scholarly journals Comparing Theories for the Maintenance of Late LTP and Long-Term Memory: Computational Analysis of the Roles of Kinase Feedback Pathways and Synaptic Reactivation

2020 ◽  
Vol 14 ◽  
Author(s):  
Paul Smolen ◽  
Douglas A. Baxter ◽  
John H. Byrne
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Long Term Memory ◽  
Kinase Activation ◽  
Calmodulin Kinase ◽  
Model Variant ◽  
Related Proteins ◽  
Camkii Activation ◽  
Persistent Elevation

A fundamental neuroscience question is how memories are maintained from days to a lifetime, given turnover of proteins that underlie expression of long-term synaptic potentiation (LTP) or “tag” synapses as eligible for LTP. A likely solution relies on synaptic positive feedback loops, prominently including persistent activation of Ca2+/calmodulin kinase II (CaMKII) and self-activated synthesis of protein kinase M ζ (PKMζ). Data also suggest positive feedback based on recurrent synaptic reactivation within neuron assemblies, or engrams, is necessary to maintain memories. The relative importance of these mechanisms is controversial. To explore the likelihood that each mechanism is necessary or sufficient to maintain memory, we simulated maintenance of LTP with a simplified model incorporating persistent kinase activation, synaptic tagging, and preferential reactivation of strong synapses, and analyzed implications of recent data. We simulated three model variants, each maintaining LTP with one feedback loop: autonomous, self-activated PKMζ synthesis (model variant I); self-activated CamKII (model variant II); and recurrent reactivation of strengthened synapses (model variant III). Variant I predicts that, for successful maintenance of LTP, either 1) PKMζ contributes to synaptic tagging, or 2) a low constitutive tag level persists during maintenance independent of PKMζ, or 3) maintenance of LTP is independent of tagging. Variant II maintains LTP and suggests persistent CaMKII activation could maintain PKMζ activity, a feedforward interaction not previously considered. However, we note data challenging the CaMKII feedback loop. In Variant III synaptic reactivation drives, and thus predicts, recurrent or persistent activation of CamKII and other necessary kinases, plausibly contributing to persistent elevation of PKMζ levels. Reactivation is thus predicted to sustain recurrent rounds of synaptic tagging and incorporation of plasticity-related proteins. We also suggest (model variant IV) that synaptic reactivation and autonomous kinase activation could synergistically maintain LTP. We propose experiments that could discriminate these maintenance mechanisms.

scholarly journals Comparing Theories for the Maintenance of Late LTP and Long-Term Memory: Computational Analysis of the Roles of Kinase Feedback Pathways and Synaptic Reactivation

2020 ◽  
Author(s):  
Paul Smolen ◽  
Douglas A. Baxter ◽  
John H. Byrne
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Fundamental Problem ◽  
Long Term Memory ◽  
Kinase Activation ◽  
Calmodulin Kinase ◽  
Model Variant ◽  
Related Proteins ◽  
Camkii Activation

AbstractA fundamental problem in neuroscience is how memories are maintained from days to a lifetime, given turnover of proteins that underlie expression of long-term synaptic potentiation (LTP) or ‘tag’ synapses as eligible for LTP. One likely solution relies on synaptic positive feedback loops, prominently including persistent activation of Ca2+/calmodulin kinase II (CaMKII) and self-activated synthesis of protein kinase M ζ (PKMζ). Recent studies also suggest positive feedback based on recurrent synaptic reactivation within neuron assemblies, or engrams, is necessary to maintain memories. The relative importance of these feedback mechanisms is controversial. To explore the likelihood that each mechanism is necessary or sufficient to maintain memory, we simulated maintenance of LTP with a simplified model incorporating persistent kinase activation, synaptic tagging, and preferential reactivation of strong synapses, and analyzed implications of recent data. We simulated three model variants, each maintaining LTP with one feedback loop: autonomous, self-activated PKMζ synthesis (model variant I); self-activated CamKII (model variant II); and recurrent reactivation of strengthened synapses (model variant III). Variant I requires and predicts that, for successful maintenance, PKMζ must contribute to synaptic tagging. Variant II maintains LTP and suggests persistent CaMKII activation could maintain PKMζ activity, a feedforward interaction not previously considered. However we note data challenging this feedback loop. In Variant III synaptic reactivation drives, and thus predicts, recurrent or persistent activity elevations of CamKII and other necessary kinases, plausibly contributing to empirically persistent elevation of PKMζ levels. Reactivation is thus predicted to sustain recurrent rounds of synaptic tagging and incorporation of plasticity-related proteins. We also suggest (model variant IV) that synaptic reactivation and autonomous kinase activation could synergistically maintain LTP. We propose experiments that could discriminate these maintenance mechanisms.

scholarly journals Autocrine signaling by an Aplysia neurotrophin forms a presynaptic positive feedback loop

