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• W1972446274 abstract "A recent study has used optogenetics to identify the source of excitatory drive for locomotion in zebrafish, revealing unexpected differences in the command signals from hindbrain to spinal cord. A recent study has used optogenetics to identify the source of excitatory drive for locomotion in zebrafish, revealing unexpected differences in the command signals from hindbrain to spinal cord. As the saying goes, seeing is believing. If this is true, then optogenetic analysis of neural circuitry in transparent zebrafish should convert even the most skeptical neuroscientists. The arrival of optogenetic technology has revolutionized functional studies of the nervous system [1Gross M. Shining new light on the brain.Curr. Biol. 2011; 21: R831-R833PubMed Scopus (3) Google Scholar, 2Deisseroth K. Feng G. Majewska A.K. Miesenbock G. Ting A. Schnitzer M.J. Next-generation optical technologies for illuminating genetically targeted brain circuits.J. Neurosci. 2006; 26: 10380-10386Crossref PubMed Scopus (566) Google Scholar]. Neural activity can now be precisely controlled in freely behaving animals by simply illuminating light-sensitive actuators expressed in different groups of neurons. In this issue, Kimura and colleagues [3Kimura Y. Satou C. Fujioka S. Shoji W. Umeda K. Ishizuka T. Yawo H. Higashijima S. Hindbrain V2a neurons in the excitation of spinal locomotor circuits during zebrafish swimming.Curr. Biol. 2013; 23: 843-849Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar] report how the use of optogenetics in zebrafish allowed them to identify a population of neurons in the hindbrain that enable locomotion. They went on to use electrophysiology to demonstrate unexpected heterogeneity in the locomotor command signals from neurons within this population to spinal cord. Before launching into their experiments, it will help to briefly cover some basic principles of spinal cord development. All vertebrate locomotor networks are assembled from cells arising from one of four postmitotic domains in spinal cord, numbered V0–V3 [4Arber S. Motor circuits in action: specification, connectivity, and function.Neuron. 2012; 74: 975-989Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 5Goulding M. Circuits controlling vertebrate locomotion: moving in a new direction.Nat. Rev. Neurosci. 2009; 10: 507-518Crossref PubMed Scopus (535) Google Scholar]. Neurons in each domain can be identified by the expression of specific transcription factors that regulate gene expression (Figure 1). The new work described here focuses on cells arising from the V2 region, more specifically those marked by the transcription factor Chx10 (V2a neurons). In the zebrafish spinal cord, these neurons provide rhythmic excitatory drive to motoneurons on the same side of the body during locomotion [6Kimura Y. Okamura Y. Higashijima S. alx, a zebrafish homolog of Chx10, marks ipsilateral descending excitatory interneurons that participate in the regulation of spinal locomotor circuits.J. Neurosci. 2006; 26: 5684-5697Crossref PubMed Scopus (221) Google Scholar, 7Eklof-Ljunggren E. Haupt S. Ausborn J. Dehnisch I. Uhlen P. Higashijima S. El Manira A. Origin of excitation underlying locomotion in the spinal circuit of zebrafish.Proc. Natl. Acad. Sci. USA. 2012; 109: 5511-5516Crossref PubMed Scopus (65) Google Scholar]. However, V2a neurons also extend from the spinal cord well into the brain [6Kimura Y. Okamura Y. Higashijima S. alx, a zebrafish homolog of Chx10, marks ipsilateral descending excitatory interneurons that participate in the regulation of spinal locomotor circuits.J. Neurosci. 2006; 26: 5684-5697Crossref PubMed Scopus (221) Google Scholar]. Although hindbrain V2a cells share a number of morphological features with spinal ones [8Kinkhabwala A. Riley M. Koyama M. Monen J. Satou C. Kimura Y. Higashijima S. Fetcho J. A structural and functional ground plan for neurons in the hindbrain of zebrafish.Proc. Natl. Acad. Sci. USA. 2011; 108: 1164-1169Crossref PubMed Scopus (141) Google Scholar], until now their contribution to locomotion was largely a mystery. In all vertebrates, including zebrafish, spinal networks generate locomotion, but it is descending commands from the brain that decide when to move, where to move and for how long [9Le Ray D. Juvin L. Ryczko D. Dubuc R. Supraspinal control of