Abstract
Neuromodulators play an important role in activating rhythmically-active motor networks; however, what remains unclear are the network interactions whereby neuromodulators recruit spinal motor networks to produce rhythmic activity. Evidence from invertebrate systems has demonstrated that the effect of neuromodulators depends on the pre-existing state of the network. We explored how network excitation state affects the ability of dopamine to evoke rhythmic locomotor activity in the neonatal mouse isolated spinal cord. We found that dopamine can evoke unique patterns of motor activity that are dependent on the excitability state of motor networks. Different patterns of motor activity ranging from tonic, non-rhythmic activity to multi-rhythmic, non-locomotor activity to locomotor activity were produced by altering global motor network excitability through manipulations of the extracellular potassium and bath NMDA concentration. A similar effect was observed when network excitation was manipulated during an unstable multi-rhythm evoked by a low concentration (15 µM) of 5-HT – suggesting our results are not neuromodulator specific. Our data show in vertebrate systems that modulation is a two-way street and that modulatory actions are largely influenced by the network state. The level of network excitation can account for variability between preparations and is an additional factor to be considered when circuit elements are removed from the network.
Significance Statement: We show that as in the invertebrate systems the action of monoamine modulators on rhythmic motor networks of the mammalian spinal cord is state-dependent. Our work shows that neuromodulation in the spinal cord is fundamentally linked to the excitability state of the network. These findings have broad significance on mammalian network function since variations in network excitation can account for 1) diversity of neuromodulator function, 2) is an additional factor that must be considered when circuit elements are removed from a network to infer network function and 3) can account for variability often found between experimental preparations.
Footnotes
Authors report no conflict of interest.
Authors Contributions: S.A.S performed experiments and analyzed the data. S.A.S., and P.J.W. interpreted results of experiments, prepared figures, drafted, revised the manuscript and approved the final version of the manuscript. P.J.W. conceived and designed the research.
Funding for S.A.S was provided by the Natural Sciences and Engineering Research Council of Canada (NSERC-PGS-D), Alberta Innovates Health Solutions (AIHS), and a Dr. T. Chen Fong Doctoral Scholarship from the Hotchkiss Brain Institute. This research is supported by grants provided by the Canadian Institute of Health Research (P.J.W) and a NSERC Discovery grant (P.J.W).
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