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MicroRNA-34 Contributes to the Stress-related Behavior and Affects 5-HT Prefrontal/GABA Amygdalar System through Regulation of Corticotropin-releasing Factor Receptor 1

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A Correction to this article was published on 10 December 2019

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Abstract

Recent studies show that microRNA-34 (miR-34) family is critical in the regulation of stress response also suggesting that it may contribute to the individual responsiveness to stress. We have recently demonstrated that mice carrying a genetic deletion of all miR-34 isoforms (triple knockout, TKO) lack the stress-induced serotonin (5-HT) and GABA release in the medial prefrontal cortex (mpFC) and basolateral amygdala (BLA), respectively. Here, we evaluated if the absence of miR-34 was also able to modify the stress-coping strategy in the forced swimming test. We found that the blunted neurochemical response to stress was associated with lower levels of immobility (index of active coping behavior) in TKO compared to WT mice. Interestingly, among the brain regions mostly involved in the stress-related behaviors, the miR-34 displayed the strongest expression in the dorsal raphe nuclei (DRN) of wild-type (WT) mice. In the DRN, the corticotropin-releasing factor receptors (CRFR) 1 and 2, contribute to determine the stress-coping style and the CRFR1 is a target of miR-34. Thus, we hypothesized that the miR-34-dependent modulation of CRFR1 expression may be involved in the DRN regulation of stress-coping strategies. In line with this hypothesis, we found increased CRFR1 levels in the DNR of TKO compared to WT mice. Moreover, infusion of CRFR1 antagonist in the DRN of TKO mice reverted their behavioral and neurochemical phenotype. We propose that miR-34 modulate the mpFC 5-HT/BLA GABA response to stress acting on CRFR1 in the DRN and that this mechanism could contribute to determine individual stress-coping strategy.

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  • 10 December 2019

    The original version of this article unfortunately contained a mistake in Figure 3. The drawing superimposed on photomicrographs to identify the region of Dorsal raph�� Nuclei was inappropriately positioned. The corrected figure is given below.

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Acknowledgements

miR-34 KO mice were kindly provided by Dr. Andrea Ventura (Memorial Sloan Kettering Cancer Center, NY, USA).

Funding

This research was supported by SIR “RBSI14G1HH”, Italian Ministry of Education, Universities and Research (MIUR); and Ateneo 2015, Sapienza University of Rome “C26A15S53E”.

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Authors and Affiliations

  1. Department of Psychology and “Daniel Bovet” Center, “La Sapienza” University, Piazzale Aldo Moro 5, 00181, Rome, Italy

    Diego Andolina, Matteo Di Segni, Alessandra Accoto, Luisa Lo Iacono, Stefano Puglisi-Allegra & Rossella Ventura

  2. Santa Lucia Foundation, European Center for Brain Research, Via del Fosso di Fiorano 64, 00143, Rome, Italy

    Diego Andolina, Matteo Di Segni, Alessandra Accoto, Luisa Lo Iacono, Antonella Borreca, Donald Ielpo, Nicola Berretta, Stefano Puglisi-Allegra & Rossella Ventura

  3. CNR -Institute of Cell Biology and Neurobiology, Rome, Italy

    Antonella Borreca

  4. Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo Scalo, Rome, Italy

    Emerald Perlas

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  1. Diego Andolina
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Fig. A1

Genotyping protocol (a) and miR-34a and c expression in dorsal raphe nuclei in WT and TKO mice (b) (GIF 56 kb)

High resolution image (TIFF 33976 kb)

Fig. A2

Representative photomicrograph showing the injection sites in the dorsal raphe nuclei (DRN) (GIF 1408 kb)

High resolution image (TIFF 1136 kb)

Fig. A3

Effects of the genotype (WT n = 4; TKO n = 4) on CRFR2 levels in dorsal raphe nuclei (DRN). Detection of CRFR2 and tubulin (used as loading control) (upper line) and relative histogram (lower line). Data are shown as relative ratio ± SE (GIF 16 kb)

High resolution image (EPS 10846 kb)

Fig. A4

CRFR2 immunoreactivity in the dorsal raphe nuclei (DRN) of WT and TKO mice. Atlas diagrams reprinted from Franklin and Paxinos (Franklin and Paxinos 2004) indicating representative images of the DRN (a). Histogram of densitometric values of CRFR2 immunofluorescence expressed as mean fluorescence of individual cells normalized to total cellular surface (F/A) of WT (n = 7) and TKO (n = 7) mice. Data are reported as means ± SE (b). Triple-595 labeled confocal images of DAPI staining (blue), Serotonin (5-HT) (yellow), CRFR2 (red) plus merged of DRN (c) (GIF 40 kb)

High resolution image (EPS 24384 kb)

Fig. A5

Effects of dorsal raphe nuclei (DRN) infusion of the artificial cerebrospinal fluid (CSF, (WT n = 4; TKO n = 4)), CRF 50 ng in WT (n = 4) or NBI 35965 4.4 ng in TKO (n = 4) on distance moved (cm) in the locomotor activity test (GIF 8 kb)

High resolution image (EPS 82 kb)

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Andolina, D., Di Segni, M., Accoto, A. et al. MicroRNA-34 Contributes to the Stress-related Behavior and Affects 5-HT Prefrontal/GABA Amygdalar System through Regulation of Corticotropin-releasing Factor Receptor 1. Mol Neurobiol 55, 7401–7412 (2018). https://doi.org/10.1007/s12035-018-0925-z

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