Aberrations of cortical and subcortical integration during chronic administration of haloperidol to the dog

The character of evoked potentials (EPs) dynamics to signal light stimulus during elaboration of avoidance reaction, allows to assert that during formation of adaptive activity functional balance is established of sensory and integrative-triggering brain parts or functional balance of "motor" and "sensory" integration regimes. Each of the studied subcortical structures is characterized by simultaneous but specific functioning both in the motor and sensory regimes; such conclusion is based on different dynamics of their EPs parameters: the changes of ones correspond to EPs dynamics in the visual cortical area, of the others--in the motor area. During chronic haloperidol administration, the reorganizations of intercentral relations are observed in 10--12 days after the beginning of drug administration. They may be considered as a succession of disturbances of functional balance between "sensory" and "motor" integration regimes: at first the sensory regime domination appears in which subcortical structures are chiefly and uniformly involved (ncd, pall and n. acc.); "motor" regime is weakened; then, as a result, a distortion of the "motor" regime of integration takes place. In this case a bradykinesia is developed.     

Learning from sensory and reward prediction errors during motor adaptation

Voluntary motor commands produce two kinds of consequences. Initially, a sensory consequence is observed in terms of activity in our primary sensory organs (e.g., vision, proprioception). Subsequently, the brain evaluates the sensory feedback and produces a subjective measure of utility or usefulness of the motor commands (e.g., reward). As a result, comparisons between predicted and observed consequences of motor commands produce two forms of prediction error. How do these errors contribute to changes in motor commands? Here, we considered a reach adaptation protocol and found that when high quality sensory feedback was available, adaptation of motor commands was driven almost exclusively by sensory prediction errors. This form of learning had a distinct signature: as motor commands adapted, the subjects altered their predictions regarding sensory consequences of motor commands, and generalized this learning broadly to neighboring motor commands. In contrast, as the quality of the sensory feedback degraded, adaptation of motor commands became more dependent on reward prediction errors. Reward prediction errors produced comparable changes in the motor commands, but produced no change in the predicted sensory consequences of motor commands, and generalized only locally. Because we found that there was a within subject correlation between generalization patterns and sensory remapping, it is plausible that during adaptation an individual''s relative reliance on sensory vs. reward prediction errors could be inferred. We suggest that while motor commands change because of sensory and reward prediction errors, only sensory prediction errors produce a change in the neural system that predicts sensory consequences of motor commands.     

Tactile Gap Detection Deteriorates during Bimanual Symmetrical Movements under Mirror Visual Feedback

It has been suggested that incongruence between signals for motor intention and sensory input can cause pain and other sensory abnormalities. This claim is supported by reports that moving in an environment of induced sensorimotor conflict leads to elevated pain and sensory symptoms in those with certain painful conditions. Similar procedures can lead to reports of anomalous sensations in healthy volunteers too. In the present study, we used mirror visual feedback to investigate the effects of sensorimotor incongruence on responses to stimuli that arise from sources external to the body, in particular, touch. Incongruence between the sensory and motor signals for the right arm was manipulated by having the participants make symmetrical or asymmetrical movements while watching a reflection of their left arm in a parasagittal mirror, or the left hand surface of a similarly positioned opaque board. In contrast to our prediction, sensitivity to the presence of gaps in tactile stimulation of the right forearm was not reduced when participants made asymmetrical movements during mirror visual feedback, as compared to when they made symmetrical or asymmetrical movements with no visual feedback. Instead, sensitivity was reduced when participants made symmetrical movements during mirror visual feedback relative to the other three conditions. We suggest that small discrepancies between sensory and motor information, as they occur during mirror visual feedback with symmetrical movements, can impair tactile processing. In contrast, asymmetrical movements with mirror visual feedback may not impact tactile processing because the larger discrepancies between sensory and motor information may prevent the integration of these sources of information. These results contrast with previous reports of anomalous sensations during exposure to both low and high sensorimotor conflict, but are nevertheless in agreement with a forward model interpretation of perceptual modulations during goal directed movement.     

