Bifurcation and singularity analysis of a molecular network for the induction of long-term memory.
Bifurcation and singularity analysis of a molecular network for the induction of long-term memory.
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DOI：
10.1529/biophysj.105.074500
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发表时间：
2006-04
影响因子：
3.4
通讯作者：
Hao Song;P. Smolen;Evyatar Av-Ron;D. A. Baxter;J. Byrne
中科院分区：
文献类型：
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作者：
Hao Song;P. Smolen;Evyatar Av-Ron;D. A. Baxter;J. Byrne
软体动物的退缩反射表现出敏感化，一种简单的长期记忆（LTM）形式。致敏部分是由于感觉运动神经元突触的长期易化（LTF）。LTF是由血清素（5-HT）的调节作用诱导的。Pettigrew等人建立了一个非线性细胞内信号传导和基因网络的计算模型，该模型是5- ht诱导LTF的基础。该模型模拟了反复应用5-HT诱导蛋白激酶A （PKA）持续激活的经验观察，并且这种持续激活需要超过5-HT的阈值暴露。本文运用分岔分析、奇点理论和数值模拟等方法对Pettigrew模型进行了扩展。利用奇异性理论，构造了参数空间的分类图，识别出具有定性不同稳态行为的区域。这些区域的图形表示说明了这些区域对模型参数变化的鲁棒性。由于持续蛋白激酶A （PKA）活性与apilsia LTM相关，因此分析的重点是模型中倾向于维持PKA活性的正反馈回路。在这个环中，PKA使转录因子（TF-1）磷酸化，从而增加泛素水解酶（Ap-Uch）的表达。然后，Ap-Uch作用于增加PKA活性，闭合循环。这个正反馈回路显示了多个共存的稳定状态，或多重性，这为PKA活动中的双稳态开关提供了一种机制。去除5-HT后，PKA活性要么恢复到基础水平（可逆开关），要么保持在较高水平（不可逆开关）。这种不可逆的转换可能是促成LTM持久性的一种机制。分类图还确定了可能被操纵的参数和过程，也许是药理学上的，以增强记忆的诱导。影响记忆形成等复杂过程的合理药物设计可以从这种分析中受益。
Withdrawal reflexes of the mollusk Aplysia exhibit sensitization, a simple form of long-term memory (LTM). Sensitization is due, in part, to long-term facilitation (LTF) of sensorimotor neuron synapses. LTF is induced by the modulatory actions of serotonin (5-HT). Pettigrew et al. developed a computational model of the nonlinear intracellular signaling and gene network that underlies the induction of 5-HT-induced LTF. The model simulated empirical observations that repeated applications of 5-HT induce persistent activation of protein kinase A (PKA) and that this persistent activation requires a suprathreshold exposure of 5-HT. This study extends the analysis of the Pettigrew model by applying bifurcation analysis, singularity theory, and numerical simulation. Using singularity theory, classification diagrams of parameter space were constructed, identifying regions with qualitatively different steady-state behaviors. The graphical representation of these regions illustrates the robustness of these regions to changes in model parameters. Because persistent protein kinase A (PKA) activity correlates with Aplysia LTM, the analysis focuses on a positive feedback loop in the model that tends to maintain PKA activity. In this loop, PKA phosphorylates a transcription factor (TF-1), thereby increasing the expression of an ubiquitin hydrolase (Ap-Uch). Ap-Uch then acts to increase PKA activity, closing the loop. This positive feedback loop manifests multiple, coexisting steady states, or multiplicity, which provides a mechanism for a bistable switch in PKA activity. After the removal of 5-HT, the PKA activity either returns to its basal level (reversible switch) or remains at a high level (irreversible switch). Such an irreversible switch might be a mechanism that contributes to the persistence of LTM. The classification diagrams also identify parameters and processes that might be manipulated, perhaps pharmacologically, to enhance the induction of memory. Rational drug design, to affect complex processes such as memory formation, can benefit from this type of analysis.