PT  - JOURNAL ARTICLE
AU  - Simon A. Sharples
AU  - Patrick J. Whelan
TI  - Modulation of rhythmic activity in mammalian spinal networks is dependent on excitability state
AID  - 10.1523/ENEURO.0368-16.2017
DP  - 2017 Jan 19
TA  - eneuro
PG  - ENEURO.0368-16.2017
4099  - http://www.eneuro.org/content/early/2017/01/19/ENEURO.0368-16.2017.short
4100  - http://www.eneuro.org/content/early/2017/01/19/ENEURO.0368-16.2017.full
AB  - 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.