Neurotensin induces hypothermia by activating both neuronal neurotensin receptor 1 and astrocytic neurotensin receptor 2 in the median preoptic nucleus.
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ABSTRACT:
SUBMITTER: Tabarean IV
PROVIDER: S-EPMC7274271 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Whole-cell patch-clamp recordings were performed on acute brain slices of male rats to investigate the ability of the neurons of the median preoptic nucleus (MnPO) to detect fluctuation in extracellular osmolarity and sodium concentration ([Na+]out). Local application of hypotonic and hypertonic artificial CSF hyperpolarized and depolarized the neurons, respectively. Similar responses obtained under synaptic isolation (0.5 microM TTX) highlighted the intrinsic ability of the MnPO neurons to detect changes in extracellular osmolarity and [Na+]out. Manipulating extracellular osmolarity, [Na+]out, and [Cl-]out showed in an independent manner that the MnPO neurons responded to a change in [Na+]out exclusively. The specific Na+ response was voltage insensitive and depended on the driving force for Na+ ions, indicating that a sustained background Na+ permeability controlled the membrane potential of the MnPO neurons. This specific response was not reduced by Gd3+, amiloride, or benzamil, ruling out the participation of mechanosensitive cationic channels, specific epithelial Na+ channels, and Phe-Met-Arg-Phe-gated Na+ channels, respectively. Combination of in situ hybridization, using a riboprobe directed against the atypical Na+ channel (Na(X)), and immunohistochemistry, using an antibody against neuron-specific nuclei protein, revealed that a substantial population of MnPO neurons expressed the Na(X) channel, which was characterized recently as a concentration-sensitive Na+ channel. This study shows that a neuronal population of the MnPO acts as functional Na+ sensors and that the Na(X) channel might represent the molecular basis for the extracellular sodium level sensing in these neurons.
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Project description:Chronic intermittent hypoxia (CIH) is a model of the hypoxemia from sleep apnea that causes a sustained increase in blood pressure. Inhibition of the central renin-angiotensin system or FosB in the median preoptic nucleus (MnPO) prevents the sustained hypertensive response to CIH. We tested the hypothesis that angiotensin type 1a (AT1a) receptors in the MnPO, which are upregulated by CIH, contribute to this hypertension. In preliminary experiments, retrograde tract tracing studies showed AT1a receptor expression in MnPO neurons projecting to the paraventricular nucleus. Adult male rats were exposed to 7 days of intermittent hypoxia (cycling between 21% and 10% O2 every 6 min, 8 h/day during light phase). Seven days of CIH was associated with a FosB-dependent increase in AT1a receptor mRNA without changes in the permeability of the blood-brain barrier in the MnPO. Separate groups of rats were injected in the MnPO with an adeno-associated virus containing short hairpin (sh)RNA against AT1a receptors to test their role in intermittent hypoxia hypertension. Injections of shRNA against AT1a in MnPO blocked the increase in mRNA associated with CIH, prevented the sustained component of the hypertension during normoxia, and reduced circulating advanced oxidation protein products, an indicator of oxidative stress. Rats injected with shRNA against AT1a and exposed to CIH had less FosB staining in MnPO and the rostral ventrolateral medulla after intermittent hypoxia than rats injected with the control vector that were exposed to CIH. Our results indicate AT1a receptors in the MnPO contribute to the sustained blood pressure increase to intermittent hypoxia.
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Project description:Therapeutic hypothermia at 32-34 °C during or after cerebral ischaemia is neuroprotective. However, peripheral cold sensor-triggered hypothermia is ineffective and evokes vigorous counteractive shivering thermogenesis and complications that are difficult to tolerate in awake patients. Here, we show in mice that deep brain stimulation (DBS) of warm-sensitive neurones (WSNs) in the medial preoptic nucleus (MPN) produces tolerable hypothermia. In contrast to surface cooling-evoked hypothermia, DBS mice exhibit a torpor-like state without counteractive shivering. Like hypothermia evoked by chemogenetic activation of WSNs, DBS in free-moving mice elicits a rapid lowering of the core body temperature to 32-34 °C, which confers significant brain protection and motor function reservation. Mechanistically, activation of WSNs contributes to DBS-evoked hypothermia. Inhibition of WSNs prevents DBS-evoked hypothermia. Maintaining the core body temperature at normothermia during DBS abolishes DBS-mediated brain protection. Thus, the MPN is a DBS target to evoke tolerable therapeutic hypothermia for stroke treatment.
