Motor neurons and the sense of place

Seventy years ago George Romanes began to document the anatomical organization of the spinal motor system, uncovering a multilayered topographic plan that links the clustering and settling position of motor neurons to the spatial arrangement and biomechanical features of limb muscles. To this day, these findings have provided a structural foundation for analysis of the neural control of movement and serve as?a guide for studies to explore mechanisms that direct the wiring of spinal motor circuits. In this brief essay we outline the?core of Romanes's findings and place them in the context of recent studies that begin to provide insight?into molecular programs that assign motor pool position and to resolve how motor neuron position shapes circuit assembly. Romanes's findings reveal how and why neuronal positioning contributes to sensory-motor connectivity and may have relevance to circuit organization in other regions of the central nervous system.     

The neural circuits and synaptic mechanisms underlying motor initiation in C. elegans

C. elegans is widely used to dissect how neural circuits and genes generate behavior. During locomotion, worms initiate backward movement to change locomotion direction spontaneously or in response to sensory cues; however, the underlying neural circuits are not well defined. We applied a multidisciplinary approach to map neural circuits in freely behaving worms by integrating functional imaging, optogenetic interrogation, genetic manipulation, laser ablation, and electrophysiology. We found that a disinhibitory circuit and a stimulatory circuit together promote initiation of backward movement and that circuitry dynamics is differentially regulated by sensory cues. Both circuits require glutamatergic transmission but depend on distinct glutamate receptors. This dual mode of motor initiation control is found in mammals, suggesting that distantly related organisms with anatomically distinct nervous systems may adopt similar strategies for motor control. Additionally, our studies illustrate how a multidisciplinary approach facilitates dissection of circuit and synaptic mechanisms underlying behavior in a genetic model organism.     

Regulation of motor circuit assembly by spatial and temporal mechanisms

Precision of synaptic connections in neuronal circuits is the product of an orderly assembly process during development. Circuits controlling motor behavior have been studied extensively in many animal species, allowing an assessment of evolutionarily conserved organizational principles that underlie neuronal subtype specification, connectivity and function. Across phylogenetically distant species, motor circuit assembly is based on spatial organization of interconnected circuit elements. Developmental molecular coordinate systems demarcate dendritic and axonal targeting territories, thereby regulating convergence of synaptic partners. Additional mechanisms subsequently control fine synaptic connection specificity within these domains. Spatial organization often correlates with the orderly sequence of neurogenesis contributing to the generation of distinct postmitotic neuronal subpopulations, a developmental strategy implemented far beyond motor circuits.     

A dye mixture (Neurobiotin and Alexa 488) reveals extensive dye-coupling among neurons in leeches; physiology confirms the connections

Although the neuronal circuits that generate leech movements have been studied for over 30 years, the list of interneurons (INs) in these circuits remains incomplete. Previous studies showed that some motor neurons (MNs) are electrically coupled to swim-related INs, e.g., rectifying junctions connect IN 28 to MN DI-1 (dorsal inhibitor), so we searched for additional neurons in these behavioral circuits by co-injecting Neurobiotin and Alexa Fluor 488 into segmental MNs DI–1, VI–2, DE–3 and VE–4. The high molecular weight Alexa dye is confined to the injected cell, whereas the smaller Neurobiotin molecules diffuse through gap junctions to reveal electrical coupling. We found that MNs were each dye-coupled to approximately 25 neurons, about half of which are likely to be INs. We also found that (1) dye-coupling was reliably correlated with physiologically confirmed electrical connections, (2) dye-coupling is unidirectional between MNs that are linked by rectifying connections, and (3) there are novel electrical connections between excitatory and inhibitory MNs, e.g. between excitatory MN VE-4 and inhibitory MN DI-1. The INs found in this study provide a pool of novel candidate neurons for future studies of behavioral circuits, including those underlying swimming, crawling, shortening, and bending movements.     

