Area Postrema Cell Types that Mediate Nausea-Associated Behaviors.
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ABSTRACT:
SUBMITTER: Zhang C
PROVIDER: S-EPMC7864887 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Nausea, the unpleasant sensation of visceral malaise, remains a mysterious process. The area postrema is implicated in some nausea responses, and contains poorly understood brain-resident sensory neurons that are anatomically privileged to detect bloodborne signals. To investigate nausea mechanisms, we built an area postrema cell atlas through single-nucleus RNA sequencing, revealing a few neuron types. Using mouse genetic tools for cell-specific manipulation, we discovered excitatory neurons that induce nausea-related behaviors, with one neuron type mediating aversion imposed by multiple poisons. Nausea-associated responses were observed to agonists of identified area postrema receptors, and suppressed by targeted cell ablation and/or gene knockout. Anatomical mapping revealed a distributed network of long-range excitatory but not inhibitory projections with subtype-specific patterning. These studies reveal the basic organization of area postrema nausea circuitry, and provide a framework towards understanding and therapeutically controlling nausea.
2020-12-07 | GSE160938 | GEO
Project description:Area postrema cell types that mediate nausea-associated behaviors
| PRJNA674867 | ENA
Project description:ObjectiveTo characterize the neuropathologic features of neuromyelitis optica (NMO) at the medullary floor of the fourth ventricle and area postrema. Aquaporin-4 (AQP4) autoimmunity targets this region, resulting in intractable nausea associated with vomiting or hiccups in NMO.MethodsThis neuropathologic study was performed on archival brainstem tissue from 15 patients with NMO, 5 patients with multiple sclerosis (MS), and 8 neurologically normal subjects. Logistic regression was used to evaluate whether the presence of lesions at this level increased the odds of a patient with NMO having an episode of nausea/vomiting.ResultsSix patients with NMO (40%), but no patients with MS or normal controls, exhibited unilateral or bilateral lesions involving the area postrema and the medullary floor of the fourth ventricle. These lesions were characterized by tissue rarefaction, blood vessel thickening, no obvious neuronal or axonal pathology, and preservation of myelin in the subependymal medullary tegmentum. AQP4 immunoreactivity was lost or markedly reduced in all 6 cases, with moderate to marked perivascular and parenchymal lymphocytic inflammatory infiltrates, prominent microglial activation, and in 3 cases, eosinophils. Complement deposition in astrocytes, macrophages, and/or perivascularly, and a prominent astroglial reaction were also present. The odds of nausea/vomiting being documented clinically was 16-fold greater in NMO cases with area postrema lesions (95% confidence interval 1.43-437, p = 0.02).ConclusionsThese neuropathologic findings suggest the area postrema may be a selective target of the disease process in NMO, and are compatible with clinical reports of nausea and vomiting preceding episodes of optic neuritis and transverse myelitis or being the heralding symptom of NMO.
| S-EPMC3068006 | biostudies-literature
Project description:Purines such as adenosine 5'-triphosphate (ATP) act as extracellular messengers through specific purinergic receptors. Three different classes of purinergic receptors have been identified and termed P1, P2X, and P2Y. The purinergic receptor subunit P2X2 is a ligand-gated ion channel that is widely expressed by neurons in the CNS. In the brainstem medulla oblongata, the ionotropic P2X2 receptor (P2X2R) is enriched in the area postrema (AP). Two different antisera to P2X2R were used to determine the chemical nature of P2X2R immunoreactive cell bodies in the rat AP, an area lacking a blood-brain barrier. Subcellularly, P2X2R immunoreactivity was located to the periphery of individual cell bodies. The majority of P2X2R-immunoreactive cells were shown to contain tyrosine hydroxylase (TH) (63.5 ± 7.7%) and dopamine β-hydroxylase (61.5 ± 5.1%). Phenylethanolamine N-methyltransferase (PNMT)-containing cells were not detected in the AP, supporting a noradrenergic nature of P2X2R cells in the AP. There were no P2X2R-immunoreactive cells in the AP that contained the GABA-synthesizing enzyme glutamic acid decarboxylase 65. Only single vesicular glutamate transporter 2-immunoreactive cell bodies that were not P2X2R-positive were demonstrated in the AP. Some P2X2R-positive cells in the AP were immunoreactive for the neuropeptides substance P and pituitary adenylate cyclase-activating polypeptide, whereas dynorphin-, enkephalin-, or cholecystokinin-positive cells were not P2X2R-immunoreactive. Presence of P2X2R in a majority of noradrenergic cells of the AP implies that ATP may have a regulatory action on neuronal noradrenaline release from the AP, a circumventricular organ with a strategic position enabling interactions between circulating substances and the central nervous system.
