Stress regulation of sustained attention and the cholinergic attention system
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ABSTRACT:
PROVIDER: PRJNA619064 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11458800_1.fastq.gz | Fastqsanger.gz | |||
| SRR11458800_2.fastq.gz | Fastqsanger.gz | |||
| SRR11458801_1.fastq.gz | Fastqsanger.gz | |||
| SRR11458801_2.fastq.gz | Fastqsanger.gz | |||
| SRR11458802_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Stress exacerbates symptoms of schizophrenia and attention deficit hyperactivity disorder, which are characterized by impairments in sustained attention. Yet how stress regulates attention remains largely unexplored. Here we investigated whether a 6-day variable stressor (VS) altered sustained attention and the cholinergic attention system in male and female rats. Methods: Sustained attention was tested with the sustained attention task (SAT). Successful performance on SAT relies on the release of acetylcholine (ACh) into the cortex from cholinergic neurons in the nucleus basalis of Meynert (NBM). Thus, we evaluated whether VS altered the morphology of these neurons with a novel approach using Cre-dependent virus in genetically modified ChAT::Cre rats, a species used for this manipulation only. Next, electrochemical recordings measured cortical ACh following VS. Finally, we used RNAseq to identify VS-induced transcriptional changes in the NBM. Results: VS impaired attentional performance in SAT and increased the dendritic complexity of NBM cholinergic neurons in both sexes. NBM cholinergic neurons are mainly under inhibitory control, so this morphological change could increase inhibition on these neurons, reducing downstream ACh release to impair attention. Indeed, VS decreased ACh release in the prefrontal cortex of males. Quantification of global transcriptional changes revealed that, although VS induced many sex-specific changes in gene expression, it increased several signaling molecules in both sexes.
2020-05-01 | GSE147806 | GEO
Project description:BackgroundStress exacerbates symptoms of schizophrenia and attention-deficit/hyperactivity disorder, which are characterized by impairments in sustained attention. Yet how stress regulates attention remains largely unexplored. We investigated whether a 6-day variable stressor altered sustained attention and the cholinergic attention system in male and female rats.MethodsSustained attention was tested with the sustained attention task. Successful performance on the sustained attention task relies on the release of acetylcholine (ACh) into the cortex from cholinergic neurons in the nucleus basalis of Meynert (NBM). Thus, we evaluated whether variable stress (VS) altered the morphology of these neurons with a novel approach using a Cre-dependent virus in genetically modified ChAT::Cre rats, a species used for this manipulation only. Next, electrochemical recordings measured cortical ACh following VS. Finally, we used RNA sequencing to identify VS-induced transcriptional changes in the NBM.ResultsVS impaired attentional performance in the sustained attention task and increased the dendritic complexity of NBM cholinergic neurons in both sexes. NBM cholinergic neurons are mainly under inhibitory control, so this morphological change could increase inhibition on these neurons, reducing downstream ACh release to impair attention. Indeed, VS decreased ACh release in the prefrontal cortex of male rats. Quantification of global transcriptional changes revealed that although VS induced many sex-specific changes in gene expression, it increased several signaling molecules in both sexes.ConclusionsThese studies suggest that VS impairs attention by inducing molecular and morphological changes in the NBM. Identifying mechanisms by which stress regulates attention may guide the development of novel treatments for psychiatric disorders with attention deficits.
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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.
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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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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:PD is the second most common neurodegenerative disease worldwide with growing prevalence. MPTP is a neurotoxin which causes the appearance of Parkinson's disease (PD) pathology. The involvement of the cholinergic system in PD has been identified decades ago and anti-cholinergic drugs were upon the first drugs used for symptomatic treatment of PD. Of note, MPTP intoxication is a model of choice for symptomatic neuroprotective therapies since it have been quite predictive. Mice were exposed to the dopaminergic neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), with or without the protective acetylcholinesterase (AChE-R) variant. Transgenic AChE-S (the synaptic variant), AChE-R (the shorter, protective variant) and FVB/N control mice were included in this study. Two brain regions were examined: the pre-frontal cortex (PFC) and the striatal caudate-putamen (CPu). Each condition (i.e brain region and transgenic variant) was examined on both naive and MPTP-exposed mice. 29 microarrays including hybridizations of control FVB/N PFC, control FVB/N CPu,control S transgenics PFC, control S transgenics CPu, control R transgenics PFC, control R transgenice CPu, MPTP FVB/N PFC, MPTP FVB/N CPu, MPTP S transgenics PFC, MPTP S transgenics CPu, MPTP R transgenics PFC and MPTP R transgenice CPu mRNA.
2012-01-09 | E-GEOD-31458 | biostudies-arrayexpress
Project description:Background: The importance of the brain renin-angiotensin system (RAS) incardiovascular function is well accepted. However, not knowing the precise source ofrenin in the brain has been a limitation towards a complete understanding of how the brainRAS operates. Methods: Highly sensitive in situ hybridization techniques and conditionalknockout mice were used to address the location and function of renin in the brainstem.Results: We identified novel renin-expressing cholinergic neurons in the nucleusambiguus (NuAm), a major vagal cardioinhibitory center in the brainstem. The expressionof RAS genes was relatively abundant in the NuAm, implying that angiotensin II mightmediate an important regulatory role in this nucleus and other regions with neuralconnectivity to the NuAm. Then, we generated conditional knockout mice lacking theclassical renin isoform (Ren-aChAT-KO), specifically in cholinergic neurons. Ablation of Ren-a in cholinergic neurons abrogated renin expression in the NuAm. Moreover, studiesusing radiotelemetry, heart rate variability analyses, and pharmacological approachesrevealed that the parasympathetic nervous system is depressed in Ren-aChAT-KO maleswhile augmented in the Ren-aChAT-KO females. Subsequently, transcriptomic approacheswere used to infer putative genes and signaling pathways regulated by renin within theNuAm. Conclusions: This study revealed that renin in cholinergic neurons plays afundamental role in preserving autonomic balance and cardiovascular homeostasis in asex-dependent manner. These findings define the NuAm as an endogenous, local sourceof renin with biological function and serve as conclusive evidence for the presence andfunctionality of the brain RAS.
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Project description:PD is the second most common neurodegenerative disease worldwide with growing prevalence. MPTP is a neurotoxin which causes the appearance of Parkinson's disease (PD) pathology. The involvement of the cholinergic system in PD has been identified decades ago and anti-cholinergic drugs were upon the first drugs used for symptomatic treatment of PD. Of note, MPTP intoxication is a model of choice for symptomatic neuroprotective therapies since it have been quite predictive. Mice were exposed to the dopaminergic neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), with or without the protective acetylcholinesterase (AChE-R) variant. Transgenic AChE-S (the synaptic variant), AChE-R (the shorter, protective variant) and FVB/N control mice were included in this study. Two brain regions were examined: the pre-frontal cortex (PFC) and the striatal caudate-putamen (CPu). Each condition (i.e brain region and transgenic variant) was examined on both naive and MPTP-exposed mice.
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