Paul D. Cheney

Corticomotoneuronal cells contribute to long-latency stretch reflexes in the rhesus monkey.

To test the hypothesis that a transcortical reflex contributes to the stretch‐evoked long‐latency electromyographic (e.m.g.) response we documented the responses of identified corticomotoneuronal (c.m.) cells and their target muscles to perturbations of active wrist movements. Macaque monkeys performed ramp‐and‐hold wrist movements against elastic loads, alternating between flexion and extension zones; brief (25 ms) torque pulses were intermittently applied during the hold period. C.m. cells were identified by a clear post‐spike facilitation in spike‐triggered averages of forelimb muscle e.m.g. activity. Activity of c.m. cells and twelve wrist and digit flexor and extensor muscles was recorded during: (a) active ramp‐and‐hold wrist movements, (b) passive ramp‐and‐hold wrist movements, and (c) torque perturbations applied during the hold phase of active flexion and extension which either lengthened or shortened the c.m. cells target muscles. Muscle‐lengthening perturbations evoked a reproducible pattern of average e.m.g. activity in the stretched muscles, consisting of two peaks: the first response (M1) had an onset latency of 11.2 +/‐ 2.1 ms (mean +/‐ S.D.), and the second (M2) began at 27.9 +/‐ 5.1 ms. Torque perturbations which shortened the active muscles also evoked a characteristic e.m.g. response consisting of an initial cessation of activity at 13.5 +/‐ 3.4 ms followed by a peak beginning at 33.9 +/‐ 3.0 ms. The responses of twenty‐one c.m. cells which facilitated wrist muscles were documented with torque pulse perturbations applied during active muscle contraction. Twenty of twenty‐one c.m. cells responded at short latency (23.4 +/‐ 8.8 ms) to torque perturbations which stretched their target muscles. For each c.m. cell‐target muscle pair, transcortical loop time was calculated as the sum of the onset latency of the c.m. cells response to lengthening perturbations (afferent time) and the onset latency of post‐spike facilitation (efferent time). The mean transcortical loop time was 30.4 +/‐ 10.2 ms, comparable to the mean onset latency of the M2 peak (27.9 +/‐ 5.1). The duration of a c.m. cells response to torque perturbations provides a further measure of the extent of its potential contribution to the M2 muscle response. In all cases but two, the c.m. cell response, delayed by the latency of the post‐spike facilitation, overlapped the M2 e.m.g. peak.

Neural mechanisms underlying corticospinal and rubrospinal control of limb movements.

Publisher Summary This chapter reviews the present understanding of the organization and functional properties of descending systems and recent advances that have come from single unit recording in awake monkeys using new techniques that reveal the synaptic connections of single premotor neurons with motoneurons of agonist and antagonist muscles. The technique of spike-triggered averaging of electromyogram activity in awake monkeys is yielding new information at the level of individual premotor neurons concerning the sign, strength, and distribution of synaptic effects from descending systems to spinal motoneurons. The chapter emphasizes the role of descending systems in the control of limb movements, although it is recognized that locomotion and other motor behaviors involving axial, head, and/or facial muscles may involve similar principles. It also emphasizes motor control in primates, although relevant data from the cat and other species will be included where no primate data are available.

Encoding of motor parameters by corticomotoneuronal (CM) and rubromotoneuronal (RM) cells producing postspike facilitation of forelimb muscles in the behaving monkey

This paper compares the properties of corticomotoneuronal (CM) and rubromotoneuronal (RM) cells identified by postspike facilitation (PSF) of rectified EMG activity in the awake monkey. The postspike effects of CM and RM cells in flexors and extensors of the wrist and fingers have been determined, as have the discharge properties of these cells in relation to alternating ramp-and-hold wrist movements. The characteristics of postspike facilitation and postspike suppression (PSS) were similar for RM and CM cells. The magnitude of RM-PSF was weaker than CM-PSF and RM cells showed a stronger preference for facilitation of extensor muscles than CM cells. As with CM cells, the onset of discharge in RM cells preceded the onset of EMG activity in their target muscles. Tonic discharge related to static torque was more prominent in CM cells, whereas phasic discharge was more prominent in RM cells; however, many RM cells showed some tonic activity weakly related to static torque. We conclude that CM and RM cells share many common features; however, RM cells are concerned primarily with the dynamics of muscle contraction.

