Modulation of central synapse remodeling after remote peripheral injuries by the CCL2-CCR2 axis and microglia.

Microglia-mediated synaptic plasticity after CNS injury varies depending on injury severity, but the mechanisms that adjust synaptic plasticity according to injury differences are largely unknown. This study investigates differential actions of microglia on essential spinal motor synaptic circuits following different kinds of nerve injuries. Following nerve transection, microglia and C-C chemokine receptor type 2 signaling permanently remove Ia axons and synapses from the ventral horn, degrading proprioceptive feedback during motor actions and abolishing stretch reflexes. However, Ia synapses and reflexes recover after milder injuries (nerve crush). These different outcomes are related to the length of microglia activation, being longer after nerve cuts, with slower motor-axon regeneration and extended expression of colony-stimulating factor type 1 in injured motoneurons. Prolonged microglia activation induces CCL2 expression, and Ia synapses recover after ccl2 is deleted from microglia. Thus, microglia Ia synapse removal requires the induction of specific microglia phenotypes modulated by nerve regeneration efficiencies. However, synapse preservation was not sufficient to restore the stretch-reflex function.

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.

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.

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.

Cancer survivors post-chemotherapy exhibit unimpaired short-latency stretch reflexes in the proximal upper extremity.

Oxaliplatin (OX) chemotherapy can lead to long-term sensorimotor impairments in cancer survivors. The impairments are often thought to be caused by OX-induced progressive degeneration of sensory afferents known as length-dependent dying-back sensory neuropathy. However, recent preclinical work has identified functional defects in the encoding of muscle proprioceptors and in motoneuron firing. These functional defects in the proprioceptive sensorimotor circuitry could readily impair muscle stretch reflexes, a fundamental building block of motor coordination. Given that muscle proprioceptors are distributed throughout skeletal muscle, defects in stretch reflexes could be widespread, including in the proximal region where dying-back sensory neuropathy is less prominent. All previous investigations on chemotherapy-related reflex changes focused on distal joints, leading to results that could be influenced by dying-back sensory neuropathy rather than more specific changes to sensorimotor circuitry. Our study extends this earlier work by quantifying stretch reflexes in the shoulder muscles in 16 cancer survivors and 16 healthy controls. Conduction studies of the sensory nerves in hand were completed to detect distal sensory neuropathy. We found no significant differences in the short-latency stretch reflexes (amplitude and latency) of the shoulder muscles between cancer survivors and healthy controls, contrasting with the expected differences based on the preclinical work. Our results may be linked to differences between the human and preclinical testing paradigms including, among many possibilities, differences in the tested limb or species. Determining the source of these differences will be important for developing a complete picture of how OX chemotherapy contributes to long-term sensorimotor impairments.NEW & NOTEWORTHY Our results showed that cancer survivors after oxaliplatin (OX) treatment exhibited stretch reflexes that were comparable with age-matched healthy individuals in the proximal upper limb. The lack of OX effect might be linked to differences between the clinical and preclinical testing paradigms. These findings refine our expectations derived from the preclinical study and guide future assessments of OX effects that may have been insensitive to our measurement techniques.

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.

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 make 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-hold-release, and triangular stretches were analyzed to examine potential changes in muscle spindle instantaneous firing rates (IFRs) in locomotor- and perturbation-like stretches as well as 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 firing rates were reduced and IFR was strongly correlated with fascicle velocity. During ramp stretches, SEEs reduced the dynamic and static responses of the spindle during lengthening but had no effect on initial bursts at the onset of stretch. 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 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 and velocity.

Mechanosensory encoding dysfunction emerges from cancer-chemotherapy interaction.

