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Journal ArticleDOI

Modulation of Rhythmic Activity in Mammalian Spinal Networks Is Dependent on Excitability State

01 Jan 2017-Vol. 4, Iss: 1
TL;DR: It is found that dopamine can evoke unique patterns of motor activity that are dependent on the excitability state of motor networks, and the data show in vertebrate systems that modulation is a two-way street and that modulatory actions are largely influenced by the network state.
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, nonrhythmic activity to multirhythmic, nonlocomotor 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 multirhythm evoked by a low concentration (15 µm) of 5-HT, suggesting that 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.
Citations
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Journal ArticleDOI
TL;DR: Evidence is provided in support of dedicated spinal network components that are controlled by excitatory D1 and inhibitory D2 receptors that is reminiscent of the classic dopaminergic indirect and direct pathway within the striatum, indicating that network state is an important factor that dictates receptor-specific and therefore dose-dependent control of neuromodulators on spinal network output.
Abstract: Dopamine is well known to regulate movement through the differential control of direct and indirect pathways in the striatum that express D1 and D2 receptors respectively. The spinal cord also expresses all dopamine receptors; however, how the specific receptors regulate spinal network output in mammals is poorly understood. We explore the receptor-specific mechanisms that underlie dopaminergic control of spinal network output of neonatal mice during changes in spinal network excitability. During spontaneous activity, which is a characteristic of developing spinal networks operating in a low excitability state, we found that dopamine is primarily inhibitory. We uncover an excitatory D1-mediated effect of dopamine on motoneurons and network output that also involves co-activation with D2 receptors. Critically, these excitatory actions require higher concentrations of dopamine; however, analysis of dopamine concentrations of neonates indicates that endogenous levels of spinal dopamine are low. Because endogenous levels of spinal dopamine are low, this excitatory dopaminergic pathway is likely physiologically-silent at this stage in development. In contrast, the inhibitory effect of dopamine, at low physiological concentrations is mediated by parallel activation of D2, D3, D4 and α2 receptors which is reproduced when endogenous dopamine levels are increased by blocking dopamine reuptake and metabolism. We provide evidence in support of dedicated spinal network components that are controlled by excitatory D1 and inhibitory D2 receptors that is reminiscent of the classic dopaminergic indirect and direct pathway within the striatum. These results indicate that network state is an important factor that dictates receptor-specific and therefore dose-dependent control of neuromodulators on spinal network output and advances our understanding of how neuromodulators regulate neural networks under dynamically changing excitability.

50 citations

Journal ArticleDOI
TL;DR: This work examines approach and avoidance behaviors and the circuits that lead to the production and arrest of locomotion, with an emphasis on descending modulation arising from various regions of the brainstem.
Abstract: Over the past decade there has been a renaissance in our understanding of spinal cord circuits; new technologies are beginning to provide key insights into descending circuits which project onto spinal cord central pattern generators. By integrating work from both the locomotor and animal behavioral fields, we can now examine context-specific control of locomotion, with an emphasis on descending modulation arising from various regions of the brainstem. Here we examine approach and avoidance behaviors and the circuits that lead to the production and arrest of locomotion.

48 citations


Cites background from "Modulation of Rhythmic Activity in ..."

  • ...It has also been shown that dopamine modulates mammalian spinal CPG networks (Barrière et al., 2004; Humphreys andWhelan, 2012; Sharples et al., 2015; Picton et al., 2017; Sharples, 2017; Sharples and Whelan, 2017)....

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Journal ArticleDOI
TL;DR: It is demonstrated that spasms are generated in part by sensory activation of V3 neurons and associated CPG circuits and thus provide a promising target for restoring residual motor function.
Abstract: We investigated whether locomotor-related excitatory interneurons (V3) play a role in coordinating muscle spasm activity after spinal cord injury (SCI). Unexpectedly, we found that these neurons no...

33 citations


Cites background from "Modulation of Rhythmic Activity in ..."

  • ...More generally, by spasms engaging V3 neurons, the whole CPG may also be engaged in evoking spasms, an idea we also investigated by facilitating CPG activity with N-methyl-D-aspartate (NMDA) (Sharples and Whelan 2017)....

