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  • Proceedings of the National Academy of Sciences  (6)
  • 1
    Online-Ressource
    Online-Ressource
    Operant matching is a generic outcome of synaptic plasticity based on the covariance between reward and neural activity
    Proceedings of the National Academy of Sciences ; 2006
    In:  Proceedings of the National Academy of Sciences Vol. 103, No. 41 ( 2006-10-10), p. 15224-15229
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 41 ( 2006-10-10), p. 15224-15229
    Kurzfassung: The probability of choosing an alternative in a long sequence of repeated choices is proportional to the total reward derived from that alternative, a phenomenon known as Herrnstein's matching law. This behavior is remarkably conserved across species and experimental conditions, but its underlying neural mechanisms still are unknown. Here, we propose a neural explanation of this empirical law of behavior. We hypothesize that there are forms of synaptic plasticity driven by the covariance between reward and neural activity and prove mathematically that matching is a generic outcome of such plasticity. Two hypothetical types of synaptic plasticity, embedded in decision-making neural network models, are shown to yield matching behavior in numerical simulations, in accord with our general theorem. We show how this class of models can be tested experimentally by making reward not only contingent on the choices of the subject but also directly contingent on fluctuations in neural activity. Maximization is shown to be a generic outcome of synaptic plasticity driven by the sum of the covariances between reward and all past neural activities.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0505220103
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2006
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 2
    Online-Ressource
    Online-Ressource
    Plasticity and tuning by visual feedback of the stability of a neural integrator
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 20 ( 2004-05-18), p. 7739-7744
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 20 ( 2004-05-18), p. 7739-7744
    Kurzfassung: Persistent neural firing is of fundamental importance to working memory and other brain functions because it allows information to be held “online” following an input and to be integrated over time. Many models of persistent activity rely on some kind of positive feedback internal to the neural circuit concerned; however, too much feedback causes runaway firing (instability), and too little results in loss of persistence (leak). This parameter sensitivity leads to the hypothesis that the brain uses an error signal (external feedback) to tune the stability of persistent firing by adjusting the amount of internal feedback. We test this hypothesis by manipulating external visual feedback, a putative sensory error signal, in a model system for persistent firing, the goldfish oculomotor neural integrator. Over tens of minutes to hours, electronically controlled visual feedback consistent with a leaky or unstable integrator can drive the integrator progressively more unstable or leaky, respectively. Eye fixation time constants can be reduced 〉 100-fold to 〈 1 s. Normal visual feedback gradually retunes the integrator back to stability. Changes in the phase of the sinusoidal vestibulo-ocular response are consistent with integrator detuning, as are changes in ocular drift following eye position shifts compensating for brief passive head movements during fixations. Corresponding changes in persistent firing of integrator neurons are presented in the accompanying article. The presence, strength, and reversibility of the plasticity demonstrate that, in this system, external visual feedback plays a vital role in gradually tuning the stability of the neural integrator.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0401970101
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2004
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 3
    Online-Ressource
    Online-Ressource
    Plasticity and tuning of the time course of analog persistent firing in a neural integrator
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 20 ( 2004-05-18), p. 7745-7750
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 20 ( 2004-05-18), p. 7745-7750
    Kurzfassung: In a companion paper, we reported that the goldfish oculomotor neural integrator could be trained to instability or leak by rotating the visual surround with a velocity proportional to +/- horizontal eye position, respectively. Here we analyze changes in the firing rate behavior of neurons in area I in the caudal brainstem, a central component of the oculomotor neural integrator. Persistent firing could be detuned to instability and leak, respectively, along with fixation behavior. Prolonged training could reduce the time constant of persistent firing of some cells by more than an order of magnitude, to 〈 1 s. Normal visual feedback gradually retuned persistent firing of integrator neurons toward stability, along with fixation behavior. In animals with unstable fixations, approximately half of the eye position-related cells had upward or unstable firing rate drift. In animals with leaky fixations, two-thirds of the eye position-related cells showed leaky firing drift. The remaining eye position-related cells, generally those with lower eye position thresholds, showed a more complex pattern of history-dependent/predictive firing rate drift in relation to eye drift. These complex drift cells often showed a drop in maximum persistent firing rate after training to leak. Despite this diversity, firing drift and the degree of instability or leak in firing rates were broadly correlated with fixation performance. The presence, strength, and reversibility of this plasticity demonstrate that, in this system, visual feedback plays a vital role in gradually tuning the time course of persistent neural firing.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0401992101
