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.

Chronic Pharmacological Increase of Neuronal Activity Improves Sensory-Motor Dysfunction in Spinal Muscular Atrophy Mice.

Dysfunction of neuronal circuits is an important determinant of neurodegenerative diseases. Synaptic dysfunction, death, and intrinsic activity of neurons are thought to contribute to the demise of normal behavior in the disease state. However, the interplay between these major pathogenic events during disease progression is poorly understood. Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the ubiquitously expressed protein SMN and is characterized by motor neuron death, skeletal muscle atrophy, as well as dysfunction and loss of both central and peripheral excitatory synapses. These disease hallmarks result in an overall reduction of neuronal activity in the spinal sensory-motor circuit. Here, we show that increasing neuronal activity by chronic treatment with the FDA-approved potassium channel blocker 4-aminopyridine (4-AP) improves motor behavior in both sexes of a severe mouse model of SMA. 4-AP restores neurotransmission and number of proprioceptive synapses and neuromuscular junctions (NMJs), while having no effects on motor neuron death. In addition, 4-AP treatment with pharmacological inhibition of p53-dependent motor neuron death results in additive effects, leading to full correction of sensory-motor circuit pathology and enhanced phenotypic benefit in SMA mice. Our in vivo study reveals that 4-AP-induced increase of neuronal activity restores synaptic connectivity and function in the sensory-motor circuit to improve the SMA motor phenotype.SIGNIFICANCE STATEMENT Spinal muscular atrophy (SMA) is a neurodegenerative disease, characterized by synaptic loss, motor neuron death, and reduced neuronal activity in spinal sensory-motor circuits. However, whether these are parallel or dependent events is unclear. We show here that long-term increase of neuronal activity by the FDA-approved drug 4-aminopyridine (4-AP) rescues the number and function of central and peripheral synapses in a SMA mouse model, resulting in an improvement of the sensory-motor circuit and motor behavior. Combinatorial treatment of pharmacological inhibition of p53, which is responsible for motor neuron death and 4-AP, results in additive beneficial effects on the sensory-motor circuit in SMA. Thus, neuronal activity restores synaptic connections and improves significantly the severe SMA phenotype.

Chemogenetic stimulation of proprioceptors remodels lumbar interneuron excitability and promotes motor recovery after SCI.

Motor recovery after severe spinal cord injury (SCI) is limited due to the disruption of direct descending commands. Despite the absence of brain-derived descending inputs, sensory afferents below injury sites remain intact. Among them, proprioception acts as an important sensory source to modulate local spinal circuits and determine motor outputs. Yet, it remains unclear whether enhancing proprioceptive inputs promotes motor recovery after severe SCI. Here, we first established a viral system to selectively target lumbar proprioceptive neurons and then introduced the excitatory Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADD) virus into proprioceptors to achieve specific activation of lumbar proprioceptive neurons upon CNO administration. We demonstrated that chronic activation of lumbar proprioceptive neurons promoted the recovery of hindlimb stepping ability in a bilateral hemisection SCI mouse model. We further revealed that chemogenetic proprioceptive stimulation led to coordinated activation of proprioception-receptive spinal interneurons and facilitated transmission of supraspinal commands to lumbar motor neurons, without affecting the regrowth of proprioceptive afferents or brain-derived descending axons. Moreover, application of 4-aminopyridine-3-methanol (4-AP-MeOH) that enhances nerve conductance further improved the transmission of supraspinal inputs and motor recovery in proprioception-stimulated mice. Our study demonstrates that proprioception-based combinatorial modality may be a promising strategy to restore the motor function after severe SCI.

Successful and unsuccessful attempts to swallow in a reduced Aplysia preparation regulate feeding responses and produce memory at different neural sites.

