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  • 1
    Abstract: Dicer's essential role in development and neuronal survival has precluded studying its role in learning and memory. The study by Konopka et al. uses modern mouse genetics to address this question showing that loss of neuronal miRNA enhances learning and memory. Dicer is essential for the production of miRNA and Dicer loss of function leads to embryonic lethality. Using a number of Dicer conditional alleles, it has been demonstrated that miRNA is required for the survival of developing neurons (1-4). These important observations, however, have shed no light on the function of miRNA in mature adult neurons. Using a tamoxifen-inducible Cre transgene expressed in forebrain neurons, Konopka et al. disrupt miRNA biogenesis after neuronal maturation has occurred. Not surprisingly, at later timepoints after deletion of Dicer, significant neuronal loss in the hippocampus and cortex is observed. However, in a window of time 10-14 weeks after deletion, the authors observe improved performance in a variety of learning and memory-related tasks. Correlated with the improved performance the authors observed increases in post-tetanic potentiation and signs of increases in dendritic spine growth and mobility. Though not directly demonstrated by the result of miRNA depletion, the authors observed enhanced levels of brain-derived neurotrophic factor (BDNF), glutamate receptors, post-synaptic density protein 95 (PSD95), and matrix-metalloprotease 9 (MMP9). The increase in these proteins' levels may be the cause, or the consequence, of the improved memory of the Dicer mutant mice. Though loss of miRNAs leads to improved memory, this effect is only transient and eventually the mice show significant neurodegeneration. At this time it remains unclear whether the changes in protein levels that improve cognitive performance are the same proteins that eventually lead to neurodegeneration. References: 1 Schaefer et al. J Exp Med 2007, 204:1553-8 [PMID:17606634]. 2 Kim et al. Science 2007, 317:1220-4 [PMID:17761882]. 3 Cuellar et al. Proc Natl Acad Sci U S A 2008, 105:5614-9 [PMID:18385371]. 4 Davis et al. J Neurosci 2008, 28:4322-30 [PMID:18434510]. Competing interests: None declared
    Type of Publication: Miscellaneous publication
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  • 2
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    Neuroscientist 17 (5), 468-474 
    Keywords: EXPRESSION ; COMPLEX ; MESSENGER-RNA ; TARGET ; LONG-TERM POTENTIATION ; synaptic plasticity ; c-Fos ; REVEALS ; MUTANT MICE ; NEURONS ; MATRIX-METALLOPROTEINASE-9 ; MMP-9 ; learning and memory ; MICRORNA ; BDNF ; MAMMALIAN NEURONS
    Abstract: Learning and memory refer to an animal's ability to respond adequately to environmental signals that may be negative (aversive learning) or positive (appetitive learning) in nature. The extremely elaborate connectivity network of neurons in the brain is capable of governing animals' reactions (e.g., by enhancing or weakening single or multiple synapses). Such circuit plasticity is largely believed to be the very essence of memory formation. It has been suggested that long-term memory, in contrast to short-term memory, requires de novo protein synthesis and can be prevented by protein synthesis inhibitors. The local protein translation in dendrites allows neurons to selectively rebuild only those synapses that have been activated. However, substrates of protein synthesis (i.e., mRNA) have to be kept suppressed until they are needed. MicroRNAs-short, non-protein-coding RNA regulatory sequences that guide an RNA-induced silencing complex to target mRNAs-seem to be perfect candidates in fulfilling this function in neurons. In this article, the authors discuss the recently recognized role of microRNAs as regulators of memory formation and endurance.
