Asynchronous τ -leaping

Salinas

Tewatia

et al. 2018

Eur J of Neuroscience

Self Cite

The striatum, the input structure of the basal ganglia, is a major site of learning and memory for goal-directed actions and habit formation. Spiny projection neurons of the striatum integrate cortical, thalamic, and nigral inputs to learn associations, with cortico-striatal synaptic plasticity as a learning mechanism. Signaling molecules implicated in synaptic plasticity are altered in alcohol withdrawal, which may contribute to overly strong learning and increased alcohol seeking and consumption. To understand how interactions among signaling molecules produce synaptic plasticity, we implemented a mechanistic model of signaling pathways activated by dopamine D1 receptors, acetylcholine receptors, and glutamate. We use our novel, computationally efficient simulator, NeuroRD, to simulate stochastic interactions both within and between dendritic spines. Dopamine release during theta burst and 20-Hz stimulation was extrapolated from fast-scan cyclic voltammetry data collected in mouse striatal slices. Our results show that the combined activity of several key plasticity molecules correctly predicts the occurrence of either LTP, LTD, or no plasticity for numerous experimental protocols. To investigate spatial interactions, we stimulate two spines, either adjacent or separated on a 20-μm dendritic segment. Our results show that molecules underlying LTP exhibit spatial specificity, whereas 2-arachidonoylglycerol exhibits a spatially diffuse elevation. We also implement changes in NMDA receptors, adenylyl cyclase, and G protein signaling that have been measured following chronic alcohol treatment. Simulations under these conditions suggest that the molecular changes can predict changes in synaptic plasticity, thereby accounting for some aspects of alcohol use disorder.

Section: Methodsmentioning

confidence: 99%

Molecular mechanisms underlying striatal synaptic plasticity: relevance to chronic alcohol consumption and seeking

Salinas

Tewatia

et al. 2018

Eur J of Neuroscience

Self Cite

“…The model is implemented using a stochastic reaction–diffusion simulator NeuroRD ( Jȩdrzejewski-Szmek and Blackwell, 2016 ), version 3.2.4 ( Jędrzejewski-Szmek and Blackwell, 2018 ), using the adaptive (asynchronous tau-leap) numerical method and tolerance of 0.1. Even though stochastic fluctuations observed using small compartments do not impact the results, the stochastic algorithm is extremely fast, especially for stiff systems; thus, there would be no advantage to switching to a potentially less accurate deterministic simulator.…”

Section: Methodsmentioning

confidence: 99%

Temporal pattern and synergy influence activity of ERK signaling pathways during L-LTP induction

Zobon

Jędrzejewska-Szmek

2021

eLife

Long-lasting long-term potentiation (L-LTP) is a cellular mechanism of learning and memory storage. Studies have demonstrated a requirement for extracellular signal-regulated kinase (ERK) activation in L-LTP produced by a diversity of temporal stimulation patterns. Multiple signaling pathways converge to activate ERK, with different pathways being required for different stimulation patterns. To answer whether and how different temporal patterns select different signaling pathways for ERK activation, we developed a computational model of five signaling pathways (including two novel pathways) leading to ERK activation during L-LTP induction. We show that calcium and cAMP work synergistically to activate ERK and that stimuli given with large inter-trial intervals activate more ERK than shorter intervals. Furthermore, these pathways contribute to different dynamics of ERK activation. These results suggest that signaling pathways with different temporal sensitivity facilitate ERK activation to diversity of temporal patterns.

“…The model is implemented using a stochastic reaction-diffusion simulator NeuroRD (Jędrzejewski-Szmek and Blackwell, 2016), version 3.2.4 (https://github.com/neurord/stochdiff/releases), using the adaptive (asynchronous tau-leap) numerical method and tolerance of 0.1. All model files needed to run the simulations or examine molecules quantities or reactions rate constants are available on GitHub (https://github.com/neurord/ERK).…”

Section: Methodsmentioning

confidence: 99%

“…The model is implemented using a stochastic reaction-diffusion simulator NeuroRD (Jȩdrzejewski-Szmek and Blackwell, 2016), version 3.2.4…”

Section: Simulation and Analysismentioning

confidence: 99%

Temporal pattern and synergy influence activity of ERK signaling pathways during L-LTP induction

Zobon

2020

Preprint

Self Cite

Long lasting long-term potentiation (L-LTP) is a cellular mechanism of learning and memory storage. Studies have demonstrated a requirement for the extracellular signal-regulated kinase (ERK) activation in L-LTP produced by a diversity of temporal stimulation patterns. Multiple signaling pathways converge to activate ERK, with different pathways being required for different stimulation patterns. We addressed the critical questions of whether maximal activation of ERK requires multiple pathways, and whether different temporal patterns select different signaling pathways for ERK activation. We developed a computational model of five signaling pathways (including two novel pathways) leading to ERK activation during L-LTP. Simulations show that calcium and cAMP work synergistically to activate ERK, and that stimuli given with large inter-trial intervals activate more ERK than shorter intervals, a temporal sensitivity similar to PKA but contrary to CaMKII. These results suggest that signaling pathways with different temporal sensitivity facilitate ERK activation to diversity of temporal patterns.