Relationships between unitary motor and sensory activity in the walking legs of cancer pagurus (Decapoda,Brachyura)†

Muscular tension and sensory activity in the flexor apodeme sensory nerve were recorded during stimulation of single motor afferents innervating the M‐C flexor. Muscular tension and unitary sensory activity both varied, depending upon the motor fiber stimulated. Differences in the abililty of individual motor fibers to elicit sensory activity were only partially accounted for by differences in tension development. Some tension afferent units were more readily excited by a muscular contraction elicited by one motor axon than they were by another, even when the tension elicited by the more effective motor fiber was less than that evoked by the less effective efferent.     

Spatiotemporal dynamics of cortical sensorimotor integration in behaving mice

Tactile information is actively acquired and processed in the brain through concerted interactions between movement and sensation. Somatosensory input is often the result of self-generated movement during the active touch of objects, and conversely, sensory information is used to refine motor control. There must therefore be important interactions between sensory and motor pathways, which we chose to investigate in the mouse whisker sensorimotor system. Voltage-sensitive dye was applied to the neocortex of mice to directly image the membrane potential dynamics of sensorimotor cortex with subcolumnar spatial resolution and millisecond temporal precision. Single brief whisker deflections evoked highly distributed depolarizing cortical sensory responses, which began in the primary somatosensory barrel cortex and subsequently excited the whisker motor cortex. The spread of sensory information to motor cortex was dynamically regulated by behavior and correlated with the generation of sensory-evoked whisker movement. Sensory processing in motor cortex may therefore contribute significantly to active tactile sensory perception.     

Npn-1 contributes to axon-axon interactions that differentially control sensory and motor innervation of the limb

The initiation, execution, and completion of complex locomotor behaviors are depending on precisely integrated neural circuitries consisting of motor pathways that activate muscles in the extremities and sensory afferents that deliver feedback to motoneurons. These projections form in tight temporal and spatial vicinities during development, yet the molecular mechanisms and cues coordinating these processes are not well understood. Using cell-type specific ablation of the axon guidance receptor Neuropilin-1 (Npn-1) in spinal motoneurons or in sensory neurons in the dorsal root ganglia (DRG), we have explored the contribution of this signaling pathway to correct innervation of the limb. We show that Npn-1 controls the fasciculation of both projections and mediates inter-axonal communication. Removal of Npn-1 from sensory neurons results in defasciculation of sensory axons and, surprisingly, also of motor axons. In addition, the tight coupling between these two heterotypic axonal populations is lifted with sensory fibers now leading the spinal nerve projection. These findings are corroborated by partial genetic elimination of sensory neurons, which causes defasciculation of motor projections to the limb. Deletion of Npn-1 from motoneurons leads to severe defasciculation of motor axons in the distal limb and dorsal-ventral pathfinding errors, while outgrowth and fasciculation of sensory trajectories into the limb remain unaffected. Genetic elimination of motoneurons, however, revealed that sensory axons need only minimal scaffolding by motor axons to establish their projections in the distal limb. Thus, motor and sensory axons are mutually dependent on each other for the generation of their trajectories and interact in part through Npn-1-mediated fasciculation before and within the plexus region of the limbs.     

Anatomical coupling of sensory and motor nerve trajectory via axon tracking

It is a long-standing question how developing motor and sensory neuron projections cooperatively form?a common principal grid of peripheral nerve pathways relaying behavioral outputs and somatosensory inputs. Here, we explored this issue through targeted cell lineage and gene manipulation in mouse, combined with in?vitro live axon imaging. In the absence of motor projections, dorsal (epaxial) and ventral (hypaxial) sensory projections form in a randomized manner, while removal of EphA3/4 receptor tyrosine kinases expressed by epaxial motor axons triggers selective failure to form epaxial sensory projections. EphA3/4 act non-cell-autonomously by inducing sensory axons to track along preformed epaxial motor projections. This involves cognate ephrin-A proteins on sensory axons but is independent from EphA3/4 signaling in motor axons proper. Assembly of peripheral nerve pathways thus involves motor axon subtype-specific signals that couple sensory projections to discrete motor pathways.     