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Journal ArticleDOI
TL;DR: The data show that photostimulation of ChR2 transfected neurons in the A11 region enhances motor activity often leading to locomotion, and this monoaminergic-based motor circuit may be involved in the control of motor behavior as part of a broader diencephalic motor region.
Abstract: Limbic brain regions drive goal-directed behaviors. These behaviors often require dynamic motor responses, but the functional connectome of limbic structures in the diencephalon that control locomotion is not well known. The A11 region, within the posterior diencephalon has been postulated to contribute to motor function and control of pain. Here we show that the A11 region initiates movement. Photostimulation of channelrhodopsin 2 (ChR2) transfected neurons in A11 slice preparations showed that neurons could follow stimulation at frequencies of 20 Hz. Our data show that photostimulation of ChR2 transfected neurons in the A11 region enhances motor activity often leading to locomotion. Using vGluT2-reporter and vGAT-reporter mice we show that the A11 tyrosine hydroxylase positive (TH) dopaminergic neurons are vGluT2 and vGAT negative. We find that in addition to dopaminergic neurons within the A11 region, there is another neuronal subtype which expresses the monoenzymatic aromatic L-amino acid decarboxylase (AADC), but not TH, a key enzyme involved in the synthesis of catecholamines including dopamine. This monoaminergic-based motor circuit may be involved in the control of motor behavior as part of a broader diencephalic motor region.

26 citations

Journal ArticleDOI
TL;DR: Both the coherent and controversial aspects of 5-HT modulation of locomotor activity from basal vertebrates to mammals are highlighted, which may inspire future studies aiming at dissecting the complex effects of5-HT on locomotor function.
Abstract: During the last 50 years, the serotonergic (5-HT) system was reported to exert a complex modulation of locomotor activity. Here, we focus on two key factors that likely contribute to such complexity. First, locomotion is modulated directly and indirectly by 5-HT neurons. The locomotor circuitry is directly innervated by 5-HT neurons in the caudal brainstem and spinal cord. Also, indirect control of locomotor activity results from ascending projections of 5-HT cells in the rostral brainstem that innervate multiple brain centers involved in motor action planning. Second, each approach used to manipulate the 5-HT system likely engages different 5-HT-dependent mechanisms. This includes the recruitment of different 5-HT receptors, which can have excitatory or inhibitory effects on cell activity. These receptors can be located far or close to the 5-HT release sites, making their activation dependent on the level of 5-HT released. Here we review the activity of different 5-HT nuclei during locomotor activity, and the locomotor effects of 5-HT precursors, exogenous 5-HT, selective 5-HT reuptake inhibitors (SSRI), electrical or chemical stimulation of 5-HT neurons, genetic deletions, optogenetic and chemogenetic manipulations. We highlight both the coherent and controversial aspects of 5-HT modulation of locomotor activity from basal vertebrates to mammals. This mini review may hopefully inspire future studies aiming at dissecting the complex effects of 5-HT on locomotor function.

19 citations

References
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Journal ArticleDOI
01 Nov 1991-Science
TL;DR: The respiratory rhythm in the mammalian neonatal nervous system may result from a population of conditional bursting pacemaker neurons in the pre-Bötzinger Complex.
Abstract: The location of neurons generating the rhythm of breathing in mammals is unknown. By microsection of the neonatal rat brainstem in vitro, a limited region of the ventral medulla (the pre-Botzinger Complex) that contains neurons essential for rhythmogenesis was identified. Rhythm generation was eliminated by removal of only this region. Medullary slices containing the pre-Botzinger Complex generated respiratory-related oscillations similar to those generated by the whole brainstem in vitro, and neurons with voltage-dependent pacemaker-like properties were identified in this region. Thus, the respiratory rhythm in the mammalian neonatal nervous system may result from a population of conditional bursting pacemaker neurons in the pre-Botzinger Complex.

