Table 2 Characteristics of the animal studies.
Study | Disease model | Animal description | n | Groups | Behavioral test | Measure Timing of the EFs | MicroRNA model | Tissue analyzed/manipulated |
|---|---|---|---|---|---|---|---|---|
Berchenko [115] | AD: stereotactic administration of aggregated Aβ40 Human in hippocampus. | Male, 15-16 months rats | 33 | Experimental group (n = 17), comparison group (n = 16) | Novel object recognition | Baseline, 5–6 days after intrahippocampal Aβ40 aggregates administration, 8–9 days after intranasal miR administration. | Experimental group: Intranasal administration of liposomal miR-101 for 10 days. Control group: No intervention. | Hippocampus |
Chu [119] | Intoxication: Administration of PS NPs. | Male, 5-week-old, C57BL/6 mice | 40 | 4 groups of 10, based on doses: 0, 10, 25, 50 mg/kg of PS NPs | Eight-arm radial maze | After six months of the beginning of trial. | RNA sequencing in PFCs for microRNAs, for two groups: 0 and 50 mg/kg. | PFC |
Diamantopoulou [118] | 22q11.2 deletion: Df(16)A +/− deficiency and Mirta22/Emc10 loss of function | Male, 8-week-old transgenic mice | 60 | Df (16)A + /– and Mirta22 + /–: 16; Mirta22 + /–: 14; Df(16)A + /–: 13; and WT: 17 | T-maze | At 8 weeks | Transgenic mice | mPFC slice |
Fenelon [114] | 22q11.2 deletion: 1.3-Mb chromosomal deficiency on mouse syntenic chromosome 16, [Df(16)A + /− mice]. And heterozygous Dgcr8 mutant mice | Male, 4-6 weeks old, Dgcr8 +/− mutant and wild type mice | NR | NR | Electrophysiology study | NR | Deletion of the Dgcr8 gene | PFC |
Fenelon [113] | 22q11.2 deletion: Df(16)A +/- mice | Male, adult Df(16)A +/- and wildtype mice | 28 | [n = 14 WT, n = 14 Df(16)A +/− ] | Novel object recognition | NR | Deletion of the Dgcr8 gene | Brain |
Gai [112] | Hypoxia ischemia in neonates: ligation (active) or separation (sham) of common carotid artery at PND7. | Neonatal C57BL/6 J | NR | Sham and active. Active included: ligation + negative control, and ligation + miR mimics. | Y maze test | 28 days after the HI injury | Stereotactic injection of miR-9-5p mimics or negative control (NC) into the lateral ventricle at PND4. | Brain |
Henry [111] | TBI: Controlled cortical impact (CCI) | Male, 10- 12 weeks old, C57Bl/6 J mice | >10 | Study 1: Sham vs CCI, perfused at 1 h, 24 h, 72 h, and 7 days post-injury. One set for RNA extraction, another only at 7 days for microglia differentiation (n = 6/g). Study 2: CCI mice (n = 5-6/g) plus antagomir or NC injection. Study 3: CCI mice (n = 8/g) with miR-155 antagomir vs NC. Study 4: CCI continuous infusion vs NC, and sham injured as controls. Study 5: CCI mice (n = 12–15/g) plus delayed infusion vs NC | Y maze test | 7 days post injury (PID7, “acute”), and PID11 (“chronic”) | Acute intracerebral ventricular (ICV) administration: Injection of miR-155 antagomir or negative control (artificial cerebrospinal fluid) into the left lateral ventricle 15 min post injury. Delayed continuous ICV administration: Immediately prior to CCI, the right lateral ventricle was stereotaxically perforated. 24 h after injury, the infusion cannula was connected to a mini-osmotic pump implanted behind the scapula. Osmotic pumps were primed for ~8 h prior to implantation and were filled with miR-155 antagomir (0.5 nmol/day) or NC, with continuous infusion for 6 days at a rate of 0.5 μl/h. | Cortex and Hippocampus |
