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Dopaminergic Control of Locomotor Patterning during Development: A Tail for the Ages.

Lambert AM - Front Cell Neurosci (2016)

View Article: PubMed Central - PubMed

Affiliation: Masino Lab, Neuroscience, University of Minnesota Twin CitiesMinneapolis, MN, USA; Engert Lab, Molecular and Cellular Biology, Harvard UniversityCambridge, MA, USA.

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While the somata of all dopaminergic (DAergic) neurons in zebrafish and mammals are supraspinal, some of these, termed diencephalospinal neurons (DDNs), send long-distance descending projections into the spinal cord (Figure 1A) and have recently been implicated in spinal network (Reimer et al., ) and locomotor development (Lambert et al., ) in zebrafish... After many years of seminal research on the morphology and genetic specification of zebrafish DDNs and the DAergic diencephalospinal tract (DDT) (Schweitzer and Driever, ), our recent study was the first to explicitly investigate DDN function (Lambert et al., )... We combined pharmacological DAergic perturbations, demarcated transections, and selective chemogenetic ablation of orthopedia (otp) neurons to demonstrate that conserved DAergic otp neurons–a subset of which are DDNs (Fujimoto et al., ; Figure 1A2)—provide the impetus for endogenous DA receptor 4 (D4R) signaling to initiate and maintain a developmental switch, between 80 and 96 h post fertilization (hpf), to the mature episodic locomotor pattern of zebrafish... However, activity patterns of murine DAergic mesostriatal neurons (DMNs) have been studied extensively and show that they exhibit two distinct outputs: phasic bursting that acts on low-affinity D1-like receptors, and tonic firing that acts on high-affinity D2-like receptors (Dreyer et al., )... Jay et al. found that zebrafish DDNs also exhibit phasic and tonic outputs, which plausibly may also differentially drive D1-like and D2-like signaling, respectively... Interestingly, periods of fictive locomotor activity correlated to DDN phasic bursting, but not tonic firing (Jay et al., )... However, further examination revealed that DDN phasic bursting did not reliably drive locomotor episodes or modulate their durations... Furthermore, 3 dpa of DDNs could allow for developing DAergic projections to the hindbrain to homeostatically extend into the spinal cord, or induce a shift from supraspinal (Kimura et al., ) and spinal (Lambert et al., ) modulation of episode duration, to more exclusive supraspinal control... Alternatively, it is possible that non-DDN DAergic otp neurons, which Jay et al. did not target, act supraspinally for the in vivo DAergic modulation of spontaneous episode durations that we and others have reported (Thirumalai and Cline, ; Lambert et al., ; Lange et al., ; Decker et al., ), including previous work from the same lab as in Jay et al. (Tong and McDearmid, )... While, Jay et al. did not explore any DA receptor (DAR) or localized spinal mechanisms, our study recapitulated the consquences of otp ablations on episode duration via systemic and localized DAR pharmacology to the transected spinal cord (Lambert et al., ); these manipulations also circumvented any caveats of recovery in the DDN or otp ablation experiments (Figure 1C)... Aside from any of the above, the discrepancy of behavioral results between studies could simply be due to our study recording multiple fish in a 50 mm arena, compared to Jay et al. recording fish in isolation in a five-fold smaller arena... Hence, future studies testing whether DDNs directly modulate spinal locomotor circuits in vivo should circumvent any potential DDN influences on supraspinal or peripheral DAergic signaling... The author confirms being the sole contributor of this work and approved it for publication... This work was supported by my competitive predoctoral fellowship on the MnDRIVE Neuromodulation Initiative, as well as NINDS funding from Florian Engert (5U01NS090449-02), my postdoctoral advisor.

