Table 1.
List of miRNAs implicated in affective-like behavior through functional studies in animal models.
| Animal model | Behavioral phenotype | Molecular mechanism | Ref | |
|---|---|---|---|---|
| Serotonin neurotransmission | ||||
| miR-16 | KD of miR-16 in the rat hippocampus with an anti-miR-16. | Antidepressant-like effect in the FST and SPT. | Targets SERT and Bcl-2. Increases hippocampal neurogenesis. | 22 |
| KD of miR-16 by i.c.v. injection of anti-miR-16 in rats. | Depressive-like phenotype in the FST and SPT. | Targets SERT. Decreased serotonin in the CSF. | 23 | |
| miR-34 family | TKO mouse. | Antidepressant-like phenotype in the FST. | Prevents stress-induced release of serotonin in the mPFC. | 42 |
| TKO mouse. | Antidepressant-like phenotype in the FST. | Targets CRFR1. Prevents stress-induced release of serotonin in the mPFC and GABA release in the BLA. | 43 | |
| miR-135a | Overexpression of miR-135a in in serotonergic neurons of the raphe nuclei of mice. | Antidepressant-like phenotype in the FST. | Targets 5-HTR1A and SERT. Increases synaptic serotonin levels. | 44 |
| Glucocorticoid signaling | ||||
| miR-17–92 cluster | cKO mouse of miR-17–92 cluster in adult neural progenitors of the hippocampus. | Depressive-like phenotype in the FST, TST, and SPT. | Targets SGK1. Decreases the number of proliferative progenitors, and newborn neurons in the hippocampal DG. | 58 |
| miR-15 | KD of miR-15a in BLA with a sponge lentivirus. | Anxiety-like phenotype in the elevated plus maze. | Regulated by glucocorticoids and targets FKBP51. | 59 |
| Neurotrophic factors | ||||
| miR-101 | Overexpression of miR-101 in the VLO with a mimic | Antidepressant-like phenotype in the FST and SPT. | Targets DUSP1. | 67 |
| miR-182 | Overexpression of miR-182 in the hippocampus with a lentivirus | Depressive-like phenotype in the FST, SPT, and NSFT. | Targets BDNF. | 73 |
| miR-323 | KD of miR-323 in the mouse Cg1/2 with a sponge AAV. | Antidepressant-like phenotype in the TST. | Targets ErbB4. | 77 |
| Cytoskeletal-regulatory proteins | ||||
| miR-134 | Overexpression in the rat mPFC with an AAV-miR-134. | Depressive-like phenotype in the FST and SPT. | Targets Limk1. Decreases dendritic spine density and synapse number in the vmPFC. | 79 |
| miR-212/132 | tTA::miR-132 transgenic mice. | Moderate overexpression of miR-132 enhanced spatial memory and cognitive capacity in the Barnes maze task and NORT. Supra-physiological level of miR-132 impaired cognition. | Supra-physiological levels of miR-132 increase dendritic spine density in hippocampal neurons. | 102 |
| AChE-R overexpressing TgR mice. | Cognitive impairments in the two-unit serial maze. | Targets AChE. Cholinergic hyper-excitation when exposed to pilocarpine. | 103 | |
| cKO of miR-132/-212 in excitatory neurons of the mouse forebrain. | Cognitive deficits in spatial memory, recognition memory, and in the NORT, Barnes maze, and contextual fear-conditioning tests. | miR-212 targets Stx1a. miR-132 targets Mash1. | 104 | |
| miR-132 transgenic and miR-132/212 knockout mice. | Anxiety-like phenotype in the elevated plus maze and open field assay. | Targets SIRT1 and PTEN. | 105 | |
| miR-218 | Overexpression in the mouse mPFC with an AAV-miR-218. | Antidepressant-like phenotype in the FST and SIT. | Targets DCC. Increases density of dendritic spines the mPFC. | 107 |
| Wnt signaling | ||||
| miR-124 | KD of miR-124 in the rat hippocampus using lentivirus. | Antidepressant-like phenotype in the FST and SPT. | Targets BDNF. | 118 |
| KD of miR-124 in the rat PFC using lentivirus. | Antidepressant-like phenotype in the FST, SPT, and NSFT. | Targets SIRT1. | 119 | |
| KD of miR-124 by i.c.v. injection of an antagomir in mice. | Antidepressant-like phenotype in the TST and SPT. | Targets GR. Increases hippocampal neuron proliferation. | 120 | |
| Overexpression of miR-124 in excitatory hippocampal neurons with an AAV-miR-124 | Antidepressant-like phenotype in the SIT, SPT, and NSFT. | Targets HDAC4/5, and GSK3β. Increases spine density in the DG neurons. | 123 | |
| Overexpression of miR-124 in the mouse hippocampus with a lentivirus. | Antidepressant-like phenotype in the FST, TST, SPT, and SIT. | Targets STAT3. Decreases microglia activation. | 124 | |
| miR-214 | KD of miR-214 by i.c.v. injection of an antagomir in mice. | Antidepressant-like phenotype in the TST and SIT. | Targets β-catenin. Decreases amplitude of mEPSC, and number of dendritic spines in hippocampal neurons. | 125 |
| miR-221 | KD of miR-221 by i.c.v. injection of an antagomir in mice. | Antidepressant-like phenotype in the FST, TST, and SPT. | Targets Wnt-2. Decreases neuronal proliferation and promotes neuronal apoptosis in the hippocampus. | 127 |
| New insights | ||||
| miR-9 | Overexpression of CircDYM in the hippocampus. CircDYM acts as an endogenous sponge of miR-9. | Antidepressant-like phenotype in the FST and TST. | Targets HECTD1. CircDYM overexpression prevented miR-9-induced microglia activation. | 131 |
| miR-139 | KD of miR-139 via intranasal administration of an antagomir in mice. | Antidepressant-like phenotype in the FST, TST, and NSFT. | Increases the number of immature neurons and newborn mature neurons in the mouse hippocampal DG. | 135 |
KD knockdown, 5-HTR1A 5-hydroxytryptamine/serotonin receptor 1A, BDNF brain-derived neurotrophic factor, BLA basolateral amygdala, cKO conditional knockout, CRFR1 corticotropin-releasing factor receptor 1, CSF cerebrospinal fluid, PTEN phosphatase and tensin homolog, DCC deleted in colorectal cancer, DG dentate gyrus, DUSP1 dual-specific phosphatase 1, FKBP51 FK506-binding protein 51, FST forced swim test, GABA γ-aminobutyric acid, GR glucocorticoid receptor, GSK3β glycogen synthase kinase 3 beta, HDAC4/5 histone deacetylase 4/5, HECTD1 HECT domain E3 ubiquitin protein ligase 1, i.c.v. intracerebroventricular, KD knockdown, Limk1 LIM motif-containing protein kinase 1, miRNA or miR microRNA, mPFC medial prefrontal cortex, NORT novel object recognition test, NSFT novelty-suppressed feeding test, SERT serotonin transporter, SGK1 serum- and glucocorticoid-inducible protein kinase-1, SIRT1 sirtuin 1, SIT social interaction test, mEPSC mini excitatory postsynaptic currents, SPT sucrose preference test, STAT3 signal transducer and activator of transcription 3, TKO triple constitutive knockout, TST tail suspension test, VLO ventrolateral orbital cortex, vmPFC ventromedial prefrontal cortex.