Structural Preservation Does Not Ensure Function at Sensory Ia-Motoneuron Synapses following Peripheral Nerve Injury and Repair.

Injury that severs peripheral nerves often results in long-lasting motor behavioral deficits and in reorganization of related spinal motor circuitry, neither of which reverse even after nerve regeneration. Stretch areflexia and gait ataxia, for example, emerge from a combination of factors including degeneration of Ia-motoneuron synapses between peripherally damaged Ia muscle spindle afferents and motoneurons. Based on evidence that nerve injury acts via immune responses to induce synapse degeneration, we hypothesized that suppressing inflammatory responses would preserve Ia-motoneuron connectivity and aid in restoring normal function. We tested our hypothesis by administering the anti-inflammatory agent minocycline in male and female rats following axotomy of a peripheral nerve. The connectivity of Ia-motoneuron synapses was then assessed both structurally and functionally at different time points. We found that minocycline treatment overcame the physical loss of Ia contacts on motoneurons which are otherwise lost after axotomy. While necessary for functional recovery, synaptic preservation was not sufficient to overcome functional decline expressed as smaller than normal stretch-evoked synaptic potentials evoked monosynaptically at Ia-motoneuron connections and an absence of the stretch reflex. These findings demonstrate a limited capacity of minocycline to rescue normal sensorimotor behavior, illustrating that structural preservation of synaptic connectivity does not ensure normal synaptic function.SIGNIFICANCE STATEMENT Here we demonstrate that acute treatment with the semisynthetic tetracycline anti-inflammatory agent minocycline permanently prevents the comprehensive loss of synaptic contacts made between sensory neurons and spinal motoneurons following peripheral nerve injury and eventual regeneration. Treatment failed, however, to rescue normal function of those synapses or the reflex circuit they mediate. These findings demonstrate that preventing synaptic disconnection alone is not sufficient to restore neural circuit operation and associated sensorimotor behaviors.

Mechanosensory encoding in ex vivo muscle-nerve preparations.

Our objective was to evaluate an ex vivo muscle-nerve preparation used to study mechanosensory signalling by low threshold mechanosensory receptors (LTMRs). Specifically, we aimed to assess how well the ex vivo preparation represents in vivo firing behaviours of the three major LTMR subtypes of muscle primary sensory afferents, namely type Ia and II muscle spindle (MS) afferents and type Ib tendon organ afferents. Using published procedures for ex vivo study of LTMRs in mouse hindlimb muscles, we replicated earlier reports on afferent firing in response to conventional stretch paradigms applied to non-contracting, that is passive, muscle. Relative to in vivo studies, stretch-evoked firing for confirmed MS afferents in the ex vivo preparation was markedly reduced in firing rate and deficient in encoding dynamic features of muscle stretch. These deficiencies precluded conventional means of discriminating type Ia and II afferents. Muscle afferents, including confirmed Ib afferents were often indistinguishable based on their similar firing responses to the same physiologically relevant stretch paradigms. These observations raise uncertainty about conclusions drawn from earlier ex vivo studies that either attribute findings to specific afferent types or suggest an absence of treatment effects on dynamic firing. However, we found that replacing the recording solution with bicarbonate buffer resulted in afferent firing rates and profiles more like those seen in vivo. Improving representation of the distinctive sensory encoding properties in ex vivo muscle-nerve preparations will promote accuracy in assigning molecular markers and mechanisms to heterogeneous types of muscle mechanosensory neurons.

Attenuation of muscle spindle firing with artificially increased series compliance during stretch of relaxed muscle.