Sensory feedback shapes ongoing behavior and may produce learning and memory. Motor responses to edible or inedible food in a reduced Aplysia preparation were examined to test how sensory feedback affects behavior and memory. Feeding patterns were initiated by applying a cholinomimetic onto the cerebral ganglion. Feedback from buccal muscles increased the response variability and response rate. Repeated application of the cholinomimetic caused decreased responses, expressed in part by lengthening protractions. Swallowing strips of "edible" food, which in intact animals induces learning that enhances ingestion, increased the response rate, and shortened the protraction length, reflecting more swallowing. Testing memory by repeating the procedure prevented the decrease in response rate observed with the cholinomimetic alone, and shortened protractions. Training with "inedible" food that in intact animals produces learning expressed by decreased responses caused lengthened protractions. Testing memory by repeating the procedure did not cause decreased responses or lengthened protractions. After training and testing with edible or inedible food, all preparations were exposed to the cholinomimetic alone. Preparations previously trained with edible food displayed memory expressed as decreased protraction length. Preparations previously trained with inedible food showed decreases in many response parameters. Memory for inedible food may arise in part via a postsynaptic decrease in response to acetylcholine released by afferents sensing food. The lack of change in response number, and in the time that responses are maintained during the two training sessions preceding application of the cholinomimetic alone suggests that memory expression may differ from behavioral changes during training.

Geranylgeranylacetone exerts neuroprotective roles through medicating the phosphatidylinositol-3 kinase/Akt signaling pathway in an intracerebral hemorrhage rat model.

AIM: Previous studies have demonstrated that geranylgeranylacetone exerts neuroprotective effects in experimental intracerebral hemorrhage. This study is designed to explore the underlying mechanism. MATERIALS AND METHODS: One hundred and eighty male Sprague-Dawley rats were subjected to intracerebral hemorrhage by stereotactic injection of collagenase and were pretreated without or with different doses of geranylgeranylacetone. At 6 h, 24 h, 48 h, 72 h and 7 days after the operation, the neurological deficits were examined with the scoring scale method. To explore the underlying mechanism, wortmannin (Wort), a specific phosphatidylinositol-3 kinase (PI3K) inhibitor, was used. The protein expression of Akt was determined by Western blotting. The brain water content and the hematoma volume assessment were measured and compared among the different groups. RESULTS: We first found that geranylgeranylacetone pretreatment significantly reduced neurological deficit in intracerebral hemorrhage rats, indicating its neuroprotective role. Then, we found wort treatment significantly decreased the geranylgeranylacetone-induced Akt expression level in intracerebral hemorrhage rats. Besides, wort not only reversed the effects of geranylgeranylacetone on neurological function, but also reversed the effects of geranylgeranylacetone on reducing brain edema and decreasing hematoma volume in intracerebral hemorrhage rats. CONCLUSION: Geranylgeranylacetone exerts neuroprotective roles, at least partially, through medicating the PI3K/Akt signaling pathway in an experimental intracerebral hemorrhage rat model.

Loss of Gas6 and Axl signaling results in extensive axonal damage, motor deficits, prolonged neuroinflammation, and less remyelination following cuprizone exposure.

The TAM (Tyro3, Axl, and MerTK) family of receptor tyrosine kinases (RTKs) and their ligands, Gas6 and ProS1, are important for innate immune responses and central nervous system (CNS) homeostasis. While only Gas6 directly activates Axl, ProS1 activation of Tyro3/MerTK can indirectly activate Axl through receptor heterodimerization. Therefore, we generated Gas6-/- Axl-/- double knockout (DKO) mice to specifically examine the contribution of this signaling axis while retaining ProS1 signaling through Tyro3 and MerTK. We found that naïve young adult DKO and WT mice have comparable myelination and equal numbers of axons and oligodendrocytes in the corpus callosum. Using the cuprizone model of demyelination/remyelination, transmission electron microscopy revealed extensive axonal swellings containing autophagolysosomes and multivesicular bodies, and fewer myelinated axons in brains of DKO mice at 3-weeks recovery from a 6-week cuprizone diet. Analysis of immunofluorescent staining demonstrated more SMI32+ and APP+ axons and less myelin in the DKO mice. There were no significant differences in the number of GFAP+ astrocytes or Iba1+ microglia/macrophages between the groups of mice. However, at 6-weeks cuprizone and recovery, DKO mice had increased proinflammatory cytokine and altered suppressor of cytokine signaling (SOCS) mRNA expression supporting a role for Gas6-Axl signaling in proinflammatory cytokine suppression. Significant motor deficits in DKO mice relative to WT mice on cuprizone were also observed. These data suggest that Gas6-Axl signaling plays an important role in maintaining axonal integrity and regulating and reducing CNS inflammation that cannot be compensated for by ProS1/Tyro3/MerTK signaling.