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2004
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 4
    Online-Ressource
    Online-Ressource
    Oligodendrocyte precursor cells ingest axons in the mouse neocortex
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 48 ( 2022-11-29)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 48 ( 2022-11-29)
    Kurzfassung: Neurons in the developing brain undergo extensive structural refinement as nascent circuits adopt their mature form. This physical transformation of neurons is facilitated by the engulfment and degradation of axonal branches and synapses by surrounding glial cells, including microglia and astrocytes. However, the small size of phagocytic organelles and the complex, highly ramified morphology of glia have made it difficult to define the contribution of these and other glial cell types to this crucial process. Here, we used large-scale, serial section transmission electron microscopy (TEM) with computational volume segmentation to reconstruct the complete 3D morphologies of distinct glial types in the mouse visual cortex, providing unprecedented resolution of their morphology and composition. Unexpectedly, we discovered that the fine processes of oligodendrocyte precursor cells (OPCs), a population of abundant, highly dynamic glial progenitors, frequently surrounded small branches of axons. Numerous phagosomes and phagolysosomes (PLs) containing fragments of axons and vesicular structures were present inside their processes, suggesting that OPCs engage in axon pruning. Single-nucleus RNA sequencing from the developing mouse cortex revealed that OPCs express key phagocytic genes at this stage, as well as neuronal transcripts, consistent with active axon engulfment. Although microglia are thought to be responsible for the majority of synaptic pruning and structural refinement, PLs were ten times more abundant in OPCs than in microglia at this stage, and these structures were markedly less abundant in newly generated oligodendrocytes, suggesting that OPCs contribute substantially to the refinement of neuronal circuits during cortical development.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2202580119
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2022
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 5
    Online-Ressource
    Online-Ressource
    De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 5 ( 2020-02-04), p. 2560-2569
    Kurzfassung: De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains 〈 1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability ( h 2 ), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1902766117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2020
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 6
    Online-Ressource
    Online-Ressource
    Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 47 ( 2013-11-19)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 47 ( 2013-11-19)
    Kurzfassung: Expanded hexanucleotide repeats in the chromosome 9 open reading frame 72 ( C9orf72 ) gene are the most common genetic cause of ALS and frontotemporal degeneration (FTD). Here, we identify nuclear RNA foci containing the hexanucleotide expansion (GGGGCC) in patient cells, including white blood cells, fibroblasts, glia, and multiple neuronal cell types (spinal motor, cortical, hippocampal, and cerebellar neurons). RNA foci are not present in sporadic ALS, familial ALS/FTD caused by other mutations ( SOD1, TDP-43 , or tau ), Parkinson disease, or nonneurological controls. Antisense oligonucleotides (ASOs) are identified that reduce GGGGCC-containing nuclear foci without altering overall C9orf72 RNA levels. By contrast, siRNAs fail to reduce nuclear RNA foci despite marked reduction in overall C9orf72 RNAs. Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations. Genome-wide RNA profiling identifies an RNA signature in fibroblasts from patients with C9orf72 expansion. ASOs targeting sense strand repeat-containing RNAs do not correct this signature, a failure that may be explained, at least in part, by discovery of abundant RNA foci with C9orf72 repeats transcribed in the antisense (GGCCCC) direction, which are not affected by sense strand-targeting ASOs. Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat-containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1318835110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2013
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
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