MicroRNAs: a potential interface between the circadian clock and human health

The biochemical activity of a stunning diversity of cell types and organ systems is shaped by a 24-hour (circadian) clock. This rhythmic drive to a good deal of the transcriptome (up to 15% of all coding genes) imparts circadian modulation over a wide range of physiological and behavioral processes (from cell division to cognition). Further, dysregulation of the clock has been implicated in the pathogenesis of a large and diverse array of disorders, such as hypertension, cancer and depression. Indeed, the possibility of utilizing therapeutic approaches that target clock physiology (that is, chronotherapy) has gained broad interest. However, a deeper understanding of the underlying molecular mechanisms that modulate the clock, and give rise to organ-specific clock transcriptomes, will be required to fully realize the power of chronotherapies. Recently, microRNAs have emerged as significant players in circadian clock timing, thus raising the possibility that clock-controlled microRNAs could contribute to disorders of the human circadian timing system. Here, we highlight recent work revealing a key role for microRNAs in clock physiology, and discuss potential approaches to unlocking their utility as effectors of circadian physiology and pathophysiology

The miR-132/212 locus: a complex regulator of neuronal plasticity, gene expression and cognition

The microRNA (miRNA) class of small (typically 22-24 nt) non-coding RNA affects a wide range of physiological processes in the mammalian central nervous system (CNS). By acting as potent regulators of mRNA translation and stability, miRNAs fine-tune the expression of a multitude of genes that play critical roles in complex cognitive processes, including learning and memory. Of note, within the CNS, miRNAs can be expressed in an inducible, and cell-type specific manner. Here, we provide a brief overview of the expression and functional effects of the miR-132/212 gene locus in forebrain circuits of the CNS, and then discuss a recent publication that explored the contributions of miR-132 and miR-212 to cognition and to transcriptome regulation. We also discuss mechanisms by which synaptic activity regulates miR-132/212 expression, how miR-132 and miR-212 affect neuronal plasticity, and how the dysregulation of these two miRNAs could contribute to the development of cognitive impairments

Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome

miR-132 and miR-212 are structurally related microRNAs that have been found to exert powerful modulatory effects within the central nervous system (CNS). Notably, these microRNAs are tandomly processed from the same noncoding transcript, and share a common seed sequence: thus it has been difficult to assess the distinct contribution of each microRNA to gene expression within the CNS. Here, we employed a combination of conditional knockout and transgenic mouse models to examine the contribution of the miR-132/-212 gene locus to learning and memory, and then to assess the distinct effects that each microRNA has on hippocampal gene expression. Using a conditional deletion approach, we show that miR-132/-212 double-knockout mice exhibit significant cognitive deficits in spatial memory, recognition memory, and in tests of novel object recognition. Next, we utilized transgenic miR-132 and miR-212 overexpression mouse lines and the miR-132/-212 double-knockout line to explore the distinct effects of these two miRNAs on the transcriptional profile of the hippocampus. Illumina sequencing revealed that miR-132/-212 deletion increased the expression of 1138 genes; Venn analysis showed that 96 of these genes were also downregulated in mice overexpressing miR-132. Of the 58 genes that were decreased in animals overexpressing miR-212, only four of them were also increased in the knockout line. Functional gene ontology analysis of downregulated genes revealed significant enrichment of genes related to synaptic transmission, neuronal proliferation, and morphogenesis, processes known for their roles in learning, and memory formation. These data, coupled with previous studies, firmly establish a role for the miR-132/-212 gene locus as a key regulator of cognitive capacity. Further, although miR-132 and miR-212 share a seed sequence, these data indicate that these miRNAs do not exhibit strongly overlapping mRNA targeting profiles, thus indicating that these two genes may function in a complex, nonredundant manner to shape the transcriptional profile of the CNS. The dysregulation of miR-132/-212 expression could contribute to signaling mechanisms that are involved in an array of cognitive disorders

Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science

It is well documented that the majority of adults, children and families in need of evidence-based behavioral health interventionsi do not receive them [1, 2] and that few robust empirically supported methods for implementing evidence-based practices (EBPs) exist. The Society for Implementation Research Collaboration (SIRC) represents a burgeoning effort to advance the innovation and rigor of implementation research and is uniquely focused on bringing together researchers and stakeholders committed to evaluating the implementation of complex evidence-based behavioral health interventions. Through its diverse activities and membership, SIRC aims to foster the promise of implementation research to better serve the behavioral health needs of the population by identifying rigorous, relevant, and efficient strategies that successfully transfer scientific evidence to clinical knowledge for use in real world settings [3]. SIRC began as a National Institute of Mental Health (NIMH)-funded conference series in 2010 (previously titled the “Seattle Implementation Research Conference”; $150,000 USD for 3 conferences in 2011, 2013, and 2015) with the recognition that there were multiple researchers and stakeholdersi working in parallel on innovative implementation science projects in behavioral health, but that formal channels for communicating and collaborating with one another were relatively unavailable. There was a significant need for a forum within which implementation researchers and stakeholders could learn from one another, refine approaches to science and practice, and develop an implementation research agenda using common measures, methods, and research principles to improve both the frequency and quality with which behavioral health treatment implementation is evaluated. SIRC’s membership growth is a testament to this identified need with more than 1000 members from 2011 to the present.ii SIRC’s primary objectives are to: (1) foster communication and collaboration across diverse groups, including implementation researchers, intermediariesi, as well as community stakeholders (SIRC uses the term “EBP champions” for these groups) – and to do so across multiple career levels (e.g., students, early career faculty, established investigators); and (2) enhance and disseminate rigorous measures and methodologies for implementing EBPs and evaluating EBP implementation efforts. These objectives are well aligned with Glasgow and colleagues’ [4] five core tenets deemed critical for advancing implementation science: collaboration, efficiency and speed, rigor and relevance, improved capacity, and cumulative knowledge. SIRC advances these objectives and tenets through in-person conferences, which bring together multidisciplinary implementation researchers and those implementing evidence-based behavioral health interventions in the community to share their work and create professional connections and collaborations

The miR-132/212 locus: a complex regulator of neuronal plasticity, gene expression and cognition: DOI: 10.14800/rd.1375

The microRNA (miRNA) class of small (typically 22-24 nt) non-coding RNA affects a wide range of physiological processes in the mammalian central nervous system (CNS). By acting as potent regulators of mRNA translation and stability, miRNAs fine-tune the expression of a multitude of genes that play critical roles in complex cognitive processes, including learning and memory. Of note, within the CNS, miRNAs can be expressed in an inducible, and cell-type specific manner. Here, we provide a brief overview of the expression and functional effects of the miR-132/212 gene locus in forebrain circuits of the CNS, and then discuss a recent publication that explored the contributions of miR-132 and miR-212 to cognition and to transcriptome regulation. We also discuss mechanisms by which synaptic activity regulates miR-132/212 expression, how miR-132 and miR-212 affect neuronal plasticity, and how the dysregulation of these two miRNAs could contribute to the development of cognitive impairments

Transgenic miR132 Alters Neuronal Spine Density and Impairs Novel Object Recognition Memory

Inducible gene expression plays a central role in neuronal plasticity, learning, and memory, and dysfunction of the underlying molecular events can lead to severe neuronal disorders. In addition to coding transcripts (mRNAs), non-coding microRNAs (miRNAs) appear to play a role in these processes. For instance, the CREB-regulated miRNA miR132 has been shown to affect neuronal structure in an activity-dependent manner, yet the details of its physiological effects and the behavioral consequences in vivo remain unclear. To examine these questions, we employed a transgenic mouse strain that expresses miR132 in forebrain neurons. Morphometric analysis of hippocampal neurons revealed that transgenic miR132 triggers a marked increase in dendritic spine density. Additionally, miR132 transgenic mice exhibited a decrease in the expression of MeCP2, a protein implicated in Rett Syndrome and other disorders of mental retardation. Consistent with these findings, miR132 transgenic mice displayed significant deficits in novel object recognition. Together, these data support a role for miR132 as a regulator of neuronal structure and function, and raise the possibility that dysregulation of miR132 could contribute to an array of cognitive disorders

