Generation of Locus Coeruleus Norepinephrine Neurons from Human Pluripotent Stem Cells [snRNA-seq]
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PROVIDER: PRJNA917198 | ENA |
REPOSITORIES: ENA
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Project description:Central norepinephrine (NE) neurons, mainly located in the Locus coeruleus (LC), play roles in a wide range of behavioral and physiological processes. How the human LC-NE neurons develop and what roles they play in the pathophysiology of human diseases is poorly understood, partly due to the unavailability of functional human LC-NE neurons. Here we established a technology for efficient generation of LC-NE neurons from human pluripotent stem cells by identifying a novel role of ACTIVIN A in regulating the LC-NE transcription factors in the dorsal rhombomere 1 (r1) progenitors. The in vitro generated human LC-NE neurons not only display extensive axonal arborization and release/uptake NE, but also exhibit the pacemaker activity, calcium oscillation, and in particular chemoreceptor activity in response to CO2. Multiple timepoint single nucleus RNA-Seq (snRNA-Seq) analysis captured the dynamic NE differentiation process, confirmed the NE cell population and revealed the differentiation trajectory from hindbrain progenitors to NE neurons via ASCL1 expressing precursor stage. The LC-NE neurons engineered with a NE sensor reliably reported the extracellular NE level. The availability of functional human LC-NE neurons enables investigation of their roles in the pathogenesis of and development of therapeutics for neural psychiatric and degenerative diseases.
2023-08-24 | GSE221988 | GEO
Project description:Children exposed to cocaine during gestation have a higher incidence of neurobehavioral deficits. The neurochemical bases of these deficits have not been determined, but the pharmacology of cocaine and the nature of the abnormalities suggest that disruptions in catecholaminergic systems may be involved. In the current study, we used a rat model of prenatal cocaine exposure to examine the impact that this exposure has on the locus coeruleus (LC) noradrenergic system in offspring. Pregnant rats received twice-daily i.v. injections of cocaine (3 mg/kg) or saline between gestational days 10 and 20, and progeny were tested as juveniles. Exposure to a mild stressor elevated an index of norepinephrine turnover in the prefrontal cortex and also increased Fos expression in tyrosine hydroxylase-positive LC neurons in rats exposed to prenatal cocaine but not in rats exposed to prenatal saline. No change in the number of tyrosine hydroxylase-positive neurons in the LC was observed between the two prenatal treatment groups. Specific binding of [125I]-para-iodoclonidine, a radioligand with specificity for high affinity alpha2A-adrenergic receptors, was decreased in the LC of rats exposed to prenatal cocaine compared with prenatal saline controls. As alpha2-adrenergic receptors on LC norepinephrine neurons function as autoreceptors, their down-regulation by prenatal cocaine exposure provides a plausible mechanism for the observed heightened reactivity of norepinephrine neurons in these animals. These data indicate that prenatal cocaine exposure results in lasting changes to the regulation and responsivity of rat LC norepinephrine neurons. A similar dysregulation of LC norepinephrine neurons may occur in children exposed to cocaine during gestation, and this may explain, at least partly, the increased incidence of cognitive deficits that have been observed in these subjects.
| S-EPMC2855228 | biostudies-literature
Project description:The endocannabinoid (eCB) system has been implicated in a variety of physiological functions due to abundant expression of its receptors and endogenous ligands in the central nervous system. Substantial progress has been made in understanding how the eCB system influences the brain norepinephrine (NE) system, an important neurochemical target in the continued development of new therapies for stress-induced psychiatric disorders. We, and others, have characterized the neuroanatomical, biochemical and pharmacological effects of cannabinoid receptor modulation on brain noradrenergic circuitry and defined how molecular elements of the eCB system are positioned to directly impact the locus coeruleus (LC)-prefrontal cortex pathway, a neural circuit well recognized for contributing to symptoms of hyperarousal, a key pathophysiological feature of stress-related disorders. We also described molecular and electrophysiological properties of LC noradrenergic neurons and NE release in the medial prefrontal cortex under conditions of cannabinoid type 1 receptor deletion. Finally, we identified how stress influences cannabinoid modulation of the coeruleo-cortical pathway. A number of significant findings emerged from these studies that will be summarized in the present review and have important implications for clinical studies targeting the eCB system in the treatment of stress-induced psychiatric disorders.