Islam [40] | Age-associated memory decline | Male, 12 months-old, C57B/6 J wild‐type mice | 66 | Discovery sample (n = 10). Validation groups: 3-month-old control (n = 18), 16,5-month-old injected with scrambled (n = 18), and 16,5-month-old mice injected with microRNA inhibitors (n = 20) | Morris water maze | At 13.5, 15, 16.5 months | High-throughput Small RNA sequencing and bioinformatic analysis from the blood and brain regions from mice. Stereotactic injection of anti-miR-mix (candidate microRNAs) vs scramble oligonucleotides. | NGS: Blood, ACC, CA1, CA3, and DG regions. Injection: hippocampal CA region |
Kawakita [117] | AD: senescence‑accelerated mouse prone 8 (SAMP8), and senescence‑accelerated mouse resistant 1 (SAMR1) mice as controls. | Male, 5-month-old, 30-40 g, SAMR1 and SAMP8 mice. | 12 | SAMP8 (n = 6/g) and SAMR1 mice (n = 6/g). | Y maze test | 5 months of age | RNA was extracted from the tissue (brainstem) using the miRNeasy Mini Kit (Qiagen, Inc.). Micro arrays were ensembled and expression levels of miRNA were measured with qPCR normalized to sno‑RNA‑202. | Brainstem |
Koh [110] | AD: 5XFAD | 8 months old, B6SJLF1/J (JAX#100012) and 5XFAD transgenic mice | 10–14 | control (n = 5-7) or miR-485-3p ASO (n = 5-7) | Y maze test | Not reported | Intracerebroventricular (ICV) stereotactic injection, of both the miR-485-3p antisense oligonucleotide samples and the NC at 8- or 10-months of age once weekly for 2 weeks. | Brain |
Liu [116] | AD: infusion of Aβ1-42 | Male, Sprague-Dawley rats (200-250 g) | 42 | control (n = 10); AD (n = 12); AD infused with and miR-155 inhibitor (n = 12); AD + miR155 inhibitor scramble (n = 8); and AD and individual PIC receptor inhibitor | Y maze | Two and four weeks after infusion of Ab1-42 | Using intracerebroventricular canulation, miR-155 inhibitor was injected as continuous infusion. | Parietal cortex, hippocampus and amygdala. |
Liu [109] | Age-related cognitive decline | Aged rats, and genetically modified mice | Not reported | Not reported | Delayed Matching-to-Place (DMP) water maze | Not reported | 1) miR-124-3 knockout mice: 2) Overexpression model: stereotactic injection of viral vector with miRNA mimic in both hemispheres. | In rats: Hippocampus and parietal cortex. In mice: systemic effects |
Malmevik [108] | Inhibition of microRNA in hippocampus | Male, 10-weeks old, C57BL/6 mice | 12 | For each miRNA experiment (miR-9 and miR-34), three mice injected with AAV-GFP control (GFP Ctrl) and three mice injected with either AAV-GFP-miR-9sp or –miR-34sp were used. | Custom-made closed plus maze | Two weeks after injection | miRNA inhibition: by intra-hippocampal injections of AAV vector suspensions containing miRNA sponges. Transgenic mice: Transgenic miR.34.T.GFP sensor mice using lentiviral transgenesis, and miR-124.T.GFP and miR-9.T.GFP transgenic mice. | Hippocampi |
Ouchi [107] | 22q11.2 DS: transgenic KO Dgcr8 mice | Male and female 2-month-old, Dgcr8 +/− or -/- mice | 31 | Dgcr8 + /+, n = 10 for males, n = 5 for females; Dgcr8 +/− , n = 10 for males, n = 6 for Females. | Y maze | NR | Deletion of the Dgcr8 genes | Hippocampus |
Qiu [106] | Altered Biogenesis: DICER ablation | Male, 2 months-old VIPCre, Dicerf, and Ai14 mice | Not reported | Not reported | Y maze test | 2 months of age | VIPCre, Dicerf, and Ai14 transgenic mice as reported previously. | Systemic effects |