Development of larval motor circuits in Drosophila

How are functional neural circuits formed during development? Despite recent advances in our understanding of the development of individual neurons, little is known about how complex circuits are assembled to generate specific behaviors. Here, we describe the ways in which Drosophila motor circuits serve as an excellent model system to tackle this problem. We first summarize what has been learned during the past decades on the connectivity and development of component neurons, in particular motor neurons and sensory feedback neurons. We then review recent progress in our understanding of the development of the circuits as well as studies that apply optogenetics and other innovative techniques to dissect the circuit diagram. New approaches using Drosophila as a model system are now making it possible to search for developmental rules that regulate the construction of neural circuits.     

Alterations in brain connectivity underlying beta oscillations in Parkinsonism

Cortico-basal ganglia-thalamocortical circuits are severely disrupted by the dopamine depletion of Parkinson's disease (PD), leading to pathologically exaggerated beta oscillations. Abnormal rhythms, found in several circuit nodes are correlated with movement impairments but their neural basis remains unclear. Here, we used dynamic causal modelling (DCM) and the 6-hydroxydopamine-lesioned rat model of PD to examine the effective connectivity underlying these spectral abnormalities. We acquired auto-spectral and cross-spectral measures of beta oscillations (10-35 Hz) from local field potential recordings made simultaneously in the frontal cortex, striatum, external globus pallidus (GPe) and subthalamic nucleus (STN), and used these data to optimise neurobiologically plausible models. Chronic dopamine depletion reorganised the cortico-basal ganglia-thalamocortical circuit, with increased effective connectivity in the pathway from cortex to STN and decreased connectivity from STN to GPe. Moreover, a contribution analysis of the Parkinsonian circuit distinguished between pathogenic and compensatory processes and revealed how effective connectivity along the indirect pathway acquired a strategic importance that underpins beta oscillations. In modelling excessive beta synchrony in PD, these findings provide a novel perspective on how altered connectivity in basal ganglia-thalamocortical circuits reflects a balance between pathogenesis and compensation, and predicts potential new therapeutic targets to overcome dysfunctional oscillations.     

Organized variability in the neuromuscular system: a survey of task-related adaptations.

This survey concerns the physiology of the neuromuscular system, as studied at the level of the single mammalian limb muscle and its motoneurones (MNs). Particular attention is devoted to the ways in which the properties and the organization of spinal MNs are adapted for the control of muscle (unit) force. These questions are discussed in relation to: a) The general and basic task of the system: providing a smooth and finely gradeable force by the mechanisms of rate- and recruitment-modulation of MN activity. b) Gradation problems in relation to specific peripheral requirements in connection with: (i) tasks of different duty-time (i.e. problems related to fatigue and endurance); (ii) tasks of different speed; (iii) task using different muscle lengths; (iv) tasks requiring different adjustment-gains. c) The adaptational properties of the neuromuscular system as it is subjected to long-term changes in its motor tasks. These matters are largely discussed in relation to experiments for studying the responses of the neuromuscular system to different patterns of chronic electrical stimulation. d) The manner in which the neuromuscular system, at the level of a single unidirectional muscle, is used for different motor programs. Evidence is summarized which shows the presence of task-related variations in MN recruitment patterns, and it is pointed out that such variations may be related to the intraspinal topography of the respective MNs. It is suggested that these task-related variations in MN recruitment behaviour might largely reflect topographic (and other) differences in the organization of spinal interneuronal systems responsible for the execution of different motor programs.     

Biological pattern generation: the cellular and computational logic of networks in motion

In 1900, Ramón y Cajal advanced the neuron doctrine, defining the neuron as the fundamental signaling unit of the nervous system. Over a century later, neurobiologists address the circuit doctrine: the logic of the core units of neuronal circuitry that control animal behavior. These are circuits that can be called into action for perceptual, conceptual, and motor tasks, and we now need to understand whether there are coherent and overriding principles that govern the design and function of these modules. The discovery of central motor programs has provided crucial insight into the logic of one prototypic set of neural circuits: those that generate motor patterns. In this review, I discuss the mode of operation of these pattern generator networks and consider the neural mechanisms through which they are selected and activated. In addition, I will outline the utility of computational models in analysis of the dynamic actions of these motor networks.     