| S-EPMC3350578 | biostudies-literature
Project description:Objective:Area postrema (AP) syndrome (defined as: nausea and/or emesis and/or singultus at onset of brainstem dysfunction) comprises complex pathophysiologic mechanisms triggered by different entities. The first objective was to assess the frequency of AP syndrome as a clinical feature in brainstem encephalitis (BE). Finding an especially high prevalence of AP syndrome in Bickerstaff brainstem encephalitis (BBE), we also analyzed the frequency of AP syndrome in other autoimmune diseases with anti-ganglioside antibodies (Guillain-Barré syndrome (GBS) and its variants). Methods:We systematically evaluated the prevalence of AP syndrome in BE in all patients treated at our university hospital during a 15-year period. In a second step, BBE patients were compared to GBS and Miller Fisher syndrome (MFS) patients as clinical subtypes of a disease continuum without brainstem dysfunction. Results:We found AP syndrome in 8 of 21 BE patients, including 3 of 7 BBE and in 4 of 112 GBS/MFS patients. AP syndrome was as a frequent but under-recognized feature of BE with a significant impact on patients' well being. Interpretation:Manifestation of AP syndrome in BBE but also in GBS and its subtypes point toward a role of autoimmune antibodies that should be investigated in future studies. Considerable misdiagnosis or nonrecognition complicates diagnostic and therapeutic management. Therefore, AP syndrome should be considered in any episode of otherwise unexplained nausea, emesis, or singultus.
| S-EPMC6292382 | biostudies-literature
Project description:ATP-induced inward currents and increases in the cytosolic Ca(2+) concentration ([Ca](in)) were investigated in neurons acutely dissociated from rat area postrema using whole-cell patch-clamp recordings and fura-2 microfluorometry, respectively. The ATP-induced current (I (ATP)) and [Ca](in) increases were mimicked by 2-methylthio-ATP and ATP-gammaS, and were inhibited by P2X receptor (P2XR) antagonists. The current-voltage relationship of the I (ATP) exhibited a strong inward rectification, and the amplitude of the I (ATP) was concentration-dependent. The I (ATP) was markedly reduced in the absence of external Na(+), and the addition of Ca(2+) to Na(+)-free saline increased the I (ATP). ATP did not increase [Ca](in) in the absence of external Ca(2+), and Ca(2+) channel antagonists partially inhibited the ATP-induced [Ca](in) increase, indicating that ATP increases [Ca](in) by Ca(2+) influx through both P2XR channels and voltage-dependent Ca(2+) channels. There was a negative interaction between P2XR- and nicotinic ACh receptor (nAChR)-channels, which depended on the amplitude and direction of current flow through either channel. Current occlusion was observed at V (h)s between -70 and -10 mV when the I (ATP) and ACh-induced current (I (ACh)) were inward, but no occlusion was observed when these currents were outward at a V (h) of +40 mV. The I (ATP) was not inhibited by co-application of ACh when the I (ACh) was markedly decreased either by removal of permeant cations, by setting V (h) close to the equilibrium potential of I (ACh), or by the addition of d-tubocurarine or serotonin. These results suggest that the inhibitory interaction is attributable to inward current flow of cations through the activated P2XR- and nAChR-channels.