Sarkar [105] | Cognitive impairment: Transgenic miR-34a +/- mice. | miR-34a + /− mice | Not reported | Not reported | T-maze forced alternation and Y-maze | 49–65 days of continuous NC or doxy exposure, starting at 4 – 4.5 d | Transgenic conditional (tetracycline) overexpressing miR-34a mice. | Entorhinal cortex, hippocampus, PFC and thalamus |
Shan [104] | Intoxication: anesthetics-induced dysfunction | Male, 18 months (aged) Wistar rats | 60 | 1.5% isoflurane, 3% sevoflurane, vehicle gas each for 2 and 4 h. | Y-maze test | Four days after stopping anesthesia (day 8) | Aged rats were exposed to isoflurane, and after perfusion, the expression of miR-190a, miR-190b, miR-31, and miR-30a in one-side whole hippocampus and mPFC were measured with qRT-PCR. | Hippocampus and mPFC |
Toyama [103] | Vascular cognitive impairment: bilateral common carotid artery stenosis (BCAS) surgery | Male, C57BL/6 wild-type mice | 19 (1° cohort), 18 (2° cohort) | 1st cohort: sham (n = 6); scr-miR–treated BCAS [n = 6]; and anti-miR–treated BCAS (n = 7). 2nd cohort: sham (n = 5); scr-miR–treated BCAS (n = 6); and anti-miR treated BCAS [n = 7]). | Y maze test | at 11 weeks old, and 12 weeks old | Intraperitoneal injection of either LNA-anti-miR-501-3p or scrambled miR as control). The concentrations of anti-miR or scrambled miR included both 1 and 10 mg/kg-body weight. A single injection was performed 1 h after BCAS surgery. | White matter and Hippocampus |
Wang [102] | Intoxication: Perinatal fluoride exposure | Both genders, pups of ICR mice | 15 | Pregnant mice receiving: 0, 25, 50, and 100 mg/L NaF until ablactation | 8- arm maze | Trial lasted 7 days, PN day of beginning NR. | Expression levels of two microRNAs were measured using RT-qPCR. | Hippocampus |
Xu [100] | Cognitive impairment: miR-30e over expressing rat. | Male, 4 weeks old, Sprague-Dawley (SD) rats | 40 | 8 in each group: i) Control; ii) lenti-GFP; iii) lenti-miR-30e; iv) lenti-miR-30e plus CG; and v) lenti-miR-30e plus fluoxetine group. | Morris water maze | Rats were 8 weeks old (at the end of drug administration) | Injection of lentivirus containing rat miR-30e into the hippocampal dentate gyrus at a rate of 0.2 µl/min. The rats were allowed to recover for 14 days | Hippocampal dentate gyrus |
Xu [101] | ADHD: spontaneously hypertensive rat (SHR) | male, 4 weeks old, SHR and Wistar Kyoto (WKY) rats | 46 | Four groups: miR-OV (n = 11), NC (n = 11), miR-SH (n = 12), NC-SH (n = 12) | Morris water maze | One week after injection of lentivirus (at 5 weeks old) | Lentiviral vectors were injected into the lateral ventricles stereotactically. | Brain, PFC |
Zhang [99] | Induced aging: Administration of D-galactose | male, 17-week-old male C57BL/6 J mice | 60 | normal (n = 15) control group, D-gal+PBS (n = 15), D-gal+Cell (n = 15), D-gal+Cell-anti-miR-206 (n = 15) | Y-maze | during a 10-day rest period after treatment | miR-206 inhibitors and NC were transfected into hUCMSCs (50 nmol/L). At P5, they were transferred into 6-well plates to a density of 80–90%, and the suspension was injected in the lateral ventricle. | Hippocampus |
Zhu [98] | HIV: ecoHIV infected mice | Male 8–12-week-old C57BL/6 J mice | 6–8 | EcoHIV infected vs controls. In each group two subgroups: PDDC treatment or sham injection. | RAWM | After at least 10 days of daily drug treatment. | Measure of microRNA expression by small RNA sequencing. | PFC and HPC |
