Search

The flexibility of locomotor movements requires an accurate control of their start, duration, and speed. How brainstem circuits encode and convey these locomotor parameters remains unclear. Here, we have combined in vivo calcium imaging, electrophysiology, anatomy, and behavior in adult zebrafish to address these questions. We reveal that the detailed parameters of locomotor movements are encoded by two molecularly, topographically, and functionally segregated glutamatergic neuron subpopulations within the nucleus of the medial longitudinal fasciculus. The start, duration, and changes of locomotion speed are encoded by vGlut2

During development, all animals undergo major adaptations to accommodate behavioral flexibility and diversity. How these adaptations are reflected in the changes in the motor circuits controlling our behaviors remains poorly understood. Here, we show, using a combination of techniques applied at larval and adult zebrafish stages, that the pattern-generating V0d inhibitory interneurons within the locomotor circuit undergo a developmental switch in their role. In larvae, we show that V0d interneurons have a primary function in high-speed motor behavior yet are redundant for explorative swimming. By contrast, adult V0d interneurons have diversified into speed-dependent subclasses, with an overrepresentation of those active at the slowest speeds. The ablation of V0d interneurons in adults disrupts slow explorative swimming, which is associated with a loss of mid-cycle inhibition onto target motoneurons. Thus, we reveal a developmental switch in V0d interneuron function from a role in high-speed motor behavior to a function in timing and thus coordinating slow explorative locomotion. Our study suggests that early motor circuit composition is not predictive of the adult system but instead undergoes major functional transformations during development.

While often considered to be a simple and stereotyped motor behavior, effective locomotion entails complex changes in vigor, speed, and gait. Studies over several decades in many species have uncovered the basic building blocks of the spinal locomotor CPG. More recently, however, the combination of molecular, electrophysiological, and anatomical tools has begun to uncover a higher degree of neuronal and circuit diversity that endows the locomotor CPG with the necessary flexibility to adjust the vigor, speed, and gait of locomotor movements to internal and external demands. In this review, we summarize some of these recent studies with a focus on how the diversity of neurons in zebrafish generates a modular organization of the locomotor CPG, with individual module components engaged in a task-dependent manner. In addition, we highlight recent evidence on the role of motoneurons as an integral member of the locomotor CPG in vertebrates. Thus, studies of the spinal locomotor networks are beginning to provide direct links between neuronal diversity, their circuit organization and behavioral relevance.

In vertebrates, specific command centers in the brain can selectively drive slow-explorative or fast-speed locomotion. However, it remains unclear how the locomotor central pattern generator (CPG) processes descending drive into coordinated locomotion. Here, we reveal, in adult zebrafish, a logic of the V2a interneuron rhythm-generating circuits involving recurrent and hierarchical connectivity that acts in tandem with pacemaker properties to provide an ignition and gear-shift mechanism to start locomotion and change speed. A comprehensive mapping of synaptic connections reveals three recurrent circuit modules engaged sequentially to increase locomotor speed. The connectivity between V2a interneurons of different modules displayed a clear asymmetry in favor of connections from faster to slower modules. The interplay between V2a interneuron pacemaker properties and their organized connectivity provides a mechanism for locomotor initiation and speed control. Thus, our results provide mechanistic insights into how the spinal CPG transforms descending drive into locomotion and align its speed with the initial intention.

Proprioception is essential for behavior and provides a sense of our body movements in physical space. Proprioceptor organs are thought to be only in the periphery. Whether the central nervous system can intrinsically sense its own movement remains unclear. Here we identify a segmental organ of proprioception in the adult zebrafish spinal cord, which is embedded by intraspinal mechanosensory neurons expressing Piezo2 channels. These cells are late-born, inhibitory, commissural neurons with unique molecular and physiological profiles reflecting a dual sensory and motor function. The central proprioceptive organ locally detects lateral body movements during locomotion and provides direct inhibitory feedback onto rhythm-generating interneurons responsible for the central motor program. This dynamically aligns central pattern generation with movement outcome for efficient locomotion. Our results demonstrate that a central proprioceptive organ monitors self-movement using hybrid neurons that merge sensory and motor entities into a unified network.

Locomotor behaviors are critical for survival and enable animals to navigate their environment, find food and evade predators. The circuits in the brain and spinal cord that initiate and maintain such different modes of locomotion in vertebrates have been studied in numerous species for over a century. In recent decades, the zebrafish has emerged as one of the main model systems for the study of locomotion, owing to its experimental amenability, and work in zebrafish has revealed numerous new insights into locomotor circuit function. Here, we review the literature that has led to our current understanding of the neural circuits controlling swimming and escape in zebrafish. We highlight recent studies that have enriched our comprehension of key topics, such as the interactions between premotor excitatory interneurons (INs) and motoneurons (MNs), supraspinal and spinal circuits that coordinate escape maneuvers, and developmental changes in overall circuit composition. We also discuss roles for neuromodulators and sensory inputs in modifying the relative strengths of constituent circuit components to provide flexibility in zebrafish behavior, allowing the animal to accommodate changes in the environment. We aim to provide a coherent framework for understanding the circuitry in the brain and spinal cord of zebrafish that allows the animal to flexibly transition between different speeds, and modes, of locomotion.

