Consistent neural circuit output through convergent co-modulation

神经调节剂调节神经元和突触的属性，为神经回路的活动和行为提供灵活性。调节器受体和离子通道等调节器靶标的表达在不同个体之间可能有相当大的差异。面对这种变化，电路输出以及调制器如何塑造电路输出需要稳定和一致。因此，神经调节不仅提供灵活性，还需要确保稳定和一致的电路激活。神经回路在任何时候都可能受到多个调节器的控制，因此了解它们如何在亚细胞和细胞靶点以及在电路活动的水平上相互作用是很重要的。提出共调制是影响输出一致性的一种机制，旨在首次分析共调制对电路活动的灵活性和稳健性的影响，不同的调制器可能针对特定的神经元子集，从而产生特定的电路输出。除了这种细胞类型的差异外，它们还可能针对给定神经元中的不同亚细胞成分。然而，许多调制器汇聚到相同的目标上。如果每个调制器对同一靶点的影响在不同个体之间独立不同，则共调制可能通过平均变异性而导致一致的反应。我将使用螃蟹口胃神经节的有节奏活动的幽门回路来检验收敛调制降低电路输出变异性的假设。调节剂在多个层面上影响电路：固有离子电导和突触离子电导的组成水平，突触强度和神经元兴奋性的细胞水平，以及电路活性水平。我将在所有水平上测量不同共调节条件下的个体间变异性，以了解每个水平的变异性是否降低，以及电路输出变异性的降低是否源于组件变异性的降低。我将使用三种神经肽，它们影响幽门回路中重叠的神经元亚群。在有两到三个这些多肽受体的神经元中，它们会聚到相同的电压门控电流上，从而增加神经元的兴奋性。此外，它们会汇聚到突触上并加强突触。这些多肽的单独作用得到了很好的描述，但它们对元件和电路输出变异性的共同调制效应尚未被研究。除了监测电路活动外，我还将进行电压和电流钳实验，以检查离子电流的可变性，以及神经元的兴奋性和突触功能。我将使用动态钳位来模拟调制器激活的电导，以检查它们在减少变异性方面的作用。这些实验提供的关于共同调节作用的知识为所有神经系统，包括哺乳动物大脑的大型网络，提供了一种新的视角和方法来理解神经系统活动的稳健性，从而对所有神经系统都产生了影响。

Neuromodulators tune neuronal and synaptic properties to provide flexibility to neural circuit activity and behavior. Expression of modulator receptors, and of modulator targets like ion channels, can vary considerably across individuals. Circuit output, and how modulators shape it, needs to be stable and consistent in the face of this variability. Therefore, neuromodulation does not just provide flexibility, but also needs to ensure stable and consistent circuit activation. Neural circuits are likely under control of multiple modulators at any time, making it important to understand how they interact at subcellular and cellular targets, and at the level of circuit activity. I propose that co-modulation is one mechanism underlying output consistency, aiming to provide a first analysis of co-modulatory effects on the flexibility and robustness of circuit activity.Different modulators may target specific subsets of neurons, and hence elicit a specific circuit output. In addition to this divergence across cell types, they may target different subcellular components in a given neuron. However, many modulators converge onto the same targets. If the effects of each modulator on a common target vary independently across individuals, co-modulation may lead to consistent responses by averaging out variability.I will test the hypothesis that convergent modulation reduces circuit output variability using the rhythmically active pyloric circuit of the crab stomatogastric ganglion. Modulators influence circuits at multiple levels: the component level of intrinsic and synaptic ionic conductances, the cellular level of synaptic strength and neuronal excitability, and the circuit activity level. I will measure interindividual variability in different co-modulatory conditions at all levels to understand whether variability is reduced at each level, and if a reduction of circuit output variability emerges from reduced component variability.I will use three neuropeptides, which affect overlapping subsets of neurons in the pyloric circuit. In neurons with receptors to two or three of these peptides, they converge onto the same voltage-gated current that increases neuron excitability. In addition, they converge onto and strengthen synapses. The individual actions of the peptides are well described, but their co-modulatory effects on component and circuit output variability have not been investigated. In addition to monitoring circuit activity, I will conduct voltage- and current-clamp experiments to examine the variability of ionic currents, as well as neuron excitability and synaptic function. I will use the dynamic clamp to mimic modulator-activated conductances to examine their role in reducing variability. The knowledge of co-modulatory actions provided by these experiments has ramifications for all neural systems, including large networks of the mammalian brain, by providing a novel viewpoint and approach to understand robustness of nervous system activity.