Sensory initiation of a co-ordinated motor response: synaptic excitation underlying simple decision-making.

This is the final version of the article. Available from Wiley via the DOI in this record.KEY POINTS: Deciding whether or how to initiate a motor response to a stimulus can be surprisingly slow and the underlying processes are not well understood. The neuronal circuitry that allows frog tadpoles to swim in response to touch is well characterized and includes excitatory reticulospinal neurons that drive swim circuit neurons. Build-up of excitation to reticulospinal neurons is the key decision-making step for swimming. Asymmetry in this build-up between the two sides allows bilateral initiation at the same time as avoiding inappropriate co-activation of motor antagonists. Following stronger stimuli, reticulospinal neurons are excited through a trigeminal nucleus pathway and swimming starts first on the stimulated side. If this pathway fails or is lesioned, swimming starts later on the unstimulated side. The mechanisms underlying initiation of a simple tadpole motor response may share similarities with more complex decisions in other animals, including humans. ABSTRACT: Animals take time to make co-ordinated motor responses to a stimulus. How can sensory input initiate organized movements, activating all necessary elements at the same time as avoiding inappropriate co-excitation of antagonistic muscles? In vertebrates, this process usually results in the activation of reticulospinal pathways. Young Xenopus tadpoles can respond to head-skin touch by swimming, which may start on either side. We investigate how motor networks in the brain are organized, and whether asymmetries in touch sensory pathways avoid co-activation of antagonists at the same time as producing co-ordinated movements. We record from key reticulospinal neurons in the network controlling swimming. When the head skin is stimulated unilaterally, excitation builds up slowly and asymmetrically in these neurons such that those on both sides do not fire synchronously. This build-up of excitation to threshold is the key decision-making step and determines whether swimming will start, as well as on which side. In response to stronger stimuli, the stimulated side tends to 'win' because excitation from a shorter, trigeminal nucleus pathway becomes reliable and can initiate swimming earlier on the stimulated side. When this pathway fails or is lesioned, swimming starts later and on the unstimulated side. Stochasticity in the trigeminal nucleus pathway allows unpredictable turning behaviour to weaker stimuli, conferring potential survival benefits. We locate the longer, commissural sensory pathway carrying excitation to the unstimulated side and record from its neurons. These neurons fire to head-skin stimuli but excite reticulospinal neurons indirectly. We propose that asymmetries in the sensory pathways exciting brainstem reticulospinal neurons ensure alternating and co-ordinated swimming activity from the start.This work was supported by the BBSRC grant (BB/G006652/1)

Developmental changes in spinal neuronal properties, motor network configuration, and neuromodulation at free-swimming stages of Xenopus tadpoles

We describe a novel preparation of the isolated brainstem and spinal cord from pro-metamorphic tadpole stages of the South African clawed frog (Xenopus laevis) that permits whole cell patch-clamp recordings from neurons in the ventral spinal cord. Previous research on earlier stages of the same species has provided one of the most detailed understandings of the design and operation of a CPG circuit. Here we have addressed how development sculpts complexity from this more basic circuit. The preparation generates bouts of fictive31 swimming activity either spontaneously or in response to electrical stimulation of the optic tectum, allowing an investigation into how the neuronal properties, activity patterns and neuromodulation of locomotor rhythm generation change during development. We describe an increased repertoire of cellular responses compared to younger larval stages and investigate the cellular level effects of nitrergic neuromodulation as well as the development of a sodium pump-mediated ultra-slow afterhyperpolarisation (usAHP) in these free-swimming larval animals.PostprintPeer reviewe

Mechanisms underlying the activity-dependent regulation of locomotor network performance by the Na⁺ pump

