Cholinergic stress signals promote microRNA-mediated stereotypic behavior via glutamatergic neuromodulation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA602520 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10919800.fastq.gz | Fastqsanger.gz | |||
| SRR10919801.fastq.gz | Fastqsanger.gz | |||
| SRR10919802.fastq.gz | Fastqsanger.gz | |||
| SRR10919803.fastq.gz | Fastqsanger.gz | |||
| SRR10919804.fastq.gz | Fastqsanger.gz |
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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
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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: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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