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Cholinergic stress signals promote microRNA-mediated stereotypic behavior via glutamatergic neuromodulation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE144022 | GEO | 2023/01/21

REPOSITORIES: GEO

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Project description:Prenatal exposure to synthetic corticosteroids can significantly alter postnatal development through changes in neurotransmitters, peptides and their receptors, and thus having long-lasting behavioral effects. Some of these changes have been observed in animal experiments, others also in humans prenatally exposed to synthetic corticosteroids. Here, we focused on transcriptomic changes within the ARC of rats prenatally exposed to either betamethasone or saline. The expression of transcriptome has been assessed by novel computational tools to determine complex changes that may have life-long effects on phenotype, i.e., behavior. Total of 18,094 unigenes were quantified in the hypothalamic ARC of P14 male and female rats prenatally exposed to betametasone used in this experiment. Out of these genes, Kyoto Encyclopedia for Genes and Genomes (http://www.genome.jp) selected 112 for the dopaminergic synapse, 75 for the GABAergic and 97 for the glutamatergic synapse. We further analyzed composition, topology and modulatory networks of the genomic fabric of the dopaminergic, GABAergic, and glutamatergic synapse (the transcriptome of the most interconnected and stably expressed gene network responsible for specific transmission). Finally we investigated the M-bM-^@M-^\transcriptomic landscapeM-bM-^@M-^] of the GSF in the ARC of P14 males (M) and females (F) prenatally (G15) exposed to betamethasone (B) or saline (S). We combined in one measure (PWR = Pair-Wise Relevance) expression levels, controls and coordination of all pairs that can be formed by synapse genes with the other synapse genes, higher PWRs indicating larger influence of that gene pair to the fabric modulation. We found that prenatal exposure to betamethasone caused sex-dependent changes in the dopaminergic/GABA/glutamatergic synapse genes:. In males, 10 dopaminergic (9%), 4 GABAergic (5%) and 5 glutamatergic synapse genes (5%) were down-regulated. While in females, 9 dopaminergic (8%), 3 GABAergic (4%) and 6 glutamatergic (6%) synapse genes were downregulated. The data indicate that in both sexes the dopaminergic synapse was the most affected. In contrast, in control animals, no significant differences between male and female were present in these synapse genes. Since the most noticeable transcritpomic changes were found in the transcriptome of DA glutamatergic synapse, we investigated the expression of tyrosine-hydroxylase (TH) NMDA receptor subunits in the ARC. The western blot analyses and immunohistochemistry confirmed the sex-specific differences between prenatally betamethasone-exposed and saline-exposed P15 rats. Accordingly to the changes in gene expression, prenatal exposure to synthetic corticosteroids was associated with postnatal changes in behavior and susceptibility to certain types of seizures. While we did not find any significant impairements in normal behavioral patterns (open field activity), there was a sex-specific change in the novel object recognition test. We found that behavioral lateralization in females is lost after prenatal betamethasone exposure and both male and female prenatally betamethasone exposed rats were avoiding novelty. This trait is similar to children with autism and suggests that certain elements of autistic behaviors can be present after prenatal exposure to synthetic corticosteroids. Additionally, there were changes in the search patterns in the Morris water maze as well as in the Barnes maze. In conclusion, our work is consistent with findings of profound reprogramming changes in the brain after prenatal corticosteroid exposure associated with alterations cognitive functions and seizure susceptibility. Two-sexes (M, F) x two-condition (B = betamethasone prenataly exposed vs S = saline prenataly exposed) experiment. Biological replicates: 4 MS, 4 FS, 4 MB, 4 FB.

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Cholinergic stress signals promote microRNA-mediated stereotypic behavior via glutamatergic neuromodulation

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