Neuroscience Institute, Georgia State University, Atlanta, Georgia 30303.
Department of Biology, Emory University, Atlanta, Georgia 30322.
J Neurosci. 2021 Jul 28;41(30):6468-6483. doi: 10.1523/JNEUROSCI.0158-21.2021. Epub 2021 Jun 8.
Central pattern generators (CPGs), specialized oscillatory neuronal networks controlling rhythmic motor behaviors such as breathing and locomotion, must adjust their patterns of activity to a variable environment and changing behavioral goals. Neuromodulation adjusts these patterns by orchestrating changes in multiple ionic currents. In the medicinal leech, the endogenous neuromodulator myomodulin speeds up the heartbeat CPG by reducing the electrogenic Na/K pump current and increasing h-current in pairs of mutually inhibitory leech heart interneurons (HNs), which form half-center oscillators (HN HCOs). Here we investigate whether the comodulation of two currents could have advantages over a single current in the control of functional bursting patterns of a CPG. We use a conductance-based biophysical model of an HN HCO to explain the experimental effects of myomodulin. We demonstrate that, in the model, comodulation of the Na/K pump current and h-current expands the range of functional bursting activity by avoiding transitions into nonfunctional regimes, such as asymmetric bursting and plateau-containing seizure-like activity. We validate the model by finding parameters that reproduce temporal bursting characteristics matching experimental recordings from HN HCOs under control, three different myomodulin concentrations, and Cs treated conditions. The matching cases are located along the border of an asymmetric regime away from the border with more dangerous seizure-like activity. We found a simple comodulation mechanism with an inverse relation between the pump and h-currents makes a good fit of the matching cases and comprises a general mechanism for the robust and flexible control of oscillatory neuronal networks. Rhythm-generating neuronal circuits adjust their oscillatory patterns to accommodate a changing environment through neuromodulation. In different species, chemical messengers participating in such processes may target two or more membrane currents. In medicinal leeches, the neuromodulator myomodulin speeds up the heartbeat central pattern generator by reducing Na/K pump current and increasing h-current. In a computational model, we show that this comodulation expands the range of central pattern generator's functional activity by navigating the circuit between dysfunctional regimes resulting in a much wider range of cycle period. This control would not be attainable by modulating only one current, emphasizing the synergy of combined effects. Given the prevalence of h-current and Na/K pump current in neurons, similar comodulation mechanisms may exist across species.
中央模式发生器 (CPG) 是一种专门的振荡神经元网络,可控制呼吸和运动等节律性运动行为,它必须根据可变的环境和不断变化的行为目标调整其活动模式。神经调制通过协调多种离子电流的变化来调整这些模式。在医用水蛭中,内源性神经调质肌抑肽通过减少电致 Na/K 泵电流并增加相互抑制的水蛭心脏中间神经元 (HN) 中的 h 电流来加速心跳 CPG,这些 HN 形成半中心振荡器 (HN HCO)。在这里,我们研究了在控制 CPG 的功能性爆发模式方面,两种电流的共调制是否比单一电流具有优势。我们使用 HN HCO 的基于电导率的生物物理模型来解释肌抑肽的实验效应。我们证明,在该模型中,Na/K 泵电流和 h 电流的共调制通过避免过渡到非功能状态(例如非对称爆发和含有平台的癫痫样活动)来扩展功能爆发活动的范围。我们通过找到与在控制、三种不同肌抑肽浓度和 Cs 处理条件下从 HN HCO 记录的时间爆发特征匹配的参数来验证模型。匹配的情况位于远离更危险的癫痫样活动边界的非对称状态边界沿线。我们发现了一种简单的共调制机制,泵电流和 h 电流之间存在反比关系,这种机制很好地适应了匹配情况,并构成了一种用于振荡神经元网络的稳健和灵活控制的一般机制。产生节律的神经元电路通过神经调制来调整其振荡模式以适应不断变化的环境。在不同的物种中,参与这些过程的化学信使可能针对两种或更多种膜电流。在医用水蛭中,神经调质肌抑肽通过减少 Na/K 泵电流并增加 h 电流来加速心跳中央模式发生器。在计算模型中,我们表明这种共调制通过在导致周期更长的功能失调状态之间进行导航,扩展了中央模式发生器的功能活动范围。仅通过调节一个电流是无法实现这种控制的,这强调了联合效应的协同作用。鉴于 h 电流和 Na/K 泵电流在神经元中的普遍性,类似的共调制机制可能存在于不同的物种中。