Persistent sensory, motor and cognitive disabilities comprise chemotherapy-induced neural disorders (CIND) that limit quality of life with little therapeutic relief for cancer survivors. Our recent preclinical study provides new insight into a condition impacting the severity of chronic CIND. We find that sensorimotor disability observed following cancer treatment exceeds that attributable to chemotherapy alone. A possible explanation for intensified disability emerged from evidence that codependent effects of cancer and chemotherapy amplify defective firing in primary sensory neurons supplying one type of low threshold mechanosensory receptor (LTMR). Here we test whether cancer's modification of chemotherapy-induced sensory defects generalizes across eight LTMR submodalities that collectively generate the signals of origin for proprioceptive and tactile perception and guidance of body movement. Preclinical study enabled controlled comparison of the independent contributions of chemotherapy and cancer to their clinically relevant combined effects. We compared data sampled from rats that were otherwise healthy or bearing colon cancer and treated, or not, with human-scaled, standard-of-care chemotherapy with oxaliplatin. Action potential firing patterns encoding naturalistic mechanical perturbations of skeletal muscle and skin were measured electrophysiologically in vivo from multiple types of LTMR neurons. All expressed aberrant encoding of dynamic and/or static features of mechanical stimuli in healthy rats treated with chemotherapy, and surprisingly also by some LTMRs in cancer-bearing rats that were not treated. By comparison, chemotherapy and cancer in combination worsened encoding aberrations, especially in slowly adapting LTMRs supplying both muscle and glabrous skin. Probabilistic modeling best predicted observed encoding defects when incorporating interaction effects of cancer and chemotherapy. We conclude that for multiple mechanosensory submodalities, the severity of encoding defects is modulated by a codependence of chemotherapy side effects and cancer's systemic processes. We propose that the severity of CIND might be reduced by therapeutically targeting the mechanisms, yet to be determined, by which cancer magnifies chemotherapy's neural side effects as an alternative to reducing chemotherapy and its life-saving benefits.

Cancer survivors post-chemotherapy exhibit unique proprioceptive deficits in proximal limbs.

BACKGROUND: Oxaliplatin (OX) chemotherapy for colorectal cancer is associated with adverse neurotoxic effects that can contribute to long-term sensorimotor impairments in cancer survivors. It is often thought that the sensorimotor impairments are dominated by OX-induced dying-back sensory neuropathy that primarily affects the distal regions of the limb. Recent preclinical studies have identified encoding dysfunction of muscle proprioceptors as an alternative mechanism. Unlike the dying-back sensory neuropathy affecting distal limbs, dysfunction of muscle proprioceptors could have more widespread effects. Most investigations of chemotherapy-induced sensorimotor impairments have considered only the effects of distal changes in sensory processing; none have evaluated proximal changes or their influence on function. Our study fills this gap by evaluating the functional use of proprioception in the shoulder and elbow joints of cancer survivors post OX chemotherapy. We implemented three multidirectional sensorimotor tasks: force matching, target reaching, and postural stability tasks to evaluate various aspects of proprioception and their use. Force and kinematic data of the sensorimotor tasks were collected in 13 cancer survivors treated with OX and 13 age-matched healthy controls. RESULTS: Cancer survivors exhibited less accuracy and precision than an age-matched control group when they had to rely only on proprioceptive information to match force, even for forces that required only torques about the shoulder. There were also small differences in the ability to maintain arm posture but no significant differences in reaching. The force deficits in cancer survivors were significantly correlated with self-reported motor dysfunction. CONCLUSIONS: These results suggest that cancer survivors post OX chemotherapy exhibit proximal proprioceptive deficits, and that the deficits in producing accurate and precise forces are larger than those for producing unloaded movements. Current clinical assessments of chemotherapy-related sensorimotor dysfunction are largely limited to distal symptoms. Our study suggests that we also need to consider changes in proximal function. Force matching tasks similar to those used here could provide a clinically meaningful approach to quantifying OX-related movement dysfunction during and after chemotherapy.

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.

Imbalanced Subthreshold Currents Following Sepsis and Chemotherapy: A Shared Mechanism Offering a New Therapeutic Target?

Both sepsis and treatment of cancer with chemotherapy are known to cause neurologic dysfunction. The primary defects seen in both groups of patients are neuropathy and encephalopathy; the underlying mechanisms are poorly understood. Analysis of preclinical models of these disparate conditions reveal similar defects in ion channel function contributing to peripheral neuropathy. The defects in ion channel function extend to the central nervous system where lower motoneurons are affected. In motoneurons the defect involves ion channels responsible for subthreshold currents that convert steady depolarization into repetitive firing. The inability to correctly translate depolarization into steady, repetitive firing has profound effects on motor function, and could be an important contributor to weakness and fatigue experienced by both groups of patients. The possibility that disruption of function, either instead of, or in addition to neurodegeneration, may underlie weakness and fatigue leads to a novel approach to therapy. Activation of serotonin (5HT) receptors in a rat model of sepsis restores the normal balance of subthreshold currents and normal motoneuron firing. If an imbalance of subthreshold currents also occurs in other central nervous system neurons, it could contribute to encephalopathy. We hypothesize that pharmacologically restoring the proper balance of subthreshold currents might provide effective therapy for both neuropathy and encephalopathy in patients recovering from sepsis or treatment with chemotherapy.

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.

Axon initial segment geometry in relation to motoneuron excitability.