Axonal degeneration within the tympanal nerve of Schistocerca gregaria

This study describes time course and ultrastructural changes during axonal degeneration of different neurones within the tympanal nerve of the locust Schistocerca gregaria. The tympanal nerve innervates the tergit and pleurit of the first abdominal segment and contains the axons of both sensory and motor neurones. The majority of axons (approx. 97%) belong to several types of sensory neurones: mechano- and chemosensitive hair sensilla, multipolar neurones, campaniform sensilla and sensory cells of a scolopidial organ, the auditory organ. Axons of campaniform sensilla, of auditory sensory cells and of motor neurones are wrapped by glial cell processes. In contrast, the very small and numerous axons (diameter <1 microm) of multipolar neurones and hair sensilla are not separated individually by glia sheets. Distal parts of sensory and motor axons show different reactions to axotomy: 1 week after separation from their somata, distal parts of motor axons are invaded by glial cell processes. This results in fascicles of small axon bundles. In contrast, distal parts of most sensory axons degenerate rapidly after being lesioned. The time to onset of degeneration depends on distance from the lesion site and on the type of sensory neurone. In axons of auditory sensory neurones, ultrastructural signs of degeneration can be found as soon as 2 days after lesion. After complete lysis of distal parts of axons, glial cell processes invade the space formerly occupied by sensory axons. The rapid degeneration of distal auditory axon parts allows it to be excluded that they provide a structure that leads regenerating axons to their targets. Proximal parts of severed axons do not degenerate.     

The interaction of positive and negative sensory feedback loops in dynamic regulation of a motor pattern

In many rhythmic behaviors, phasic sensory feedback modifies the motor pattern. This modification is assumed to depend on feedback sign (positive vs. negative). While on a phenomenological level feedback sign is well defined, many sensory pathways also process antagonistic, and possibly contradictory, sensory information. We here model the locust flight pattern generator and proprioceptive feedback provided by the tegula wing receptor to test the functional significance of sensory pathways processing antagonistic information. We demonstrate that the tegula provides delayed positive feedback via interneuron 301, while all other pathways provide negative feedback. Contradictory to previous assumptions, the increase of wing beat frequency when the tegula is activated during flight is due to the positive feedback. By use of an abstract model we reveal that the regulation of motor pattern frequency by sensory feedback critically depends on the interaction of positive and negative feedback, and thus on the weighting of antagonistic pathways.     

Why Are Sensory Axons More Vulnerable for Ischemia than Motor Axons?

Objective

In common peripheral neuropathies, sensory symptoms usually prevail over motor symptoms. This predominance of sensory symptoms may result from higher sensitivity of sensory axons to ischemia.

Methods

We measured median nerve compound sensory action potentials (CSAPs), compound muscle action potentials (CMAPs), and excitability indices in five healthy subjects during forearm ischemia lasting up to disappearance of both CSAPs and CMAPs.

Results

Ischemia induced: (1) earlier disappearance of CSAPs than CMAPs (mean ± standard deviation 30±5 vs. 46±6 minutes), (2) initial changes compatible with axonal depolarization on excitability testing (decrease in threshold, increase in strength duration time constant (SDTC) and refractory period, and decrease in absolute superexcitability) which were all more prominent in sensory than in motor axons, and (3) a subsequent decrease of SDTC reflecting a decrease in persistent Na⁺ conductance during continuing depolarisation.

