A central pattern generator in the spinal cord for the central control of micturition: An opportunity for first-in-class drug treatments

Motoneurons are traditionally viewed as the output of the spinal cord that do not influence locomotor rhythmogenesis. We assessed the role of motoneuron firing during ongoing locomotor-like activity in neonatal mice expressing archaerhopsin-3 (Arch), halorhodopsin (eNpHR), or channelrhodopsin-2 (ChR2) in Choline acetyltransferase neurons (ChAT+) or Arch in LIM-homeodomain transcription factor Isl1+ neurons. Illumination of the lumbar cord in mice expressing eNpHR or Arch in ChAT+ or Isl1+ neurons, depressed motoneuron discharge, transiently decreased the frequency, and perturbed the phasing of the locomotor-like rhythm. When the light was turned off motoneuron firing and locomotor frequency both transiently increased. These effects were not due to cholinergic neurotransmission, persisted during partial blockade of gap junctions and were mediated, in part, by AMPAergic transmission. In spinal cords expressing ChR2, illumination increased motoneuron discharge and transiently accelerated the rhythm. We conclude that motoneurons provide feedback to the central pattern generator (CPG) during drug-induced locomotor-like activity.

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Cholinergic contribution to excitation in a spinal locomotor central pattern generator in Xenopus embryos

Journal of Neurophysiology ◽

10.1152/jn.1995.73.3.1013 ◽

1995 ◽

Vol 73 (3) ◽

pp. 1013-1019 ◽

Cited By ~ 46

Author(s):

R. Perrins ◽

A. Roberts

Keyword(s):

Spinal Cord ◽

Central Pattern Generator ◽

Excitatory Amino Acid ◽

Pattern Generator ◽

Excitatory Input ◽

Intracellular Recordings ◽

Electrical Excitation ◽

Spinal Interneurons ◽

Xenopus Embryos ◽

Spike Firing

1. We have investigated whether in Xenopus embryos, spinal interneurons of the central pattern generator (CPG) receive cholinergic or electrical excitatory input during swimming. The functions of cholinergic excitation during swimming were also investigated. 2. Intracellular recordings were made from rhythmically active presumed premotor interneurons in the dorsal third of the spinal cord. After locally blocking inhibitory potentials with 2 microM strychnine and 40 microM bicuculline, the reliability of spike firing and the amplitude of fast, on-cycle, excitatory postsynaptic potentials (EPSPs) underlying the single on-cycle spikes were measured during fictive swimming. 3. The nicotinic antagonists d-tubocurarine and dihydro-beta-erythroidine (DH beta E, both 10 microM) reversibly reduced the reliability of the spike firing during swimming and reduced the amplitude of the on-cycle EPSP by 16%. DH beta E also reduced the EPSP amplitude in spinalized embryos by 22%. These results indicate that interneurons receive rhythmic cholinergic excitation from a source within the spinal cord. 4. Combined applications of nicotinic and excitatory amino acid (EAA) antagonists or cadmium (Cd2+, 100-200 microM) resulted in complete block of the fast EPSP, suggesting that interneurons do not receive electrical excitation. 5. The nicotinic antagonists mecamylamine and d-tubocurarine (both 5 microM) reduced the duration of episodes of fictive swimming recorded from the ventral roots, in spinal embryos. When applied in the middle of a long episode, d-tubocurarine decreased the swimming frequency, ruling out an effect on the initiation pathway. The cholinesterase inhibitor eserine (10 microM) increased the duration of swimming episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

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Isoflurane Disrupts Central Pattern Generator Activity and Coordination in the Lamprey Isolated Spinal Cord

Anesthesiology ◽

10.1097/00000542-200509000-00020 ◽

2005 ◽

Vol 103 (3) ◽

pp. 567-575 ◽

Cited By ~ 24

Author(s):

Steven L. Jinks ◽

Richard J. Atherley ◽

Carmen L. Dominguez ◽

Karen A. Sigvardt ◽

Joseph F. Antognini

Keyword(s):