Exosome-mediated shuttling of microRNA-29 regulates HIV Tat and morphine-mediated neuronal dysfunction.

Neuronal damage is a hallmark feature of HIV-associated neurological disorders (HANDs). Opiate drug abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Opiates such as morphine have been shown to enhance HIV transactivation protein Tat-mediated toxicity in both human neurons and neuroblastoma cells. In the present study, we demonstrate reduced expression of the tropic factor platelet-derived growth factor (PDGF)-B with a concomitant increase in miR-29b in the basal ganglia region of the brains of morphine-dependent simian immunodeficiency virus (SIV)-infected macaques compared with the SIV-infected controls. In vitro relevance of these findings was corroborated in cultures of astrocytes exposed to morphine and HIV Tat that led to increased release of miR-29b in exosomes. Subsequent treatment of neuronal SH-SY5Y cell line with exosomes from treated astrocytes resulted in decreased expression of PDGF-B, with a concomitant decrease in viability of neurons. Furthermore, it was shown that PDGF-B was a target for miR-29b as evidenced by the fact that binding of miR-29 to the 3′-untranslated region of PDGF-B mRNA resulted in its translational repression in SH-SY5Y cells. Understanding the regulation of PDGF-B expression may provide insights into the development of potential therapeutic targets for neuronal loss in HIV-1-infected opiate abusers.

Output Properties and Organization of the Forelimb Representation of Motor Areas on the Lateral Aspect of the Hemisphere in Rhesus Macaques

Motor output capabilities of the forelimb representation of dorsal motor area (PMd) and ventral motor area (PMv) were compared with primary motor cortex (M1) in terms of latency, strength, sign, and distribution of effects. Stimulus-triggered averages (60 microA) of electromyographic activity collected from 24 forelimb muscles were computed at 314 tracks in 2 monkeys trained to perform a reach-to-grasp task. The onset latency and magnitude of facilitation effects from PMd and PMv were significantly longer and 7- to 9-fold weaker than those from M1. Proximal muscles were predominantly represented in PMd and PMv. A joint-dependent flexor or extensor preference was also present. Distal and proximal muscle representations were intermingled in PMd and PMv. A gradual increase in latency and decrease in magnitude of effects were observed in moving from M1 surface sites toward more anterior sites in PMd. For many muscles, segregated areas producing suppression effects were found along the medial portion of PMd and adjacent M1. Although some facilitation effects from PMd and PMv had onset latencies as short as those from M1 in the same muscle, suggesting equal direct linkage, the vast majority had properties consistent with a more indirect linkage to motoneurons either through corticocortical connections with M1 and/or interneuronal linkages in the spinal cord.

Hijacking Cortical Motor Output with Repetitive Microstimulation

High-frequency repetitive microstimulation has been widely used as a method of investigating the properties of cortical motor output. Despite its widespread use, few studies have investigated how activity evoked by high-frequency stimulation may interact with the existing activity of cortical cells resulting from natural synaptic inputs. A reasonable assumption might be that the stimulus-evoked activity sums with the existing natural activity. However, another possibility is that the stimulus-evoked firing of cortical neurons might block and replace the natural activity. We refer to this latter possibility as “neural hijacking.” Evidence from analysis of EMG activity evoked by repetitive microstimulation (200 Hz, 500 ms) of primary motor cortex in two rhesus monkeys during performance of a reach-to-grasp task strongly supports the neural hijacking hypothesis.

