Cholinergic stress signals promote microRNA-mediated stereotypic behavior via glutamatergic neuromodulation
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ABSTRACT:
PROVIDER: PRJNA602520 | ENA |
REPOSITORIES: ENA
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Project description:Stereotypic behavior (SB) is common in emotional stress-involved psychiatric disorders and is often attributed to glutamatergic impairments, but the underlying mechanisms are unknown. To challenge the causal involvement of cholinergic neuromodulation in SB, we studied TgR mice with impaired cholinergic transmission due to over-expression of the stress-inducible soluble ‘readthrough’ acetylcholinesterase-R (AChE-R) variant. RNA-sequencing revealed 37 differentially expressed microRNAs in TgR mice hippocampi, 8 of which targeting over 5 human cholinergic-related transcripts each. Further, microarray tests of TgR prefrontal cortices displayed up to 428 long RNA transcripts differentially expressed from those of FVB/N mice, primarily glutamatergic-related mRNA transcripts (P<1x10-3). Suggesting behavioral relevance, TgR brains presented c-fos over-expression at motor behavior-regulating brain regions and immune-labeled AChE-R excess in SB-regulating basal ganglia, limbic brain nuclei and the brain stem. Compatible with this, TgR mice showed impaired organization of behavior, performance errors in a serial maze test, escape-like locomotion and less rearing under changed environmental familiarity/novelty conditions. Our findings attribute stress-induced SB to previously unknown microRNA-mediated perturbation of cholinergic/glutamatergic networks, support malfunctioning hierarchical control of cholinergic signaling as impairing the behavioral inhibitory regulation via glutamatergic neuromodulation and underscore new therapeutic strategies for correcting stereotypic behaviors.
2023-01-21 | GSE144022 | GEO
Project description:Stereotypic behavior (SB) is common in emotional stress-involved psychiatric disorders and is often attributed to glutamatergic impairments, but the underlying molecular mechanisms are unknown. Given the neuro-modulatory role of acetylcholine, we sought behavioral-transcriptomic links in SB using TgR transgenic mice with impaired cholinergic transmission due to over-expression of the stress-inducible soluble 'readthrough' acetylcholinesterase-R splice variant AChE-R. TgR mice showed impaired organization of behavior, performance errors in a serial maze test, escape-like locomotion, intensified reaction to pilocarpine and reduced rearing in unfamiliar situations. Small-RNA sequencing revealed 36 differentially expressed (DE) microRNAs in TgR mice hippocampi, 8 of which target more than 5 cholinergic transcripts. Moreover, compared to FVB/N mice, TgR prefrontal cortices displayed individually variable changes in over 400 DE mRNA transcripts, primarily acetylcholine and glutamate-related. Furthermore, TgR brains presented c-fos over-expression in motor behavior-regulating brain regions and immune-labeled AChE-R excess in the basal ganglia, limbic brain nuclei and the brain stem, indicating a link with the observed behavioral phenotypes. Our findings demonstrate association of stress-induced SB to previously unknown microRNA-mediated perturbations of cholinergic/glutamatergic networks and underscore new therapeutic strategies for correcting stereotypic behaviors.
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Project description:FACS sorted Drosophila Embryo Cultured Neurons allowed to differentiate 3-5 days in culture. Positively sorted samples Keywords = Cholinergic Neurons Keywords: other
2004-07-04 | GSE1047 | GEO
Project description:Basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Down syndrome (DS) and Alzheimer's disease (AD). Current therapeutics in these disorders have been unsuccessful in slowing disease progression, likely due to poorly understood complex pathological interactions and dysregulated pathways. The Ts65Dn trisomic mouse model recapitulates both cognitive and morphological deficits of DS and AD, including BFCN degeneration and has shown lifelong behavioral changes due to maternal choline supplementation (MCS). To test the impact of MCS on trisomic BFCN, we performed laser capture microdissection to individually isolate choline acetyltransferase-immunopositive neurons in Ts65Dn and disomic littermates, in conjunction with MCS at the onset of BFCN degeneration. We utilized single population RNA sequencing (RNA-seq) to interrogate transcriptomic changes within medial septal nucleus (MSN) BFCN. Leveraging multiple bioinformatic analysis programs on differentially expressed genes (DEGs) by genotype and diet, we identified key canonical pathways and altered physiological functions within Ts65Dn MSN BFCN, which were attenuated by MCS in trisomic offspring, including the cholinergic, glutamatergic and GABAergic pathways. We linked differential gene expression bioinformatically to multiple neurological functions, including motor dysfunction/movement disorder, early onset neurological disease, ataxia and cognitive impairment via Ingenuity Pathway Analysis. DEGs within these identified pathways may underlie aberrant behavior in the DS mice, with MCS attenuating the underlying gene expression changes. We propose MCS ameliorates aberrant BFCN gene expression within the septohippocampal circuit of trisomic mice through normalization of principally the cholinergic, glutamatergic, and GABAergic signaling pathways, resulting in attenuation of underlying neurological disease functions.
