Volen Center and Biology Department, Brandeis University, Waltham, MA 02454.
Proc Natl Acad Sci U S A. 2023 Jun 27;120(26):e2222016120. doi: 10.1073/pnas.2222016120. Epub 2023 Jun 20.
Neurons and neuronal circuits must maintain their function throughout the life of the organism despite changing environments. Previous theoretical and experimental work suggests that neurons monitor their activity using intracellular calcium concentrations to regulate their intrinsic excitability. Models with multiple sensors can distinguish among different patterns of activity, but previous work using models with multiple sensors produced instabilities that lead the models' conductances to oscillate and then to grow without bound and diverge. We now introduce a nonlinear degradation term that explicitly prevents the maximal conductances to grow beyond a bound. We combine the sensors' signals into a master feedback signal that can be used to modulate the timescale of conductance evolution. Effectively, this means that the negative feedback can be gated on and off according to how far the neuron is from its target. The modified model recovers from multiple perturbations. Interestingly, depolarizing the models to the same membrane potential with current injection or with simulated high extracellular produces different changes in conductances, arguing that caution must be used in interpreting manipulations that serve as a proxy for increased neuronal activity. Finally, these models accrue traces of prior perturbations that are not visible in their control activity after perturbation but that shape their responses to subsequent perturbations. These cryptic or hidden changes may provide insight into disorders such as posttraumatic stress disorder that only become visible in response to specific perturbations.
神经元和神经元回路必须在整个生物体的生命周期中保持其功能，尽管环境在不断变化。以前的理论和实验工作表明，神经元通过细胞内钙离子浓度来监测其活动，从而调节其固有兴奋性。具有多个传感器的模型可以区分不同的活动模式，但以前使用具有多个传感器的模型进行的工作会产生不稳定性，导致模型的电导率发生振荡，然后无限制地增长并发散。我们现在引入了一个非线性退化项，该项明确防止最大电导率增长超过界限。我们将传感器的信号组合成一个主反馈信号，该信号可用于调节电导率演化的时间尺度。实际上，这意味着可以根据神经元与目标的距离，根据需要打开和关闭负反馈。修改后的模型可以从多种干扰中恢复。有趣的是，用电流注入或模拟的高细胞外液对模型进行去极化，会导致电导发生不同的变化，这表明在解释那些被用作神经元活动增加的代理的操作时必须谨慎。最后，这些模型会累积先前干扰的痕迹，这些痕迹在干扰后其对照活动中不可见，但会影响它们对后续干扰的反应。这些隐藏或隐藏的变化可能为创伤后应激障碍等疾病提供一些见解，这些疾病只有在对特定干扰作出反应时才会显现出来。
