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

摘要

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. 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)~( zc 77)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)~( zc 77)line, whereas in Reimer et al. ( 2013 ) was via otpa~( m 866)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). Since the later role of DDNs suggests a mechanism of ongoing DAergic neurotransmission to sculpt episodic locomotion, monitoring activity patterns of DDNs during neural locomotor output in vivo could elucidate potential DDN-spinal locomotor circuit dyna