miRNA-132: a dynamic regulator of cognitive capacity

Within the central nervous system, microRNAs have emerged as important effectors of an array of developmental, physiological, and cognitive processes. Along these lines, the CREB-regulated microRNA miR-132 has been shown to influence neuronal maturation via its effects on dendritic arborization and spinogenesis. In the mature nervous system, dysregulation of miR-132 has been suggested to play a role in a number of neurocognitive disorders characterized by aberrant synaptogenesis. However, little is known about the inducible expression and function of miR-132 under normal physiological conditions in vivo. Here, we begin to explore this question within the context of learning and memory. Using in situ hybridization, we show that the presentation of a spatial memory task induced a significant ~1.5-fold increase in miR-132 expression within the CA1, CA3, and GCL excitatory cell layers of the hippocampus. To examine the role of miR-132 in hippocampal-dependent learning and memory, we employ a doxycycline-regulated miR-132 transgenic mouse strain to drive varying levels of transgenic miR-132 expression. These studies revealed that relatively low levels of transgenic miR-132 expression, paralleling the level of expression in the hippocampus following a spatial memory task, significantly enhanced cognitive capacity. In contrast, higher (supra-physiological) levels of miR-132 (>3-fold) inhibited learning. Interestingly, both the impaired cognition and elevated levels of dendritic spines resulting from supra-physiological levels of transgenic miR-132 were reversed by doxycycline suppression of transgene expression. Together, these data indicate that miR-132 functions as a key activity-dependent regulator of cognition, and that miR-132 expression must be maintained within a limited range to ensure normal learning and memory formation

The involvement of micrornas in major depression, suicidal behavior, and related disorders: A focus on miR-185 and miR-491-3p

Major depressive disorders are common and disabling conditions associated with significant psychosocial impairment and suicide risk. At least 3-4 % of all depressive individuals die by suicide. Evidence suggests that small non-coding RNAs, in particular microRNAs (miRNAs), play a critical role in major affective disorders as well as suicide. We performed a detailed review of the current literature on miRNAs and their targets in major depression and related disorders as well as suicidal behavior, with a specific focus on miR-185 and miR-491-3p, which have been suggested to participate in the pathogenesis of major depression and/or suicide. miRNAs play a fundamental role in the development of the brain. Several miRNAs are reported to influence neuronal and circuit formation by negatively regulating gene expression. Global miRNA reduced expression was found in the prefrontal cortex of depressed suicide completers when compared to that of nonpsychiatric controls who died of other causes. One particular miRNA, miR-185, was reported to regulate TrkB-T1, which has been associated with suicidal behavior upon truncation. Furthermore, cAMP response element-binding protein-brain-derived neurotrophic factor pathways may regulate, through miRNAs, the homeostasis of neural and synaptic pathways playing a crucial role in major depression. miRNAs have gained attention as key players involved in nervous system development, physiology, and disease. Further evidence is needed to clarify the exact role that miRNAs play in major depression and related disorders and suicidal behavior. © 2013 Springer Science+Business Media New York

The involvement of micrornas in major depression, suicidal behavior, and related disorders: A focus on miR-185 and miR-491-3p

Major depressive disorders are common and disabling conditions associated with significant psychosocial impairment and suicide risk. At least 3-4 % of all depressive individuals die by suicide. Evidence suggests that small non-coding RNAs, in particular microRNAs (miRNAs), play a critical role in major affective disorders as well as suicide. We performed a detailed review of the current literature on miRNAs and their targets in major depression and related disorders as well as suicidal behavior, with a specific focus on miR-185 and miR-491-3p, which have been suggested to participate in the pathogenesis of major depression and/or suicide. miRNAs play a fundamental role in the development of the brain. Several miRNAs are reported to influence neuronal and circuit formation by negatively regulating gene expression. Global miRNA reduced expression was found in the prefrontal cortex of depressed suicide completers when compared to that of nonpsychiatric controls who died of other causes. One particular miRNA, miR-185, was reported to regulate TrkB-T1, which has been associated with suicidal behavior upon truncation. Furthermore, cAMP response element-binding protein-brain-derived neurotrophic factor pathways may regulate, through miRNAs, the homeostasis of neural and synaptic pathways playing a crucial role in major depression. miRNAs have gained attention as key players involved in nervous system development, physiology, and disease. Further evidence is needed to clarify the exact role that miRNAs play in major depression and related disorders and suicidal behavior. \ua9 2013 Springer Science+Business Media New York