This research was funded by BBSRC (project grants to KTS (BB/F015488/1) and W-CL; EastBio studentship to LP) and Wellcome Trust (ISSF to H-YZ).Activity-dependent modification of neural network output usually results from changes in neurotransmitter release and/or membrane conductance. In Xenopus frog tadpoles, spinal locomotor network output is adapted by an ultraslow afterhyperpolarization (usAHP) mediated by an increase in Na+ pump current. Here we systematically explore how the interval between two swimming episodes affects the second episode, which is shorter and slower than the first episode. We find the firing reliability of spinal rhythmic neurons to be lower in the second episode, except for excitatory descending interneurons (dINs). The sodium/proton antiporter, monensin, which potentiates Na+ pump function, induced similar effects to short inter-swim intervals. A usAHP induced by supra-threshold pulses reduced neuronal firing reliability during swimming. It also increased the threshold current for spiking and introduced a delay to the first spike in a train, without reducing subsequent firing frequency. This delay was abolished by ouabain or zero K+ saline, which eliminate the usAHP. We present evidence for an A-type K+ current in spinal CPG neurons which is inactivated by depolarization and de-inactivated by hyperpolarization, and accounts for the prolonged delay. We conclude that the usAHP attenuates neuronal responses to excitatory network inputs by both membrane hyperpolarization and enhanced de-inactivation of an A-current.Publisher PDFPeer reviewe

Longitudinal neuronal organization and coordination in a simple vertebrate: a continuous, semi-quantitative computer model of the central pattern generator for swimming in young frog tadpoles

When frog tadpoles hatch their swimming requires co-ordinated contractions of trunk muscles, driven by motoneurons and controlled by a Central Pattern Generator (CPG). To study this co-ordination we used a 3.5 mm long population model of the young tadpole CPG with continuous distributions of neurons and axon lengths as estimated anatomically. We found that: (1) alternating swimming-type activity fails to self-sustain unless some excitatory interneurons have ascending axons, (2) a rostro-caudal (R-C) gradient in the distribution of excitatory premotor interneurons with short axons is required to obtain the R-C gradient in excitation and resulting progression of motoneuron firing necessary for forward swimming, (3) R-C delays in motoneuron firing decrease if excitatory motoneuron to premotor interneuron synapses are present, (4) these feedback connections and the electrical synapses between motoneurons synchronise motoneuron discharges locally, (5) the above findings are independent of the detailed membrane properties of neurons

A simple decision to move in response to touch reveals basic sensory memory and mechanisms for variable response times

Many motor responses to sensory input, like locomotion or eye movements, are much slower than reflexes. Can simpler animals provide fundamental answers about the cellular mechanisms for motor decisions? Can we observe the ‘accumulation’ of excitation to threshold proposed to underlie decision making elsewhere? We explore how somatosensory touch stimulation leads to the decision to swim in hatchling Xenopus tadpoles. Delays measured to swimming in behaving and immobilized tadpoles are long and variable. Activity in their extensively studied sensory and sensory pathway neurons is too short-lived to explain these response delays. Instead, whole-cell recordings from the hindbrain reticulospinal neurons that drive swimming show these receive prolonged, variable synaptic excitation lasting for nearly a second following a brief stimulus. They fire and initiate swimming when this excitation reaches threshold. Analysis of the summation of excitation requires us to propose extended firing in currently undefined presynaptic hindbrain neurons. Simple models show that a small excitatory recurrent-network inserted in the sensory pathway can mimic this process. We suggest that such a network may generate slow, variable summation of excitation to threshold. This excitation provides a simple memory of the sensory stimulus. It allows temporal and spatial integration of sensory inputs and explains the long, variable delays to swimming. The process resembles the ‘accumulation’ of excitation proposed for cortical circuits in mammals. We conclude that fundamental elements of sensory memory and decision making are present in the brainstem at a surprisingly early stage in development

Interactions via electrical coupling in axial and appendicular motor networks during metamorphosis in Xenopus laevis tadpoles

