RESUMEN
Veterinary pathology credentials serve as a concise means attesting to educational attainments and experiences indicating a readiness for professional practice. Given the cost, time, and stress associated with obtaining different qualifications, pathologists must consider what credentials enhance their readiness. In this commentary, the authors describe how their various degrees and certifications have facilitated their individual and organizational success. The minimum credentials for proficient veterinary pathology practice are a veterinary medical degree (DVM or equivalent) and advanced pathology training (residency and/or on-the-job "apprenticeship") ideally culminating in board certification in pathology (American College of Veterinary Pathologists [ACVP] diplomate status or equivalent). Graduate degrees (MS, PhD, MPH, etc) and/or other qualifications in allied biomedical fields (eg, board certification in internal medicine, laboratory animal medicine, poultry medicine, preventive medicine, or toxicology) may improve employability by affirming specialty knowledge in another complementary discipline. The authors note that pathology positions may be obtained without a long list of degrees or certifications, and that more credentials may provide occupational flexibility for some employers. However, a good work ethic, experience in the field, ability to adapt to changes, job satisfaction, good attitude, and demonstrated productivity are also important, and indeed, they are often the paramount criteria for career success as a veterinary pathologist.
RESUMEN
Dorsal root ganglia (DRG), trigeminal ganglia (TG), other sensory ganglia, and autonomic ganglia may be injured by some test article classes, including anti-neoplastic chemotherapeutics, adeno-associated virus-based gene therapies, antisense oligonucleotides, nerve growth factor inhibitors, and aminoglycoside antibiotics. This article reviews ganglion anatomy, cytology, and pathology (emphasizing sensory ganglia) among common nonclinical species used in assessing product safety for such test articles (TAs). Principal histopathologic findings associated with sensory ganglion injury include neuron degeneration, necrosis, and/or loss; increased satellite glial cell and/or Schwann cell numbers; and leukocyte infiltration and/or inflammation. Secondary nerve fiber degeneration and/or glial reactions may occur in nerves, dorsal spinal nerve roots, spinal cord (dorsal and occasionally lateral funiculi), and sometimes the brainstem. Ganglion findings related to TA administration may result from TA exposure and/or trauma related to direct TA delivery into the central nervous system or ganglia. In some cases, TA-related effects may need to be differentiated from a spectrum of artifactual and/or spontaneous background changes.
Asunto(s)
Ganglios Espinales , Fibras Nerviosas , Animales , Médula Espinal , BiologíaRESUMEN
Certain biopharmaceutical products consistently affect dorsal root ganglia, trigeminal ganglia, and/or autonomic ganglia. Product classes targeting ganglia include antineoplastic chemotherapeutics, adeno-associated virus-based gene therapies, antisense oligonucleotides, and anti-nerve growth factor agents. This article outlines "points to consider" for sample collection, processing, evaluation, interpretation, and reporting of ganglion findings; these points are consistent with published best practices for peripheral nervous system evaluation in nonclinical toxicity studies. Ganglion findings often occur as a combination of neuronal injury (e.g., degeneration, necrosis, and/or loss) and/or glial effects (e.g., increased satellite glial cell cellularity) with leukocyte accumulation (e.g., mononuclear cell infiltration or inflammation). Nerve fiber degeneration and/or glial reactions may be seen in nerves, dorsal spinal nerve roots, spinal cord, and occasionally brainstem. Interpretation of test article (TA)-associated effects may be confounded by incidental background changes or experimental procedure-related changes and limited historical control data. Reports should describe findings at these sites, any TA relationship, and the criteria used for assigning severity grades. Contextualizing adversity of ganglia findings can require a weight-of-evidence approach because morphologic changes of variable severity occur in ganglia but often are not accompanied by observable overt in-life functional alterations detectable by conventional behavioral and neurological testing techniques.