Neural control of the pyloric region in the foregut of the shrimp Penaeus (Decapoda: Penaeidae)

Pyloric pattern-generating neurons that control the pyloric region of the foregut were identified in the stomatogastric ganglion of the most primitive decapod genus Penaeus. Five types of motor neurons and one interneuron are involved in generation of pyloric motor pattern. One cell type of motor neurons innervates muscles of both the gastric mill and the pylorus like the gastric motor neurons in Cancer, but unlike those in Panulirus. These identified neurons are connected to each other either by electrical or inhibitory chemical synapses to construct the neural circuit. This pyloric circuit is similar to the homologous circuit of other crustacean species though some differences are seen in synaptic connections, supporting the hypothesis that the basic design of the neural circuit has been conserved during evolution of the Malacostraca, and that differences have occurred in the synaptic connectivity as the foregut structure has become complex. The motor neurons use either acetylcholine or glutamate as a neurotransmitter like in reptantians. The foregut structure, the number of the pyloric cells, muscle innervation, neurotransmitters, and circuitry are compared among malacostracan crustaceans to provide insight into how the neural circuits change and evolve to produce the motor patterns mediating behaviour. Accepted: 18 April 1997     

Modulation of Neural Circuits in Crustacea

Recent research has shown that neuromodulators play importantroles in shaping simple behaviors. They act at many differentsites within the animal in a coordinated fashion, modulatingthe motor circuits in the central nervous system, altering motoneuronexcitability, and modulating muscle response to motoneuron input.Within the central circuits that co-ordinate simple movements,neuromodulators play a dramatic sculpting role, changing thecells that participate in the circuit, altering their intrinsicproperties, and affecting the strength of synaptic interactionsthat form the "wiring diagram" of the circuit. As a result,they are able to shape a family of related circuits out of asingle anatomically identified network, each driving a uniquevariant on the basic motor theme. Examples of these actionsfrom the Crustacea are described in this paper, focussing onthe modulation of posture in the lobster, and on modulationof rhythmic motor programs for stomach movements in the stomatogastricganglion of lobsters and crabs.     

Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9.

Sonic hedgehog (Shh) specifies the identity of both motor neurons (MNs) and interneurons with morphogen-like activity. Here, we present evidence that the homeodomain factor HB9 is critical for distinguishing MN and interneuron identity in the mouse. Presumptive MN progenitors and postmitotic MNs express HB9, whereas interneurons never express this factor. This pattern resembles a composite of the avian homologs MNR2 and HB9. In mice lacking Hb9, the genetic profile of MNs is significantly altered, particularly by upregulation of Chx10, a gene normally restricted to a class of ventral interneurons. This aberrant gene expression is accompanied by topological disorganization of motor columns, loss of the phrenic and abducens nerves, and intercostal nerve pathfinding defects. Thus, MNs actively suppress interneuron genetic programs to establish their identity.     

Embryonic electrical connections appear to prefigure a behavioral circuit in the leech CNS

During development, many embryos show electrical coupling among neurons that is spatially and temporally regulated. For example, in vertebrate embryos extensive dye coupling is seen during the period of circuit formation, suggesting that electrical connections could prefigure circuits, but it has been difficult to identify which neuronal types are coupled. We have used the leech Hirudo medicinalis to follow the development of electrical connections within the circuit that produces local bending. This circuit consists of three layers of neurons: four mechanosensory neurons (P cells), 17 identified interneurons, and approximately 24 excitatory and inhibitory motor neurons. These neurons can be identified in embryos, and we followed the spatial and temporal dynamics as specific connections developed. Injecting Neurobiotin into identified cells of the circuit revealed that electrical connections were established within this circuit in a precise manner from the beginning. Connections first appeared between motor neurons; mechanosensory neurons and interneurons started to connect at least a day later. This timing correlates with the development of behaviors, so the pattern of emerging connectivity could explain the appearance first of spontaneous behaviors (driven by a electrically coupled motor network) and then of evoked behaviors (when sensory neurons and interneurons are added to the circuit).