Muscle spindles relay vital mechanosensory information for movement and posture, but muscle spindle feedback is coupled to skeletal motion by a compliant tendon. Little is known about the effects of tendon compliance on muscle spindle feedback during movement, and the complex firing of muscle spindles makes these effects difficult to predict. Our goal was to investigate changes in muscle spindle firing using added series elastic elements (SEEs) to mimic a more compliant tendon, and to characterize the accompanying changes in firing with respect to muscle-tendon unit (MTU) and muscle fascicle displacements (recorded via sonomicrometry). Sinusoidal, ramp-and-hold and triangular stretches were analysed to examine potential changes in muscle spindle instantaneous firing rates (IFRs) in locomotor- and perturbation-like stretches as well as serial history dependence. Added SEEs effectively reduced overall MTU stiffness and generally reduced muscle spindle firing rates, but the effect differed across stretch types. During sinusoidal stretches, peak and mean firing rates were not reduced and IFR was best-correlated with fascicle velocity. During ramp stretches, SEEs reduced the initial burst, dynamic and static responses of the spindle. Notably, IFR was negatively related to fascicle displacement during the hold phase. During triangular stretches, SEEs reduced the mean IFR during the first and second stretches, affecting the serial history dependence of mean IFR. Overall, these results demonstrate that tendon compliance may attenuate muscle spindle feedback during movement, but these changes cannot be fully explained by reduced muscle fascicle length or velocity, or MTU force.

Biophysical model of muscle spindle encoding.

Muscle spindles encode mechanosensory information by mechanisms that remain only partially understood. Their complexity is expressed in mounting evidence of various molecular mechanisms that play essential roles in muscle mechanics, mechanotransduction and intrinsic modulation of muscle spindle firing behaviour. Biophysical modelling provides a tractable approach to achieve more comprehensive mechanistic understanding of such complex systems that would be difficult/impossible by more traditional, reductionist means. Our objective here was to construct the first integrative biophysical model of muscle spindle firing. We leveraged current knowledge of muscle spindle neuroanatomy and in vivo electrophysiology to develop and validate a biophysical model that reproduces key in vivo muscle spindle encoding characteristics. Crucially, to our knowledge, this is the first computational model of mammalian muscle spindle that integrates the asymmetric distribution of known voltage-gated ion channels (VGCs) with neuronal architecture to generate realistic firing profiles, both of which seem likely to be of great biophysical importance. Results predict that particular features of neuronal architecture regulate specific characteristics of Ia encoding. Computational simulations also predict that the asymmetric distribution and ratios of VGCs is a complementary and, in some instances, orthogonal means to regulate Ia encoding. These results generate testable hypotheses and highlight the integral role of peripheral neuronal structure and ion channel composition and distribution in somatosensory signalling.

Neural circuit mechanisms of sensorimotor disability in cancer treatment.

Cancer survivors rank sensorimotor disability among the most distressing, long-term consequences of chemotherapy. Disorders in gait, balance, and skilled movements are commonly assigned to chemotoxic damage of peripheral sensory neurons without consideration of the deterministic role played by the neural circuits that translate sensory information into movement. This oversight precludes sufficient, mechanistic understanding and contributes to the absence of effective treatment for reversing chemotherapy-induced disability. We rectified this omission through the use of a combination of electrophysiology, behavior, and modeling to study the operation of a spinal sensorimotor circuit in vivo in a rat model of chronic, oxaliplatin (chemotherapy)-induced neuropathy (cOIN). Key sequential events were studied in the encoding of propriosensory information and its circuit translation into the synaptic potentials produced in motoneurons. In cOIN rats, multiple classes of propriosensory neurons expressed defective firing that reduced accurate sensory representation of muscle mechanical responses to stretch. Accuracy degraded further in the translation of propriosensory signals into synaptic potentials as a result of defective mechanisms residing inside the spinal cord. These sequential, peripheral, and central defects compounded to drive the sensorimotor circuit into a functional collapse that was consequential in predicting the significant errors in propriosensory-guided movement behaviors demonstrated here in our rat model and reported for people with cOIN. We conclude that sensorimotor disability induced by cancer treatment emerges from the joint expression of independent defects occurring in both peripheral and central elements of sensorimotor circuits.

Total knee arthroplasty without patella resurfacing leads to worse results in patients with patellafemoral osteoarthritis Iwano Stages 3-4: a study based on arthroplasty registry data.