2018 ◽  
Vol 115 (47) ◽  
pp. E11168-E11177 ◽  
Author(s):  
Iksung Jin ◽  
Hiroshi Udo ◽  
Russell Nicholls ◽  
Huixiang Zhu ◽  
Eric R. Kandel ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Autocrine Signaling ◽  
Positive Feedback Loop ◽  
Short Term Plasticity ◽  
Extracellular Signaling ◽  
Presynaptic Protein ◽  
Long Term Facilitation

Whereas short-term plasticity is often initiated on one side of the synapse, long-term plasticity involves coordinated changes on both sides, implying extracellular signaling. We have investigated the possible signaling role of an Aplysia neurotrophin (ApNT) in facilitation induced by serotonin (5HT) at sensory-to-motor neuron synapses in culture. ApNT is an ortholog of mammalian BDNF, which has been reported to act as either an anterograde, retrograde, or autocrine signal, so that its pre- and postsynaptic sources and targets remain unclear. We now report that ApNT acts as a presynaptic autocrine signal that forms part of a positive feedback loop with ApTrk and PKA. That loop stimulates spontaneous transmitter release, which recruits postsynaptic mechanisms, and presynaptic protein synthesis during the transition from short- to intermediate-term facilitation and may also initiate gene regulation to trigger the transition to long-term facilitation. These results suggest that a presynaptic ApNT feedback loop plays several key roles during consolidation of learning-related synaptic plasticity.

scholarly journals Loss of Ca2+/Calmodulin Kinase Kinase β Affects the Formation of Some, But Not All, Types of Hippocampus-Dependent Long-Term Memory

2003 ◽  
Vol 23 (30) ◽  
pp. 9752-9760 ◽  
Author(s):  
Marco Peters ◽  
Keiko Mizuno ◽  
Laurence Ris ◽  
Marco Angelo ◽  
Emile Godaux ◽  
...  
Keyword(s):  
Long Term Memory ◽  
Term Memory ◽  
Calmodulin Kinase

scholarly journals Modulated Response of Subtropical Gyres: Positive Feedback Loop, Subharmonic Modes, Resonant Solar and Orbital Forcing

2018 ◽  
Vol 6 (3) ◽  
pp. 107 ◽  
Author(s):  
Jean-Louis Pinault
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Rossby Waves ◽  
Resonance Phenomenon ◽  
Polar Coordinates ◽  
Western Boundary ◽  
Orbital Forcing ◽  
Positive Feedback Loop ◽  
The Mean

Evidence of long-term variability in the upper ocean has emerged for two decades. Most of the issues discussed raise a lot of questions. What is the driver of the decadal oscillation of rainfall in Europe that has been observed since the end of the 20th century? How to explain low-frequency variability as observed in the Atlantic Multidecadal Oscillation (AMO)? More generally, how does solar and orbital forcing occur during very long-term climate change? The observations suggest that both a positive feedback loop amplifies the effects of the insolation gradient on the climate system and a resonance phenomenon occurs, filtering out some frequencies in favour of others. Throughout this paper, some answers to these problems are given from a new concept based on the modulated response of subtropical gyres to solar and orbital forcing. Subtropical gyres turn out to be the main driver of long-term climate variability because they tightly control, via the western boundary currents, heat transport from the tropics into middle and high latitudes. Specifically, the theoretical foundations of long-period Rossby waves winding around the subtropical gyres are laid, suggested by the observations of persistent sea surface temperature anomalies at mid-latitudes. Multi-frequency Gyral Rossby Waves (GRWs) exhibit properties resulting from their annular structure and their coupling. Using a β-cone approximation, the momentum equations are solved in polar coordinates. The gradient β of the Coriolis parameter depends on the mean radius of the annulus and remains constant all around the latter. GRWs result from the variation in the Coriolis Effect with the mean radius of the annulus. The speed of the anti-cyclonically wind-driven circulation being higher than the phase velocity of cyclonically propagating GRWs, amplified forcing effects occur as well as resonances for periods consistent with the observations.

scholarly journals Long-Term Memory Deficits in Pavlovian Fear Conditioning in Ca2+/Calmodulin Kinase Kinase α-Deficient Mice

2006 ◽  
Vol 26 (23) ◽  
pp. 9105-9115 ◽  
Author(s):  
Frank Blaeser ◽  
Matthew J. Sanders ◽  
Nga Truong ◽  
Shanelle Ko ◽  
Long Jun Wu ◽  
...  
Keyword(s):  
Fear Conditioning ◽  
Long Term Potentiation ◽  
Long Term Memory ◽  
Term Memory ◽  
Calmodulin Kinase ◽  
Element Binding Protein ◽  
Long Term Follow Up ◽  
Responsive Element ◽  
Deficient Mice

