Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein. Although MECP2 is ...expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2(+/-) females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.
As high latitudes warm, vast stocks of carbon and nitrogen stored in permafrost will become available for transport to aquatic ecosystems. While there is a growing understanding of the potential ...effects of permafrost collapse (thermokarst) on aquatic biogeochemical cycles, neither the spatial extent nor temporal duration of these effects is known. To test hypotheses concerning patterns and persistence of elemental export from upland thermokarst, we sampled hydrologic outflow from 83 thermokarst features in various stages of development across the North Slope of Alaska. We hypothesized that an initial pulse of carbon and nutrients would be followed by a period of elemental retention during feature recovery, and that the duration of these stages would depend on feature morphology. Thermokarst caused substantial increases in dissolved organic carbon and other solute concentrations with a particularly large impact on inorganic nitrogen. Magnitude and duration of thermokarst effects on water chemistry differed by feature type and secondarily by landscape age. Most solutes returned to undisturbed concentrations after feature stabilization, but elevated dissolved carbon, inorganic nitrogen, and sulfate concentrations persisted through stabilization for some feature types, suggesting that aquatic disturbance by thermokarst for these solutes is long-lived. Dissolved methane decreased by 90% for most feature types, potentially due to high concentrations of sulfate and inorganic nitrogen. Spatial patterns of carbon and nutrient export from thermokarst suggest that upland thermokarst may be a dominant linkage transferring carbon and nutrients from terrestrial to aquatic ecosystems as the Arctic warms.
To investigate the prevalence and cause of concentration‐discharge (C‐Q) relationships for carbon, nutrients, major ions, and particulates, we analyzed 40 years of water quality data from 293 ...monitoring stations in France. Catchments drained diverse landscapes and ranged from 50 to 110,000 km2, together covering nearly half of France. To test for differences during low and high flows, we calculated independent C‐Q slopes above and below the median discharge. We found that 84% of all catchment‐element combinations were chemodynamic for at least half of the hydrograph and 60% of combinations showed nonlinear C‐Q curves. Only two or three of the nine possible C‐Q modalities were manifest for each parameter, and these modalities were stable through time, suggesting that intrinsic and extrinsic elemental properties (e.g., solubility, reactivity, and source dynamics) set basic C‐Q templates for each parameter, which are secondarily influenced by biological activity during low flows, and the interaction between hydrology and catchment characteristics at high flows. Several patterns challenged current C‐Q views, including low‐flow chemostasis for TSS in 66% of catchments, low‐flow biological mediation of
NO3− in 71% of catchments, and positive C‐Q for dissolved organic carbon independent of catchment size in 80% of catchments. Efforts to reduce nutrient loading decreased phosphorus concentration and altered C‐Q curves, but
NO3− continued to increase. While C‐Q segmentation requires more data than a single analysis, the prevalence of nonlinear C‐Q slopes demonstrates the potential information loss associated with linear or monotonic analysis of C‐Q relationships, and conversely, the value of long‐term monitoring.