Reversal of alcohol-induced effects on response control due to changes in proprioceptive information processing.

Recent research has drawn interest to the effects of binge drinking on response selection. However, choosing an appropriate response is a complex endeavor that usually requires us to process and integrate several streams of information. One of them is proprioceptive information about the position of limbs. As to now, it has however remained elusive how binge drinking affects the processing of proprioceptive information during response selection and control in healthy individuals. We investigated this question using neurophysiological (EEG) techniques in a response selection task, where we manipulated proprioceptive information. The results show a reversal of alcohol-induced effects on response control due to changes in proprioceptive information processing. The most likely explanation for this finding is that proprioceptive information does not seem to be properly integrated in response selection processes during acute alcohol intoxication as found in binge drinking. The neurophysiological data suggest that processes related to the preparation and execution of the motor response, but not upstream processes related to conflict monitoring and spatial attentional orienting, underlie these binge drinking-dependent modulations. Taken together, the results show that even high doses of alcohol have very specific effects within the cascade of neurophysiological processes underlying response control and the integration of proprioceptive information during this process.

Skeletal ligament healing using the recombinant human amelogenin protein.

Injuries to ligaments are common, painful and debilitating, causing joint instability and impaired protective proprioception sensation around the joint. Healing of torn ligaments usually fails to take place, and surgical replacement or reconstruction is required. Previously, we showed that in vivo application of the recombinant human amelogenin protein (rHAM(+)) resulted in enhanced healing of the tooth-supporting tissues. The aim of this study was to evaluate whether amelogenin might also enhance repair of skeletal ligaments. The rat knee medial collateral ligament (MCL) was chosen to prove the concept. Full thickness tear was created and various concentrations of rHAM(+), dissolved in propylene glycol alginate (PGA) carrier, were applied to the transected MCL. 12 weeks after transection, the mechanical properties, structure and composition of transected ligaments treated with 0.5 µg/µl rHAM(+) were similar to the normal un-transected ligaments, and were much stronger, stiffer and organized than control ligaments, treated with PGA only. Furthermore, the proprioceptive free nerve endings, in the 0.5 µg/µl rHAM(+) treated group, were parallel to the collagen fibres similar to their arrangement in normal ligament, while in the control ligaments the free nerve endings were entrapped in the scar tissue at different directions, not parallel to the axis of the force. Four days after transection, treatment with 0.5 µg/µl rHAM(+) increased the amount of cells expressing mesenchymal stem cell markers at the injured site. In conclusion application of rHAM(+) dose dependently induced mechanical, structural and sensory healing of torn skeletal ligament. Initially the process involved recruitment and proliferation of cells expressing mesenchymal stem cell markers.

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.

Contribution of tactile dysfunction to manual motor dysfunction in type II diabetes.

INTRODUCTION: Changes in sensory and motor functions of the hand in type II diabetes (T2D) patients have been reported; there is speculation that these changes are driven by tactile dysfunction. The purpose of this study was to evaluate the effects of tactile feedback on manual function in T2D patients. METHODS: T2D patients and healthy controls underwent median nerve blocks at the wrist and elbow. All participants underwent traditional timed motor evaluations, force dynamometry, laboratory-based kinetic evaluations, and sensory evaluation. RESULTS: Tactile sensation in the T2D group at baseline was found to be equivalent to tactile function of the control group after median nerve block. Traditional timed evaluation results were negatively impacted by anesthesia, but more sensitive kinetic measures were not impacted. CONCLUSIONS: These data suggest that mechanisms outside of tactile dysfunction play a significant role in motor dysfunction in T2D. Muscle Nerve 54: 895-902, 2016.

Low back skin sensitivity has minimal impact on active lumbar spine proprioception and stability in healthy adults.