Spinal Cord ◽

Central Pattern Generator ◽

Motor Neurons ◽

Central Pattern Generators ◽

Volatile Anesthetics ◽

Pattern Generator ◽

Motor Output ◽

Petroleum Jelly ◽

Burst Frequency ◽

Generator Activity

Background Although volatile anesthetics such as isoflurane can depress sensory and motor neurons in the spinal cord, movement occurring during anesthesia can be coordinated, involving multiple limbs as well as the head and trunk. However, it is unclear whether volatile anesthetics depress locomotor interneurons comprising central pattern generators or disrupt intersegmental central pattern generator coordination. Methods Lamprey spinal cords were excised during anesthesia and placed in a bath containing artificial cerebrospinal fluid and D-glutamate to induce fictive swimming. The rostral, middle, and caudal regions were bath-separated using acrylic partitions and petroleum jelly, and in each compartment, the authors recorded ventral root activity. The authors selectively delivered isoflurane (0.5, 1, and 1.5%) only to the middle segments of the spinal cord. Spectral analyses were then used to assess isoflurane effects on central pattern generator activity and coordination. Results Isoflurane dose-dependently reduced fictive locomotor activity in all three compartments, with 1.5% isoflurane nearly eliminating activity in the middle compartment and reducing spectral amplitudes in the anesthetic-free rostral and caudal compartments to 23% and 31% of baseline, respectively. Isoflurane decreased burst frequency in the caudal compartment only, to 53% of baseline. Coordination of central pattern generator activity between the rostral and caudal compartments was also dose-dependently decreased, to 42% of control at 1.5% isoflurane. Conclusion Isoflurane disrupts motor output by reducing interneuronal central pattern generator activity in the spinal cord. The effects of isoflurane on motor output outside the site of isoflurane application were presumably independent of effects on sensory or motor neurons.

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Opposing modulatory effects of D1- and D2-like receptor activation on a spinal central pattern generator

Journal of Neurophysiology ◽

10.1152/jn.00366.2011 ◽

2012 ◽

Vol 107 (8) ◽

pp. 2250-2259 ◽

Cited By ~ 49

Author(s):

S. Clemens ◽

A. Belin-Rauscent ◽

J. Simmers ◽

D. Combes

Keyword(s):

Spinal Cord ◽

Central Pattern Generator ◽

Sch 23390 ◽

Receptor Activation ◽

Pattern Generator ◽

High Concentration ◽

Bath Application ◽

D1 Agonist ◽

Rhythmic Behaviors

The role of dopamine in regulating spinal cord function is receiving increasing attention, but its actions on spinal motor networks responsible for rhythmic behaviors remain poorly understood. Here, we have explored the modulatory influence of dopamine on locomotory central pattern generator (CPG) circuitry in the spinal cord of premetamorphic Xenopus laevis tadpoles. Bath application of exogenous dopamine to isolated brain stem-spinal cords exerted divergent dose-dependent effects on spontaneous episodic patterns of locomotory-related activity recorded extracellularly from spinal ventral roots. At low concentration (2 μM), dopamine reduced the occurrence of bursts and fictive swim episodes and increased episode cycle periods. In contrast, at high concentration (50 μM) dopamine reversed its actions on fictive swimming, now increasing both burst and swim episode occurrences while reducing episode periods. The low-dopamine effects were mimicked by the D2-like receptor agonists bromocriptine and quinpirole, whereas the D1-like receptor agonist SKF 38393 reproduced the effects of high dopamine. Furthermore, the motor response to the D1-like antagonist SCH 23390 resembled that to the D2 agonists, whereas the D2-like antagonist raclopride mimicked the effects of the D1 agonist. Together, these findings indicate that dopamine plays an important role in modulating spinal locomotor activity. Moreover, the transmitter's opposing influences on the same target CPG are likely to be accomplished by a specific, concentration-dependent recruitment of independent D2- and D1-like receptor signaling pathways that differentially mediate inhibitory and excitatory actions.

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Shining light into the black box of spinal locomotor networks

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2009.0322 ◽

2010 ◽

Vol 365 (1551) ◽

pp. 2383-2395 ◽

Cited By ~ 21

Author(s):

Patrick J. Whelan

Keyword(s):

Spinal Cord ◽

Central Pattern Generator ◽

Rhythmic Activity ◽

Pattern Generator ◽

Black Box ◽

Motor Functions ◽

Network Function ◽

Stepping Pattern

Rhythmic activity is responsible for numerous essential motor functions including locomotion, breathing and chewing. In the case of locomotion, it has been realized for some time that the spinal cord contains sufficient circuitry to produce a sophisticated stepping pattern. However, the central pattern generator for locomotion in mammals has remained a ‘black box’ where inputs to the network were manipulated and the outputs interpreted. Over the last decade, new genetic approaches and techniques have been developed that provide ways to identify and manipulate the activity of classes of interneurons. The use of these techniques will be critically discussed and related to current models of network function.

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