Summary Locomotion relies on the coordinated activity of rhythmic neurons in the hindbrain and spinal cord and depends critically on the intrinsic properties of excitatory interneurons. Therefore, understanding how ion channels sculpt the properties of these interneurons, and the consequences for circuit function and behavior, is an important task. The hyperpolarization-activated cation current, Ih, is known to play important roles in shaping neuronal properties and for rhythm generation in many neuronal networks. We show in stage 42 Xenopus laevis frog tadpoles that Ih is strongly expressed only in excitatory descending interneurons (dINs), an important ipsilaterally projecting population that drives swimming activity. The voltage-dependent HCN channel blocker ZD7288 completely abolished a prominent depolarizing sag potential in response to hyperpolarization, the hallmark of Ih, and hyperpolarized dINs. ZD7288 also affected dIN post-inhibitory rebound firing, upon which locomotor rhythm generation relies, and disrupted locomotor output. Block of Ih also unmasked an activity-dependent ultraslow afterhyperpolarization (usAHP) in dINs following swimming, mediated by a dynamic Na/K pump current. This usAHP, unmasked in dINs by ZD7288, resulted in suprathreshold stimuli failing to evoke swimming at short inter-swim intervals, indicating an important role for Ih in maintaining swim generation capacity and in setting the post-swim refractory period of the network. Collectively, our data suggest that the selective expression of Ih in dINs determines specific dIN properties that are important for rhythm generation and counteracts an activity-dependent usAHP to ensure that dINs can maintain coordinated swimming over a wide range of inter-swim intervals., Highlights • Ih is strongly expressed in Xenopus locomotor-rhythm-generating dIN interneurons • Ih is active at rest in dINs, contributing to their distinct electrical properties • dINs normally lack a Na pump-dependent ultra-slow afterhyperpolarization (usAHP) • Ih counterbalances dIN usAHPs to preserve tadpole rhythm generating capacity, Picton et al. reveal that a hyperpolarization-activated current, Ih, selectively affects the electrical properties of locomotor rhythm generating interneurons in the Xenopus tadpole spinal motor circuit. By counterbalancing a dynamic hyperpolarizing Na pump current, Ih preserves rhythm generating capacity at short inter-swim intervals.

Scientific Reports 5: Article number: 16188; published online: 06 November 2015; updated: 22 December 2017. In this Article, ‘Centre for Neuroregeneration, University of Edinburgh, Chancellor’s Building, 49 Little France Crescent, Edinburgh, EH16 4SB’ is incorrectly listed as a present address for Hong-Yan Zhang and should be listed as a second affiliation.

The authors are grateful for the financial support of the BBSRC (grant numbers: BB/M024946/1 and BB/JO1446X/1), the Carnegie Trust and the University of St Andrews. Sodium pumps are ubiquitously expressed membrane proteins that extrude three Na+ ions in exchange for two K+ ions using ATP as an energy source. Recent studies have illuminated additional, dynamic roles for sodium pumps in regulating the excitability of neuronal networks in an activity-dependent fashion. Here we review their role in a novel form of short-term memory within rhythmic locomotor networks. The data we review derives mainly from recent studies on Xenopus tadpoles and neonatal mice. The role and underlying mechanisms of pump action broadly match previously published data from an invertebrate, the Drosophila larva. We therefore propose a highly conserved mechanism by which sodium pump activity increases following a bout of locomotion. This results in an ultraslow afterhyperpolarisation (usAHP) of the membrane potential that lasts around 1 minute, but which only occurs in around half the network neurons. This usAHP in turn alters network excitability so that network output is reduced in a locomotor interval-dependent manner. The pumps therefore confer on spinal locomotor networks a temporary memory trace of recent network performance. Postprint

Dopamine plays important roles in the development and modulation of motor control circuits. Here we show that dopamine exerts potent effects on the central pattern generator circuit controlling locomotory swimming in post-embryonic Xenopus tadpoles. Dopamine (0.5–100 μM) reduced fictive swim bout occurrence and caused both spontaneous and evoked episodes to become shorter, slower and weaker. The D2-like receptor agonist quinpirole mimicked this repertoire of inhibitory effects on swimming, whilst the D4 receptor antagonist, L745,870, had the opposite effects. The dopamine reuptake inhibitor bupropion potently inhibited fictive swimming, demonstrating that dopamine constitutes an endogenous modulatory system. Both dopamine and quinpirole also inhibited swimming in spinalised preparations, suggesting spinally located dopamine receptors. Dopamine and quinpirole hyperpolarised identified rhythmically active spinal neurons, increased rheobase and reduced spike probability both during swimming and in response to current injection. The hyperpolarisation was TTX-resistant and was accompanied by decreased input resistance, suggesting that dopamine opens a K+ channel. The K+ channel blocker barium chloride (but not TEA, glybenclamide or tertiapin-Q) significantly occluded the hyperpolarisation. Overall, we show that endogenously released dopamine acts upon spinally located D2-like receptors, leading to a rapid inhibitory modulation of swimming via the opening of a K+ channel.

The current study investigated error monitoring and subsequent control adjustments in a joint choice RT task. External feedback relating to the combined performance of both actors was provided. Participants slowed down only after their own but not after the co-actor's mistakes. In order to investigate the neural correlates of interpersonal error monitoring, ERPs associated with error processing (Ne/ERN, Pe) and feedback-related processing (FRN, f-P300) were analysed. The Ne/ERN and Pe were only affected by own but not the co-actor's actions. Conversely, at the feedback stage both the FRN and the f-P300 were larger when external feedback indicated a co-actor's error, yet despite this finding, co-actor errors did not affect the actor's subsequent performance. These findings are in line with previous research suggesting that we monitor not only our own but also others' errors. Importantly, however, monitoring others' performance seems insufficient to trigger subsequent behavioural adjustment in the form of post-error slowing, but might only occur when a surprising outcome is evaluated as negative.