The purpose of the current work was to (1) determine whether low back cutaneous sensitivity could be reduced through the use of a topical lidocaine-prilocaine anesthetic (EMLA(®)) to mirror reductions reported in chronic lower back pain (CLBP) patients, as well as to (2) identify whether reductions in cutaneous sensitivity resulted in decreased lumbar spine proprioception, neuromuscular control and dynamic stability. Twenty-eight healthy participants were divided equally into matched EMLA and PLACEBO treatment groups. Groups completed cutaneous minimum monofilament and two-point discrimination (TPD) threshold tests, as well as tests of sagittal and axial lumbar spine active repositioning error, seated balance and repeated lifting dynamic stability. These tests were administered both before and after the application of an EMLA or PLACEBO treatment. Results show that low back minimum monofilament and TPD thresholds were significantly increased within the EMLA group. Skin sensitivity remained unchanged in the PLACEBO group. In the EMLA group, decreases in low back cutaneous sensitivity had minimal effect on low back proprioception (active sagittal and axial repositioning) and dynamic stability (seated balance and repeated lifting). These findings demonstrate that treating the skin of the low back with an EMLA anesthetic can effectively decrease the cutaneous sensitivity of low back region. Further, these decreases in peripheral cutaneous sensitivity are similar in magnitude to those reported in CLBP patients. Within this healthy population, decreased cutaneous sensitivity of the low back region has minimal influence on active lumbar spine proprioception, neuromuscular control and dynamic stability.

Distributed effects of biological sex define sex-typical motor behavior in Caenorhabditis elegans.

Sex differences in shared behaviors (for example, locomotion and feeding) are a nearly universal feature of animal biology. Though these behaviors may share underlying neural programs, their kinematics can exhibit robust differences between males and females. The neural underpinnings of these differences are poorly understood because of the often-untested assumption that they are determined by sex-specific body morphology. Here, we address this issue in the nematode Caenorhabditis elegans, which features two sexes with distinct body morphologies but similar locomotor circuitry and body muscle. Quantitative behavioral analysis shows that C. elegans and related nematodes exhibit significant sex differences in the dynamics and geometry of locomotor body waves, such that the male is generally faster. Using a recently proposed model of locomotor wave propagation, we show that sex differences in both body mechanics and the intrinsic dynamics of the motor system can contribute to kinematic differences in distinct mechanical contexts. By genetically sex-reversing the properties of specific tissues and cells, however, we find that sex-specific locomotor frequency in C. elegans is determined primarily by the functional modification of shared sensory neurons. Further, we find that sexual modification of body wall muscle together with the nervous system is required to alter body wave speed. Thus, rather than relying on a single focus of modification, sex differences in motor dynamics require independent modifications to multiple tissue types. Our results suggest shared motor behaviors may be sex-specifically optimized though distributed modifications to several aspects of morphology and physiology.

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.

Calcifediol versus vitamin D3 effects on gait speed and trunk sway in young postmenopausal women: a double-blind randomized controlled trial.

UNLABELLED: In this double-blind RCT, 4-month treatment with calcifediol compared with vitamin D3 improved gait speed by 18% among young postmenopausal women. Consistently, change in 25(OH)D blood levels over time were significantly correlated with improvement in gait speed in these women. No effect could be demonstrated for trunk sway. INTRODUCTION: The aim of this study is to test the effect of calcifediol compared with vitamin D3 on gait speed and trunk sway. METHODS: Twenty healthy postmenopausal women with an average 25(OH)D level of 13.2 ng/ml (SD = ±3.9) and a mean age of 61.5 years (SD = ±7.2) were randomized to either 20 µg of calcifediol or 20 µg (800 IU) of vitamin D3 per day in a double-blind manner. At baseline and at 4 months of follow-up, the same physiotherapist blinded to treatment allocation tested 8-m gait speed and a body sway test battery (Sway star pitch and roll angle plus velocity while walking 8 m, and standing on both legs on a hard and soft surface). All analyses adjusted for baseline measurement, age, and body mass index. RESULTS: Mean 25(OH)D levels increased to 69.3 ng/ml (SD = ±9.5) in the calcifediol group and to 30.5 ng/ml (SD = ±5.0) in the vitamin D3 group (p < 0.0001). Women receiving calcifediol compared with vitamin D3 had an 18% greater improvement in gait speed at 4-month follow-up (p = 0.046) adjusting for baseline gait speed, age, and body mass index. Also, change in gait speed was significantly correlated with change in serum 25(OH)D concentrations (r = 0.5; p = 0.04). Across three tests of trunk sway, there were no consistent differences between groups and no significant correlation between change in 25(OH)D serum concentrations and change in trunk sway. CONCLUSIONS: Calcifediol improved gait speed in early postmenopausal women compared with vitamin D3 and change in 25(OH)D level was moderately correlated with improvement in gait speed. A benefit on trunk sway could not be demonstrated.