PURPOSE: To determine whether the preoperative degree of degeneration of the patellofemoral joint really affects the outcome of total knee arthroplasty (TKA) surgery without patella resurfacing and thus to establish a parameter that might serve as a guiding factor to decide whether or not to perform retropatellar resurfacing. It was hypothesized that patients with preoperative mild patellofemoral osteoarthritis (Iwano Stages 0-2) would significantly differ from patients with preoperative severe patellofemoral osteoarthritis (Iwano Stages 3-4) in terms of patient-reported outcome (Hypothesis 1) and revision rates/survival (Hypothesis 2) after TKA without patella resurfacing. METHODS: Application of a retrospective-comparative design on the basis of Arthroplasty Registry data that included patients with primary TKA without patella resurfacing. Patients were allocated to the following groups based on preoperative radiographic stage of patellofemoral joint degeneration: (a) mild patellofemoral osteoarthritis (Iwano Stage ≤ 2) and (b) severe patellofemoral osteoarthritis (Iwano Stages 3-4). The Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC) score was assessed preoperative and 1 year postoperative (0: best, 100 worst). In addition, implant survival was calculated from the Arthroplasty Registry data. RESULTS: In 1209 primary TKA without patella resurfacing, postoperative WOMAC total and WOMAC subscores did not differ significantly between groups, but potentially suffered from type 2 error. Three-year survival was 97.4% and 92.5% in patients with preoperative mild and severe patellofemoral osteoarthritis, respectively (p = 0.002). Five-year survival was 95.8% vs. 91.4% (p = 0.033) and 10-year survival was 93.3% vs. 88.6% (p = 0.033), respectively. CONCLUSIONS: From the study findings, it is concluded that patients with preoperative severe patellofemoral osteoarthritis have significantly higher risks for reoperation than do those with preoperative mild patellofemoral osteoarthritis-when treated with TKA without patella resurfacing. Hence, it is recommended that patella resurfacing be applied in patients with severe Iwano Stage 3 or 4 patellofemoral osteoarthritis during TKA. LEVEL OF EVIDENCE: III, Retrospective comparative.

Moonlight surgery: no influence of moon phase or Friday 13th on outcomes of total knee arthroplasty.

OBJECTIVES: The purpose of the present study was to investigate associations between revision-free survival and functional scores of total knee arthroplasty (TKA) and moon phase on the day of surgery, as well as operations performed on a Friday 13th. PARTICIPANTS: The data of all patients that received TKA between 2003 and 2019 were extracted from the Tyrol arthroplasty registry. Patients that had undergone previous total or partial knee arthroplasty as well as patients that had missing pre- or post-operative WOMAC were excluded. Patients were allocated to one of the following four groups according to moon phase on the day of surgery: new, waxing, full and waning. Patients operated on a Friday 13th were also identified and compared to patients operated on any other days/dates. A total of 5923 patients met the inclusion criteria, with mean age of 69 ± 9 years, and comprising 62% women. RESULTS: There were no significant differences in revision-free survival among the four moon phase groups (p = 0.479), and no significant differences in preoperative and postoperative total WOMAC (p = 0.260, p = 0.122), There were no significant differences in revision-free survival patients operated on Friday 13th vs. other days/dates (p = 0.440). The preoperative total WOMAC was significantly worse for patients operated on a Friday 13th (p = 0.013), which was observed in the pain (p = 0.032) and function (p = 0.010) subscales. There were no significant differences in postoperative total WOMAC at 1 year follow-up (p = 0.122). CONCLUSIONS: Neither moon phase on the day of surgery nor Friday 13th were associated with revision-free survival or clinical scores of TKA. Patients operated on a Friday 13th had significantly worse preoperative total WOMAC but similar postoperative total WOMAC at 1-year follow-up. These findings could help reassure patients that TKA renders consistent outcomes regardless of the preoperative pain or function, and in spite of bad omens or moon phases.

Detection of epimuscular myofascial forces by Golgi tendon organs.