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Descending dopaminergic control of spinal network and locomotor development. (A) Schematics of dorsal views of the zebrafish brain and spinal cord, by 4-days-old, of: (A1) dopaminergic diencephalic clusters (DC) DC1-DC6. Note that DC2, DC4, and DC5 are the exclusive dopaminergic diencephalospinal neurons (DDNs) that comprise the dopaminergic diencephalospinal tract (DDT). (A2) orthopedia-specified neurons in the Tg(otpb.A:nfsB–egfp)zc77 line used in Lambert et al. (2012), combined with systemic and localized dopamine receptor (DAR) pharmacology. (A3) DDNs targeted in Jay et al. (2015), but with no DAR pharmacology. (A4) single cell morphology of DC2 DDNs that tile virtually the entire rostrocaudal central neuraxis, as well as the peripheral sensory targets of the otic capsule, lateral line, and head and trunk neuromasts. (B) Putative model of the role of DDN-spinal D4R signaling in: (B, left) spinal neuron differentiation (24–48 hpf) via direct influence on spinal motor progenitor cells (pMNS) and (B, right) locomotor development (80–96 hpf) via influence on unknown spinal targets. (C) Timeline of DDN/D4R perturbations, recovery, and testing for the studies specified. Test results denote changes, at the color-coded time of testing, in the number of HB9 motor neurons (MN), total distance traveled (TDT), and episode duration (ED) as a function of each DDN/D4R perturbation. The Otp DDN perturbation in Lambert et al. (2012) was via chemogenetic ablation in the Tg(otpb.A:nfsB–egfp)zc77 line, whereas in Reimer et al. (2013) was via otpam866 mutants (where otpa expression begins at 18 hpf). All perturbations labeled as D4R were systemic pharmacological D4R antagonism/agonism, except:  localized application of D4R agonist to transected spinal cord,  and  in addition to systemic pharmacology, recapitulated via D4Ra mRNA knockdown and rescue (respectively),  recapitulated via localized application of D4R agonist to transected spinal cord in an adult zebrafish model of spinal cord injury. Abbreviations in (A4) denote the following: telencephalon (Telen), diencephalon (Dien), mesencephalon (Mesen), hindbrain (HB), and spinal cord (SC).
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Figure 1: Descending dopaminergic control of spinal network and locomotor development. (A) Schematics of dorsal views of the zebrafish brain and spinal cord, by 4-days-old, of: (A1) dopaminergic diencephalic clusters (DC) DC1-DC6. Note that DC2, DC4, and DC5 are the exclusive dopaminergic diencephalospinal neurons (DDNs) that comprise the dopaminergic diencephalospinal tract (DDT). (A2) orthopedia-specified neurons in the Tg(otpb.A:nfsB–egfp)zc77 line used in Lambert et al. (2012), combined with systemic and localized dopamine receptor (DAR) pharmacology. (A3) DDNs targeted in Jay et al. (2015), but with no DAR pharmacology. (A4) single cell morphology of DC2 DDNs that tile virtually the entire rostrocaudal central neuraxis, as well as the peripheral sensory targets of the otic capsule, lateral line, and head and trunk neuromasts. (B) Putative model of the role of DDN-spinal D4R signaling in: (B, left) spinal neuron differentiation (24–48 hpf) via direct influence on spinal motor progenitor cells (pMNS) and (B, right) locomotor development (80–96 hpf) via influence on unknown spinal targets. (C) Timeline of DDN/D4R perturbations, recovery, and testing for the studies specified. Test results denote changes, at the color-coded time of testing, in the number of HB9 motor neurons (MN), total distance traveled (TDT), and episode duration (ED) as a function of each DDN/D4R perturbation. The Otp DDN perturbation in Lambert et al. (2012) was via chemogenetic ablation in the Tg(otpb.A:nfsB–egfp)zc77 line, whereas in Reimer et al. (2013) was via otpam866 mutants (where otpa expression begins at 18 hpf). All perturbations labeled as D4R were systemic pharmacological D4R antagonism/agonism, except: localized application of D4R agonist to transected spinal cord, and in addition to systemic pharmacology, recapitulated via D4Ra mRNA knockdown and rescue (respectively), recapitulated via localized application of D4R agonist to transected spinal cord in an adult zebrafish model of spinal cord injury. Abbreviations in (A4) denote the following: telencephalon (Telen), diencephalon (Dien), mesencephalon (Mesen), hindbrain (HB), and spinal cord (SC).