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Project description:One of the main clinical features of obstructive sleep apnea is sustained hypertension and elevated sympathetic activity during waking hours. Chronic intermittent hypoxia (CIH), animal model of the hypoxemia associated with obstructive sleep apnea, produces a similar sustained increase in blood pressure. This study determined the role of ΔFosB in the median preoptic nucleus (MnPO) in the sustained increase in mean arterial pressure associated with CIH. Rats were injected in the MnPO with viral vectors that expressed green fluorescent protein alone or green fluorescent protein plus a dominant-negative construct that inhibits the transcriptional effects of ΔFosB. In green fluorescent protein-injected rats and uninjected controls, 7-day exposure to CIH increased mean arterial pressure by 7 to 10 mm Hg during both intermittent hypoxia exposure and normoxia. Dominant-negative inhibition of MnPO ΔFosB did not affect changes in mean arterial pressure during intermittent hypoxia exposure but significantly reduced the sustained component of the blood pressure response to CIH during the normoxic dark phase. Inhibition of MnPO ΔFosB reduced the FosB/ΔFosB staining in the paraventricular nucleus and rostral ventrolateral medulla but not the nucleus of the solitary tract. PCR array analysis identified 6 activator protein 1-regulated genes expressed in the MnPO that were increased by CIH exposure, ace, ace2, nos1, nos3, prdx2, and map3k3. Dominant-negative inhibition of ΔFosB in the MnPO blocked increased expression of each of these genes in rats exposed to CIH except for Prdx2. ΔFosB may mediate transcriptional activity in MnPO necessary for sustained CIH hypertension, suggesting that neural adaptations may contribute to diurnal hypertension in obstructive sleep apnea.
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Project description:Astrocytes of the suprachiasmatic nucleus (SCN) can regulate sleep-wake cycles in mammals. However, the nature of the information provided by astrocytes to control circadian patterns of behavior is unclear. Neuronal circadian activity across the SCN is organized into spatiotemporal waves that govern seasonal adaptations and timely engagement of behavioral outputs. Here, we show that astrocytes across the mouse SCN exhibit instead a highly uniform, pulse-like nighttime activity. We find that rhythmic astrocytic GABA production via polyamine degradation provides an inhibitory nighttime tone required for SCN circuit synchrony, thereby acting as an internal astrocyte zeitgeber (or "astrozeit"). We further identify synaptic GABA and astrocytic GABA as two key players underpinning coherent spatiotemporal circadian patterns of SCN neuronal activity. In describing a new mechanism by which astrocytes contribute to circadian timekeeping, our work provides a general blueprint for understanding how astrocytes encode temporal information underlying complex behaviors in mammals.
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Project description:The suprachiasmatic nucleus (SCN) of the hypothalamus consists of a highly heterogeneous neuronal population networked together to allow precise and robust circadian timekeeping in mammals. While the critical importance of SCN neurons in regulating circadian rhythms has been extensively studied, the roles of SCN astrocytes in circadian system function are not well understood. Recent experiments have demonstrated that SCN astrocytes are circadian oscillators with the same functional clock genes as SCN neurons. Astrocytes generate rhythmic outputs that are thought to modulate neuronal activity through pre- and postsynaptic interactions. In this study, we developed an in silico multicellular model of the SCN clock to investigate the impact of astrocytes in modulating neuronal activity and affecting key clock properties such as circadian rhythmicity, period, and synchronization. The model predicted that astrocytes could alter the rhythmic activity of neurons via bidirectional interactions at tripartite synapses. Specifically, astrocyte-regulated extracellular glutamate was predicted to increase neuropeptide signaling from neurons. Consistent with experimental results, we found that astrocytes could increase the circadian period and enhance neural synchronization according to their endogenous circadian period. The impact of astrocytic modulation of circadian rhythm amplitude, period, and synchronization was predicted to be strongest when astrocytes had periods between 0 and 2 h longer than neurons. Increasing the number of neurons coupled to the astrocyte also increased its impact on period modulation and synchrony. These computational results suggest that signals that modulate astrocytic rhythms or signaling (e.g., as a function of season, age, or treatment) could cause disruptions in circadian rhythm or serve as putative therapeutic targets.