Key Points
Only 2 or 3 of the possible 9 C‐Q modalities occurred for any given element, and these shapes were stable through time
Elemental properties set C‐Q templates for each parameter, secondarily influenced by biology, catchment characteristics, and hydrology
Nearly two‐thirds of C‐Q relationships were nonlinear, emphasizing information cost of monotonic C‐Q analysis
As Arctic regions warm and frozen soils thaw, the large organic carbon pool stored in permafrost becomes increasingly vulnerable to decomposition or transport. The transfer of newly mobilized carbon ...to the atmosphere and its potential influence upon climate change will largely depend on the degradability of carbon delivered to aquatic ecosystems. Dissolved organic carbon (DOC) is a key regulator of aquatic metabolism, yet knowledge of the mechanistic controls on DOC biodegradability is currently poor due to a scarcity of long-term data sets, limited spatial coverage of available data, and methodological diversity. Here, we performed parallel biodegradable DOC (BDOC) experiments at six Arctic sites (16 experiments) using a standardized incubation protocol to examine the effect of methodological differences commonly used in the literature. We also synthesized results from 14 aquatic and soil leachate BDOC studies from across the circum-arctic permafrost region to examine pan-arctic trends in BDOC. An increasing extent of permafrost across the landscape resulted in higher DOC losses in both soil and aquatic systems. We hypothesize that the unique composition of (yedoma) permafrost-derived DOC combined with limited prior microbial processing due to low soil temperature and relatively short flow path lengths and transport times, contributed to a higher overall terrestrial and freshwater DOC loss. Additionally, we found that the fraction of BDOC decreased moving down the fluvial network in continuous permafrost regions, i.e. from streams to large rivers, suggesting that highly biodegradable DOC is lost in headwater streams. We also observed a seasonal (January-December) decrease in BDOC in large streams and rivers, but saw no apparent change in smaller streams or soil leachates. We attribute this seasonal change to a combination of factors including shifts in carbon source, changing DOC residence time related to increasing thaw-depth, increasing water temperatures later in the summer, as well as decreasing hydrologic connectivity between soils and surface water as the thaw season progresses. Our results suggest that future climate warming-induced shifts of continuous permafrost into discontinuous permafrost regions could affect the degradation potential of thaw-released DOC, the amount of BDOC, as well as its variability throughout the Arctic summer. We lastly recommend a standardized BDOC protocol to facilitate the comparison of future work and improve our knowledge of processing and transport of DOC in a changing Arctic.
Basic and clinical observations suggest that the caudal hypothalamus comprises a key node of the ascending arousal system, but the cell types underlying this are not fully understood. Here we report ...that glutamate-releasing neurons of the supramammillary region (SuM
) produce sustained behavioral and EEG arousal when chemogenetically activated. This effect is nearly abolished following selective genetic disruption of glutamate release from SuM
neurons. Inhibition of SuM
neurons decreases and fragments wake, also suppressing theta and gamma frequency EEG activity. SuM
neurons include a subpopulation containing both glutamate and GABA (SuM
) and another also expressing nitric oxide synthase (SuM
). Activation of SuM
neurons produces minimal wake and optogenetic stimulation of SuM
terminals elicits monosynaptic release of both glutamate and GABA onto dentate granule cells. Activation of SuM
neurons potently drives wakefulness, whereas inhibition reduces REM sleep theta activity. These results identify SuM
neurons as a key node of the wake-sleep regulatory system.
Stimulation of glutamatergic neurons in the subfornical organ drives drinking behavior, but the brain targets that mediate this response are not known. The densest target of subfornical axons is the ...anterior tip of the third ventricle, containing the median preoptic nucleus (MnPO) and organum vasculosum of the lamina terminalis (OVLT), a region that has also been implicated in fluid and electrolyte management. The neurochemical composition of this region is complex, containing both GABAergic and glutamatergic neurons, but the possible roles of these neurons in drinking responses have not been addressed. In mice, we show that optogenetic stimulation of glutamatergic neurons in MnPO/OVLT drives voracious water consumption, and that optogenetic stimulation of GABAergic neurons in the same region selectively reduces water consumption. Both populations of neurons have extensive projections to overlapping regions of the thalamus, hypothalamus, and hindbrain that are much more extensive than those from the subfornical organ, suggesting that the MnPO/OVLT serves as a key link in regulating drinking responses.
Neurons in the median preoptic nucleus (MnPO) and organum vasculosum of the lamina terminalis (OVLT) are known to regulate fluid/electrolyte homeostasis, but few studies have examined this issue with an appreciation for the neurochemical heterogeneity of these nuclei. Using Cre-Lox genetic targeting of Channelrhodospin-2 in transgenic mice, we demonstrate that glutamate and GABA neurons in the MnPO/OVLT reciprocally regulate water consumption. Stimulating glutamatergic MnPO/OVLT neurons induced water consumption, whereas stimulating GABAergic MnPO neurons caused a sustained and specific reduction in water consumption in dehydrated mice, the latter highlighting a heretofore unappreciated role of GABAergic MnPO neurons in thirst regulation. These observations represent an important advance in our understanding of the neural circuits involved in the regulation of fluid/electrolyte homeostasis.