Asunto(s)
Ganglios Espinales , Sistema Nervioso Periférico , Humanos , Sistema Nervioso Periférico/patología , Neuronas/patología , Médula Espinal/patología , Fibras Nerviosas/patología , Degeneración Nerviosa/patologíaRESUMEN
Beagle dogs are a key nonrodent species in nonclinical safety evaluation of new biomedical products. The Society of Toxicologic Pathology (STP) has published "best practices" recommendations for nervous system sampling in nonrodents during general toxicity studies (Toxicol Pathol 41[7]: 1028-1048, 2013), but their adaptation to the Beagle dog has not been defined specifically. Here we provide 2 trimming schemes suitable for evaluating the unique neuroanatomic features of the dog brain in nonclinical toxicity studies. The first scheme is intended for general toxicity studies (Tier 1) to screen test articles with unknown or no anticipated neurotoxic potential; this plan using at least 7 coronal hemisections matches the STP "best practices" recommendations. The second trimming scheme for neurotoxicity studies (Tier 2) uses up to 14 coronal levels to investigate test articles where the brain is a suspected or known target organ. Collection of spinal cord, ganglia (somatic and autonomic), and nerves for dogs during nonclinical studies should follow published STP "best practices" recommendations for sampling the central (Toxicol Pathol 41[7]: 1028-1048, 2013) and peripheral (Toxicol Pathol 46[4]: 372-402, 2018) nervous systems. This technical guide also demonstrates the locations and approaches to collecting uncommonly sampled peripheral nervous system sites.
Asunto(s)
Síndromes de Neurotoxicidad , Pruebas de Toxicidad , Animales , Perros , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/veterinaria , Sistema Nervioso Periférico , Manejo de Especímenes , Médula EspinalRESUMEN
Adeno-associated virus (AAV)-induced dorsal root ganglia (DRG) toxicity has been observed in several nonclinical species, where lesions are characterized by neuronal degeneration/necrosis, nerve fiber degeneration, and mononuclear cell infiltration. As AAV vectors become an increasingly common platform for novel therapeutics, non-invasive biomarkers are needed to better characterize and manage the risk of DRG neurotoxicity in both nonclinical and clinical studies. Based on biological relevance, reagent availability, antibody cross-reactivity, DRG protein expression, and assay performance, neurofilament light chain (NF-L) emerged as a promising biomarker candidate. Dose- and time-dependent changes in NF-L were evaluated in male Wistar Han rats and cynomolgus monkeys following intravenous or intrathecal AAV injection, respectively. NF-L profiles were then compared against microscopic DRG lesions on day 29 post-dosing. In animals exhibiting DRG toxicity, plasma/serum NF-L was strongly associated with the severity of neuronal degeneration/necrosis and nerve fiber degeneration, with elevations beginning as early as day 8 in rats (≥5 × 1013 vg/kg) and day 14 in monkeys (≥3.3 × 1013 vg/dose). Consistent with the unique positioning of DRGs outside the blood-brain barrier, NF-L in cerebrospinal fluid was only weakly associated with DRG findings. In summary, circulating NF-L is a promising biomarker of AAV-induced DRG toxicity in nonclinical species.
RESUMEN
Recombinant adeno-associated viruses (AAVs) have emerged as promising vectors for human gene therapy, but some variants have induced severe toxicity in Rhesus monkeys and piglets following high-dose intravenous (IV) administration. To characterize biodistribution, transduction, and toxicity among common preclinical species, an AAV9 neurotropic variant expressing the survival motor neuron 1 (SMN1) transgene (AAV-PHP.B-CBh-SMN1) was administered by IV bolus injection to Wistar Han rats and cynomolgus monkeys at doses of 2 × 1013, 5 × 1013, or 1 × 1014 vg/kg. A dose-dependent degeneration/necrosis of neurons without clinical manifestations occurred in dorsal root ganglia (DRGs) and sympathetic thoracic ganglia in rats, while liver injury was not observed in rats. In monkeys, one male at 5 × 1013 vg/kg was found dead on day 4. Clinical pathology data on days 3 and/or 4 at all doses suggested liver dysfunction and coagulation disorders, which led to study termination. Histologic evaluation of the liver in monkeys showed hepatocyte degeneration and necrosis without inflammatory cell infiltrates or intravascular thrombi, suggesting that hepatocyte injury is a direct effect of the vector following hepatocyte transduction. In situ hybridization demonstrated a dose-dependent expression of SMN1 transgene mRNA in the cytoplasm and DNA in the nucleus of periportal to panlobular hepatocytes, while quantitative polymerase chain reaction confirmed the dose-dependent presence of SMN1 transgene mRNA and DNA in monkeys. Monkeys produced a much greater amount of transgene mRNA compared with rats. In DRGs, neuronal degeneration/necrosis and accompanying findings were observed in monkeys as early as 4 days after test article administration. The present results show sensory neuron toxicity following IV delivery of AAV vectors at high doses with an early onset in Macaca fascicularis and after 1 month in rats, and suggest adding the autonomic system in the watch list for preclinical and clinical studies. Our data also suggest that the rat may be useful for evaluating the potential DRG toxicity of AAV vectors, while acute hepatic toxicity associated with coagulation disorders appears to be highly species-dependent.