Interpretation

Our study shows that peripheral sensory axons are more vulnerable for ischemia than motor axons, with faster inexcitability during ischemia. Excitability studies during ischemia showed that this was associated with faster depolarization and faster persistent Na⁺ channel inactivation in sensory than in motor axons. These findings might be attributed to differences in ion channel composition between sensory and motor axons and may contribute to the predominance of sensory over motor symptoms in common peripheral neuropathies.     

Cerebral cortical representation of reflexive and volitional swallowing in humans

The purpose of this study was to compare cerebral cortical representation of experimentally induced reflexive swallow with that of volitional swallow. Eight asymptomatic adults (24-27 yr) were studied by a single-trial functional magnetic resonance imaging technique. Reflexive swallowing showed bilateral activity concentrated to the primary sensory/motor regions. Volitional swallowing was represented bilaterally in the insula, prefrontal, cingulate, and parietooccipital regions in addition to the primary sensory/motor cortex. Intrasubject comparison showed that the total volume of activity during volitional swallowing was significantly larger than that activated during reflexive swallows in either hemisphere (P < 0.001). For volitional swallowing, the primary sensory/motor region contained the largest and the insular region the smallest volumes of activation in both hemispheres, and the total activated volume in the right hemisphere was significantly larger compared with the left (P < 0.05). Intersubject comparison showed significant variability in the volume of activity in each of the four volitional swallowing cortical regions. We conclude that reflexive swallow is represented in the primary sensory/motor cortex and that volitional swallow is represented in multiple regions, including the primary sensory/motor cortex, insular, prefrontal/cingulate gyrus, and cuneus and precuneus region. Non-sensory/motor regions activated during volitional swallow may represent swallow-related intent and planning and possibly urge.     

Adaptation to visual feedback delay influences visuomotor learning

Computational theory of motor control suggests that the brain continuously monitors motor commands, to predict their sensory consequences before actual sensory feedback becomes available. Such prediction error is a driving force of motor learning, and therefore appropriate associations between motor commands and delayed sensory feedback signals are crucial. Indeed, artificially introduced delays in visual feedback have been reported to degrade motor learning. However, considering our perceptual ability to causally bind our own actions with sensory feedback, demonstrated by the decrease in the perceived time delay following repeated exposure to an artificial delay, we hypothesized that such perceptual binding might alleviate deficits of motor learning associated with delayed visual feedback. Here, we evaluated this hypothesis by investigating the ability of human participants to adapt their reaching movements in response to a novel visuomotor environment with 3 visual feedback conditions--no-delay, sudden-delay, and adapted-delay. To introduce novelty into the trials, the cursor position, which originally indicated the hand position in baseline trials, was rotated around the starting position. In contrast to the no-delay condition, a 200-ms delay was artificially introduced between the cursor and hand positions during the presence of visual rotation (sudden-delay condition), or before the application of visual rotation (adapted-delay condition). We compared the learning rate (representing how the movement error modifies the movement direction in the subsequent trial) between the 3 conditions. In comparison with the no-delay condition, the learning rate was significantly degraded for the sudden-delay condition. However, this degradation was significantly alleviated by prior exposure to the delay (adapted-delay condition). Our data indicate the importance of appropriate temporal associations between motor commands and sensory feedback in visuomotor learning. Moreover, they suggest that the brain is able to account for such temporal associations in a flexible manner.     

The use of hormonally induced mosaics to study alterations in the synaptic connections made by persistent sensory neurons during insect metamorphosis

During the initial phase of metamorphosis in the hawkmoth, Manduca sexta, persistent mechanosensory neurons expand their terminal arborizations within the CNS and evoke a reflex response in the pupa which is different than in the larva. In an effort to determine the contribution of sensory neuron modifications to the difference in reflex responses, manipulations of juvenile hormone and 20-hydroxyecdysone were used to generate mosaic animals in which the sensory neurons were advanced or delayed developmentally with respect to the rest of the animal, including circuit components within the CNS. In the larval stage electrical stimulation of the sensory axons evokes a slow depolarization and a prolonged burst of action potentials in the ipsilateral intersegmental muscle motor neurons. By contrast, in pupal preparations the same motor neurons respond to an identical stimulus with a larger, more rapid depolarization which leads to a relatively brief, high-frequency burst of action potentials. Motor responses on the contralateral side of the body are also altered during pupal development. In mosaic animals where larval-like sensory neurons interact with a pupal CNS, a larval reflex response is generated. In the converse situation, pupal-like sensory neurons interacting with a larval or prepupal CNS evoke a motor response that is typical of larvae or prepupae. We conclude, therefore, that pupal development of the sensory neurons is necessary, but not sufficient, for the production of the pupal reflex.     

