scholarly journals Mitf links neuronal activity and long-term homeostatic intrinsic plasticity

2018 ◽  
Author(s):  
Diahann A. M. Atacho ◽  
Hallur Reynisson ◽  
Anna Þóra Pétursdóttir ◽  
Thor Eysteinsson ◽  
Eiríkur Steingrímsson ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Neuronal Activity ◽  
Molecular Mechanisms ◽  
Neuronal Response ◽  
Regulatory Elements ◽  
Mutant Mice ◽  
Projection Neurons ◽  
Olfactory Adaptation ◽  
Intrinsic Plasticity

AbstractNeuroplasticity forms the basis for neuronal circuit complexity and can determine differences between otherwise similar circuits. Although synaptic plasticity is fairly well characterized, much less is known about the molecular mechanisms underlying intrinsic plasticity, especially its transcriptional regulation. We show that the Microphthalmia-associated transcription factor (Mitf), best known as the master regulator of melanocytic cell fate and differentiation, plays a central role in homeostatic intrinsic plasticity of olfactory bulb (OB) projection neurons. Mitral and tufted (M/T) neurons from Mitf mutant mice are hyperexcitable due to reduced Type-A potassium current (IA) and they exhibit reduced expression of Kcnd3, which encodes a potassium voltage-gated channel subunit (Kv4.3) important for generating the IA. Furthermore, expression of the Mitf and Kcnd3 genes is activity-dependent in OB projection neurons, The MITF protein binds to and activates expression from Kcnd3 regulatory elements. Activity can therefore affect Kcnd3 expression directly via MITF. Moreover, Mitf mutant mice have changes in olfactory habituation and have increased habitutation for an odourant following long-term exposure, indicating that regulation of Kcnd3 is pivotal for long-term olfactory adaptation. Our findings show that Mitf acts as a direct regulator of intrinsic homeostatic feedback, plays a key role in olfactory adaptation and links neuronal activity, transcriptional changes and neuronal function.Significance statementA direct, Mitf-dependent link between neuronal activity and homeostatic changes in the expression of a key potassium channel subunit is demonstrated in projection neurons of the mouse OB. This is one of the first studies that directly link activity and genetically defined changes in intrinsic plasticity, leading to changes in neuronal response. These findings broaden the general understanding of transcriptional regulation of homeostatic intrinsic plasticity in learning and memory. The results are also important for understanding the role of Mitf in other cell types. Regulation of intrinsic plasticity has wide-ranging implications and fundamental importance for neurological diseases such as neurodegeneration, autism and epilepsy.

scholarly journals Systematic identification of 3′-UTR regulatory elements in activity-dependent mRNA stability in hippocampal neurons

2014 ◽  
Vol 369 (1652) ◽  
pp. 20130509 ◽  
Author(s):  
Jonathan E. Cohen ◽  
Philip R. Lee ◽  
R. Douglas Fields
Keyword(s):  
Neuronal Activity ◽  
Mrna Stability ◽  
Hippocampal Neurons ◽  
Transcriptional Control ◽  
Regulatory Elements ◽  
Memory Storage ◽  
Long Term Memory ◽  
Synaptic Connections ◽  
Activity Dependent

Ongoing neuronal activity during development and plasticity acts to refine synaptic connections and contributes to the induction of plasticity and ultimately long-term memory storage. Activity-dependent, post-transcriptional control of mRNAs occurs through transport to axonal and dendritic compartments, local translation and mRNA stability. We have identified a mechanism that contributes to activity-dependent regulation of mRNA stability during synaptic plasticity in rat hippocampal neurons. In this study, we demonstrate rapid, post-transcriptional control over process-enriched mRNAs by neuronal activity. Systematic analysis of the 3′-UTRs of destabilized transcripts, identifies enrichment in sequence motifs corresponding to microRNA (miRNA)-binding sites. The miRNAs that were identified, miR-326-3p/miR-330-5p, miR-485-5p, miR-666-3p and miR-761 are predicted to regulate networks of genes important in plasticity and development. We find that these miRNAs are developmentally regulated in the hippocampus, many increasing by postnatal day 14. We further find that miR-485-5p controls NGF-induced neurite outgrowth in PC12 cells, tau expression and axonal development in hippocampal neurons. miRNAs can function at the synapse to rapidly control and affect short- and long-term changes at the synapse. These processes likely occur during refinement of synaptic connections and contribute to the induction of plasticity and learning and memory.

scholarly journals Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
David Levitan ◽  
Chenghao Liu ◽  
Tracy Yang ◽  
Yasuyuki Shima ◽  
Jian-You Lin ◽  
...  
Keyword(s):  
Basolateral Amygdala ◽  
Molecular Mechanisms ◽  
Neuronal Excitability ◽  
Early Gene ◽  
Intrinsic Excitability ◽  
Long Term Memory ◽  
Projection Neurons ◽  
Impaired Memory ◽  
Kinase Pathway

Conditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms remain poorly understood. RNAseq from BLApn identified changes in multiple candidate learning-related transcripts including the expected immediate early gene Fos and Stk11, a master kinase of the AMP-related kinase pathway with important roles in growth, metabolism and development, but not previously implicated in learning. Deletion of Stk11 in BLApn blocked memory prior to training, but not following it and increased neuronal excitability. Conversely, BLApn had reduced excitability following CTA. BLApn knockout of a second learning-related gene, Fos, also increased excitability and impaired learning. Independently increasing BLApn excitability chemogenetically during CTA also impaired memory. STK11 and C-FOS activation were independent of one another. These data suggest key roles for Stk11 and Fos in CTA long-term memory formation, dependent at least partly through convergent action on BLApn intrinsic excitability.

scholarly journals Mitf Links Neuronal Activity and Long-Term Homeostatic Intrinsic Plasticity

eNeuro ◽  
2020 ◽  
Vol 7 (2) ◽  
pp. ENEURO.0412-19.2020 ◽  
Author(s):  
Diahann A. M. Atacho ◽  
Hallur Reynisson ◽  
Anna Thora Petursdottir ◽  
Thor Eysteinsson ◽  
Eirikur Steingrimsson ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Intrinsic Plasticity

scholarly journals AMPA receptor subunit GluR1 (GluA1) serine-845 site is involved in synaptic depression but not in spine shrinkage associated with chemical long-term depression

2011 ◽  
Vol 105 (4) ◽  
pp. 1897-1907 ◽  
Author(s):  
Kaiwen He ◽  
Angela Lee ◽  
Lihua Song ◽  
Patrick O. Kanold ◽  
Hey-Kyoung Lee
Keyword(s):  
Ampa Receptor ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Low Frequency ◽  
Morphological Plasticity ◽  
Mutant Mice ◽  
Long Term Depression ◽  
Spine Head ◽  
Nmdar Activation

The structure of dendritic spines is highly plastic and can be modified by neuronal activity. In addition, there is evidence that spine head size correlates with the synaptic α-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptor (AMPAR) content, which suggests that they may be coregulated. Although there is evidence that there are overlapping mechanisms for structural and functional plasticity, the extent of the overlap needs further investigation. Specifically, it is unknown whether AMPAR levels determine spine size or whether both are regulated via parallel pathways. We studied the correlation between spine structural plasticity and long-term synaptic plasticity following chemical-induced long-term depression (chemLTD). In particular, we examined whether the regulation of AMPARs, which is implicated in LTD, is critical for spine morphological plasticity. We used mutant mice specifically lacking the serine-845 site on the type 1 glutamate receptor (GluR1, or GluA1) subunit of AMPARs (mutants). These mice specifically lack N-methyl-d-aspartate (NMDA) receptor (NMDAR)-dependent LTD and NMDAR activation-induced AMPAR endocytosis. We found that chemLTD causes a rapid and persistent shrinkage in spine head volume of hippocampal CA1 pyramidal neurons in wild types similar to that reported in other studies using low-frequency stimulation (LFS)-induced LTD. Surprisingly, we found that although S845A mutant mice display impaired chemLTD, the shrinkage of spine head volume occurred to a similar magnitude to that observed in wild types. Our results suggest that there is dissociation in the molecular mechanisms underlying functional LTD and spine shrinkage and that GluR1-S845 regulation is not necessary for spine morphological plasticity.

scholarly journals Neuronal activity–driven oligodendrogenesis in selected brain regions is required for episodic memories

2021 ◽  
Author(s):  
Luendreo Barboza ◽  
Benjamin Bessieres ◽  
Omina Nazarzoda ◽  
Cristina Alberini
Keyword(s):  
Neuronal Activity ◽  
Medial Temporal Lobe ◽  
Molecular Mechanisms ◽  
Dorsal Hippocampus ◽  
Brain Regions ◽  
Memory Formation ◽  
Anterior Cingulate ◽  
Long Term Memory ◽  
Episodic Memories