Asunto(s)
Dependovirus , Vectores Genéticos , Animales , Dependovirus/genética , Vectores Genéticos/genética , Macaca fascicularis , Masculino , Neuronas Motoras , Necrosis , ARN Mensajero , Ratas , Ratas Wistar , Porcinos , Distribución Tisular , Transducción GenéticaRESUMEN
BACKGROUND: CBA/J mice are standard experimental animals in auditory studies, and age-related changes in auditory pathways are well documented. However, changes in locomotion-related brain regions have not been systematically explored. RESULTS: We showed an increase in immunoreactivity for glial fibrillary acidic protein (GFAP) in the cerebellar molecular layer associated with Purkinje cells in mice at 24 weeks of age but not in the younger mice. Increased GFAP immunoreactivity appeared in the form of clusters and distributed multifocally consistent with hyperplasia of astrocytes that were occasionally associated with Purkinje cell degeneration. Three out of 12 animals at 16 and 24 weeks of age exhibited pre-convulsive clinical signs. Two of these 3 animals also showed increased GFAP immunoreactivity in the cerebellum. Rotarod behavioral assessments indicated decreased performance at 24 weeks of age. CONCLUSIONS: These results suggest minimal to mild reactive astrocytosis likely associated with Purkinje cell degeneration in the cerebellum at 24 weeks of age in CBA/J mice. These findings should be taken into consideration prior to using this mouse strain for studying neuroinflammation or aging.
RESUMEN
The use of minipigs as an alternative nonclinical species has increased in the last 20 years. The Society of Toxicologic Pathology (STP) has produced generic "best practice" recommendations for nervous system sampling in nonrodents during general toxicity studies (Toxicol Pathol 41[7]: 1028-1048, 2013), but their adaptation to the minipig has not been attempted. Here, we describe 2 trimming schemes suitable for evaluating the unique neuroanatomic features of the minipig brain in nonclinical toxicity studies. The first scheme is intended for general toxicity studies (Tier 1) to screen agents with unknown or no anticipated neurotoxic potential; this approach using 7 coronal hemisections accords with the published STP "best practice" recommendations. The second trimming scheme for neurotoxicity studies (Tier 2) uses 14 coronal hemisections and 2 full coronal sections to investigate toxicants where the nervous system is a suspected or known target organ. Collection of spinal cord, ganglia (somatic and autonomic), and nerves from minipigs during nonclinical studies should follow published STP "best practice" recommendations for sampling the central (CNS, Toxicol Pathol 41[7]: 1028-1048, 2013) and peripheral (PNS, Toxicol Pathol 46[4]: 372-402, 2018) nervous systems.
Asunto(s)
Laboratorios , Síndromes de Neurotoxicidad , Animales , Técnicas Histológicas , Médula Espinal , Porcinos , Porcinos EnanosRESUMEN
The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project (www.toxpath.org/inhand.asp) is a joint initiative of the societies of toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in most tissues and organs from the dog used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions, lesions induced by exposure to test materials, and relevant infectious and parasitic lesions. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.