C1 neurons: the body's EMTs Guyenet, Patrice G; Stornetta, Ruth L; Bochorishvili, Genrieta ...
American journal of physiology. Regulatory, integrative and comparative physiology,
08/2013, Letnik:
305, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The C1 neurons reside in the rostral and intermediate portions of the ventrolateral medulla (RVLM, IVLM). They use glutamate as a fast transmitter and synthesize catecholamines plus various ...neuropeptides. These neurons regulate the hypothalamic pituitary axis via direct projections to the paraventricular nucleus and regulate the autonomic nervous system via projections to sympathetic and parasympathetic preganglionic neurons. The presympathetic C1 cells, located in the RVLM, are probably organized in a roughly viscerotopic manner and most of them regulate the circulation. C1 cells are variously activated by hypoglycemia, infection or inflammation, hypoxia, nociception, and hypotension and contribute to most glucoprivic responses. C1 cells also stimulate breathing and activate brain stem noradrenergic neurons including the locus coeruleus. Based on the various effects attributed to the C1 cells, their axonal projections and what is currently known of their synaptic inputs, subsets of C1 cells appear to be differentially recruited by pain, hypoxia, infection/inflammation, hemorrhage, and hypoglycemia to produce a repertoire of stereotyped autonomic, metabolic, and neuroendocrine responses that help the organism survive physical injury and its associated cohort of acute infection, hypoxia, hypotension, and blood loss. C1 cells may also contribute to glucose and cardiovascular homeostasis in the absence of such physical stresses, and C1 cell hyperactivity may contribute to the increase in sympathetic nerve activity associated with diseases such as hypertension.
Key points
Glutamatergic neurons in the median preoptic area were stimulated using genetically targeted Channelrhodopsin 2 in transgenic mice.
Stimulation of glutamatergic median preoptic area ...neurons produced a profound hypothermia due to cutaneous vasodilatation.
Stimulation also produced drinking behaviour that was inhibited as water was ingested, suggesting pre‐systemic feedback gating of drinking.
Anatomical mapping of the stimulation sites showed that sites associated with hypothermia were more anteroventral than those associated with drinking, although there was substantial overlap.
The median preoptic nucleus (MnPO) serves an important role in the integration of water/electrolyte homeostasis and thermoregulation, but we have a limited understanding these functions at a cellular level. Using Cre–Lox genetic targeting of Channelrhodospin 2 in VGluT2 transgenic mice, we examined the effect of glutamatergic MnPO neuron stimulation in freely behaving mice while monitoring drinking behaviour and core temperature. Stimulation produced a strong hypothermic response in 62% (13/21) of mice (core temperature: −4.6 ± 0.5°C, P = 0.001 vs. controls) caused by cutaneous vasodilatation. Stimulating glutamatergic MnPO neurons also produced robust drinking behaviour in 82% (18/22) of mice. Mice that drank during stimulation consumed 912 ± 163 μl (n = 8) during a 20 min trial in the dark phase, but markedly less during the light phase (421 ± 83 μl, P = 0.0025). Also, drinking during stimulation was inhibited as water was ingested, suggesting pre‐systemic feedback gating of drinking. Both hypothermia and drinking during stimulation occurred in 50% of mice tested. Anatomical mapping of the stimulation sites showed that sites associated with hypothermia were more anteroventral than those associated with drinking, although there was substantial overlap. Thus, activation of separate but overlapping populations of glutamatergic MnPO neurons produces effects on drinking and autonomic thermoregulatory mechanisms, providing a structural basis for their frequently being coordinated (e.g. during hyperthermia).
Key points
Glutamatergic neurons in the median preoptic area were stimulated using genetically targeted Channelrhodopsin 2 in transgenic mice.
Stimulation of glutamatergic median preoptic area neurons produced a profound hypothermia due to cutaneous vasodilatation.
Stimulation also produced drinking behaviour that was inhibited as water was ingested, suggesting pre‐systemic feedback gating of drinking.
Anatomical mapping of the stimulation sites showed that sites associated with hypothermia were more anteroventral than those associated with drinking, although there was substantial overlap.
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