Cholinergic stress signals accompany microrna-associated stereotypic behavior and glutamatergic neuromodulation in the prefrontal cortex

Gilli Moshitzky, Shai Shoham, Nimrod Madrer, Amir Mouhammed Husain, David S. Greenberg, Raz Yirmiya, Yoram Ben-Shaul, Hermona Soreq*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageAmerican English
Article number848
Issue number6
StatePublished - Jun 2020

Bibliographical note

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.


  • Acetylcholinesterase
  • Cholinergic
  • Glutamatergic
  • Hippocampus
  • MicroRNAs
  • Motor control
  • Prefrontal cortex
  • Stereotypic behavior


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