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Project description:Drug-induced alterations in gene expression play an important role in the development of addictive behavior. Methionine has been proven to inhibit addictive behaviors of cocaine dependence. However, the mechanisms underlying how methionine use corresponds to drug-induced behaviors still remain unclear. We performed mRNA and miRNA high-throughput sequencing of the prefrontal cortex in a mouse model of cocaine CPP combined with L-methionine in order to identify L-methionine target miRNAs and genes that participate in the cocaine conditioned place preference (CPP). We found that the L-methionine inhibits cocaine CPP. Sequencing data analysis showed that L-methionine down-regulates genes enriched in the Glutamatergic Synapse pathways and significantly reversed the cocaine-induced expression changes of the substance dependence pathways (Morphine addiction and Nicotine addiction) and the neurotransmitter synapse pathways (Glutamatergic Synapse, Cholinergic Synapse and GABAergic Synapse). Furthermore, the Glutamatergic synapse was either overlapped between DEGs with DEGs-miRNA induced by cocaine CPP, or with the MET effects on cocaine CPP. Nineteen targeted genes were investigated and five were identified (Gria4, Grid1, Grik4, Grik5 and Grin3a) to belong to iGluR family. Interestingly, there were several miRNAs that had the same sequence which targets the iGluR family: Mmu-miR-30e-50p and mmu-miR-380-5p share UUGAC motif and targets Grik4; mmu-miR-6940-3p and mmu-miR-212-5p both share UGGCU motif which targets Gria4 and Grid1 respectively. Thus, we demonstrated the efficacy of L-methionine in counteracting the effects of cocaine CPP and identified specific genes of synaptic plasticity pathways, especially the Glutamatergic synapse pathway, which is modulated by L-methionine in response to cocaine dependence.
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Project description:The capacity to deal with stress declines during the aging process, and preservation of cellular stress responses is critical to healthy aging. The unfolded protein response of the endoplasmic reticulum (UPRER) is one such conserved mechanism which is critical for the maintenance of several major functions of the ER during stress, including protein folding and lipid metabolism. Hyperactivation of the UPRER by overexpression of the major transcription factor, xbp-1s, solely in neurons drives lifespan extension as neurons send a neurotransmitter-based signal to other tissue to activate UPRER in a non-autonomous fashion. Previous work identified serotonergic and dopaminergic neurons in this signaling paradigm. To further expand our understanding of the neural circuitry that underlies the non-autonomous signaling of ER stress, we activated UPRER solely in glutamatergic, octopaminergic, and GABAergic neurons in C. elegans and paired whole-body transcriptomic analysis with functional assays. We found that UPRER-induced signals from glutamatergic neurons increased expression of canonical protein homeostasis pathways and octopaminergic neurons promoted pathogen response pathways, while minor, but statistically significant changes were observed in lipid metabolism-related genes with GABAergic UPRER activation. These findings provide further evidence for the distinct role neuronal subtypes play in driving the diverse response to ER stress.
2024-06-15 | E-MTAB-14132 | biostudies-arrayexpress
Project description:Neuronal Gene Expression We are interested in genes that determine the neuronal cellular fate and specific neurotransmitter phenotypes of cells in the nervous system. The reasons for our interest are two fold. First, identification of the genetic pathways operating in specific types of neurons could explain why they die in neurodegenerative diseases such as Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis. All of these disorders have in common the property that only certain types of neurotransmitter specific neurons degenerate. Secondly, neuronal cell replacement therapies using differentiated stem cell progeny hold the potential to reverse the devastating consequences of neurodegenerative diseases. The genetic personality of specific kinds of neurons must first be defined in order to use proper cells for neuronal replacement and this information will be essential in directing stem cell differentiation into proper developmental pathways. Our current approach to the problems of specification and neurotransmitter phenotype is to create transgenic animals where different neurotransmitter phenotypes are labeled with a fluorescent reporter gene. Labeled neurons are then isolated using Fluorescence Activated Cell Sorting. The purified populations of neurons are analyzed for their whole genome expression patterns using DNA microarray technology. We have successfully applied this approach using Drosophila cholinergic neurons and are now extending our observations to other classes of neurons that use GABA or glutamate as neurotransmitters. Cholinergic neurons express unique sets of ion channels, receptors and other types of genes. We also see unique sets of transcriptional regulatory proteins, and these may be important in the developmental pathways that result in the production of cholinergic neurons. This SuperSeries is composed of the SubSeries listed below.
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