ABSTRACT Signaling by the Ca2+/calmodulin kinase (CaMK) cascade has been implicated in neuronal gene transcription, synaptic plasticity, and long-term memory consolidation. The CaM kinase kinase α (CaMKKα) isoform is an upstream component of the CaMK cascade whose function in different behavioral and learning and memory paradigms was analyzed by targeted gene disruption in mice. CaMKKα mutants exhibited normal long-term spatial memory formation and cued fear conditioning but showed deficits in context fear during both conditioning and long-term follow-up testing. They also exhibited impaired activation of the downstream kinase CaMKIV/Gr and its substrate, the transcription factor cyclic AMP-responsive element binding protein (CREB) upon fear conditioning. Unlike CaMKIV/Gr-deficient mice, the CaMKKα mutants exhibited normal long-term potentiation and normal levels of anxiety-like behavior. These results demonstrate a selective role for CaMKKα in contextual fear memory and suggest that different combinations of upstream and downstream components of the CaMK cascade may serve distinct physiological functions.

scholarly journals A Positive Feedback Loop of lncRNA MIR31HG-miR-361-3p -YY1 Accelerates Colorectal Cancer Progression Through Modulating Proliferation, Angiogenesis, and Glycolysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Tao Guo ◽  
Defeng Liu ◽  
Shihao Peng ◽  
Meng Wang ◽  
Yangyang Li
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Positive Feedback Loop ◽  
Related Proteins

BackgroundColorectal cancer (CRC) is a common malignant tumor with high metastatic and recurrent rates. This study probes the effect and mechanism of long non-coding RNA MIR31HG on the progression of CRC cells.Materials and MethodsQuantitative real-time PCR (qRT-PCR) was used to analyze the expression of MIR31HG and miR-361-3p in CRC tissues and normal tissues. Gain- or loss-of-function assays were conducted to examine the roles of MIR31HG, miR-361-3p and YY1 transcription factor (YY1) in the CRC progression. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and colony formation experiment were conducted to test CRC cell proliferation. CRC cell invasion was determined by Transwell assay. The glucose detection kit and lactic acid detection kit were utilized to monitor the levels of glucose and lactate in CRC cells. The glycolysis level in CRC cells was examined by the glycolytic stress experiment. Western blot was performed to compare the expression of glycolysis-related proteins (PKM2, GLUT1 and HK2) and angiogenesis-related proteins (including VEGFA, ANGPT1, HIF1A and TIMP1) in HUVECs. The binding relationships between MIR31HG and miR-361-3p, miR-361-3p and YY1 were evaluated by the dual-luciferase reporter assay and RNA immunoprecipitation (RIP).ResultsMIR31HG was up-regulated in CRC tissues and was associated with poorer prognosis of CRC patients. The in-vitro and in-vivo experiments confirmed that overexpressing MIR31HG heightened the proliferation, growth, invasion, glycolysis and lung metastasis of CRC cells as well as the angiogenesis of HUVECs. In addition, MIR3HG overexpression promoted YY1 mRNA and protein level, and forced overexpression of YY1 enhanced MIR31HG level. Overexpressing YY1 reversed the tumor-suppressive effect mediated by MIR31HG knockdown. miR-361-3p, which was inhibited by MIR31HG overexpression, repressed the malignant behaviors of CRC cells. miR-361-3p-mediated anti-tumor effects were mostly reversed by upregulating MIR31HG. Further mechanism studies illustrated that miR-361-3p targeted and negatively regulated the expression of YY1.ConclusionThis study reveals that MIR31HG functions as an oncogenic gene in CRC via forming a positive feedback loop of MIR31HG-miR-361-3p-YY1.

Protein Synthesis and Synapse Specificity in Functional Plasticity

2019 ◽  
Author(s):  
Radha Raghuraman ◽  
Amrita Benoy ◽  
Sreedharan Sajikumar
Keyword(s):  
Protein Synthesis ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Synaptic Activity ◽  
Long Term Memory ◽  
Term Potentiation ◽  
Synaptic Tagging And Capture ◽  
Dendritic Protein Synthesis ◽  
Related Proteins

This chapter discusses the role of protein synthesis in the maintenance of long-term potentiation (LTP) and its associative properties, synaptic tagging and capture, which are cellular correlates of long-term memory. Starting from a brief overview of the early and late phases of LTP, the chapter discusses various existing models for synaptic activity-induced protein synthesis and its roles in late-LTP. The synaptic tagging and capture and cross-tagging theories are given emphasis, along with the elucidation of local dendritic protein synthesis and its significance in the maintenance of LTP. Inverse synaptic tagging, synaptic competition for plasticity-related proteins, and metaplasticity are also covered. The importance of the balance between proteasomal degradation and synthesis of plasticity-related proteins in persistent potentiation is briefly discussed. This chapter touches upon the physiological implications of epigenetic regulation in the control of neuronal functions and the molecular mechanisms within the neurons that translate epigenetic changes into long-lasting responses.

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