locomotion: the mesencephalic locomotor region.Prog. Brain Res. 2011; 188: 51-70Crossref PubMed Scopus (56) Google Scholar]. Kimura et al. [3Kimura Y. Satou C. Fujioka S. Shoji W. Umeda K. Ishizuka T. Yawo H. Higashijima S. Hindbrain V2a neurons in the excitation of spinal locomotor circuits during zebrafish swimming.Curr. Biol. 2013; 23: 843-849Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar] took advantage of the conserved genetic coding of neuronal identity to explore whether hindbrain V2a cells represent a well-known source of descending ‘reticulo-spinal’ drive during locomotion. There are two obvious predictions if hindbrain V2a cells are responsible for activating and sustaining locomotion in zebrafish: if you stimulate hindbrain V2a cells, the fish should swim; if you silence the cells, they should stop. These predictions are tailor-made for optogenetic evaluation and reflect the gold standard for assessing the contribution of neurons to behavior, namely sufficiency and necessity. Kimura et al. [3Kimura Y. Satou C. Fujioka S. Shoji W. Umeda K. Ishizuka T. Yawo H. Higashijima S. Hindbrain V2a neurons in the excitation of spinal locomotor circuits during zebrafish swimming.Curr. Biol. 2013; 23: 843-849Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar] began by creating a heroic number of stable transgenic fish lines using the Gal4:UAS system. This approach provides a greater deal of flexibility for expressing different DNA constructs in the same population of neurons [10Scott E.K. The Gal4/UAS toolbox in zebrafish: new approaches for defining behavioral circuits.J. Neurochem. 2009; 110: 441-456Crossref PubMed Scopus (47) Google Scholar]. To ensure sufficient expression levels of early-onset Chx10-dependent constructs, the authors performed their experiments at the earliest point zebrafish begin swimming spontaneously (about three days old). To test the idea that activation of hindbrain V2a cells would evoke swimming, they selectively expressed channelrhodopsin (ChR) in V2a neurons. ChR is an ion channel that generates inward current flow in response to blue light [11Boyden E.S. Zhang F. Bamberg E. Nagel G. Deisseroth K. Millisecond-timescale, genetically targeted optical control of neural activity.Nat. Neurosci. 2005; 8: 1263-1268Crossref PubMed Scopus (3378) Google Scholar, 12Wang H. Sugiyama Y. Hikima T. Sugano E. Tomita H. Takahashi T. Ishizuka T. Yawo H. Molecular determinants differentiating photocurrent properties of two channelrhodopsins from Chlamydomonas.J. Biol. Chem. 2009; 284: 5685-5696Crossref PubMed Scopus (144) Google Scholar], which makes neurons fire action potentials or ‘spike’. Different regions of the nervous system were then illuminated from above using custom designed optical equipment and the response of the freely moving tail of head-fixed fish was monitored from below using a high-speed camera. In the first of a number of technically demanding experiments, Kimura et al. [3Kimura Y. Satou C. Fujioka S. Shoji W. Umeda K. Ishizuka T. Yawo H. Higashijima S. Hindbrain V2a neurons in the excitation of spinal locomotor circuits during zebrafish swimming.Curr. Biol. 2013; 23: 843-849Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar] confirmed that briefly shining blue light on ChR–V2a cells in hindbrain consistently evokes swimming behavior. The authors then activated more local regions of hindbrain, which revealed that some V2a neurons were more effective at evoking swimming than others. In particular, the caudal hindbrain was consistently the most reliable location (Figure 2A). The next step was to silence the V2a cells. To do this, the authors used either eNpHR3.0 (Halo3) or archaeorhodopsin-3 (Arch), both of which generate outward current flow in response to green light and silence neurons [13Chow B.Y. Han X. Dobry A.S. Qian X. Chuong A.S. Li M. Henninger M.A. Belfort G.M. Lin Y. Monahan P.E. et al.High-performance genetically targetable optical neural silencing by light-driven proton pumps.Nature. 2010; 463: 98-102Crossref PubMed Scopus (880) Google Scholar, 14Zhang F. Wang L.P. Brauner M. Liewald J.F. Kay K. Watzke N. Wood P.G. Bamberg E. Nagel G. Gottschalk A. et al.Multimodal fast optical interrogation of neural circuitry.Nature. 