Differences between mammalian ventral and dorsal spinal roots in response to blockade of potassium channels during maturation

Differences in potassium channel organization between motor and sensory fibres have been described in amphibians but have not previously been examined in mammals. In the present investigation, we studied whole nerve and single axon responses following pharmacological blockade of potassium conductance in rat ventral and dorsal spinal roots during maturation. Our results indicate a differential sensitivity in maturing mammalian motor and sensory fibres which is most apparent in younger roots. Specifically, application of 4-aminopyridine (4-AP) results in a broadening of the compound action potential in ventral roots which is associated with a delayed repolarization of the individual action potential of single fibres. In contrast, blockade of potassium channels in young dorsal roots results in a late negativity in the compound response which is correlated with multispike bursting activity recorded from single sensory fibres. The effects of 4-AP on ventral root fibres diminish earlier in the course of maturation than do the effects of 4-AP in dorsal root fibres. These results demonstrate developmental differences in the functional organization of potassium channels in mammalian motor and sensory axons which may have implications for differences in coding properties between these two classes of axons.     

Reflex actions of the functional divisions in the crayfish oculomotor system

Summary The electrical responses of motor neurons in different anatomical subdivisions of the crayfish oculomotor system were examined during various kinds of experimentally manipulated sensory stimulation. Geotactic reflexes are effected by neurons in the anterior motor cluster and the medulla terminalis. Optokinetic and proprioceptive nystagmus are generated by neurons in the lateral motor cluster. This functional diversity in the major subdivisions contrasts with an intradivisional homogeneity of function, in that the different motor neurons of each all contribute to reflexes initiated by different kinds of sensory input.This research was supported by USPHS Research Grant NS 04989.     

Spinal nerve segmentation in the chick embryo: analysis of distinct axon-repulsive systems

In higher vertebrates, the segmental organization of peripheral spinal nerves is established by a repulsive mechanism whereby sensory and motor axons are excluded from the posterior half-somite. A number of candidate axon repellents have been suggested to mediate this barrier to axon growth, including Sema3A, Ephrin-B, and peanut agglutinin (PNA)-binding proteins. We have tested the candidacy of these factors in vitro by examining their contribution to the growth cone collapse-inducing activity of somite-derived protein extracts on sensory, motor, and retinal axons. We find that Sema3A is unlikely to play a role in the segmentation of sensory or motor axons and that Ephrin-B may contribute to motor but not sensory axon segmentation. We also provide evidence that the only candidate molecule(s) that induces the growth cone collapse of both sensory and motor axons binds to PNA and is not Sema3A or Ephrin-B. By grafting primary sensory, motor, and quail retinal neurons into the chick trunk in vivo, we provide further evidence that the posterior half-somite represents a universal barrier to growing axons. Taken together, these results suggest that the mechanisms of peripheral nerve segmentation should be considered in terms of repellent molecules in addition to the identified molecules.     