Skeletal muscles embed multiple tendon organs, both at the proximal and distal ends of muscle fibers. One of the functions of such spatial distribution may be to provide locally unique force feedback, which may become more important when stresses are distributed non-uniformly within the muscle. Forces exerted by connections between adjacent muscles (i.e. epimuscular myofascial forces) may cause such local differences in force. The aim of this exploratory study was to investigate the effects of mechanical interactions between adjacent muscles on sensory encoding by tendon organs. Action potentials from single afferents were recorded intra-axonally in response to ramp-hold release (RHR) stretches of a passive agonistic muscle at different lengths or relative positions of its passive synergist. The tendons of gastrocnemius (GAS), plantaris (PL) and soleus (SO) muscles were cut from the skeleton for attachment to servomotors. Connective tissues among these muscles were kept intact. Lengthening GAS + PL decreased the force threshold of SO tendon organs (p = 0.035). The force threshold of lateral gastrocnemius (LG) tendon organs was not affected by SO length (p = 0.371). Also displacing LG + PL, kept at a constant muscle-tendon unit length, from a proximal to a more distal position resulted in a decrease in force threshold of LG tendon organs (p = 0.007). These results indicate that tendon organ firing is affected by changes in length and/or relative position of adjacent synergistic muscles. We conclude that tendon organs can provide the central nervous system with information about local stresses caused by epimuscular myofascial forces.

Mid-Term Results After 517 Primary Total Hip Arthroplasties With a Shortened and Shoulderless Double-Taper Press-Fit Stem: High Rates of Aseptic Loosening.

BACKGROUND: Shorter double-taper stems with reduced lateral shoulders facilitate implantation via the muscle-sparing direct anterior approach and are becoming increasingly popular. We observed an unusually high number of cases of aseptic loosening with the use of a modified stem. Therefore, the aim of this prospective single-center study was to assess safety and efficacy of this cementless stem. METHODS: A total of 486 consecutive patients receiving 517 primary total hip arthroplasties using the MonoconMIS stem were prospectively followed up for a mean period of 5.29 years (standard deviation [SD], 1.47). Surgical and clinical data, complications, and revision surgeries were analyzed. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) score was recorded before surgery and at one year and five years after surgery. RESULTS: The overall 5-year implant survival rate was 95.2%. The individual component survival rates were 96.1% for the stem, 99.4% for the acetabular cup, and 99.0% for the isolated mobile component exchange. The most common reasons for revision were periprosthetic fracture (1.5%), aseptic stem loosening (1.4%), and infection (1.0%). The WOMAC score improved significantly from 49.57 (SD, 21.42) at baseline to 13.33 (SD, 16.47) at one year and 9.84 (SD, 14.45) at five years after surgery. Aseptic stem loosening occurred only in patients with Dorr type A proximal femur morphology. CONCLUSION: The evaluated femoral stem is associated with revision rates higher than what has been reported for other implants. The WOMAC scores suggest adequate efficacy. Our data do not support the use of the MonoconMIS for primary total hip arthroplasty in patients with Dorr type A proximal femur morphology.

Does the type of surgical approach affect the clinical outcome of total knee arthroplasty?

BACKGROUND: The aim of the study was to investigate the issue of medial midvastus (MMV) vs. medial parapatellar (MPP) approaches in total knee arthroplasty (TKA). It was hypothesized that the two surgical approaches would produce significantly different results with respect to patient-reported knee score outcome (hypothesis 1), short-term postoperative range of motion (ROM) (hypothesis 2), long-term postoperative ROM (hypothesis 3) and prosthesis survival (hypothesis 4). METHODS: A retrospective comparative study design was applied. Data sets were obtained from the state arthroplasty registry. The Western Ontario and McMaster Universities osteoarthritis index (WOMAC) data were analyzed from preoperative and 1 year postoperatively. The ROM data were analyzed for the time points preoperative, postoperative days 4 and 10 and 1 year. RESULTS: Available were 627 cases (407 MMV vs. 220 MPP) and 1 year postoperatively there were no significant differences between groups regarding the WOMAC scores (hypothesis 1). Early postoperatively on days 4 and 10 after TKA there were no differences between groups (p = 0.305 and p = 0.383, respectively, hypothesis 2). Likewise, ROM did not significantly differ between the groups 1 year after TKA (p = 0.338, hypothesis 3). The 5­year prosthesis survival did not differ between the groups and showed 94.46% (95% confidence interval, CI 90.69-96.73%) in the MMV group and 94.33% (95% CI 89.96-96.83%) in the MPP group (p = 0.664, hypothesis 4). CONCLUSION: Both surgical approaches produce equivalent clinical results in terms of early postoperative ROM, late postoperative ROM and 1­year WOMAC. The same prosthesis survival rates can be expected.