    Type of Publication: Journal article published
    PubMed ID: 21734154
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  • 3
    Keywords: brain ; PROTEIN ; transcription ; synaptic plasticity ; DISRUPTION ; CELL-GROWTH ; FACTOR TIF-IA ; neurogenesis ; SEX-DIFFERENCES ; NUCLEOLAR STRESS
    Abstract: Decreased rRNA synthesis and nucleolar disruption, known as nucleolar stress, are primary signs of cellular stress associated with aging and neurodegenerative disorders. Silencing of rDNA occurs during early stages of Alzheimer's disease (AD) and may play a role in dementia. Moreover, aberrant regulation of the protein synthesis machinery is present in the brain of suicide victims and implicates the epigenetic modulation of rRNA. Recently, we developed unique mouse models characterized by nucleolar stress in neurons. We inhibited RNA polymerase I by genetic ablation of the basal transcription factor TIF-IA in adult hippocampal neurons. Nucleolar stress resulted in progressive neurodegeneration, although with a differential vulnerability within the CA1, CA3, and dentate gyrus (DG). Here, we investigate the consequences of nucleolar stress on learning and memory. The mutant mice show normal performance in the Morris water maze and in other behavioral tests, suggesting the activation of adaptive mechanisms. In fact, we observe a significantly enhanced learning and re-learning corresponding to the initial inhibition of rRNA transcription. This phenomenon is accompanied by aberrant synaptic plasticity. By the analysis of nucleolar function and integrity, we find that the synthesis of rRNA is later restored. Gene expression profiling shows that 36 transcripts are differentially expressed in comparison to the control group in absence of neurodegeneration. Additionally, we observe a significant enrichment of the putative serum response factor (SRF) binding sites in the promoters of the genes with changed expression, indicating potential adaptive mechanisms mediated by the mitogen-activated protein kinase pathway. In the DG a neurogenetic response might compensate the initial molecular deficits. These results underscore the role of nucleolar stress in neuronal homeostasis and open a new ground for therapeutic strategies aiming at preserving neuronal function.
    Type of Publication: Journal article published
    PubMed ID: 24273493
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  • 4
    Keywords: brain ; EXPRESSION ; CELL ; COMBINATION ; Germany ; VIVO ; SYSTEM ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; TRANSDUCTION ; INDUCTION ; RAT ; RATS ; TISSUES ; BIOLOGY ; TARGET ; hippocampus ; NERVOUS-SYSTEM ; VECTORS ; VECTOR ; PROMOTERS ; transgenic ; genetics ; MAMMALIAN-CELLS ; CENTRAL-NERVOUS-SYSTEM ; RAT-BRAIN ; LENTIVIRAL VECTOR ; EGFR ; HUNTINGTONS-DISEASE ; NEUROTROPHIC FACTOR ; USA ; Doxycycline ; lentiviral vectors ; TRANSGENIC RATS ; Genetic ; NEURONS IN-VITRO ; rtTA ; Tet system ; TIGHT CONTROL
    Abstract: Local and regulated expression of exogenous genes in the central nervous system is one of the major challenges of modern neuroscience. We have approached this issue by applying the inducible tetracycline system to regulate the expression of EGFP reporter gene in double transgenic rats. We have obtained a strong induction of EGFP only in male testes, which correlated with a high level of rtTA expression only in this organ. To overcome the problem of lack of rtTA protein in the transgenic rat brain, we have delivered this Tet system activator with lentiviral vectors into the dentate gyrus of hippocampus of transgenic EGFP rats. As a result, after systemic application of doxycycline we have obtained inducible, stable and restricted to the desired brain region expression of EGFR An advantage of this strategy is that the transgene is located in the same genetic milieu in every cell of the transgenic organism. This is crucial to obtain uniform expression of the regulated gene within the target brain structure. Combination of rat transgenesis and lentiviral vectors is a novel approach enabling precise spatiotemporal regulation of genes of interest strictly in the brain structure of choice or in other tissues. genesis 47:274-280, 2009. (C) 2009 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 19241392
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  • 5
    Abstract: J. Neurosci. 30, 14835-14842 (2010) Learning and memory in mice seem to be enhanced by the loss of small RNA molecules called microRNAs (miRNAs) in the brain. Witold Konopka at the German Cancer Research Center in Heidelberg and his colleagues deactivated the gene for Dicer, a key enzyme in miRNA synthesis, in forebrain neurons of adult mice. Twelve weeks later, the mice showed improved learning and memory in a behavioural test. This was mirrored by increased numbers of a type of dendritic spine in mutant neurons that is associated with learning. After 20 weeks, however, some of the neurons had degenerated, confirming the importance of microRNAs for neuronal survival.