The formation of long-term episodic memories requires the activation of molecular mechanisms in several regions of the medial temporal lobe, including the hippocampus and anterior cingulate cortex (ACC). The extent to which these regions engage distinct mechanisms and cell types to support memory formation is not well understood. Recent studies reported that oligodendrogenesis is essential for learning and long-term memory; however, whether these mechanisms are required only in selected brain regions is still unclear. Also still unknown are the temporal kinetics of engagement of learning-induced oligodendrogenesis and whether this oligodendrogenesis occurs in response to neuronal activity. Here we show that in rats and mice, episodic learning rapidly increases the oligodendrogenesis and myelin biogenesis transcripts olig2, myrf, mbp, and plp1, as well as oligodendrogenesis, in the ACC but not in the dorsal hippocampus (dHC). Region-specific knockdown and knockout of Myrf, a master regulator of oligodendrocyte maturation, revealed that oligodendrogenesis is required for memory formation in the ACC but not the dHC. Chemogenetic neuronal silencing in the ACC showed that neuronal activity is critical for learning-induced oligodendrogenesis. Hence, an activity-dependent increase in oligodendrogenesis in selected brain regions, specifically in the ACC but not dHC, is critical for the formation of episodic memories.

scholarly journals The development of reporter system for the investigation of molecular mechanisms of ecdysone response

2019 ◽  
Vol 485 (4) ◽  
pp. 515-518
Author(s):  
M. Yu. Mazina ◽  
A. N. Krasnov ◽  
P. G. Georgiev ◽  
N. E. Vorobyeva
Keyword(s):  
Transcriptional Regulation ◽  
Molecular Mechanisms ◽  
Fluorescent Protein ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Reporter System ◽  
Genetic Construct ◽  
Genome Wide ◽  
Early Late

To study the mechanisms of transcriptional regulation, a convenient experimental approach is to use the artificial chimeric constructs, carrying the regulatory elements of interest. In the present work, we describe the creation and characterization of a novel genetic construct, which makes possible to study the transcriptional regulation of the early-late gene of the ecdysone cascade. Using the data of genome-wide experiments, we have isolated the main regulatory region of the hr4 gene, which was successfully used to create a chimeric reporter construct expressing a fluorescent protein upon the treatment with the ecdysone hormone. This reporter system can be used to study the mechanisms of the ecdysone response, both in cell culture and in tissues, at various stages of the Drosophila development.

scholarly journals Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

2019 ◽  
Author(s):  
David Levitan ◽  
Chenghao Liu ◽  
Tracy Yang ◽  
Yasuyuki Shima ◽  
Jian-You Lin ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Basolateral Amygdala ◽  
Molecular Mechanisms ◽  
Early Gene ◽  
Intrinsic Excitability ◽  
Long Term Memory ◽  
Projection Neurons ◽  
Term Memory ◽  
Growth Metabolism

AbstractConditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms are poorly understood, however. We used RNAseq from BLApn to identify learning-related changes in Stk11, a kinase with well-studied roles in growth, metabolism and development, but not previously implicated in learning. Deletion of Stk11 restricted to BLApn completely blocks memory when occurring prior to training, but not following it, despite altering neither BLApn-dependent encoding of taste palatability in gustatory cortex, nor transcriptional activation of BLApn during training. Deletion of Stk11 in BLApn also increases their intrinsic excitability. Conversely, BLApn activated by CTA to express the immediate early gene Fos had reduced excitability. BLApn knockout of Fos also increased excitability and impaired learning. These data suggest that Stk11 and Fos expression play key roles in CTA long-term memory formation, perhaps by modulating the intrinsic excitability of BLApn.

scholarly journals Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Karolina Stępniak ◽  
Magdalena A. Machnicka ◽  
Jakub Mieczkowski ◽  
Anna Macioszek ◽  
Bartosz Wojtaś ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Molecular Mechanisms ◽  
Genome Mapping ◽  
Malignant Gliomas ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Multiple Tumor ◽  
Genes Encoding ◽  
Methylation Patterns

AbstractChromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas.

scholarly journals Cardiac Cell Therapy: Insights into the Mechanisms of Tissue Repair

2021 ◽  
Vol 22 (3) ◽  
pp. 1201
Author(s):  
Hsuan Peng ◽  
Kazuhiro Shindo ◽  
Renée R. Donahue ◽  
Ahmed Abdel-Latif
Keyword(s):  
Stem Cell ◽  
Immune Responses ◽  
Tissue Repair ◽  
Molecular Mechanisms ◽  
Clinical Evidence ◽  
Current Knowledge ◽  
Cell Delivery ◽  
Cardiac Cell Therapy ◽  
Stem Cell Treatment

Stem cell-based cardiac therapies have been extensively studied in recent years. However, the efficacy of cell delivery, engraftment, and differentiation post-transplant remain continuous challenges and represent opportunities to further refine our current strategies. Despite limited long-term cardiac retention, stem cell treatment leads to sustained cardiac benefit following myocardial infarction (MI). This review summarizes the current knowledge on stem cell based cardiac immunomodulation by highlighting the cellular and molecular mechanisms of different immune responses to mesenchymal stem cells (MSCs) and their secretory factors. This review also addresses the clinical evidence in the field.

Sign in / Sign up

Export Citation Format

Share Document