Elastic tissue forces mask muscle fiber forces underlying muscle spindle Ia afferent firing rates in stretch of relaxed rat muscle.

Stretches of relaxed cat and rat muscle elicit similar history-dependent muscle spindle Ia firing rates that resemble history-dependent forces seen in single activated muscle fibers ( Nichols and Cope, 2004). Owing to thixotropy, whole musculotendon forces and muscle spindle firing rates are history dependent during stretch of relaxed cat muscle, where both muscle force and muscle spindle firing rates are elevated in the first stretch in a series of stretch-shorten cycles ( Blum et al., 2017). By contrast, rat musculotendon exhibits only mild thixotropy, such that the measured forces when stretched cannot explain history-dependent muscle spindle firing rates in the same way ( Haftel et al., 2004). We hypothesized that history-dependent muscle spindle firing rates elicited in stretch of relaxed rat muscle mirror history-dependent muscle fiber forces, which are masked at the level of whole musculotendon force by extracellular tissue force. We removed estimated extracellular tissue force contributions from recorded musculotendon force using an exponentially elastic tissue model. We then showed that the remaining estimated muscle fiber force resembles history-dependent muscle spindle firing rates recorded simultaneously. These forces also resemble history-dependent forces recorded in stretch of single activated fibers that are attributed to muscle cross-bridge mechanisms ( Campbell and Moss, 2000). Our results suggest that history-dependent muscle spindle firing in both rats and cats arise from history-dependent forces owing to thixotropy in muscle fibers.

Increasing motor neuron excitability to treat weakness in sepsis.

OBJECTIVE: Weakness induced by critical illness (intensive care unit acquired weakness) is a major cause of disability in patients and is currently untreatable. We recently identified a defect in repetitive firing of lower motor neurons as a novel contributor to intensive care unit acquired weakness. To develop therapy for intensive care unit acquired weakness, it was necessary to determine the mechanism underlying the defect in repetitive firing. METHODS: Both computer simulation and in vivo dynamic voltage clamp of spinal motor neurons in septic rats were employed to explore potential mechanisms underlying defective repetitive firing. RESULTS: Our results suggest alteration in subthreshold voltage-activated currents might be the mechanism underlying defective repetitive firing. It has been shown previously that pharmacologic activation of serotonin receptors on motor neurons increases motor neuron excitability, in part by enhancing subthreshold voltage-activated inward currents. Administration of a U.S. Food and Drug Administration-approved serotonin agonist (lorcaserin) to septic rats greatly improved repetitive firing and motor unit force generation. INTERPRETATION: Our findings suggest activation of serotonin receptors with lorcaserin may provide the first ever therapy for intensive care unit acquired weakness in patients. Ann Neurol 2017;82:961-971.

Muscle proprioceptors in adult rat: mechanosensory signaling and synapse distribution in spinal cord.