Mentions: Dopamine (DA) directly modulates motor circuits in the brain and spinal cord. While the somata of all dopaminergic (DAergic) neurons in zebrafish and mammals are supraspinal, some of these, termed diencephalospinal neurons (DDNs), send long-distance descending projections into the spinal cord (Figure 1A) and have recently been implicated in spinal network (Reimer et al., 2013) and locomotor development (Lambert et al., 2012) in zebrafish. After many years of seminal research on the morphology and genetic specification of zebrafish DDNs and the DAergic diencephalospinal tract (DDT) (Schweitzer and Driever, 2009), our recent study was the first to explicitly investigate DDN function (Lambert et al., 2012). We combined pharmacological DAergic perturbations, demarcated transections, and selective chemogenetic ablation of orthopedia (otp) neurons to demonstrate that conserved DAergic otp neurons–a subset of which are DDNs (Fujimoto et al., 2011; Figure 1A2)—provide the impetus for endogenous DA receptor 4 (D4R) signaling to initiate and maintain a developmental switch, between 80 and 96 h post fertilization (hpf), to the mature episodic locomotor pattern of zebrafish. Interestingly, Reimer et al. (2013) also demonstrated that DAergic otp neurons drive endogenous D4R signaling, confirmed both pharmacologically and genetically, but for an even earlier developmental function- to influence the differentiation of spinal motor progenitor cells between 24 and 48 hpf. Both studies used additional experimental approaches to demonstrate that D4R signaling directly in the spinal cord was sufficient to emulate the developmental processes under question: localized spinal application of DA or D4R agonists was shown to influence progenitor pools, when applied for many hours (Reimer et al., 2013), or to modulate the duration of locomotor episodes, when applied for just 5–10 min (Lambert et al., 2012). Collectively, these studies unveil that DDNs may drive endogenous spinal D4R signaling, via the DDT, for two temporally distinct roles in locomotor development: (1) a transient early role that acts directly on progenitor pools but not neurons, with long lasting consequences (Figure 1B, left), and (2) a late role that likely acts through ongoing spinal neuronal signaling, for maintenance of episodic locomotor patterns (Figure 1B, right). This commentary considers the extent to which an understanding of each of these developmental roles integrates with or is modified by the most recent DDN-related findings of Jay et al.


Dopaminergic Control of Locomotor Patterning during Development: A Tail for the Ages.

Lambert AM - Front Cell Neurosci (2016)

Descending dopaminergic control of spinal network and locomotor development. (A) Schematics of dorsal views of the zebrafish brain and spinal cord, by 4-days-old, of: (A1) dopaminergic diencephalic clusters (DC) DC1-DC6. Note that DC2, DC4, and DC5 are the exclusive dopaminergic diencephalospinal neurons (DDNs) that comprise the dopaminergic diencephalospinal tract (DDT). (A2) orthopedia-specified neurons in the Tg(otpb.A:nfsB–egfp)zc77 line used in Lambert et al. (2012), combined with systemic and localized dopamine receptor (DAR) pharmacology. (A3) DDNs targeted in Jay et al. (2015), but with no DAR pharmacology. (A4) single cell morphology of DC2 DDNs that tile virtually the entire rostrocaudal central neuraxis, as well as the peripheral sensory targets of the otic capsule, lateral line, and head and trunk neuromasts. (B) Putative model of the role of DDN-spinal D4R signaling in: (B, left) spinal neuron differentiation (24–48 hpf) via direct influence on spinal motor progenitor cells (pMNS) and (B, right) locomotor development (80–96 hpf) via influence on unknown spinal targets. (C) Timeline of DDN/D4R perturbations, recovery, and testing for the studies specified. Test results denote changes, at the color-coded time of testing, in the number of HB9 motor neurons (MN), total distance traveled (TDT), and episode duration (ED) as a function of each DDN/D4R perturbation. The Otp DDN perturbation in Lambert et al. (2012) was via chemogenetic ablation in the Tg(otpb.A:nfsB–egfp)zc77 line, whereas in Reimer et al. (2013) was via otpam866 mutants (where otpa expression begins at 18 hpf). All perturbations labeled as D4R were systemic pharmacological D4R antagonism/agonism, except:  localized application of D4R agonist to transected spinal cord,  and  in addition to systemic pharmacology, recapitulated via D4Ra mRNA knockdown and rescue (respectively),  recapitulated via localized application of D4R agonist to transected spinal cord in an adult zebrafish model of spinal cord injury. Abbreviations in (A4) denote the following: telencephalon (Telen), diencephalon (Dien), mesencephalon (Mesen), hindbrain (HB), and spinal cord (SC).
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Related In: Results  -  Collection