2007; 446: 633-639Crossref PubMed Scopus (1366) Google Scholar, 15Gradinaru V. Zhang F. Ramakrishnan C. Mattis J. Prakash R. Diester I. Goshen I. Thompson K.R. Deisseroth K. Molecular and cellular approaches for diversifying and extending optogenetics.Cell. 2010; 141: 154-165Abstract Full Text Full Text PDF PubMed Scopus (737) Google Scholar]. As expected, whole hindbrain illumination of Halo3– or Arch–V2a neurons, and selective illumination of the special caudal region, prematurely terminated spontaneously generated swimming (Figure 2B). Are these neurons both sufficient and necessary for maintaining locomotion? The answer was a resounding yes. The regional differences in the ability to start or prematurely stop swimming behavior raised another question. Could differences in the projection patterns of hindbrain V2a neurons explain the discrepancies? Perhaps more rostral V2a cells do not innervate spinal cord. A creative use of the photoconvertible protein, Kaede [16Ando R. Hama H. Yamamoto-Hino M. Mizuno H. Miyawaki A. An optical marker based on the UV-induced green-to-red photoconversion of a fluorescent protein.Proc. Natl. Acad. Sci. USA. 2002; 99: 12651-12656Crossref PubMed Scopus (830) Google Scholar], along with more standard retrograde filling of V2a neurons confirmed this idea. In the caudal hindbrain region a large proportion of relatively small V2a cells project to spinal cord, while in less reliable rostral regions, only a few relatively large reticulo-spinal neurons are found. At this point, the story was already pretty convincing. Hindbrain V2a neurons provide a crucial source of excitatory drive to spinal locomotor circuits. Also, the relative ability of different regions of hindbrain to start or stop locomotion matches their extent of spinal innervation. Nonetheless, Kimura et al. [3Kimura Y. Satou C. Fujioka S. Shoji W. Umeda K. Ishizuka T. Yawo H. Higashijima S. Hindbrain V2a neurons in the excitation of spinal locomotor circuits during zebrafish swimming.Curr. Biol. 2013; 23: 843-849Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar] then took their study a step further. Are these neurons even active during locomotion? If so, are there any regional differences in spiking behavior that match the optogenetic observations? To answer these questions, the authors turned to electrophysiology. The ability to record electrical signals from hindbrain neurons relies on stability, so the recordings had to be performed in larvae immobilized by a plant toxin that blocks neuromuscular transmission. In this situation, the rhythmic motor output that would normally generate swimming movements can be monitored using a suction electrode, which picks up the electrical signals from motoneuron axons that innervate the tail muscles (Figure 2C). Hindbrain neuron activity was monitored using either whole-cell patch clamp recordings of membrane potential or cell-attached recordings of spikes. Kimura et al. [3Kimura Y. Satou C. Fujioka S. Shoji W. Umeda K. Ishizuka T. Yawo H. Higashijima S. Hindbrain V2a neurons in the excitation of spinal locomotor circuits during zebrafish swimming.Curr. Biol. 2013; 23: 843-849Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar] focused on two hindbrain regions that had the lowest and the highest influence on locomotion. In the rostral region, they targeted a large reticulo-spinal neuron that is readily identifiable based on its morphology [17Kimmel C.B. Powell S.L. Metcalfe W.K. Brain neurons which project to the spinal cord in young larvae of the zebrafish.J. Comp. Neurol. 1982; 205: 112-127Crossref PubMed Scopus (194) Google Scholar, 18Metcalfe W.K. Mendelson B. Kimmel C.B. Segmental homologies among reticulospinal neurons in the hindbrain of the zebrafish larva.J. Comp. Neurol. 1986; 251: 147-159Crossref PubMed Scopus (234) Google Scholar], known as MiV1 (middle rhombencephalon, ventral, level 1). In the caudal region, there were no easily identifiable cells, so instead they consistently targeted ventrally located neurons, which they term ‘small V2a cells’. In the latter case, they took care to demonstrate that the cells projected to spinal cord. The first observation was that MiV1 and small V2a cells are indeed active during locomotion. What followed, however, was more surprising. Circuits in the spinal cord generate rhythmic patterns of activity in response to unpatterned, ‘tonic’ excitatory drive [19Grillner S. Jessell T.M. Measured motion: searching for simplicity in spinal locomotor networks.Curr. Opin. Neurobiol. 