Ellingson Parker J, Shams Yousif O, Parker Jessica R, Calabrese Ronald L, Cymbalyuk Gennady S
Neuroscience Institute, Georgia State University, Atlanta, GA, United States.
Department of Biology, Emory University, Atlanta, GA, United States.
Front Cell Neurosci. 2024 Sep 17;18:1395026. doi: 10.3389/fncel.2024.1395026. eCollection 2024.
For animals to meet environmental challenges, the activity patterns of specialized oscillatory neural circuits, central pattern generators (CPGs), controlling rhythmic movements like breathing and locomotion, are adjusted by neuromodulation. As a representative example, the leech heartbeat is controlled by a CPG driven by two pairs of mutually inhibitory interneurons, heart interneuron (HN) half-center oscillators (HCO). Experiments and modeling indicate that neuromodulation of HCO navigates this CPG between dysfunctional regimes by employing a co-regulating inverted relation; reducing Na/K pump current and increasing hyperpolarization-activated (h-) current. Simply reducing pump activity or increasing h-current leads to either seizure-like bursting or an asymmetric bursting dysfunctional regime, respectively. Here, we demonstrate through modeling that, alongside this coregulation path, a new bursting regime emerges. Both regimes fulfill the criteria for functional bursting activity. Although the cycle periods and burst durations of these patterns are roughly the same, the new one exhibits an intra-burst spike frequency that is twice as high as the other. This finding suggests that neuromodulation could introduce additional functional regimes with higher spike frequency, and thus more effective synaptic transmission to motor neurons. We found that this new regime co-exists with the original bursting. The HCO can be switched between them by a short pulse of excitatory or inhibitory conductance. In this domain of coexisting functional patterns, an isolated cell model exhibits only one regime, a severely dysfunctional plateau-containing, seizure-like activity. This aligns with widely reported notion that deficiency of inhibition can cause seizures and other dysfunctional neural activities. We show that along the coregulation path of neuromodulation, the high excitability of the single HNs induced by myomodulin is harnessed by mutually inhibitory synaptic interactions of the HCO into the functional bursting pattern.
为了应对环境挑战，动物会通过神经调节来调整专门的振荡神经回路（即控制呼吸和运动等节律性运动的中枢模式发生器，CPG）的活动模式。作为一个典型例子，水蛭的心跳由一个CPG控制，该CPG由两对相互抑制的中间神经元（心脏中间神经元，HN）半中枢振荡器（HCO）驱动。实验和建模表明，HCO的神经调节通过采用共同调节的反向关系，使该CPG在功能失调状态之间转换；降低钠钾泵电流并增加超极化激活（h-）电流。单纯降低泵活性或增加h电流分别会导致癫痫样爆发或不对称爆发功能失调状态。在此，我们通过建模证明，除了这条共同调节路径外，还出现了一种新的爆发状态。这两种状态都符合功能性爆发活动的标准。尽管这些模式的周期和爆发持续时间大致相同，但新的模式在爆发内的尖峰频率是另一种模式的两倍。这一发现表明，神经调节可能会引入具有更高尖峰频率的额外功能状态，从而实现更有效的向运动神经元的突触传递。我们发现这种新模式与原始爆发状态共存。通过短脉冲的兴奋性或抑制性电导，可以使HCO在它们之间切换。在这个共存功能模式的领域中，一个孤立细胞模型只表现出一种状态，即严重功能失调的含有平台期的癫痫样活动。这与广泛报道的观点一致，即抑制不足会导致癫痫发作和其他功能失调的神经活动。我们表明，在神经调节的共同调节路径上，由肌调蛋白诱导的单个HN的高兴奋性通过HCO的相互抑制性突触相互作用被转化为功能性爆发模式。