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Figure 1: Descending dopaminergic control of spinal network and locomotor development. (A) Schematics of dorsal views of the zebrafish brain and spinal cord, by 4-days-old, of: (A1) dopaminergic diencephalic clusters (DC) DC1-DC6. Note that DC2, DC4, and DC5 are the exclusive dopaminergic diencephalospinal neurons (DDNs) that comprise the dopaminergic diencephalospinal tract (DDT). (A2) orthopedia-specified neurons in the Tg(otpb.A:nfsB–egfp)zc77 line used in Lambert et al. (2012), combined with systemic and localized dopamine receptor (DAR) pharmacology. (A3) DDNs targeted in Jay et al. (2015), but with no DAR pharmacology. (A4) single cell morphology of DC2 DDNs that tile virtually the entire rostrocaudal central neuraxis, as well as the peripheral sensory targets of the otic capsule, lateral line, and head and trunk neuromasts. (B) Putative model of the role of DDN-spinal D4R signaling in: (B, left) spinal neuron differentiation (24–48 hpf) via direct influence on spinal motor progenitor cells (pMNS) and (B, right) locomotor development (80–96 hpf) via influence on unknown spinal targets. (C) Timeline of DDN/D4R perturbations, recovery, and testing for the studies specified. Test results denote changes, at the color-coded time of testing, in the number of HB9 motor neurons (MN), total distance traveled (TDT), and episode duration (ED) as a function of each DDN/D4R perturbation. The Otp DDN perturbation in Lambert et al. (2012) was via chemogenetic ablation in the Tg(otpb.A:nfsB–egfp)zc77 line, whereas in Reimer et al. (2013) was via otpam866 mutants (where otpa expression begins at 18 hpf). All perturbations labeled as D4R were systemic pharmacological D4R antagonism/agonism, except: localized application of D4R agonist to transected spinal cord, and in addition to systemic pharmacology, recapitulated via D4Ra mRNA knockdown and rescue (respectively), recapitulated via localized application of D4R agonist to transected spinal cord in an adult zebrafish model of spinal cord injury. Abbreviations in (A4) denote the following: telencephalon (Telen), diencephalon (Dien), mesencephalon (Mesen), hindbrain (HB), and spinal cord (SC).
Mentions: Dopamine (DA) directly modulates motor circuits in the brain and spinal cord. While the somata of all dopaminergic (DAergic) neurons in zebrafish and mammals are supraspinal, some of these, termed diencephalospinal neurons (DDNs), send long-distance descending projections into the spinal cord (Figure 1A) and have recently been implicated in spinal network (Reimer et al., 2013) and locomotor development (Lambert et al., 2012) in zebrafish. After many years of seminal research on the morphology and genetic specification of zebrafish DDNs and the DAergic diencephalospinal tract (DDT) (Schweitzer and Driever, 2009), our recent study was the first to explicitly investigate DDN function (Lambert et al., 2012). We combined pharmacological DAergic perturbations, demarcated transections, and selective chemogenetic ablation of orthopedia (otp) neurons to demonstrate that conserved DAergic otp neurons–a subset of which are DDNs (Fujimoto et al., 2011; Figure 1A2)—provide the impetus for endogenous DA receptor 4 (D4R) signaling to initiate and maintain a developmental switch, between 80 and 96 h post fertilization (hpf), to the mature episodic locomotor pattern of zebrafish. Interestingly, Reimer et al. (2013) also demonstrated that DAergic otp neurons drive endogenous D4R signaling, confirmed both pharmacologically and genetically, but for an even earlier developmental function- to influence the differentiation of spinal motor progenitor cells between 24 and 48 hpf. Both studies used additional experimental approaches to demonstrate that D4R signaling directly in the spinal cord was sufficient to emulate the developmental processes under question: localized spinal application of DA or D4R agonists was shown to influence progenitor pools, when applied for many hours (Reimer et al., 2013), or to modulate the duration of locomotor episodes, when applied for just 5–10 min (Lambert et al., 2012). Collectively, these studies unveil that DDNs may drive endogenous spinal D4R signaling, via the DDT, for two temporally distinct roles in locomotor development: (1) a transient early role that acts directly on progenitor pools but not neurons, with long lasting consequences (Figure 1B, left), and (2) a late role that likely acts through ongoing spinal neuronal signaling, for maintenance of episodic locomotor patterns (Figure 1B, right). This commentary considers the extent to which an understanding of each of these developmental roles integrates with or is modified by the most recent DDN-related findings of Jay et al.