The spinal locomotor networks in Xenopus laevis frog tadpoles undergo a remarkable transformation during metamorphosis to accommodate a switch from axial-based swimming to a limb-based kicking locomotor strategy. For a brief period during ontogeny, both the axial- and limb-based systems are present and functional, but reliant on different central pattern generators (CPGs) that are simultaneously active. However, the mechanisms controlling the functional coupling both within and between these locomotor networks are unknown. At metamorphosing larval stages (52-58), retrograde motoneuron (MN) backfilling from both axial (11th-12th post-otic segments) and hindlimb muscles with fluorescent rhodamine- and fluorescein-conjugated dextran dyes revealed two discrete MN populations (axial and appendicular) within the spinal cord. The co-labelling of both axial and appendicular cells provides evidence that the two MN pools in the lumbar enlargement are coupled. Electrophysiological data from animals at the same larval stages suggest that axial CPG excitability is modified as burst durations were increased by gap junction (GJ) blockers (18-β-glycyrrhetinic (18-β-GA) acid 100µM; CBNX 200µM), however, limb CPG burst parameters were not altered by GJ block. For spontaneous fictive locomotor bouts, the number of axial episodes initially increased, but then sharply decreased from control levels ~15-30 minutes after drug application. Coordinated and simultaneous axial and limb CPG output was observed with electrical stimulation to the optic tectum, an axial ventral root (VR), and a limb VR; GJ block did not affect the coordinated output from optic tectum stimulation, however, it decreased simultaneous output when the axial VR was stimulated. This novel finding that antidromic stimulation of an axial VR is sufficient to activate a different CPG for the limbs suggests there is synaptic coupling in the direction of axial to limb. These data suggest that axial CPG output is in part regulated by GJs. The anatomical data also suggest a connection exists between the axial and limb MN pools, and may be involved in the initial cycle-by-cycle coupling of the two CPG outputs. Thus the rhythm of the appendicular CPG is initially highly dependent on that of the axial CPG, which in turn is dependent on its own GJ connections within the spinal circuit. It appears that the immature limb MN pools in the lumbar spinal cord possess functional connections via electrical synapses to the axial locomotor system, which are presumably “pruned” as metamorphosis proceeds, and eventually lost completely by the adult stages when the limb network has become completely independent

Dynamical systems and their applications in neuroscience

This thesis deals with dynamical systems, numerical software for the continuation study of dynamical systems, and some important neurobiological applications. First there are two introductory chapters, in which a background is given in dynamical systems and neuroscience. We elucidate what the problems are with some existing classifications of neural models, and suggest an improved version. We introduce the Phase Response Curve (PRC), which is a curve that describes the effect of an input on a periodic orbit. We derive an efficient method to compute this PRC. The extended functionalities of MatCont, a software package for the study of dynamical systems and their bifurcations, are explained: the user can compute the PRC of a limit cycle and its derivative, he can detect and continue homoclinic bifurcations, initiate these curves from different bifurcations and detect many codim 2 bifurcations on these curves. The speed of the software was improved by introducing C-code among the matlab-routines. We have for the first time made a complete bifurcation diagram of the Morris-Lecar neural model. We show that PRCs can be used to determine the synchronizing and/or phase-locking abilities of neural networks, and how the connection delay plays a role in this, and demonstrate some phenomena to do with PRCs and bifurcations. In collaboration with biologists at the University of Bristol, we have built detailed models of the neurons in the spinal cord of the hatchling Xenopus laevis. The biological background and the equations and parameters for the models of individual neurons and synapses are listed elaborately. These models are used to construct biologically realistic networks of neurons. The first network was used to simulate the swimming behaviour of the tadpole and to show that to disregard some important differences in the models for different neurons, will result in breakdown of the good network output. Then we have used the individual models to study a hypothesis regarding synaptogenesis, which states that the specificity in connection between neurons could be purely based on the anatomical organization of the neurons, instead of the ability of growing synapses to make a distinction between the different neurons

The spinal locomotor circuit of the larval Zebrafish: anatomical organization and functional components

University of Minnesota Ph.D. dissertation. February 2015. Major: Neuroscience. Advisor: Mark A. Masino. 1 computer file (PDF); vi, 142 pages.Abstract not availabl