Cellular Neurophysiology Laboratory, Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
J Neurophysiol. 2024 Sep 1;132(3):991-1013. doi: 10.1152/jn.00071.2024. Epub 2024 Aug 7.
Complex systems are neither fully determined nor completely random. Biological complex systems, including single neurons, manifest intermediate regimes of randomness that recruit integration of specific combinations of functionally specialized subsystems. Such emergence of biological function provides the substrate for the expression of degeneracy, the ability of disparate combinations of subsystems to yield similar function. Here, we present evidence for the expression of degeneracy in morphologically realistic models of dentate gyrus granule cells (GCs) through functional integration of disparate ion-channel combinations. We performed a 45-parameter randomized search spanning 16 active and passive ion channels, each biophysically constrained by their gating kinetics and localization profiles, to search for valid GC models. Valid models were those that satisfied 17 sub- and suprathreshold cellular-scale electrophysiological measurements from rat GCs. A vast majority (>99%) of the 15,000 random models were not electrophysiologically valid, demonstrating that arbitrarily random ion-channel combinations would not yield GC functions. The 141 valid models (0.94% of 15,000) manifested heterogeneities in and cross-dependencies across local and propagating electrophysiological measurements, which matched with their respective biological counterparts. Importantly, these valid models were widespread throughout the parametric space and manifested weak cross-dependencies across different parameters. These observations together showed that GC physiology could neither be obtained by entirely random ion-channel combinations nor is there an entirely determined single parametric combination that satisfied all constraints. The complexity, the heterogeneities in measurement and parametric spaces, and degeneracy associated with GC physiology should be rigorously accounted for while assessing GCs and their robustness under physiological and pathological conditions. A recent study from our laboratory had demonstrated pronounced heterogeneities in a set of 17 electrophysiological measurements obtained from a large population of rat hippocampal granule cells. Here, we demonstrate the manifestation of ion-channel degeneracy in a heterogeneous population of morphologically realistic conductance-based granule cell models that were validated against these measurements and their cross-dependencies. Our analyses show that single neurons are complex entities whose functions emerge through intricate interactions among several functionally specialized subsystems.
复杂系统既不完全确定也不完全随机。包括单个神经元在内的生物复杂系统表现出中间随机性状态，这种随机性状态招募了特定功能专门化子系统的组合的整合。这种生物功能的出现为退化的表达提供了基础，即不同子系统组合产生相似功能的能力。在这里，我们通过不同离子通道组合的功能整合，在形态上逼真的齿状回颗粒细胞 (GC) 模型中为退化的表达提供了证据。我们通过 16 种主动和被动离子通道的 45 个参数随机搜索，对每个通道的门控动力学和定位分布进行生物物理约束，以搜索有效的 GC 模型。有效的模型是那些满足大鼠 GC 17 个子和超阈值细胞尺度电生理测量的模型。绝大多数 (>99%)的 15000 个随机模型在电生理上是无效的，这表明任意随机离子通道组合都不会产生 GC 功能。141 个有效模型 (15000 个中的 0.94%)在局部和传播电生理测量中表现出异质性和交叉依赖性，与它们各自的生物学对应物相匹配。重要的是，这些有效模型在参数空间中广泛分布，并表现出不同参数之间的弱交叉依赖性。这些观察结果共同表明，GC 生理学既不能通过完全随机的离子通道组合获得，也不存在满足所有约束的完全确定的单个参数组合。GC 生理学与测量和参数空间的复杂性、异质性和退化性应在评估 GC 及其在生理和病理条件下的稳健性时得到严格考虑。我们实验室最近的一项研究表明，从大鼠海马颗粒细胞的大量群体中获得的一组 17 个电生理测量值存在明显的异质性。在这里，我们在一组形态逼真的基于电导的 GC 模型中证明了离子通道退化的表现，这些模型是针对这些测量值及其交叉依赖性进行验证的。我们的分析表明，单个神经元是复杂的实体，其功能是通过几个功能专门化子系统之间的复杂相互作用而产生的。
