Histone methylation is critical for the formation and maintenance of long-term memories. Long noncoding RNAs (lncRNAs) are regulators of histone methyltransferases and other chromatin-modifying enzymes (CMEs), thereby epigenetically modifying gene expression. Here, we investigated how the lncRNA NEAT1 may epigenetically contribute to hippocampus-dependent, long-term memory formation using a combination of transcriptomics, RNA-binding protein immunoprecipitation, CRISPR-mediated gene activation (CRISPRa), and behavioral approaches. Knockdown of the lncRNA Neat1 revealed widespread changes in gene transcription, as well as perturbations of histone 3 lysine 9 dimethylation (H3K9me2), a repressive histone modification mark that was increased in the hippocampus of aging rodents. We identified a NEAT1-dependent mechanism of transcriptional repression by H3K9me2 at the c-Fos promoter, corresponding with observed changes in c-Fos mRNA expression. Overexpression of hippocampal NEAT1 using CRISPRa was sufficient to impair memory formation in young adult mice, recapitulating observed memory deficits in old adult mice, whereas knocking down NEAT1 in both young and old adult mice improved behavior test–associated memory. These results suggest that the lncRNA NEAT1 is an epigenetic suppressor of hippocampus-dependent, long-term memory formation.

A decline in long-term memory (LTM) formation is a common feature of the normal aging process, which corresponds with abnormal expression of memory-related genes in the aged hippocampus. Epigenetic modulation of chromatin structure is required for proper transcriptional control of genes, such as the brain-derived neurotrophic factor (Bdnf) and Zif268 in the hippocampus during the consolidation of new memories. Recently, the view has emerged that aberrant transcriptional regulation of memory-related genes may be reflective of an altered epigenetic landscape within the aged hippocampus, resulting in memory deficits with aging. Here, we found that baseline resting levels for tri-methylation of histone H3 at lysine 4 (H3K4me3) and acetylation of histone H3 at lysine 9 and 14 (H3K9,K14ac) were altered in the aged hippocampus as compared to levels in the hippocampus of young adult rats. Interestingly, object learning failed to increase activity-dependent H3K4me3 and di-methylation of histone H3 at lysine 9 (H3K9me2) levels in the hippocampus of aged adults as compared to young adults. Treatment with the LSD-1 histone demethylase inhibitor, t-PCP, increased baseline resting H3K4me3 and H3K9,K14ac levels in the young adult hippocampus, while young adult rats exhibited similar memory deficits as observed in aged rats. After environmental enrichment (EE), we found that object learning induced increases in H3K4me3 levels around the Bdnf, but not the Zif268, gene region in the aged hippocampus and rescued memory deficits in aged adults. Collectively, these results suggest that histone lysine methylation levels are abnormally regulated in the aged hippocampus and identify histone lysine methylation as a transcriptional mechanism by which EE may serve to restore memory formation with aging.

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The diverse functions of noncoding RNAs (ncRNAs) can influence virtually every aspect of the transcriptional process including epigenetic regulation of genes. In the CNS, regulatory RNA networks and epigenetic mechanisms have broad relevance to gene transcription changes involved in long-term memory formation and cognition. Thus, it is becoming increasingly clear that multiple classes of ncRNAs impact neuronal development, neuroplasticity, and cognition. Currently, a large gap exists in our knowledge of how ncRNAs facilitate epigenetic processes, and how this phenomenon affects cognitive function. In this review, we discuss recent findings highlighting a provocative role for ncRNAs including lncRNAs and piRNAs in the control of epigenetic mechanisms involved in cognitive function. Furthermore, we discuss the putative roles for these ncRNAs in cognitive disorders such as schizophrenia and Alzheimer's disease.

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