the skin by a water-perfused body suit. An ROI covering 4.9 +/- 0.3 mm(2) in the ventral midline of the medulla immediately caudal to the pons (the rostral medullary raphé) showed an increase in BOLD signal of 3.9% (P < 0.01) during periods of skin cooling, compared with other times. Overall, that signal showed a strong inverse correlation (R = 0.48, P < 0.001) with skin temperature. A larger ROI covering the internal medullary cross section at the same level (area, 126 +/- 15 mm(2)) showed no significant change in mean BOLD signal with cooling (+0.2%, P > 0.05). These findings demonstrate that human rostral medullary raphé neurons are selectively activated in response to a thermoregulatory challenge and point to the location of thermoregulatory neurons homologous to those of the raphé pallidus nucleus in rodents.
Asunto(s)
Regulación de la Temperatura Corporal/fisiología , Frío , Calor , Imagen por Resonancia Magnética , Bulbo Raquídeo/fisiología , Fenómenos Fisiológicos de la Piel , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To test the hypothesis that changes in gene expression that may accompany angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) gene polymorphism cause alteration in angiotensin and bradykinin peptide levels. DESIGN: Mice with one or two genes for AGT and ACE allow assessment of the effects of modest alteration in AGT and ACE gene expression on angiotensin and bradykinin peptide levels. METHODS: Angiotensin and bradykinin peptides were measured in the blood, kidney, heart, lung, adrenal, brain, and aorta of mice that were either wild-type (+/+), heterozygous (+/-) or null (-/-) for either the AGT or ACE gene. RESULTS: Angiotensin I and angiotensin II were not detectable in blood or tissues of AGT -/- mice, which had increased bradykinin levels in kidney and lung. ACE -/- mice had markedly reduced angiotensin II levels and increased bradykinin levels in blood and tissues. However, despite reduced AGT and ACE gene expression, angiotensin and bradykinin peptide levels in AGT and ACE +/- mice were no different from the levels in wild-type mice. CONCLUSION: Although the AGT and ACE genes are fundamental determinants of angiotensin and bradykinin peptide levels, compensatory mechanisms attenuate the effect of modest change in AGT and ACE gene expression on the levels of these peptides. Identification of these compensatory mechanisms may provide new candidate genes for investigation in humans.
Asunto(s)
Angiotensinógeno/genética , Angiotensinas/análisis , Bradiquinina/análisis , Dosificación de Gen , Peptidil-Dipeptidasa A/genética , Angiotensinas/metabolismo , Animales , Presión Sanguínea , Peso Corporal , Bradiquinina/metabolismo , Femenino , Genotipo , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
A renin-angiotensin system, separate to that in the periphery, has been found in the brain. Angiotensin-converting enzyme (ACE) is crucial in the synthesis of angiotensin II, breakdown of bradykinin and the hydrolysis of several other neuropeptides such as enkephalin, substance P, dynorphin and neurotensin. Changes in the levels of ACE have been found in brains of schizophrenia patients, suggesting an involvement of ACE in the illness which awaits further investigation. Prepulse inhibition (PPI) has been suggested to be an operational measure of sensorimotor gating and is disrupted in patients with schizophrenia. We found that ACE knockout mice have increased startle responses but no differences in baseline PPI compared to wildtype controls. Treatment with the dopamine receptor agonist, apomorphine, or the dopamine-releasing drug, amphetamine, produced significant disruption of PPI in control mice but not in ACE knockout mice. Pretreatment with the ACE inhibitor, captopril, which itself did not affect PPI, caused a reduction in the effect of apomorphine on PPI, similar to that seen in the ACE knockout mice. These data suggest an important role of ACE substrates in modulating dopaminergic mechanisms involved in PPI. Further studies are needed to ascertain if angiotensin or other neuropeptides are involved in these interactions and to investigate the neurochemical mechanism behind these effects.
Asunto(s)
Encéfalo/metabolismo , Dopamina/metabolismo , Inhibición Neural/fisiología , Peptidil-Dipeptidasa A/metabolismo , Reflejo de Sobresalto/fisiología , Anfetamina/farmacología , Análisis de Varianza , Animales , Apomorfina/farmacología , Conducta Animal , Encéfalo/efectos de los fármacos , Encéfalo/efectos de la radiación , Maleato de Dizocilpina/farmacología , Agonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta en la Radiación , Interacciones Farmacológicas , Estimulación Eléctrica/métodos , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Inhibición Neural/efectos de los fármacos , Inhibición Neural/efectos de la radiación , Peptidil-Dipeptidasa A/deficiencia , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/efectos de la radiaciónRESUMEN
The hypothalamus and neocortex are subdivisions of the mammalian forebrain, and yet, they have vastly different evolutionary histories, cytoarchitecture, and biological functions. In an attempt to define these attributes in terms of their genetic activity, we have compared their genetic repertoires by using the Serial Analysis of Gene Expression database. From a comparison of 78,784 hypothalamus tags with 125,296 neocortical tags, we demonstrate that each structure possesses a different transcriptional profile in terms of gene ontological characteristics and expression levels. Despite its more recent evolutionary history, the neocortex has a more complex pattern of gene activity. Gene identities and levels of gene expression were mapped to their chromosomal positions by using in silico definition of GC-rich and GC-poor genome bands. This analysis shows contrasting views of gene activity on a genome scale that is unique to each brain substructure. We show that genes that are more highly expressed in one tissue tend to be clustered together on a chromosomal scale, further defining the genetic identity of either the hypothalamus or neocortex. We propose that physical proximity of coregulated genes may facilitate transcriptional access to the genetic substrates of evolutionary selection that ultimately shape the functional subdivisions of the mammalian brain.