The axon initial segment (AIS) responsible for action potential initiation is a dynamic structure that varies and changes together with neuronal excitability. Like other neuron types, alpha motoneurons in the mammalian spinal cord express heterogeneity and plasticity in AIS geometry, including length (AISl) and distance from soma (AISd). The present study aimed to establish the relationship of AIS geometry with a measure of intrinsic excitability, rheobase current, that varies by 20-fold or more among normal motoneurons. We began by determining whether AIS length or distance differed for motoneurons in motor pools that exhibit different activity profiles. Motoneurons sampled from the medial gastrocnemius (MG) motor pool exhibited values for average AISd that were significantly greater than that for motoneurons from the soleus (SOL) motor pool, which is more readily recruited in low-level activities. Next, we tested whether AISd covaried with intrinsic excitability of individual motoneurons. In anesthetized rats, we measured rheobase current intracellularly from MG motoneurons in vivo before labeling them for immunohistochemical study of AIS structure. For 16 motoneurons sampled from the MG motor pool, this combinatory approach revealed that AISd, but not AISl, was significantly related to rheobase, as AIS tended to be located further from the soma on motoneurons that were less excitable. Although a causal relation with excitability seems unlikely, AISd falls among a constellation of properties related to the recruitability of motor units and their parent motoneurons.

Effects of route of administration on neural exposure to platinum-based chemotherapy treatment: a pharmacokinetic study in rat.

The persisting need for effective clinical treatment of chemotherapy-induced neurotoxicity (CIN) motivates critical evaluation of preclinical models of CIN for their translational relevance. The present study aimed to provide the first quantitative evaluation of neural tissue exposed in vivo to a platinum-based anticancer compound, oxaliplatin (OX) during and after two commonly used dosing regimens: slow IV infusion used clinically and bolus IP injection used preclinically. Inductively-coupled plasma mass spectrometry analysis of dorsal root ganglia indicated that while differences in the temporal dynamics of platinum distribution exist, key drivers of neurotoxicity, e.g. peak concentrations and exposure, were not different across the two routes of administration. We conclude that the IP route of OX administration achieves clinically relevant pharmacokinetic exposure of neural tissues in a rodent model of CIN.

A review of movement disorders in chemotherapy-induced neurotoxicity.

Chemotherapy agents used in the standard treatments for many types of cancer are neurotoxic and can lead to lasting sensory and motor symptoms that compromise day-to-day movement functions in cancer survivors. To date, the details of movement disorders associated with chemotherapy are known largely through self-reported symptoms and functional limitations. There are few quantitative studies of specific movement deficits, limiting our understanding of dysfunction, as well as effective assessments and interventions. The aim of this narrative review is to consolidate the current understanding of sensorimotor disabilities based on quantitative measures in cancer survivors who received chemotherapy. We performed literature searches on PubMed and found 32 relevant movement studies. We categorized these studies into three themes based on the movement deficits investigated: (1) balance and postural control; (2) gait function; (3) upper limb function. This literature suggests that cancer survivors have increased postural sway, more conservative gait patterns, and suboptimal hand function compared to healthy individuals. More studies are needed that use objective measures of sensorimotor function to better characterize movement disabilities and investigate the underlying causes, as required for developing targeted assessments and interventions. By updating our understanding of movement impairments in this population, we identify significant gaps in knowledge that will help guide the direction of future research.

Diverse and complex muscle spindle afferent firing properties emerge from multiscale muscle mechanics.

Despite decades of research, we lack a mechanistic framework capable of predicting how movement-related signals are transformed into the diversity of muscle spindle afferent firing patterns observed experimentally, particularly in naturalistic behaviors. Here, a biophysical model demonstrates that well-known firing characteristics of mammalian muscle spindle Ia afferents - including movement history dependence, and nonlinear scaling with muscle stretch velocity - emerge from first principles of muscle contractile mechanics. Further, mechanical interactions of the muscle spindle with muscle-tendon dynamics reveal how motor commands to the muscle (alpha drive) versus muscle spindle (gamma drive) can cause highly variable and complex activity during active muscle contraction and muscle stretch that defy simple explanation. Depending on the neuromechanical conditions, the muscle spindle model output appears to 'encode' aspects of muscle force, yank, length, stiffness, velocity, and/or acceleration, providing an extendable, multiscale, biophysical framework for understanding and predicting proprioceptive sensory signals in health and disease.

Chronic defects in intraspinal mechanisms of spike encoding by spinal motoneurons following chemotherapy.