Anaesthesia changes perceived finger width but not finger length.

The brain needs information about the size of the body to control our interactions with the environment. No receptor signals this information directly; the brain must determine body size from multiple sensory inputs and then store this information. This process is poorly understood, but somatosensory information is thought to play a role. In particular, anaesthetising a body part has been reported to make it feel bigger. Here, we report the first study to measure whether changes in body size following anaesthesia are uniform across dimensions (e.g. width and length). We blocked the digital nerves of ten human subjects with a clinical dose of local anaesthetic (1 % lignocaine) and again in separate sessions with a weaker dose (0.25 % lignocaine) and a saline control. Subjects reported the perceived size of their index finger by selecting templates from a set that varied in size and aspect ratio. We also measured changes in sensory signals that might contribute to the anaesthetic-induced changes using quantitative sensory testing. Subjects perceived their finger to be up to 32 % wider during anaesthesia when compared to during a saline control condition. However, changes in perceived length of the finger were much smaller (<5 %). Previous studies have shown a change in perceived body size with anaesthesia, but have assumed that the aspect ratio is preserved. Our data show that this is not the case. We suggest that nonuniform changes in perceived body size might be due to the brain increasing the body's perimeter to protect it from further injury.

Impact of Parkinson's disease on proprioceptively based on-line movement control.

Evidence suggests that Parkinson's disease (PD) patients produce large spatial errors when reaching to proprioceptively defined targets. Here, we examined whether these movement inaccuracies result mainly from impaired use of proprioceptive inputs for movement planning mechanisms or from on-line movement guidance. Medicated and non-medicated PD patients and healthy controls performed three-dimensional reaching movements in four sensorimotor conditions that increase proprioceptive processing requirements. We assessed the influence of these sensorimotor conditions on the final accuracy and initial kinematics of the movements. If the patterns of final errors are primarily determined by planning processes before the initiation of the movement, the initial kinematics of reaching movements should show similar trends and predict the pattern of final errors. Medicated and non-medicated PD patients showed a greater mean level of final 3D errors than healthy controls when proprioception was the sole source of information guiding the movement, but this difference reached significance only for medicated PD patients. However, the pattern of initial kinematics and final spatial errors were markedly different both between sensorimotor conditions and between groups. Furthermore, medicated and non-medicated PD patients were less efficient than healthy controls in compensating for their initial spatial errors (hand distance from target location at peak velocity) when aiming at proprioceptively defined compared to visually defined targets. Considered together, the results are consistent with a selective deficit in proprioceptively based movement guidance in PD. Furthermore, dopaminergic medication did not improve proprioceptively guided movements in PD patients, indicating that dopaminergic dysfunction within the basal ganglia is not solely responsible for these deficits.

Pyridoxine treatment alters embryonic motility in chicks: Implications for the role of proprioception.

Somatosensory feedback is important for the modulation of normal locomotion in adult animals, but we do not have a good understanding of when somatosensory information is first used to modulate motility during embryogenesis or how somatosensation is first used to regulate motor output. We used pyridoxine administration (vitamin B6 ), which is known to mostly kill proprioceptive neurons in adult mammals and embryonic chicks, to explore the role of proprioceptive feedback during early embryonic motility in the chick. Injection of pyridoxine on embryonic day 7 (E7) and E8 reduced the amplitude of leg movements recorded on E9 and the number of large, healthy neurons in the ventral-lateral portion of the DRGs. We conclude that proprioception is initially used during embryogenesis to modulate the strength of motor output, but that it is not incorporated into other aspects of pattern generation until later in development as poly-synaptic pathways develop.

