Tyrosinase-induced neuromelanin accumulation triggers rapid dysregulation and degeneration of the mouse locus coeruleus
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE226827 | GEO | 2023/03/17
REPOSITORIES: GEO
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Project description:To investigate changes in noradrenergic neurons of the LC following treatment with the specific neurotoxin DSP-4. We then performed gene expression profiling analysis using data obtained from RNA-seq of Pre-IP and IP samples following DSP-4 or saline treatment.
2022-12-26 | GSE221404 | GEO
Project description:Aims: This study aimed to identify and characterize the intrinsic properties of locus coeruleus (LC) noradrenergic neurons in male and female mice using a genetic approach. We also sought to investigate sex-specific differences in membrane properties, action potential generation, and protein expression profiles to understand the mechanisms underlying neuronal excitability variations. Methods: Utilizing a genetic mouse model by crossing Dbhcre knock-in mice with tdTomato Ai14 transgenic mice, LC neurons were identified using fluorescence microscopy. Neuronal properties, including capacitance, action potential frequency, and rheobase, were assessed using patch-clamp recordings. Spontaneous and evoked activity between sexes was compared. Proteomic analyses of individual LC neuron soma was conducted using mass-spectrometry to discern protein expression profiles. Results: Female LC noradrenergic neurons displayed greater membrane capacitance than those in male mice. Male LC neurons demonstrated greater spontaneous and evoked action potential generation compared to females. Male LC neurons exhibited a lower rheobase and achieved higher peak frequencies with similar current injections. Proteomic analysis revealed inherent differences in protein expression profiles between sexes, with male mice displaying a notably larger unique protein set compared to females. Notably, pathways pertinent to protein synthesis, degradation, and recycling, such as EIF2 and glucocorticoid receptor signaling, showed reduced expression in females. Conclusions: Male LC noradrenergic neurons exhibit higher intrinsic excitability compared to those from females. The discernible sex-based differences in excitability could be ascribed to varying protein expression profiles, especially within pathways that regulate protein synthesis and degradation. This study lays the groundwork for future studies focusing on the interplay between proteomics and neuronal function examined in individual cells.
2024-05-24 | PXD045844 | Pride
Project description:The locus coeruleus noradrenergic (LC-NA) system plays an important role in organizing a physiological response to acute stress. However, if and how the LC affects stress-mediated transcriptomic changes in the brain is still barely understood. Here, we extensively characterize LC mediated transcriptomic response during acute stress in the hippocampus. Combining for the first time bulk mRNA-sequencing and selective chemogenetic and optogenetic manipulations of the LC-NA system
2023-02-02 | GSE218313 | GEO
Project description:Preclinical work has long focused only on male animals, even though sexual divergence in both baseline behaviors and drug responses clearly impact treatment outcomes in patients. Psychiatric disorders are notably divergent, with males showing higher prevalence of ADHD and ASD, and females GAD and MDD. This divergence is reflected in quantitative differences in subclincal behaviors. The Noradrenergic neurotransmitter system is targeted by many psychiatric drugs, but is relatively uncharacterized at a molecular level. We developed a mouse to profile these neurons, defining their both a baseline transcriptome, including druggable receptors, and their molecular response to stimulation. We also discovered a remarkable sexual divergence in their gene expression, including functionally increased expression of the EP3 receptor in females – a difference that can be used to modulate stress-induced anxiety in a sex specific manner. These findings underscore the need to conduct preclinical studies in a manner balanced for sex, and suggest that baseline differences in noradrenergic neurons could underlay sexually divergent behaviors.
2018-04-30 | GSE100004 | GEO
Project description:Preclinical work has long focused only on male animals, even though sexual divergence in both baseline behaviors and drug responses clearly impact treatment outcomes in patients. Psychiatric disorders are notably divergent, with males showing higher prevalence of ADHD and ASD, and females GAD and MDD. This divergence is reflected in quantitative differences in subclincal behaviors. The Noradrenergic neurotransmitter system is targeted by many psychiatric drugs, but is relatively uncharacterized at a molecular level. We developed a mouse to profile these neurons, defining their both a baseline transcriptome, including druggable receptors, and their molecular response to stimulation. We also discovered a remarkable sexual divergence in their gene expression, including functionally increased expression of the EP3 receptor in females – a difference that can be used to modulate stress-induced anxiety in a sex specific manner. These findings underscore the need to conduct preclinical studies in a manner balanced for sex, and suggest that baseline differences in noradrenergic neurons could underlay sexually divergent behaviors.
2018-04-30 | GSE100002 | GEO
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: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:Cx3cr1CreER-Eyfp/wt mice contain a subset of microglia lacking Cre and EYFP expression. These microglial escape Cre-mediated recombination and gain a repopulation advantage following Cre-driven DTA-mediated microglial depletion.
2022-02-01 | GSE186700 | GEO
Project description:Local protein synthesis has not been believed to occur in adult forebrain axons. We have used translating ribosome affinity purification (TRAP) to capture mRNA from the distal amygdaloid projections of auditory cortical axons. An eYFP-tagged ribosomal protein (rpL10a) was expressed in the adult rat auditory cortex via a lentiviral vector, and rats were given Pavlovian fear conditioning or control training two hours before collection of auditory cortex and amygdala. The eYFP tag alone was used as an IP control. Polysome extraction and eYFP immunoprecipitation were performed according to published protocols (Heiman et al., 2008 Cell 135:78; Kratz et al. 2014 Genome Res. 24:1396).
2019-12-19 | GSE124592 | GEO
Project description:Background: The goal of this study was to determine the transcriptional consequences of norepinephrine transporter (NET) gene deletion in noradrenergic neuron differentiation. The norepinephrine transporter (NET) is the target of powerful mind-altering substances, such as tricyclic antidepressants and the drug of abuse, cocaine. NET function in adult noradrenergic neurons of the peripheral and central nervous systems is that of a scavenger that internalizes norepinephrine from the synaptic cleft. By contrast, norepinephrine (NE) transport has a different role in embryogenesis. It promotes differentiation of neural crest cells and locus ceruleus progenitors into noradrenergic neurons, whereas NET inhibitors, such as the tricyclic antidepressant desipramine and the drug of abuse, cocaine, inhibit noradrenergic differentiation. While NET structure und regulation of NET function is well described, little is known about downstream targets of NE transport. Results: We have determined by long serial analysis of gene expression (LongSAGE) the gene expression profiles of in vitro differentiating wild type and norepinephrine transporter-deficient (NETKO) neural crest derivatives. Comparison analyses with the wild type library (GSM 105765) have identified a number of important differentially expressed genes, including genes relevant to noradrenergic neuron differentiation and to the phenotype of NETKO mice. Furthermore we have identified novel differentially expressed genes. Conclusions: Loss of NET function during embryonic development deregulates signaling pathways that are critically involved in neural crest formation and noradrenergic neuron differentiation. The library was constructed from total RNA of 60 neural crest culture at culture day 7. The neural tubes were dissected from E9.5 embryos that lack the norepinephrine transporter gene.
2008-06-23 | E-GEOD-11788 | biostudies-arrayexpress