View Article: PubMed Central - PubMed

Affiliation: Masino Lab, Neuroscience, University of Minnesota Twin CitiesMinneapolis, MN, USA; Engert Lab, Molecular and Cellular Biology, Harvard UniversityCambridge, MA, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

While the somata of all dopaminergic (DAergic) neurons in zebrafish and mammals are supraspinal, some of these, termed diencephalospinal neurons (DDNs), send long-distance descending projections into the spinal cord (Figure 1A) and have recently been implicated in spinal network (Reimer et al., ) and locomotor development (Lambert et al., ) in zebrafish... After many years of seminal research on the morphology and genetic specification of zebrafish DDNs and the DAergic diencephalospinal tract (DDT) (Schweitzer and Driever, ), our recent study was the first to explicitly investigate DDN function (Lambert et al., )... We combined pharmacological DAergic perturbations, demarcated transections, and selective chemogenetic ablation of orthopedia (otp) neurons to demonstrate that conserved DAergic otp neurons–a subset of which are DDNs (Fujimoto et al., ; Figure 1A2)—provide the impetus for endogenous DA receptor 4 (D4R) signaling to initiate and maintain a developmental switch, between 80 and 96 h post fertilization (hpf), to the mature episodic locomotor pattern of zebrafish... However, activity patterns of murine DAergic mesostriatal neurons (DMNs) have been studied extensively and show that they exhibit two distinct outputs: phasic bursting that acts on low-affinity D1-like receptors, and tonic firing that acts on high-affinity D2-like receptors (Dreyer et al., )... Jay et al. found that zebrafish DDNs also exhibit phasic and tonic outputs, which plausibly may also differentially drive D1-like and D2-like signaling, respectively... Interestingly, periods of fictive locomotor activity correlated to DDN phasic bursting, but not tonic firing (Jay et al., )... However, further examination revealed that DDN phasic bursting did not reliably drive locomotor episodes or modulate their durations... Furthermore, 3 dpa of DDNs could allow for developing DAergic projections to the hindbrain to homeostatically extend into the spinal cord, or induce a shift from supraspinal (Kimura et al., ) and spinal (Lambert et al., ) modulation of episode duration, to more exclusive supraspinal control... Alternatively, it is possible that non-DDN DAergic otp neurons, which Jay et al. did not target, act supraspinally for the in vivo DAergic modulation of spontaneous episode durations that we and others have reported (Thirumalai and Cline, ; Lambert et al., ; Lange et al., ; Decker et al., ), including previous work from the same lab as in Jay et al. (Tong and McDearmid, )... While, Jay et al. did not explore any DA receptor (DAR) or localized spinal mechanisms, our study recapitulated the consquences of otp ablations on episode duration via systemic and localized DAR pharmacology to the transected spinal cord (Lambert et al., ); these manipulations also circumvented any caveats of recovery in the DDN or otp ablation experiments (Figure 1C)... Aside from any of the above, the discrepancy of behavioral results between studies could simply be due to our study recording multiple fish in a 50 mm arena, compared to Jay et al. recording fish in isolation in a five-fold smaller arena... Hence, future studies testing whether DDNs directly modulate spinal locomotor circuits in vivo should circumvent any potential DDN influences on supraspinal or peripheral DAergic signaling... The author confirms being the sole contributor of this work and approved it for publication... This work was supported by my competitive predoctoral fellowship on the MnDRIVE Neuromodulation Initiative, as well as NINDS funding from Florian Engert (5U01NS090449-02), my postdoctoral advisor.

No MeSH data available.


Related in: MedlinePlus