Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, United States of America.
J Neural Eng. 2018 Apr;15(2):026011. doi: 10.1088/1741-2552/aaa506.
Controlling neural activity enables the possibility of manipulating sensory perception, cognitive processes, and body movement, in addition to providing a powerful framework for functionally disentangling the neural circuits that underlie these complex phenomena. Over the last decade, optogenetic stimulation has become an increasingly important and powerful tool for understanding neural circuit function, owing to the ability to target specific cell types and bidirectionally modulate neural activity. To date, most stimulation has been provided in open-loop or in an on/off closed-loop fashion, where previously-determined stimulation is triggered by an event. Here, we describe and demonstrate a design approach for precise optogenetic control of neuronal firing rate modulation using feedback to guide stimulation continuously.
Using the rodent somatosensory thalamus as an experimental testbed for realizing desired time-varying patterns of firing rate modulation, we utilized a moving average exponential filter to estimate firing rate online from single-unit spiking measured extracellularly. This estimate of instantaneous rate served as feedback for a proportional integral (PI) controller, which was designed during the experiment based on a linear-nonlinear Poisson (LNP) model of the neuronal response to light.
The LNP model fit during the experiment enabled robust closed-loop control, resulting in good tracking of sinusoidal and non-sinusoidal targets, and rejection of unmeasured disturbances. Closed-loop control also enabled manipulation of trial-to-trial variability.
Because neuroscientists are faced with the challenge of dissecting the functions of circuit components, the ability to maintain control of a region of interest in spite of changes in ongoing neural activity will be important for disambiguating function within networks. Closed-loop stimulation strategies are ideal for control that is robust to such changes, and the employment of continuous feedback to adjust stimulation in real-time can improve the quality of data collected using optogenetic manipulation.
控制神经活动除了为功能分离这些复杂现象背后的神经回路提供有力的框架外，还使得操纵感觉感知、认知过程和身体运动成为可能。在过去的十年中，由于能够靶向特定的细胞类型并双向调节神经活动，光遗传学刺激已成为理解神经回路功能的一个越来越重要和强大的工具。到目前为止，大多数刺激都是以开环或开/关闭环方式提供的，其中以前确定的刺激是由事件触发的。在这里，我们描述并演示了一种使用反馈连续指导刺激的设计方法，以实现对神经元发放率调制的精确光遗传学控制。
我们使用啮齿动物体感丘脑作为实验测试平台，以实现所需的发放率调制的时变模式，利用移动平均指数滤波器从体外测量的单个单元放电中在线估计发放率。该瞬时速率的估计值作为比例积分（PI）控制器的反馈，该控制器是根据神经元对光的线性-非线性泊松（LNP）模型在实验过程中设计的。
实验过程中的 LNP 模型拟合实现了鲁棒的闭环控制，导致对正弦和非正弦目标的良好跟踪，以及对未测量干扰的拒绝。闭环控制还允许对试验间变异性进行操作。
由于神经科学家面临着剖析回路元件功能的挑战，因此即使在持续神经活动发生变化的情况下，仍能够保持对感兴趣区域的控制，对于在网络中辨别功能将是重要的。闭环刺激策略非常适合对这种变化具有鲁棒性的控制，并且采用实时调整刺激的连续反馈可以提高使用光遗传学操作收集的数据的质量。