2009; 19: 572-586Crossref PubMed Scopus (256) Google Scholar]. The idea is that reticulo-spinal neurons are a major source of this tonic drive. Given that V2a neurons form a continuous column from spinal cord into hindbrain, the expectation was that V2a neurons gradually transition from highly rhythmic cells in spinal cord to less rhythmic ones in more rostral regions. The assumption here is that more rostral cells would be higher up in the chain of command. Instead, what Kimura et al. [3Kimura Y. Satou C. Fujioka S. Shoji W. Umeda K. Ishizuka T. Yawo H. Higashijima S. Hindbrain V2a neurons in the excitation of spinal locomotor circuits during zebrafish swimming.Curr. Biol. 2013; 23: 843-849Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar] observed was an unexpected transition from rhythmic, to tonic, back to rhythmic drive as you move from spinal cord to rostral hindbrain (Figure 2C). The tonic activity in small V2a cells is certainly consistent with prevailing views of reticulo-spinal drive and the importance of this region in sustaining locomotion. However, the highly rhythmic activity from the rostral MiV1 cells is more difficult to explain, especially as MiV1 cells have been implicated in turning [20Orger M.B. Kampff A.R. Severi K.E. Bollmann J.H. Engert F. Control of visually guided behavior by distinct populations of spinal projection neurons.Nat. Neurosci. 2008; 11: 327-333Crossref PubMed Scopus (186) Google Scholar], which is not necessarily a rhythmic behavior. Clearly, when it comes to the functional organization of V2a neurons in zebrafish hindbrain, this finding suggests there is more to it than meets the eye. So, what did we learn? Using optogenetics, Kimura et al. [3Kimura Y. Satou C. Fujioka S. Shoji W. Umeda K. Ishizuka T. Yawo H. Higashijima S. Hindbrain V2a neurons in the excitation of spinal locomotor circuits during zebrafish swimming.Curr. Biol. 2013; 23: 843-849Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar] have unambiguously identified the source of locomotor drive from hindbrain to spinal cord. The relevance of this finding will likely extend beyond zebrafish, given the common genetic origin of brainstem and spinal circuitry in vertebrates [4Arber S. Motor circuits in action: specification, connectivity, and function.Neuron. 2012; 74: 975-989Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 5Goulding M. Circuits controlling vertebrate locomotion: moving in a new direction.Nat. Rev. Neurosci. 2009; 10: 507-518Crossref PubMed Scopus (535) Google Scholar]. The authors have also demonstrated that spinal circuits receive both tonic and rhythmic signals from hindbrain neurons. While this observation alone is not new [9Le Ray D. Juvin L. Ryczko D. Dubuc R. Supraspinal control of locomotion: the mesencephalic locomotor region.Prog. Brain Res. 2011; 188: 51-70Crossref PubMed Scopus (56) Google Scholar], what is novel is that both signals originate from a single genetically identified population, and not in a way you might predict based on anatomy. Obviously, there are still many open questions. Are there differences in the spinal neurons targeted by rhythmic versus tonic excitatory drive? Also, what are the rest of the hindbrain V2a cells doing if not controlling locomotion? Convincing answers to these questions, and many more, are surely not far off if this technical tour de force is anything to go by. Hindbrain V2a Neurons in the Excitation of Spinal Locomotor Circuits during Zebrafish SwimmingKimura et al.Current BiologyApril 25, 2013In BriefDuring locomotion in vertebrates, reticulospinal neurons in the hindbrain play critical roles in providing descending excitation to the spinal cord locomotor systems. However, despite the fact that many genes that are used to classify the neuronal identities of neurons in the hindbrain have been identified, the molecular identity of the reticulospinal neurons that are critically involved in locomotor drive is not well understood. Chx10-expressing neurons (V2a neurons) are ipsilaterally projecting glutamatergic neurons in the spinal cord and the hindbrain. Full-Text PDF Open Archive" @default.
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• W1972446274 date "2013-05-01" @default.
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• W1972446274 title "Optogenetics: Illuminating Sources of Locomotor Drive" @default.
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