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microRNAs Modulate Spatial Memory in the Hippocampus and in the Ventral Striatum in a Region-Specific Manner

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Abstract

MicroRNAs are endogenous, noncoding RNAs crucial for the post-transcriptional regulation of gene expression. Their role in spatial memory formation, however, is poorly explored. In this study, we analyzed learning-induced microRNA expression in the hippocampus and in the ventral striatum. Among miRNAs specifically downregulated by spatial training, we focused on the hippocampus-specific miR-324-5p and the ventral striatum-specific miR-24. In vivo overexpression of the two miRNAs demonstrated that miR-324-5p is able to impair memory if administered in the hippocampus but not in the ventral striatum, while the opposite is true for miR-24. Overall, these findings demonstrate a causal relationship between miRNA expression changes and spatial memory formation. Furthermore, they provide support for a regional dissociation in the post-transcriptional processes underlying spatial memory in the two brain structures analyzed.

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Acknowledgments

The authors would like to thank the colleagues Paola Paggi, Stefano Puglisi-Allegra, and Martine Ammassari-Teule for the useful discussion and the critical suggestions. This study was supported by the CNR grant AGESPAN (A.M., A.R.), Sapienza research grants (A.M., A.R., C.L.), FIRB no. RBIN06E9Z8 (R.N.). VL’s was supported by a grant from Regione Lazio.

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    Authors and Affiliations

    1. Dipartimento di Biologia e Biotecnologie C. Darwin, Sapienza Università di Roma, Rome, Italy

      F. Capitano, J. Camon, V. Ferretti, V. Licursi, F. De Vito, A. Rinaldi, S. Vincenti, C. Mannironi, P. Fragapane, I. Bozzoni, A. Oliverio, R. Negri, C. Presutti & Andrea Mele

    2. Centro di Ricerca in Neurobiologia “D. Bovet”, Sapienza Università di Roma, Rome, Italy

      F. Capitano, J. Camon, V. Ferretti, A. Rinaldi, A. Oliverio & Andrea Mele

    3. Istituto Biologia Cellulare e Neurobiologia, CNR, Rome, Italy

      F. Capitano, J. Camon, V. Ferretti, A. Rinaldi, A. Oliverio & Andrea Mele

    4. Istituto di Biologia e Patologia Molecolari, CNR, Rome, Italy

      C. Mannironi, P. Fragapane & I. Bozzoni

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    F. Capitano, J. Camon and V. Ferretti contributed equally to this work.

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    Supplemental figure 1

    Spatial training specific miRNAs expression in the HPC and VS. a. Mice trained in the hidden (spatial) and in the visible (cue) platform version of the water maze show similar learning curves, progressively decreasing the path length to reach the platform over subsequent sessions. Path length in vehicle and scramble intra-HPC administered mice is expressed as mean distance (cm) of 3 subsequent trials ± S.E.M. in training sessions. b. The scatter plot shows miRNAs relative change in the hippocampus and c. in the ventral striatum, expressed as log2 ratio, spatial - (vs. naïve controls), plotted against cue-trained (vs. naïve controls). (GIF 144 kb)

    High Resolution Image (EPS 1454 kb)

    Supplemental figure 2

    Intra-HPC and intra-VS scramble miRNA infusions do not affect spatial memory. In the top panels is represented the experimental procedure. a. Mice administered pre-training intra-HPC with either PBS or scramble-mimic show similar learning curve and similar memory for platform location on probe test, 24 hrs after training. Path length in vehicle and scramble intra-HPC administered mice is expressed as mean distance (cm) of 3 subsequent trials ± S.E.M. in training sessions (ANOVA for treatment: F1,18 = 0.46, p = 0.5; sessions F5,90 = 8.6, p < 0.0001; training X sessions F5,90 = 0.51, p = 0.77). Quadrants preference is expressed as time (seconds) ± S.E.M. spent in the four different quadrants. ANOVA for treatment F1,18 = -0.05, p = 1; quadrants F3,54 = 26.73, p < 0.0001; treatment X quadrants F3,54 = 0.71; p = 0.55. * p < 0.05 correct quadrant vs. others. b. Mice administered pre-training intra-VS with either PBS or scramble-mimic show similar learning curve and similar memory for platform location on probe test, 24 hrs after training. Path length in vehicle and scramble intra-VS administered mice is expressed as mean distance (cm) of 3 subsequent trials ± S.E.M. in training sessions (ANOVA for treatment: F1,20 = 2.02, p = 0.17; sessions F5,100 = 17.24, p < 0.0001; training X sessions F5,100 = 0.26, p = 0.93). Quadrants preference is expressed as time (seconds) ± S.E.M. spent in the four different quadrants. ANOVA for treatment F1,20 = 0.11, p = 0.75; quadrants F3,60 = 22.74, p < 0.0001; treatment X quadrants F3,60 = 0.04; p = 0.99. * p < 0.05 correct quadrant vs. others. (GIF 248 kb)

    High Resolution Image (EPS 1166 kb)

    Supplemental figure 3

    MicroRNAs over-expression in the hippocampus and in the ventral striatum does not affect mice performance during training. a-b. Mice administered with the miR-324-5p-mimic or scramble in the HPC (a) or in the VS (b) show similar performance during learning. Path length is expressed as mean distance (cm) of three subsequent trials ± S.E.M. (HPC: ANOVA for treatment F1,17 = 0.54, p = 0.47; for session F5,85 = 5.99, p < 0.0001; treatment X session F5,85 = 0.57, p = 0.72. VS: ANOVA for treatment F1,18 = 0.11, p = 0.74; for session F5,90 = 11.13, p < 0.0001; treatment X session F5,90 = 0.53, p = 0.74). c-d. Mice administered intra-HPC (c) or intra-VS (d) with miR-24-mimic, have similar performance during training sessions compared to scramble controls. Path length is expressed as mean distance (cm) of three subsequent trials ± S.E.M. (HPC ANOVA for treatment F1,26 = 3.77, p = 0.063; for session F5,130 = 5.36, p = 0.0002; treatment X session F5,130 = 0.514, p = 2.56. VS ANOVA for treatment F1,20 = 3.26, p = 0.086; for session F5,100 = 12.14, p < 0.0001; treatment X session F5,100 = 1.2, p = 0.31). (GIF 53 kb)

    High Resolution Image (EPS 310 kb)

    Supplemental figure 4

    Schematic drawing from Franklin and Paxinos (1997) of coronal sections and anteroposterior coordinates relative to bregma from HPC- and VS-infused animals in the different experiments. Each symbol represents the approximate cannula placement. a. Intra-HPC miR-324-5p-mimic infusions. Squares: PBS; triangles: scramble circles: miR-324-5p-mimic. b. Intra-VS miR-324-5p-mimic infusions. Squares: pbs; triangles: scramble; circles: miR- 324-5p-mimic. c. Intra-HPC miR-24-mimic infusions. Squares: PBS; triangles: scramble; circles: miR-24-mimic. d. Intra-VS miR-24-mimic infusions. Squares: PBS; triangles: scramble; circles: miR-24-mimic. (GIF 317 kb)

    High Resolution Image (EPS 1156 kb)

    Supplementary Table S1

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    Capitano, F., Camon, J., Ferretti, V. et al. microRNAs Modulate Spatial Memory in the Hippocampus and in the Ventral Striatum in a Region-Specific Manner. Mol Neurobiol 53, 4618–4630 (2016). https://doi.org/10.1007/s12035-015-9398-5

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