Morphine Potentiates Neuropathogenesis of SIV Infection in Rhesus Macaques

Despite the advent of antiretroviral therapy, complications of HIV-1 infection with concurrent drug abuse are an emerging problem. Opiates are well known to modulate immune responses by preventing the development of cell-mediated immune responses. Their effect on the pathogenesis of HIV-1 infection however remains controversial. Using the simian immunodeficiency virus/macaque model of HIV pathogenesis, we sought to explore the impact of morphine on disease progression and pathogenesis. Sixteen rhesus macaques were divided into two groups; four were administered saline and 12 others morphine routinely. Both groups of animals were then inoculated with SIVmacR71/17E and followed longitudinally for disease pathogenesis. The morphine group (M+V) exhibited a trend towards higher mortality rates and retardation in weight gain compared to the virus-alone group. Interestingly, a subset of M+V animals succumbed to disease within weeks post-infection. These rapid progressors also exhibited a higher incidence of other end-organ pathologies. Despite the higher numbers of circulating CD4+ and CD8+ T cells in the M+V group, CD4/CD8 ratios between the groups remained unchanged. Plasma and CSF viral load in the M+V group was at least a log higher than the control group. Similarly, there was a trend toward increased virus build-up in the brains of M+V animals compared with controls. A novel finding of this study was the increased influx of infected monocyte/macrophages in the brains of M+V animals.

Forelimb Muscle Representations and Output Properties of Motor Areas in the Mesial Wall of Rhesus Macaques

In this study, forelimb organizations and output properties of the supplementary motor area (SMA) and the dorsal cingulate motor area (CMAd) were assessed and compared with primary motor cortex (M1). Stimulus-triggered averages of electromyographic activity from 24 muscles of the forelimb were computed from layer V sites of 2 rhesus monkeys performing a reach-to-grasp task. No clear segregation of the forelimb representation of proximal and distal muscles was found in SMA. In CMAd, sites producing poststimulus effects in proximal muscles tended to be located caudal to distal muscle sites, although the number of effects was limited. For both SMA and CMAd, facilitation effects were more prevalent in distal than in proximal muscles. At an intensity of 60 microA, the mean latencies of M1 facilitation effects were 8 and 12.1 ms shorter and the magnitudes approximately 10 times greater than those from SMA and CMAd. Our results show that corticospinal neurons in SMA and CMAd provide relatively weak input to spinal motoneurons compared with the robust effects from M1. However, a small number of facilitation effects from SMA and CMAd had latencies as short as the shortest ones from M1 suggesting a minimum linkage to motoneurons as direct as that from M1.

Chronic recording of EMG activity from large numbers of forelimb muscles in awake macaque monkeys

Studies of the neural control of movement often require or benefit from long-term recording of EMG activity from large numbers of muscles involved in a particular motor task. While chronic recording of EMG activity has been described in a number of previous monkey studies, the number of muscles recorded has been somewhat limited and the implantation approach has been highly invasive procedures. This paper presents two EMG implant fabrication and surgical implantation methods that are suitable for use in monkeys, relatively non-traumatic and capable of simultaneous recording from 24 or more muscles.

Electrical stimulation of cortex improves corticospinal tract tracing in rat spinal cord using manganese-enhanced MRI.

Following bilateral injection of manganese (Mn) into the rats motor cortex, electrical stimulation of the cortex is shown to increase the transport, uptake and accumulation of Mn in the corticospinal tract (CST), as assessed by manganese-enhanced magnetic resonance imaging (MEI). T(1)-weighted gradient echo images were acquired in 3-D and displayed in different orientations to anatomically delineate the CST pathway from cortex to spinal cord (SC) at the thoracic level. T(1)-maps of the SC were produced from spin-echo based image data to demonstrate the distribution of the T(1) properties of the SC tissue and to quantitatively assess the T(1)-change occurring in the CST due to the presence of Mn therein. Implications for improving the tract tracing ability with the proposed in vivo approach and its application to spinal cord injury (SCI) research are discussed in terms of aiding future experimental investigations of neuroplasticity following an injury.