Asunto(s)
Animales de Laboratorio , Animales , Bases de Datos Factuales , Perros , Europa (Continente) , JapónRESUMEN
The peripheral nervous system (PNS) relays messages between the central nervous system (brain and spinal cord) and the body. Despite this critical role and widespread distribution, the PNS is often overlooked when investigating disease in diagnostic and experimental pathology. This review highlights key features of neuroanatomy and physiology of the somatic and autonomic PNS, and appropriate PNS sampling and processing techniques. The review considers major classes of PNS lesions including neuronopathy, axonopathy, and myelinopathy, and major categories of PNS disease including toxic, metabolic, and paraneoplastic neuropathies; infectious and inflammatory diseases; and neoplasms. This review describes a broad range of common PNS lesions and their diagnostic criteria and provides many useful references for pathologists who perform PNS evaluations as a regular or occasional task in their comparative pathology practice.
Asunto(s)
Enfermedades del Sistema Nervioso Central , Enfermedades del Sistema Nervioso Periférico , Animales , Sistema Nervioso Central , Enfermedades del Sistema Nervioso Central/veterinaria , Sistema Nervioso Periférico , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/veterinaria , Médula EspinalRESUMEN
Visual system toxicity may manifest anywhere in the visual system, from the eye proper to the visual brain. Therefore, effective screening for visual system toxicity must evaluate not only ocular structures (ie, eye and optic nerve) but also multiple key brain regions involved in vision (eg, optic tract, subcortical relay nuclei, and primary and secondary visual cortices). Despite a generally comparable pattern across species, the neuroanatomic organization and function of the visual brain in rodents and rabbits exhibit appreciable differences relative to nonrodents. Currently recognized sampling practices for general toxicity studies in animals, which are based on easily discerned external neuroanatomic landmarks and guided by extant stereotaxic brain atlases, typically will permit histopathologic evaluation of many brain centers involved in visual sensation (eg, optic chiasm, optic tract, dorsal lateral geniculate nucleus, primary and secondary visual cortices) and often some subcortical brain nuclei involved in light-modulated nonvisual activities needed for visual attention and orientation (eg, rostral colliculus in quadrupeds, termed the superior colliculus in bipeds; several cranial nerve nuclei). Pathologic findings induced by toxicants in the visual brain centers are similar to those that are produced in other brain regions.
Asunto(s)
Cuerpos Geniculados , Neuroanatomía , Animales , Encéfalo , Mamíferos , Conejos , Retina , Colículos SuperioresRESUMEN
Although manuscripts for multiple species recommending nervous system sampling for histopathology evaluation in safety assessment have been published in the past 15 years, none have addressed the laboratory rabbit. Here, we describe 2 trimming schemes for evaluating the rabbit brain in nonclinical toxicity studies. In both schemes, the intact brain is cut in the coronal plane to permit bilateral assessment. The first scheme is recommended for general toxicity studies (tier 1) in screening agents where there is no anticipated neurotoxic potential; this 6-section approach is consistent with the Society of Toxicologic Pathology (STP) "best practice" recommendations for brain sampling in nonrodents (Toxicol Pathol 41: 1028-1048, 20131). The second trimming scheme is intended for dedicated neurotoxicity studies (tier 2) to characterize known or suspected neurotoxicants where the nervous system is a key target organ. This tier 2 strategy relies on coronal trimming of the whole brain into 3-mm-thick slices and then evaluating 12 sections. Collection of spinal cord, ganglia, and nerve specimens for rabbits during nonclinical studies should follow published STP "best practice" recommendations for sampling the central nervous system1 and peripheral nervous system (Toxicol Pathol 46: 372-402, 20182).
Asunto(s)
Síndromes de Neurotoxicidad , Animales , Técnicas Histológicas , Sistema Nervioso , Síndromes de Neurotoxicidad/etiología , Sistema Nervioso Periférico , Conejos , Manejo de Especímenes , Médula EspinalRESUMEN
Axonal dystrophy (AD) is a common age-related neurohistological finding in vertebrates that can be congenital or induced by xenobiotics, vitamin E deficiency, or trauma/compression. To understand the incidence and location of AD as a background finding in Beagle dogs used in routine toxicity studies, we examined central nervous system (CNS) and selected peripheral nervous system (PNS) tissues in twenty 18- to 24-month-old and ten 4- to 5-year-old control males and females. Both sexes were equally affected. The cuneate, gracile, and cochlear nuclei and the cerebellar white matter (rostral vermis) were the most common locations for AD. Incidence of AD increased with age in the cuneate nucleus, cerebellar white matter (rostral vermis), trigeminal nuclei/tracts, and lumbar spinal cord. Axonal dystrophy in the CNS was not accompanied by neuronal degeneration/necrosis, nerve fiber degeneration, and/or glial reaction. Axonal dystrophy was not observed in the PNS (sciatic nerve, vagus nerve branches, or gastrointestinal mural autonomic plexuses).