The characteristic signaling and intraspinal projections of muscle proprioceptors best described in the cat are often generalized across mammalian species. However, species-dependent adaptations within this system seem necessary to accommodate asymmetric scaling of length, velocity, and force information required by the physics of movement. In the present study we report mechanosensory responses and intraspinal destinations of three classes of muscle proprioceptors. Proprioceptors from triceps surae muscles in adult female Wistar rats anesthetized with isoflurane were physiologically classified as muscle spindle group Ia or II or as tendon organ group Ib afferents, studied for their firing responses to passive-muscle stretch, and in some cases labeled and imaged for axon projections and varicosities in spinal segments. Afferent projections and the laminar distributions of provisional synapses in rats closely resembled those found in the cat. Afferent signaling of muscle kinematics was also similar to reports in the cat, but rat Ib afferents fired robustly during passive-muscle stretch and Ia afferents displayed an exaggerated dynamic response, even after locomotor scaling was accounted for. These differences in mechanosensory signaling by muscle proprioceptors may represent adaptations for movement control in different animal species.NEW & NOTEWORTHY Muscle sensory neurons signal information necessary for controlling limb movements. The information encoded and transmitted by muscle proprioceptors to networks in the spinal cord is known in detail only for the cat, but differences in size and behavior of other species challenge the presumed generalizability. This report presents the first findings detailing specializations in mechanosensory signaling and intraspinal targets for functionally identified subtypes of muscle proprioceptors in the rat.

Changes in muscle spindle firing in response to length changes of neighboring muscles.

Skeletal muscle force can be transmitted to the skeleton, not only via its tendons of origin and insertion but also through connective tissues linking the muscle belly to surrounding structures. Through such epimuscular myofascial connections, length changes of a muscle may cause length changes within an adjacent muscle and hence, affect muscle spindles. The aim of the present study was to investigate the effects of epimuscular myofascial forces on feedback from muscle spindles in triceps surae muscles of the rat. We hypothesized that within an intact muscle compartment, muscle spindles not only signal length changes of the muscle in which they are located but can also sense length changes that occur as a result of changing the length of synergistic muscles. Action potentials from single afferents were measured intra-axonally in response to ramp-hold release (RHR) stretches of an agonistic muscle at different lengths of its synergist, as well as in response to synergist RHRs. A decrease in force threshold was found for both soleus (SO) and lateral gastrocnemius afferents, along with an increase in length threshold for SO afferents. In addition, muscle spindle firing could be evoked by RHRs of the synergistic muscle. We conclude that muscle spindles not only signal length changes of the muscle in which they are located but also local length changes that occur as a result of changing the length and relative position of synergistic muscles.

A novel path to chronic proprioceptive disability with oxaliplatin: Distortion of sensory encoding.

Persistent neurotoxic side effects of oxaliplatin (OX) chemotherapy, including sensory ataxia, limit the efficacy of treatment and significantly diminish patient quality of life. The common explanation for neurotoxicity is neuropathy, however the degree of neuropathy varies greatly among patients and appears insufficient in some cases to fully account for disability. We recently identified an additional mechanism that might contribute to sensory ataxia following OX treatment. In the present study, we tested whether that mechanism, selective modification of sensory signaling by muscle proprioceptors might result in behavioral deficits in rats. OX was administered once per week for seven weeks (cumulative dose i.p. 70mg/kg) to adult female Wistar rats. Throughout and for three weeks following treatment, behavioral analysis was performed daily on OX and sham control rats. Compared to controls, OX rats demonstrated errors in placing their hind feet securely and/or correctly during a horizontal ladder rung task. These behavioral deficits occurred together with modification of proprioceptor signaling that eliminated sensory encoding of static muscle position while having little effect on encoding of dynamic changes in muscle length. Selective inability to sustain repetitive firing in response to static muscle stretch led us to hypothesize that OX treatment impairs specific ionic currents, possibly the persistent inward Na currents (NaPIC) that are known to support repetitive firing during static stimulation in several neuron types, including the class of large diameter dorsal root ganglion cells that includes muscle proprioceptors. We tested this hypothesis by determining whether the chronic effects of OX on the firing behavior of muscle proprioceptors in vivo were mimicked by acute injection of NaPIC antagonists. Both riluzole and phenytoin, each having multiple drug actions but having only antagonist action on NaPIC in common, reproduced selective modification of proprioceptor signaling observed in OX rats. Taken together, these findings lead us to propose that OX chemotherapy contributes to movement disability by modifying sensory encoding, possibly via a chronic neurotoxic effect on NaPIC in the sensory terminals of muscle proprioceptors.

