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Co‐modulation of the Na + /K + pump and hyperpolarization‐activated currents as a mechanism for robust neuromodulation
Author(s) -
Ellingson Parker,
Barnett William Halbert,
Vargas Alex,
Kueh Daniel,
Calabrese Ronald,
Cymbalyuk Gennady
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06762
Subject(s) - bursting , neuromodulation , central pattern generator , heartbeat , neuroscience , pacemaker potential , hyperpolarization (physics) , leech , stomatogastric ganglion , refractory period , interneuron , chemistry , biophysics , rhythm , membrane potential , inhibitory postsynaptic potential , physics , biology , computer science , central nervous system , medicine , computer security , organic chemistry , nuclear magnetic resonance spectroscopy , acoustics , world wide web
Specialized oscillatory circuits, central pattern generators (CPGs), control rhythmic motor behaviors such as locomotion and breathing. To accommodate a motor pattern to environmental changes and behavioral goals, neuromodulators adjust the dynamics of CPGs by orchestrating changes in various ionic currents in a wide range of their biophysical parameters to expand temporal characteristics of the functional pattern. Recent studies provide evidence that the Na + /K + pump contributes to the dynamics of CPGs and is controlled by neuromodulation [1– 4]. In the leech heartbeat CPG, the neuropeptide myomodulin reduces the period of bursting activity by increasing the hyperpolarization‐activated (h)‐current and decreasing the Na + /K + pump current [4]. The application of myomodulin reduces the period of oscillatory activity by 17%. Application of Cs + , which is an h‐current blocker, increases the period of bursting by 24% relative to control. The application of myomodulin along with Cs + decreases the period by 12% relative to treatment with Cs + [4]. Here we investigate how the period of a bursting can be controlled in a wide range while functional bursting is maintained with a focus on the role of the Na + /K + pump. We also investigate the risk associated with multistability in neuronal dynamics. We optimized a model of the leech heart interneuron (HN), which includes the Na + /K + pump current and intracellular Na + dynamics [1] and investigated the activity regimes of pairs of mutually inhibitory coupled HNs forming half‐center oscillators (HCOs). HCOs form the kernel of the leech heartbeat CPG. We investigated eight model variants representing combinations of three experimental treatments: the blockade of chemical synapses representing the application of bicuculline, the blockade of h‐current representing the application of Cs + , and the enhancement of the h‐current and inhibition of the Na + /K + pump current representing the application of myomodulin. The model captures the qualitative trends in change of cycle period observed in experiments with myomodulin and Cs + . We found ranges of parameters where neurons showed functional bursting. The coordinated changes of maximal conductance of h‐current (G h ) and maximal pump activity (I PumpMax ) increases the range of period of functional bursting as well as the range of parameters G h and I PumpMax . We hypothesize that myomodulin co‐modulates h‐ and pump currents to expand the domain of the functional activity. Support or Funding Information Supported by NINDS 1 R01 NS085006 to RLC and 1 R21 NS111355 to RLC and GSC.References 1 Kueh D , Barnett WH , Cymbalyuk GS , Calabrese RL ( 2016 ) Na(+)/K(+) pump interacts with the h-current to control bursting activity in central pattern generator neurons of leeches . Elife 5 . 2 Picton LD , Nascimento F , Broadhead MJ , Sillar KT , and Miles GB ( 2017 ) Sodium Pumps Mediate Activity-Dependent Changes in Mammalian Motor Networks . J Neurosci 37 : 906 – 921 . 3 Sharples , SA , & Whelan PJ ( 2017 ) Modulation of rhythmic activity in mammalian spinal networks is dependent on excitability state . eNeuro , 4 ( 1 ). 4 Tobin AE , Calabrese RL ( 2005 ) Myomodulin increases I h and inhibits the Na/K pump to modulate bursting in leech heart interneurons . J Neurophysiol , 94 ( 6 ): 3938 – 3950 .