Expression of the Immunoglobulin Superfamily Cell Adhesion Molecules in the Developing Spinal Cord and Dorsal Root Ganglion

Cell adhesion molecules belonging to the immunoglobulin superfamily (IgSF) control synaptic specificity through hetero- or homophilic interactions in different regions of the nervous system. In the developing spinal cord, monosynaptic connections of exquisite specificity form between proprioceptive sensory neurons and motor neurons, however, it is not known whether IgSF molecules participate in regulating this process. To determine whether IgSF molecules influence the establishment of synaptic specificity in sensory-motor circuits, we examined the expression of 157 IgSF genes in the developing dorsal root ganglion (DRG) and spinal cord by in situ hybridization assays. We find that many IgSF genes are expressed by sensory and motor neurons in the mouse developing DRG and spinal cord. For instance, Alcam, Mcam, and Ocam are expressed by a subset of motor neurons in the ventral spinal cord. Further analyses show that Ocam is expressed by obturator but not quadriceps motor neurons, suggesting that Ocam may regulate sensory-motor specificity in these sensory-motor reflex arcs. Electrophysiological analysis shows no obvious defects in synaptic specificity of monosynaptic sensory-motor connections involving obturator and quadriceps motor neurons in Ocam mutant mice. Since a subset of Ocam⁺ motor neurons also express Alcam, Alcam or other functionally redundant IgSF molecules may compensate for Ocam in controlling sensory-motor specificity. Taken together, these results reveal that IgSF molecules are broadly expressed by sensory and motor neurons during development, and that Ocam and other IgSF molecules may have redundant functions in controlling the specificity of sensory-motor circuits.     

Dynein-dynactin function and sensory axon growth during Drosophila metamorphosis: A role for retrograde motors

Mutations in the genes for components of the dynein-dynactin complex disrupt axon path finding and synaptogenesis during metamorphosis in the Drosophila central nervous system. In order to better understand the functions of this retrograde motor in nervous system assembly, we analyzed the path finding and arborization of sensory axons during metamorphosis in wild-type and mutant backgrounds. In wild-type specimens the sensory axons first reach the CNS 6-12 h after puparium formation and elaborate their terminal arborizations over the next 48 h. In Glued1 and Cytoplasmic dynein light chain mutants, proprioceptive and tactile axons arrive at the CNS on time but exhibit defects in terminal arborizations that increase in severity up to 48 h after puparium formation. The results show that axon growth occurs on schedule in these mutants but the final process of terminal branching, synaptogenesis, and stabilization of these sensory axons requires the dynein-dynactin complex. Since this complex functions as a retrograde motor, we suggest that a retrograde signal needs to be transported to the nucleus for the proper termination of some sensory neurons.     

Diverse mechanisms for assembly of branchiomeric nerves

The formation of branchiomeric nerves (cranial nerves V, VII, IX and X) from their sensory, motor and glial components is poorly understood. The current model for cranial nerve formation is based on the Vth nerve, in which sensory afferents are formed first and must enter the hindbrain in order for the motor efferents to exit. Using transgenic zebrafish lines to discriminate between motor neurons, sensory neurons and peripheral glia, we show that this model does not apply to the remaining three branchiomeric nerves. For these nerves, the motor efferents form prior to the sensory afferents, and their pathfinding show no dependence on sensory axons, as ablation of cranial sensory neurons by ngn1 knockdown had no effect. In contrast, the sensory limbs of the IXth and Xth nerves (but not the Vth or VIIth) were misrouted in gli1 mutants, which lack hindbrain bmn, suggesting that the motor efferents are crucial for appropriate sensory axon projection in some branchiomeric nerves. For all four nerves, peripheral glia were the intermediate component added and had a critical role in nerve integrity but not in axon guidance, as foxd3 null mutants lacking peripheral glia exhibited defasciculation of gVII, gIX, and gX axons. The bmn efferents were unaffected in these mutants. These data demonstrate that multiple mechanisms underlie formation of the four branchiomeric nerves. For the Vth, sensory axons initiate nerve formation, for the VIIth the sensory and motor limbs are independent, and for the IXth/Xth the motor axons initiate formation. In all cases the glia are patterned by the initiating set of axons and are needed to maintain axon fasciculation. These results reveal that coordinated interactions between the three neural cell types in branchiomeric nerves differ according to their axial position.