2,015 citations

Journal ArticleDOI
TL;DR: It is found that virtually indistinguishable network activity can arise from widely disparate sets of underlying mechanisms, suggesting that there could be considerable animal-to-animal variability in many of the parameters that control network activity.
Abstract: Although common sense tells us that no two brains are identical, a series of experimental strategies has evolved, on the basis of studies into the influence of controlled variables on neuronal or network function, that are designed to remove the influence of the underlying variance in neuronal properties and synaptic strengths. These strategies include averaging or normalizing data and comparing each preparation to its own control before and after a treatment. Successful as these strategies may be, they implicitly assume that variability between preparations or animals is ‘experimental noise’ rather than an essential characteristic of the nervous system. We used computational models to study this underlying variability in synaptic strengths and neuronal properties in the production of a simple motor pattern. Specifically, we searched for combinations of synaptic strengths and intrinsic properties in threeneuron model networks that produced output patterns within the range of the pyloric rhythms generated by the stomatogastric ganglia of 99 lobsters (Homarus americanus). Here we argue that network output might be more tightly regulated than many of the underlying cellular and synaptic properties. Previous computational work using models of single neurons has shown that similar electrical activity can be achieved with varying combinations of ion channels in the neuron’s membrane 1–4 . Experimental measurements of single membrane currents in the same individually identified neurons in different preparations show severalfold ranges in conductance densities 2,3,5 . Together, these data suggest that individual neurons ‘tune’ themselves to achieve combinations of conductance densities that are consistent with a given target excitability 6–9 . This conceptual framework fits with the compensation that occurs after genetic manipulation of channelgene expression, as alterations in the expression of one channel may be compensated by changes in the density of one or more other channels 10 . We also argue that compensation may occur at the network level as well: that is, each animal’s network has a target activity level, and mechanisms exist that allow each animal to produce a target network performance despite having differing sets of synaptic strengths and intrinsic membrane properties. The present study supports this notion by demonstrating that similar and functional network behavior can result from widely differing combinations of intrinsic and synaptic properties. RESULTS The pyloric rhythm of the crustacean stomatogastric ganglion (STG) is an ideal test bed for studies of how network performance depends on the properties of the neurons and synapses within a functional circuit 11 . Unlike many preparations with relatively ill-defined outputs or connectivity, this ganglion has a small number of neurons and a stereotyped motor pattern, making it relatively easy to determine when and how network behavior is influenced by changes in synaptic strength or intrinsic membrane properties 12,13 .

1,001 citations

Journal ArticleDOI
Ole Kiehn1
TL;DR: The emergent themes from this research are that the locomotor networks have a modular organization with distinct transmitter and molecular codes and that their organization is reconfigured with changes to the speed of locomotion or changes in gait.
Abstract: In vertebrates, assemblies of neurons in the spinal cord generate the precise timing and patterning of locomotor movements. In this Review, Ole Kiehn examines the organization and operation of these spinal locomotor networks in limbed and non-limbed animals.

542 citations


"Modulation of Rhythmic Activity in ..." refers background in this paper

  • ...In vertebrates, neuronal networks within the spinal cord control rhythmic movements of the limbs and axial musculature to produce various forms of locomotion (Hultborn and Nielsen, 2007; Roberts et al., 2012; Kimura et al., 2013; Kiehn, 2016)....

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  • ...…motor behaviors mediate a number of functions essential to survival, including breathing (Smith et al., 1991; Baghdadwala et al., 2016), feeding (Blitz and Nusbaum, 2012; Stadele et al., 2015), and locomotion (Gordon and Whelan, 2006; Grillner et al., 2008; Sillar et al., 2014; Kiehn, 2016)....