| S-EPMC2096647 | biostudies-other
Project description:BackgroundCentral nervous system (CNS)-mediated symptoms, such as fatigue, depression, and hyperalgesia, are common complications among patients with rheumatoid arthritis (RA). However, it remains unclear how the peripheral pathology of RA spreads to the brain. Accumulated evidence showing an association between serum cytokine levels and aberrant CNS function suggests that humoral factors participate in this mechanism. In contrast to the well-known early responses of microglia (CNS-resident immune cells) in the area postrema [AP; a brain region lacking a blood-brain barrier (BBB)] to experimental inflammation, microglial alterations in the AP during chronic inflammation like RA remain unclear. Therefore, to determine whether microglia in the AP can react to persistent autoimmune-arthritis conditions, we analyzed these cells in a mouse model of collagen-induced arthritis (CIA).MethodsMicroglial number and morphology were analyzed in the AP of CIA and control mice (administered Freund's adjuvant or saline). Immunostaining for ionized calcium-binding adaptor molecule-1 was performed at various disease phases: "pre-onset" [post-immunization day (PID) 21], "establishment" (PID 35), and "chronic" (PID 56 and 84). Quantitative analyses of microglial number and morphology were performed, with principal component analysis used to classify microglia. Interleukin-1β (IL-1β) mRNA expression was analyzed by multiple fluorescent in situ hybridization and real-time polymerase chain reaction. Behavioral changes were assessed by sucrose preference test.ResultsMicroglia in the AP significantly increased in density and exhibited changes in morphology during the establishment and chronic phases, but not the pre-onset phase. Non-subjective clustering classification of cell morphology (CIA, 1,256 cells; saline, 852 cells) showed that the proportion of highly activated microglia increased in the CIA group during establishment and chronic phases. Moreover, the density of IL-1β-positive microglia, a hallmark of functional activation, was increased in the AP. Sucrose preferences in CIA mice negatively correlated with IL-1β expression in brain regions containing the AP.ConclusionsOur findings demonstrate that microglia in the AP can sustain their activated state during persistent autoimmune arthritis, which suggests that chronic inflammation, such as RA, may affect microglia in brain regions lacking a BBB and have various neural consequences.
| S-EPMC8556992 | biostudies-literature
Project description:ObjectiveAdult neurogenesis in the subgranular zone and subventricular zone is generally accepted, but its existence in other brain areas is still controversial. Circumventricular organs, such as the area postrema (AP) have recently been described as potential neurogenic niches in the adult brain. The AP is the major site of action of the satiating hormone amylin. Amylin has been shown to promote the formation of neuronal projections originating from the AP in neonatal rodents but the role of amylin in adult neurogenesis remains unknown.MethodsTo test this, we first performed an RNA-sequencing of the AP of adult rats acutely injected with either amylin (20 μg/kg), amylin plus the amylin receptor antagonist AC187 (500 μg/kg) or vehicle. Second, animals were subcutaneously equipped with minipumps releasing either amylin (50 μg/kg/day) or vehicle for 3 weeks to assess cell proliferation and differentiation with the 5'-bromo-2-deoxyuridine (BrdU) technique.ResultsAcute amylin injections affected genes involved in pathways and processes that control adult neurogenesis. Amylin consistently upregulated NeuroD1 transcript and protein in the adult AP, and this effect was blocked by the co-administration of AC187. Further, chronic amylin treatment increased the number of newly proliferated AP-cells and significantly promoted their differentiation into neurons rather than astrocytes.ConclusionOur findings revealed a novel role of the satiating hormone amylin in promoting neurogenesis in the AP of adult rats.
| S-EPMC5034493 | biostudies-literature
Project description:To identify LPS activated cell types in the NTS and AP we region we used single-nuclei RNA seq comparing baseline cell types and cell types labeled using the TRAP2 mouse line crossed to the INTACT mouse line after labeling during LPS treatment.
2022-06-18 | GSE206144 | GEO
Project description:Amylin is a pancreatic β-cell hormone that acts as a satiating signal to inhibit food intake by binding to amylin receptors (AMYs) and activating a specific neuronal population in the area postrema (AP). AMYs are heterodimers that include a calcitonin receptor (CTR) subunit [CTR isoform a or b (CTRa or CTRb)] and a member of the receptor activity-modifying proteins (RAMPs). Here, we used single-cell quantitative polymerase chain reaction to assess co-expression of AMY subunits in AP neurons from rats that were injected with amylin or vehicle. Because amylin interacts synergistically with the adipokine leptin to reduce body weight, we also assessed the co-expression of AMY and the leptin receptor isoform b (LepRb) in amylin-activated AP neurons. Single cells were collected from Wistar rats and from transgenic Fos-GFP rats that express green fluorescent protein (GFP) under the control of the Fos promoter. We found that the mRNAs of CTRa, RAMP1, RAMP2 and RAMP3 were all co-expressed in single AP neurons. Moreover, most of the CTRa+ cells co-expressed more than one of the RAMPs. Amylin down-regulated RAMP1 and RAMP3 but not CTR mRNAs in AMY+ neurons, suggesting a possible negative feedback mechanism of amylin at its own primary receptors. Interestingly, amylin up-regulated RAMP2 mRNA. We also found that a high percentage of single cells that co-expressed all components of a functional AMY expressed LepRb mRNA. Thus, single AP cells expressed both AMY and LepRb, which formed a population of first-order neurons that presumably can be directly activated by amylin and, at least in part, also by leptin.
| S-EPMC10704335 | biostudies-literature