Normal distribution of VGLUT1 synapses on spinal motoneuron dendrites and their reorganization after nerve injury.

Peripheral nerve injury induces permanent alterations in spinal cord circuitries that are not reversed by regeneration. Nerve injury provokes the loss of many proprioceptive IA afferent synapses (VGLUT1-IR boutons) from motoneurons, the reduction of IA EPSPs in motoneurons, and the disappearance of stretch reflexes. After motor and sensory axons successfully reinnervate muscle, lost IA VGLUT1 synapses are not re-established and the stretch reflex does not recover; however, electrically evoked EPSPs do recover. The reasons why remaining IA synapses can evoke EPSPs on motoneurons, but fail to transmit useful stretch signals are unknown. To better understand changes in the organization of VGLUT1 IA synapses that might influence their input strength, we analyzed their distribution over the entire dendritic arbor of motoneurons before and after nerve injury. Adult rats underwent complete tibial nerve transection followed by microsurgical reattachment and 1 year later motoneurons were intracellularly recorded and filled with neurobiotin to map the distribution of VGLUT1 synapses along their dendrites. We found in control motoneurons an average of 911 VGLUT1 synapses; ~62% of them were lost after injury. In controls, VGLUT1 synapses were focused to proximal dendrites where they were grouped in tight clusters. After injury, most synaptic loses occurred in the proximal dendrites and remaining synapses were declustered, smaller, and uniformly distributed throughout the dendritic arbor. We conclude that this loss and reorganization renders IA afferent synapses incompetent for efficient motoneuron synaptic depolarization in response to natural stretch, while still capable of eliciting EPSPs when synchronously fired by electrical volleys.

Complex impairment of IA muscle proprioceptors following traumatic or neurotoxic injury.

The health of primary sensory afferents supplying muscle has to be a first consideration in assessing deficits in proprioception and related motor functions. Here we discuss the role of a particular proprioceptor, the IA muscle spindle proprioceptor in causing movement disorders in response to either regeneration of a sectioned peripheral nerve or damage from neurotoxic chemotherapy. For each condition, there is a single preferred and widely repeated explanation for disability of movements associated with proprioceptive function. We present a mix of published and preliminary findings from our laboratory, largely from in vivo electrophysiological study of treated rats to demonstrate newly discovered IA afferent defects that seem likely to make important contributions to movement disorders. First, we argue that reconnection of regenerated IA afferents with inappropriate targets, although often repeated as the reason for lost stretch-reflex contraction, is not a complete explanation. We present evidence that despite successful recovery of stretch-evoked sensory signaling, peripherally regenerated IA afferents retract synapses made with motoneurons in the spinal cord. Second, we point to evidence that movement disability suffered by human subjects months after discontinuation of oxaliplatin (OX) chemotherapy for some is not accompanied by peripheral neuropathy, which is the acknowledged primary cause of disability. Our studies of OX-treated rats suggest a novel additional explanation in showing the loss of sustained repetitive firing of IA afferents during static muscle stretch. Newly extended investigation reproduces this effect in normal rats with drugs that block Na(+) channels apparently involved in encoding static IA afferent firing. Overall, these findings highlight multiplicity in IA afferent deficits that must be taken into account in understanding proprioceptive disability, and that present new avenues and possible advantages for developing effective treatment. Extending the study of IA afferent deficits yielded the additional benefit of elucidating normal processes in IA afferent mechanosensory function.

Modulation of motoneuron firing by recurrent inhibition in the adult rat in vivo.