Chemotherapy-induced sensorimotor disabilities, including gait and balance disorders, as well as physical fatigue often persist for months and sometimes years into disease free survival from cancer. While associated with impaired sensory function, chronic sensorimotor disorders might also depend on chemotherapy-induced defects in other neuron types. In this report, we extend consideration to motoneurons, which, if chronically impaired, would necessarily degrade movement behavior. The present study was undertaken to determine whether motoneurons qualify as candidate contributors to chronic sensorimotor disability independently from sensory impairment. We tested this possibility in vivo from rats 5 weeks following human-scaled treatment with one of the platinum-based compounds, oxaliplatin, widely used in chemotherapy for a variety of cancers. Action potential firing of spinal motoneurons responding to different fixed levels of electrode-current injection was measured in order to assess the neurons' intrinsic capacity for stimulus encoding. The encoding of stimulus duration and intensity corroborated in untreated control rats was severely degraded in oxaliplatin treated rats, in which motoneurons invariably exhibited erratic firing that was unsustained, unpredictable from one stimulus trial to the next, and unresponsive to changes in current strength. Direct measurements of interspike oscillations in membrane voltage combined with computer modeling pointed to aberrations in subthreshold conductances as a plausible contributor to impaired firing behavior. These findings authenticate impaired spike encoding as a candidate contributor to, in the case of motoneurons, deficits in mobility and fatigue. Aberrant firing also becomes a deficit worthy of testing in other CNS neurons as a potential contributor to perceptual and cognitive disorders induced by chemotherapy in patients.

Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice.

Peripheral neurotoxicity is a debilitating condition that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells in oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity. The relevance of this transport system was verified in transporter-deficient rats as a secondary model organism, and translational significance of preventive strategies was demonstrated in preclinical models of colorectal cancer. These studies suggest that pharmacological targeting of OCT2 could be exploited to afford neuroprotection in cancer patients requiring treatment with oxaliplatin.

Synaptic Plasticity on Motoneurons After Axotomy: A Necessary Change in Paradigm.

Motoneurons axotomized by peripheral nerve injuries experience profound changes in their synaptic inputs that are associated with a neuroinflammatory response that includes local microglia and astrocytes. This reaction is conserved across different types of motoneurons, injuries, and species, but also displays many unique features in each particular case. These reactions have been amply studied, but there is still a lack of knowledge on their functional significance and mechanisms. In this review article, we compiled data from many different fields to generate a comprehensive conceptual framework to best interpret past data and spawn new hypotheses and research. We propose that synaptic plasticity around axotomized motoneurons should be divided into two distinct processes. First, a rapid cell-autonomous, microglia-independent shedding of synapses from motoneuron cell bodies and proximal dendrites that is reversible after muscle reinnervation. Second, a slower mechanism that is microglia-dependent and permanently alters spinal cord circuitry by fully eliminating from the ventral horn the axon collaterals of peripherally injured and regenerating sensory Ia afferent proprioceptors. This removes this input from cell bodies and throughout the dendritic tree of axotomized motoneurons as well as from many other spinal neurons, thus reconfiguring ventral horn motor circuitries to function after regeneration without direct sensory feedback from muscle. This process is modulated by injury severity, suggesting a correlation with poor regeneration specificity due to sensory and motor axons targeting errors in the periphery that likely render Ia afferent connectivity in the ventral horn nonadaptive. In contrast, reversible synaptic changes on the cell bodies occur only while motoneurons are regenerating. This cell-autonomous process displays unique features according to motoneuron type and modulation by local microglia and astrocytes and generally results in a transient reduction of fast synaptic activity that is probably replaced by embryonic-like slow GABA depolarizations, proposed to relate to regenerative mechanisms.

Cancer Exacerbates Chemotherapy-Induced Sensory Neuropathy.

For the constellation of neurologic disorders known as chemotherapy-induced peripheral neuropathy, mechanistic understanding and treatment remain deficient. Here, we present the first evidence that chronic sensory neuropathy depends on nonlinear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed differential expression, notably in regulators of neuronal excitability, metabolism, and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as one potential contributor to sensory neuron dysfunction. Validated measures of sensorimotor behavior in awake, behaving animals revealed dysfunction after chronic chemotherapy treatment was exacerbated by cancer. Notably, errors in precise forelimb placement emerged as a novel behavioral deficit unpredicted by our previous study of chemotherapy alone. These original findings identify novel contributors to peripheral neuropathy and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer. SIGNIFICANCE: These findings highlight the need to account for pathobiological interactions between cancer and chemotherapy as a major contributor to neuropathy and will have significant and immediate impact on future investigations in this field.