| S-EPMC6582240 | biostudies-literature
Project description:The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease
| PRJNA914251 | ENA
Project description:A defining feature of sleep is reduced responsiveness to external stimuli, but the mechanisms mediating sensory-evoked arousal remain unclear. We hypothesized that reduced locus coeruleus (LC) norepinephrine (NE) activity during sleep mediates unresponsiveness, and its action promotes sensory-evoked awakenings. We tested this using electrophysiological, behavioral, pharmacological, and optogenetic techniques alongside auditory stimulation in freely behaving rats. We found that systemic reduction in NE signaling lowered probability of sound-evoked awakenings (SEAs). The level of tonic LC activity during sleep anticipated SEAs. Optogenetic LC activation promoted arousal as evident in sleep-wake transitions, EEG desynchronization, and pupil dilation. Minimal LC excitation before sound presentation increased SEA probability. Optogenetic LC silencing using a soma-targeted anion-conducting channelrhodopsin (stGtACR2) suppressed LC spiking and constricted pupils. Brief periods of LC opto-silencing reduced the probability of SEAs. Thus, LC-NE activity determines the likelihood of sensory-evoked awakenings, and its reduction during sleep constitutes a key factor mediating behavioral unresponsiveness.
| S-EPMC7141817 | biostudies-literature
Project description:Purpose: The locus coeruleus (LC) is a small nucleus in the pons, with norepinephrine (NE) as its major transmitter. It plays key roles in wakefulness and is associated with disorders like depression. The study aims to analyze single-cell RNA-seq data to subdivide neurons in the LC and chart their neuropeptide, co-transmitter, and receptor profiles. It also seeks to build a precise map of galanin and its receptors in the mouse LC, and understand the role of neuropeptide expression and signaling. Results: The study identified 24 clusters in total, with 3 NE, 17 glutamate, and 5 GABA subtypes. NE neurons expressed at least 19 neuropeptide transcripts, mainly galanin (Gal) but not Npy, and >30 neuropeptide receptors. Among galanin receptors, Galr1 was expressed in ~19% of NE neurons, and highly expressed in GABA neurons surrounding the NE ensemble. Patch-clamp electrophysiology and cell-type-specific Ca2+-imaging using GCaMP6s revealed that a GalR1 agonist inhibits no more than ~35% of NE neurons, with the effect being direct and not relying on feed-forward GABA inhibition. Conclusions: The results define a role for the galanin system in NE functions and provide a conceptual framework for the action of many other peptides and their receptors. The study found that most NE neurons express mRNA transcripts for galanin, at least 19 neuropeptides (but not Npy), and >30 neuropeptide receptors, including Galr1 at low levels. Selective activation of GalR1 inhibited the spontaneous activity of a subset of NE neurons possibly through the activation of Kv currents. These findings offer new insights into the role of neuropeptide expression and signaling in mouse LC.
2023-07-03 | GSE236349 | GEO
Project description:The unusually high demand for metals in the brain, along with insufficient understanding of how their dysregulation contributes to neurological diseases, motivates the study of how inorganic chemistry influences neural circuitry. We now report that the transition metal copper is essential for regulating rest-activity cycles and arousal. Copper imaging and gene expression analysis in zebrafish identifies the locus coeruleus-norepinephrine (LC-NE) system, a vertebrate-specific neuromodulatory circuit critical for regulating sleep, arousal, attention, memory and emotion, as a copper-enriched unit with high levels of copper transporters CTR1 and ATP7A and the copper enzyme dopamine ?-hydroxylase (DBH) that produces NE. Copper deficiency induced by genetic disruption of ATP7A, which loads copper into DBH, lowers NE levels and hinders LC function as manifested by disruption in rest-activity modulation. Moreover, LC dysfunction caused by copper deficiency from ATP7A disruption can be rescued by restoring synaptic levels of NE, establishing a molecular CTR1-ATP7A-DBH-NE axis for copper-dependent LC function.
| S-EPMC6008210 | biostudies-literature
Project description:Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer's disease-like (AD-like) neuropathology in the human brain. However, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively in noradrenergic neurons by monoamine oxidase A metabolism of norepinephrine, activated asparagine endopeptidase that cleaved Tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of Tau pathology. Activation of asparagine endopeptidase-cleaved Tau aggregation in vitro and in intact cells was triggered by 3,4-dihydroxyphenylglycolaldehyde, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal that norepinephrine metabolism and Tau cleavage represent the specific molecular mechanism underlying the selective vulnerability of LC neurons in AD.
| S-EPMC6934194 | biostudies-literature