    Type of Publication: Miscellaneous publication
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  • 6
    Abstract: Dicer-dependent noncoding RNAs, including microRNAs (miRNAs), play an important role in a modulation of translation of mRNA transcripts necessary for differentiation in many cell types. In vivo experiments using cell type-specific Dicer1 gene inactivation in neurons showed its essential role for neuronal development and survival. However, little is known about the consequences of a loss of miRNAs in adult, fully differentiated neurons. To address this question, we used an inducible variant of the Cre recombinase (tamoxifen-inducible CreERT2) under control of Camk2a gene regulatory elements. After induction of Dicer1 gene deletion in adult mouse forebrain, weobserved a progressive loss of a whole set of brain-specific miRNAs. Animals were tested in a battery of both aversively and appetitively motivated cognitive tasks, such as Morris water maze, IntelliCage system, or trace fear conditioning. Compatible with rather long half-life of miRNAs in hippocampal neurons, we observed an enhancement of memory strength of mutant mice 12 weeks after the Dicer1 gene mutation, before the onset of neurodegenerative process. In acute brain slices, immediately after high-frequency stimulation of the Schaffer collaterals, the efficacy at CA3-to-CA1 synapses was higher in mutant than in control mice, whereas long-term potentiation was comparable between genotypes. This phenotype was reflected at the subcellular and molecular level by the elongated filopodia-like shaped dendritic spines and an increased translation of synaptic plasticity-related proteins, such as BDNF and MMP-9 in mutant animals. The presented work shows miRNAs as key players in the learning and memory process of mammals
    Type of Publication: Journal article published
    PubMed ID: 21048142
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  • 7
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  58. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC); 20070426-20070429; Leipzig; DOCP 080 /20070411/
    Publication Date: 2007-04-04
    Keywords: neural precursor ; proliferation ; glioblastoma ; Stammzellen ; Glioblastome ; Proliferation ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 8
    ISSN: 0309-1651
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Biological cybernetics 22 (1976), S. 229-234 
    ISSN: 1432-0770
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Computer Science , Physics
    Notes: Abstract A simplified model is presented of the dynamics of excitatory and inhibitory neurons in the cerebral cortex. A key feature of the model is that neurons may cease to fire when strongly depolarized (spike inactivation). Computer simulations for different parameters reveal five classes of solutons: a) steady states in which neither excitatory nor inhibitory cells are active, b) steady states in which one or both types of cells fire repetitively, c) states in which one type of cell fluctuates rapidly between bursts of action potentials and inactivity due to strong depolarization, d) rhythmic activity in which both types of cells fire in unison followed by a period of spike inactivation and e) states similar to d but in which the inhibitory cells never produce action potentials. Solutions b, c, d, and e qualitatively resemble the different firing patterns observed during experimental seizures. It is shown that changes in those parameters that are functions of potassium concentration can induce changes in the type of solution. It is therefore proposed that the increase in extracellular potassium concentration during seizures may be responsible for the progressive changes observed in firing patterns and particularly for the transition from tonic to clonic patterns. A method is also outlined for testing the predictions of the model.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Biological cybernetics 26 (1977), S. 199-208 
    ISSN: 1432-0770
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Computer Science , Physics
    Notes: Abstract A neuronal network model of epilepsy is investigated. The network is described in terms of differential delay equations in which strong depolarization of any unit in the ensemble results in spike inactivation and the attenuation of that cell's output. It can be shown that homogeneous oscillations with the qualitative features of epileptic seizures, including the progression from tonic to clonic firing patterns, appear when a highly depolarized homogeneous steady state becomes unstable. Stability calculations and the study of a simplified model that is solved analytically point to hyperexcitation as a critical determinant of epileptic activity. Spatially inhomogeneous solutions were studied in three types of connective topologies, i) uniformly densely connected networks, ii) densely connected networks containing a number of cells (microfoci) with pathologically strong connections to each other and to other normal cells, and iii) sparsely connected networks in which the strength of connections falls off as a function of the physical distance separating the cells. Homogeneous epileptic solutions remain stable to spatial perturbations in the first two types of topology. Type iii) may however give rise to a variety of spatiotemporal patterns, including travelling waves and “chaotic” behaviour. It is suggested that such inhomogeneous patterns may occur in the early stages of a seizure.
    Type of Medium: Electronic Resource
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