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Journal ArticleDOI
TL;DR: Long descending axonal projections that contain hypocretin were found that innervate all levels of the spinal cord from cervical to sacral segments, as studied in mouse, rat, and human spinal cord and not previously described, suggesting that in addition to possible roles in feeding and endocrine regulation, the descending hypocrretin fiber system may play a role in modulation of sensory input.
Abstract: Hypocretin (orexin) is synthesized by neurons in the lateral hypothalamus and has been reported to increase food intake and regulate the neuroendocrine system. In the present paper, long descending axonal projections that contain hypocretin were found that innervate all levels of the spinal cord from cervical to sacral segments, as studied in mouse, rat, and human spinal cord and not previously described. High densities of axonal innervation are found in regions of the spinal cord related to modulation of sensation and pain, notably in the marginal zone (lamina 1). Innervation of the intermediolateral column and lamina 10 as well as strong innervation of the caudal region of the sacral cord suggest that hypocretin may participate in the regulation of both the sympathetic and parasympathetic parts of the autonomic nervous system. Double-labeling experiments in mice combining retrograde transport of diamidino yellow after spinal cord injections and immunocytochemistry support the concept that hypocretin-immunoreactive fibers in the cord originate from the neurons in the lateral hypothalamus. Digital-imaging physiological studies with fura-2 detected a rise in intracellular calcium in response to hypocretin in cultured rat spinal cord neurons, indicating that spinal cord neurons express hypocretin-responsive receptors. A greater number of cervical cord neurons responded to hypocretin than another hypothalamo-spinal neuropeptide, oxytocin. These data suggest that in addition to possible roles in feeding and endocrine regulation, the descending hypocretin fiber system may play a role in modulation of sensory input, particularly in regions of the cord related to pain perception and autonomic tone.

521 citations

Journal ArticleDOI
TL;DR: The role of serotonin (5‐HT) and excitatory amino‐acids (EAAs) in the activation of the neural networks (i.e. the central pattern generators) that organize locomotion in mammals was investigated in an isolated brainstem‐spinal cord preparation from the newborn rat.
Abstract: 1. The role of serotonin (5-HT) and excitatory amino-acids (EAAs) in the activation of the neural networks (i.e. the central pattern generators) that organize locomotion in mammals was investigated in an isolated brainstem-spinal cord preparation from the newborn rat. 2. The neuroactive substances were bath applied and the activity of fictive locomotion was recorded in the ventral roots. 3. Serotonin initiated an alternating pattern of right and left action potential bursts. The period of this rhythm was dose dependent, i.e. it decreased from around 10 s at 2 x 10(-5) M to 5 s at 10(-4) M. The effects of serotonin were blocked by a 5-HT1 antagonist (propranolol) and by 5-HT2 antagonists (ketanserin, cyproheptadine, mianserin). 5-HT3 antagonists were ineffective. The effects of methoxytryptamine, a non-selective 5-HT agonist, mimicked the 5-HT effects. 4. The endogenous EAAs, glutamate and aspartate, also triggered an alternating rhythmic pattern. Their effects were blocked by 2-amino-5-phosphonovaleric acid (AP-5; a N-methyl-D-aspartate (NMDA) receptor blocker) and 6,7-dinitro-quinoxaline-2,3-dione (a non-NMDA receptor blocker). 5. Several EAA agonists (N-methyl-D,L-aspartate (NMA) and kainate) initiated rhythmic activity. The period of the induced rhythm (from 3 to 1 s) was similar with both of these substances but in a range of concentrations which was ten times lower in the case of kainate (10(-6) to 5 x 10(-6) M) than in that of NMA (10(-5) to 4 x 10(-5) M). alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionate and quisqualate occasionally triggered some episodes of fictive locomotion with a threshold at 6 x 10(-7) and 10(-5) M, respectively.

459 citations


"Modulation of Rhythmic Activity in ..." refers background in this paper

  • ...8) and inferred a discrete modulatory function (Cazalets et al., 1992; Schmidt et al., 1998; Pearson et al., 2003; Gozal et al., 2014)....

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  • ...While different laboratories use varying concentrations of NMDA, 5-HT, or dopamine to elicit rhythmic activity (Cazalets et al., 1992; Whelan et al., 2000; Bonnot et al., 2002; Madriaga et al., 2004; Zhong et al., 2010, 2011; Sharples et al., 2015), what is of note is that once state 4 is reached…...

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  • ...While different laboratories use varying concentrations of NMDA, 5-HT, or dopamine to elicit rhythmic activity (Cazalets et al., 1992; Whelan et al., 2000; Bonnot et al., 2002; Madriaga et al., 2004; Zhong et al., 2010, 2011; Sharples et al., 2015), what is of note is that once state 4 is reached it is characterized by stable alternating bursting....

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