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Project description:Angiotensin II (Ang II) stimulates water and saline intakes when injected into the brain of rats. This arises from activation of the AT1 Ang II receptor subtype. Acute repeated injections, however, decrease the water intake response to Ang II without affecting saline intake. Previous studies provide evidence that Ang II-induced water intake is mediated via the classical G protein coupling pathway, whereas the saline intake caused by Ang II is mediated by an ERK 1/2 MAP kinase signaling pathway. Accordingly, the different behavioral response to repeated injections of Ang II may reflect a selective effect on G protein coupling. To test this hypothesis, we examined the binding of a radiolabeled agonist ((125)I-sarcosine(1) Ang II) and a radiolabeled antagonist ((125)I-sarcosine(1), isoleucine(8) Ang II) in brain homogenates and tissue sections prepared from rats given repeated injections of Ang II or vehicle. Although no treatment-related differences were found in hypothalamic homogenates, a focus on specific brain structures using receptor autoradiography, found that the desensitization treatment reduced binding of both radioligands in the paraventricular nucleus of the hypothalamus (PVN) and median preoptic nucleus (MnPO), but not in the subfornical organ (SFO). Because G protein coupling is reported to have a selective effect on agonist binding without affecting antagonist binding, these findings do not support a G protein uncoupling treatment effect. This suggests that receptor number is more critical to the water intake response than the saline intake response, or that pathways downstream from the G protein mediate desensitization of the water intake response.
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Project description:Brown adipose tissue (BAT) thermogenesis is critical to maintain homoeothermia and is centrally controlled via sympathetic outputs. Body temperature and BAT activity also impact energy expenditure, and obesity is commonly associated with decreased BAT capacity and sympathetic tone. Severely obese mice that lack leptin or its receptor (LepRb) show decreased BAT capacity, sympathetic tone, and body temperature and thus are unable to adapt to acute cold exposure (Trayhurn et al., 1976). LepRb-expressing neurons are found in several hypothalamic sites, including the dorsomedial hypothalamus (DMH) and median preoptic area (mPOA), both critical sites to regulate sympathetic, thermoregulatory BAT circuits. Specifically, a subpopulation in the DMH/dorsal hypothalamic area (DHA) is stimulated by fever-inducing endotoxins or cold exposure (Dimicco and Zaretsky, 2007; Morrison et al., 2008). Using the retrograde, transsynaptic tracer pseudorabies virus (PRV) injected into the BAT of mice, we identified PRV-labeled LepRb neurons in the DMH/DHA and mPOA (and other sites), thus indicating their involvement in the regulation of sympathetic BAT circuits. Indeed, acute cold exposure induced c-Fos (as a surrogate for neuronal activity) in DMH/DHA LepRb neurons, and a large number of mPOA LepRb neurons project to the DMH/DHA. Furthermore, DMH/DHA LepRb neurons (and a subpopulation of LepRb mPOA neurons) project and synaptically couple to rostral raphe pallidus neurons, consistent with the current understanding of BAT thermoregulatory circuits from the DMH/DHA and mPOA (Dimicco and Zaretsky, 2007; Morrison et al., 2008). Thus, these data present strong evidence that LepRb neurons in the DMH/DHA and mPOA mediate thermoregulatory leptin action.
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Project description:The conformational ensembles of G protein-coupled receptors (GPCRs) include inactive and active states. Spectroscopy techniques, including NMR, show that agonists, antagonists and other ligands shift the ensemble toward specific states depending on the pharmacological efficacy of the ligand. How receptors recognize ligands and the kinetic mechanism underlying this population shift is poorly understood. Here, we investigate the kinetic mechanism of neurotensin recognition by neurotensin receptor 1 (NTS1) using 19F-NMR, hydrogen-deuterium exchange mass spectrometry and stopped-flow fluorescence spectroscopy. Our results indicate slow-exchanging conformational heterogeneity on the extracellular surface of ligand-bound NTS1. Numerical analysis of the kinetic data of neurotensin binding to NTS1 shows that ligand recognition follows an induced-fit mechanism, in which conformational changes occur after neurotensin binding. This approach is applicable to other GPCRs to provide insight into the kinetic regulation of ligand recognition by GPCRs.
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Project description:Homeotherms maintain a stable internal body temperature despite changing environments. During energy deficiency, some species can cease to defend their body temperature and enter a hypothermic and hypometabolic state known as torpor. Despite recent advances in our understanding of thermoregulation, the precise neurons that coordinate these profound thermoregulatory and metabolic changes remain largely unknown. Here, we demonstrate that estrogen-sensitive neurons in the medial preoptic area (MPA) are key drivers of hypothermia and hypometabolism in mice. We find that selectively activating estrogen-sensitive MPA neurons was sufficient to drive a coordinated depression of metabolic rate and body temperature similar to torpor, as measured by body temperature, physical activity, indirect calorimetry, heart rate, and brain activity. Inducing torpor with a prolonged fast revealed larger and more variable calcium transients from estrogen-sensitive MPA neurons during bouts of hypothermia. Finally, selective ablation of estrogen-sensitive MPA neurons demonstrated that these neurons are required for the full expression of fasting-induced torpor. Together, these findings suggest a role for estrogen-sensitive MPA neurons in directing the thermoregulatory and metabolic responses to energy deficiency.
2020-10-29 | GSE153350 | GEO