Complexity Science Group, Department of Physics and Astronomy, University of Calgary, Calgary, Alberta, Canada.
Department of Physics and Astronomy, University of Calgary, Calgary, Alberta, Canada.
PLoS One. 2021 May 7;16(5):e0251172. doi: 10.1371/journal.pone.0251172. eCollection 2021.
Within the classical eye-blink conditioning, Purkinje cells within the cerebellum are known to suppress their tonic firing rates for a well defined time period in response to the conditional stimulus after training. The temporal profile of the drop in tonic firing rate, i.e., the onset and the duration, depend upon the time interval between the onsets of the conditional and unconditional training stimuli. Direct stimulation of parallel fibers and climbing fiber by electrodes was found to be sufficient to reproduce the same characteristic drop in the firing rate of the Purkinje cell. In addition, the specific metabotropic glutamate-based receptor type 7 (mGluR7) was found responsible for the initiation of the response, suggesting an intrinsic mechanism within the Purkinje cell for the temporal learning. In an attempt to look for a mechanism for time-encoding memory formation within individual Purkinje cells, we propose a biochemical mechanism based on recent experimental findings. The proposed mechanism tries to answer key aspects of the "Coding problem" of Neuroscience by focusing on the Purkinje cell's ability to encode time intervals through training. According to the proposed mechanism, the time memory is encoded within the dynamics of a set of proteins-mGluR7, G-protein, G-protein coupled Inward Rectifier Potassium ion channel, Protein Kinase A, Protein Phosphatase 1 and other associated biomolecules-which self-organize themselves into a protein complex. The intrinsic dynamics of these protein complexes can differ and thus can encode different time durations. Based on their amount and their collective dynamics within individual synapses, the Purkinje cell is able to suppress its own tonic firing rate for a specific time interval. The time memory is encoded within the effective dynamics of the biochemical reactions and altering these dynamics means storing a different time memory. The proposed mechanism is verified by both a minimal and a more comprehensive mathematical model of the conditional response behavior of the Purkinje cell and corresponding dynamical simulations of the involved biomolecules, yielding testable experimental predictions.
在经典的眨眼条件反射中，已知小脑的浦肯野细胞在经过训练后，会在一段时间内抑制其紧张性放电率，以响应条件刺激。紧张性放电率下降的时间特征，即起始和持续时间，取决于条件和无条件训练刺激起始之间的时间间隔。通过电极直接刺激平行纤维和 climbing 纤维被发现足以重现浦肯野细胞放电率的相同特征下降。此外，特定的代谢型谷氨酸受体 7（mGluR7）被发现负责引发反应，这表明浦肯野细胞内存在用于时间学习的内在机制。为了寻找单个浦肯野细胞内时间编码记忆形成的机制，我们根据最近的实验发现提出了一种生化机制。所提出的机制试图通过关注浦肯野细胞通过训练编码时间间隔的能力来回答神经科学中“编码问题”的关键方面。根据所提出的机制，时间记忆是在一组蛋白质-mGluR7、G 蛋白、G 蛋白偶联内向整流钾离子通道、蛋白激酶 A、蛋白磷酸酶 1 和其他相关生物分子的动力学中进行编码的，这些蛋白质自我组织成一个蛋白质复合物。这些蛋白质复合物的内在动力学可以不同，因此可以编码不同的时间持续时间。基于它们的数量及其在单个突触内的集体动力学，浦肯野细胞能够在特定的时间间隔内抑制其自身的紧张性放电率。时间记忆是在生化反应的有效动力学中进行编码的，改变这些动力学意味着存储不同的时间记忆。所提出的机制通过浦肯野细胞条件反应行为的最小和更全面的数学模型以及涉及的生物分子的相应动力学模拟得到验证，产生了可测试的实验预测。