Recent reports show that synaptic inhibition can modulate postsynaptic spike timing without having strong effects on firing rate. Thus synaptic inhibition can achieve multiplicity in neural circuit operation through variable modulation of postsynaptic firing rate vs. timing. We tested this possibility for recurrent inhibition (RI) of spinal motoneurons. In in vivo electrophysiological studies of adult Wistar rats anesthetized by isoflurane, we examined repetitive firing of individual lumbosacral motoneurons recorded in current clamp and modulated by synchronous antidromic electrical stimulation of multiple motor axons and their centrally projecting collateral branches. Antidromic stimulation produced recurrent inhibitory postsynaptic potentials (RIPSPs) having properties similar to those detailed in the cat. Although synchronous RI produced marked short-term modulation of motoneuron spike timing and instantaneous firing rate, there was little or no suppression of average firing rate. The bias in firing modulation of timing over average rate was observed even for high-frequency RI stimulation (100 Hz), perhaps because of the brevity of RIPSPs, which were more than twofold shorter during motoneuron firing compared with rest. These findings demonstrate that RI in the mammalian spinal cord has the capacity to support and not impede heightened motor pool activity, possibly during rapid, forceful movements.

Expression of postsynaptic Ca2+-activated K+ (SK) channels at C-bouton synapses in mammalian lumbar -motoneurons.

Small-conductance calcium-activated potassium (SK) channels mediate medium after-hyperpolarization (AHP) conductances in neurons throughout the central nervous system. However, the expression profile and subcellular localization of different SK channel isoforms in lumbar spinal α-motoneurons (α-MNs) is unknown. Using immunohistochemical labelling of rat, mouse and cat spinal cord, we reveal a differential and overlapping expression of SK2 and SK3 isoforms across specific types of α-MNs. In rodents, SK2 is expressed in all α-MNs, whereas SK3 is expressed preferentially in small-diameter α-MNs; in cats, SK3 is expressed in all α-MNs. Function-specific expression of SK3 was explored using post hoc immunostaining of electrophysiologically characterized rat α-MNs in vivo. These studies revealed strong relationships between SK3 expression and medium AHP properties. Motoneurons with SK3-immunoreactivity exhibit significantly longer AHP half-decay times (24.67 vs. 11.02 ms) and greater AHP amplitudes (3.27 vs. 1.56 mV) than MNs lacking SK3-immunoreactivity. We conclude that the differential expression of SK isoforms in rat and mouse spinal cord may contribute to the range of medium AHP durations across specific MN functional types and may be a molecular factor distinguishing between slow- and fast-type α-MNs in rodents. Furthermore, our results show that SK2- and SK3-immunoreactivity is enriched in distinct postsynaptic domains that contain Kv2.1 channel clusters associated with cholinergic C-boutons on the soma and proximal dendrites of α-MNs. We suggest that this remarkably specific subcellular membrane localization of SK channels is likely to represent the basis for a cholinergic mechanism for effective regulation of channel function and cell excitability.

Reduced motoneuron excitability in a rat model of sepsis.

Many critically ill patients in intensive care units suffer from an infection-induced whole body inflammatory state known as sepsis, which causes severe weakness in patients who survive. The mechanisms by which sepsis triggers intensive care unit-acquired weakness (ICUAW) remain unclear. Currently, research into ICUAW is focused on dysfunction of the peripheral nervous system. During electromyographic studies of patients with ICUAW, we noticed that recruitment was limited to few motor units, which fired at low rates. The reduction in motor unit rate modulation suggested that functional impairment within the central nervous system contributes to ICUAW. To understand better the mechanism underlying reduced firing motor unit firing rates, we moved to the rat cecal ligation and puncture model of sepsis. In isoflurane-anesthetized rats, we studied the response of spinal motoneurons to injected current to determine their capacity for initiating and firing action potentials repetitively. Properties of single action potentials and passive membrane properties of motoneurons from septic rats were normal, suggesting excitability was normal. However, motoneurons exhibited striking dysfunction during repetitive firing. The sustained firing that underlies normal motor unit activity and smooth force generation was slower, more erratic, and often intermittent in septic rats. Our data are the first to suggest that reduced excitability of neurons within the central nervous system may contribute to ICUAW.