Using vertebral movement and intact paraspinal muscles to determine the distribution of intrafusal fiber innervation of muscle spindle afferents in the anesthetized cat.

Increasing our knowledge regarding intrafusal fiber distribution and physiology of paraspinal proprioceptors may provide key insights regarding proprioceptive deficits in trunk control associated with low back pain and lead to more effective clinical intervention. The use of vertebral movement as a means to reliably stretch paraspinal muscles would greatly facilitate physiological study of paraspinal muscle proprioceptors where muscle tendon isolation is either very difficult or impossible. The effects of succinylcholine (SCh) on 194 muscle spindle afferents from lumbar longissimus or multifidus muscles in response to computer-controlled, ramp-and-hold movements of the L(6) vertebra were investigated in anesthetized cats. Paraspinal muscles were stretched by moving the L(6) vertebra 1.5-1.7 mm in the dorsal-ventral direction. Initial frequency (IF), dynamic difference (DD), their changes (∆) following SCh injection (100-400 µg kg(-1)), and post-SCh dynamic difference (SChDD) were measured. Muscle spindle intrafusal fiber terminations were classified as primary or secondary fibers as well as bag(1) (b(1)c), bag(2) (b(2)c), b(1)b(2)c, or chain (c) fibers. Intrafusal fiber subpopulations were distinguished using logarithmic transformation of SChDD and ∆IF distributions as established by previous investigators. Increases in DD indicate strength of b(1)c influence while increases in IF indicate strength of b(2)c influence. Out of 194 afferents, 46.9 % of afferents terminated on b(2)c fibers, 46.4 % on b(1)b(2)c fibers, 1 % on b(1)c fibers, and 5.7 % terminated on c fibers. Based on these intrafusal fiber subpopulation distributions, controlled vertebral movement can effectively substitute for direct tendon stretch and allow further investigation of paraspinal proprioceptors in this anatomically complex body region.

Hormonal modulation of sensorimotor integration.

Neuronal circuits commonly receive simultaneous inputs from descending, ascending, and hormonal systems. Thus far, however, most such inputs have been studied individually to determine their influence on a given circuit. Here, we examine the integrated action of the hormone crustacean cardioactive peptide (CCAP) and the gastropyloric receptor (GPR) proprioceptor neuron on the biphasic gastric mill (chewing) rhythm driven by the projection neuron modulatory commissural neuron 1 (MCN1) in the isolated crab stomatogastric ganglion. In control saline, GPR stimulation selectively prolongs the gastric mill retractor phase, via presynaptic inhibition of MCN1. In the absence of GPR stimulation, CCAP does not alter retraction duration and modestly prolongs protraction. Here, we show, using computational modeling and dynamic-clamp manipulations, that the presence of CCAP weakens or eliminates the GPR effect on the gastric mill rhythm. This CCAP action results from its ability to activate the same modulator-activated conductance (G(MI)) as MCN1 in the gastric mill circuit neuron lateral gastric (LG). Because GPR prolongs retraction by weakening MCN1 activation of G(MI) in LG, the parallel G(MI) activation by CCAP reduces the impact of GPR regulation of this conductance. The CCAP-activated G(MI) thus counteracts the GPR-mediated decrease in the MCN1-activated G(MI) in LG and reduces the GPR ability to regulate the gastric mill rhythm. Consequently, although CCAP neither changes retraction duration nor alters GPR inhibition of MCN1, its activation of a modulator-activated conductance in a pivotal downstream circuit neuron enables CCAP to weaken or eliminate sensory regulation of motor circuit output.

Overestimation of force during matching of externally generated forces.

If a weight is applied to a finger and the subject asked to produce the same force, the subject generates a force larger than the weight. That is, subjects overestimate the force applied by an external target when matching it. Details of this force overestimation are not well understood. We show that subjects overestimate small target weights, but not larger ones. Furthermore we show for the first time that the force overestimation consists of two components. The first component is a constant. The second component depends on the precise magnitude of the weight and is only present when subjects hold the target weight against gravity. We suggest that the two components are generated in different phases of the force-matching task, are due to different processes, and must have an influence on all proprioceptive judgements of force.