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Cholinergic Stress Signals Accompany MicroRNA-Associated Stereotypic Behavior and Glutamatergic Neuromodulation in the Prefrontal Cortex

1
The Institute of Life Sciences and The Edmond and Lily Safra Center of Brain Science, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
2
Herzog Medical Center, Givat Shaul, P.O. Box 3900, Jerusalem 9103702, Israel
3
Department of Psychology, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
4
Department of Medical Neurobiology, The Institute of Medical Research Israel-Canada, Jerusalem 9112102, Israel
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(6), 848; https://doi.org/10.3390/biom10060848
Received: 5 May 2020 / Revised: 24 May 2020 / Accepted: 28 May 2020 / Published: 3 June 2020
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. View Full-Text
Keywords: acetylcholinesterase; cholinergic; glutamatergic; hippocampus; prefrontal cortex; microRNAs; motor control; stereotypic behavior acetylcholinesterase; cholinergic; glutamatergic; hippocampus; prefrontal cortex; microRNAs; motor control; stereotypic behavior
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MDPI and ACS Style

Moshitzky, G.; Shoham, S.; Madrer, N.; Husain, A.M.; Greenberg, D.S.; Yirmiya, R.; Ben-Shaul, Y.; Soreq, H. Cholinergic Stress Signals Accompany MicroRNA-Associated Stereotypic Behavior and Glutamatergic Neuromodulation in the Prefrontal Cortex. Biomolecules 2020, 10, 848. https://doi.org/10.3390/biom10060848

AMA Style

Moshitzky G, Shoham S, Madrer N, Husain AM, Greenberg DS, Yirmiya R, Ben-Shaul Y, Soreq H. Cholinergic Stress Signals Accompany MicroRNA-Associated Stereotypic Behavior and Glutamatergic Neuromodulation in the Prefrontal Cortex. Biomolecules. 2020; 10(6):848. https://doi.org/10.3390/biom10060848

Chicago/Turabian Style

Moshitzky, Gilli; Shoham, Shai; Madrer, Nimrod; Husain, Amir M.; Greenberg, David S.; Yirmiya, Raz; Ben-Shaul, Yoram; Soreq, Hermona. 2020. "Cholinergic Stress Signals Accompany MicroRNA-Associated Stereotypic Behavior and Glutamatergic Neuromodulation in the Prefrontal Cortex" Biomolecules 10, no. 6: 848. https://doi.org/10.3390/biom10060848

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