Asunto(s)
Encéfalo/patología , Enfermedades de los Perros/patología , Distrofias Neuroaxonales/patología , Médula Espinal/patología , Animales , Sistema Nervioso Central/patología , Modelos Animales de Enfermedad , Perros , Femenino , Masculino , Bulbo Raquídeo/patología , Degeneración Nerviosa/patologíaRESUMEN
Neuropathology of the peripheral nervous system (PNS) is an underappreciated area in toxicologic pathology. Toxicity to nerves and ganglia can result from toxic insults following exposure to environmental, occupational, and industrial chemicals; drugs and biologics; cosmetics and food additives; and even physical agents such as noise. The following introduction provides an overview of this special issue of Toxicologic Pathology on toxicologic neuropathology of the PNS and highlights the range of key topics in this field that are reviewed in this compilation.
Asunto(s)
Neuropatología , Sistema Nervioso Periférico , Toxicología , Animales , HumanosRESUMEN
Peripheral nerves are routinely examined microscopically during the nonclinical safety assessment of therapeutics. In addition to test article-related on- or off-target changes, microscopic changes in peripheral nerves may also be caused by study procedures, such as parenteral test article administration and blood or tissue sampling. We present 2 nonclinical case studies in which nonstandard peripheral nerves had study procedure-related histologic changes. The first case study describes mouse trigeminal nerve changes as a result of blood sampling via retro-orbital sinus puncture. These changes included minimal-to-mild nerve fiber (axonal) degeneration associated with macrophage infiltration. The second case study presents rat brachial plexus changes associated with animal handling and blood sampling. Brachial plexus changes included minimal-to-moderate inflammation, focal hemorrhage, and nerve fiber degeneration. In both cases, the histological changes were morphologically indistinguishable from those that might be due to test article. Therefore, careful consideration of the incidence and severity across groups and a review of study procedures to rule out handling-related nerve damage are essential before identifying a test article-related effect on peripheral nerves. Study design considerations to avoid such procedure-related changes will be discussed, as well as sampling strategies to help distinguish these from test article-related effects.
Asunto(s)
Nervios Periféricos/patología , Animales , Humanos , Ratones , Degeneración Nerviosa , Enfermedades del Sistema Nervioso Periférico , RatasRESUMEN
Toxicologic neuropathology for the peripheral nervous system (PNS) is a vital but often underappreciated element of basic translational research and safety assessment. Evaluation of the PNS may be complicated by unfamiliarity with normal nerve and ganglion biology, which differs to some degree among species; the presence of confounding artifacts related to suboptimal sampling and processing; and limited experience with differentiating such artifacts from genuine disease manifestations and incidental background changes. This compilation of key PNS neurobiology, neuropathology, and neurotoxicology references is designed to allow pathologists and toxicologists to readily access essential information that is needed to enhance their proficiency in evaluating and interpreting toxic changes in PNS tissues from many species.
Asunto(s)
Patólogos , Sistema Nervioso Periférico/patología , Toxicología , Animales , Humanos , Manejo de EspecímenesRESUMEN
The ability to differentiate among normal structures, procedural and processing artifacts, spontaneous background changes, and test article-related effects in the peripheral nervous system (PNS) is essential for interpreting microscopic features of ganglia and nerves evaluated in animal species commonly used in toxicity studies evaluating regulated products and chemicals. This atlas provides images of findings that may be encountered in ganglia and nerves of animal species commonly used in product discovery and development. Most atlas images are of tissues from control animals that were processed using routine methods (ie, immersion fixation in neutral-buffered 10% formalin, embedding in paraffin, sectioning at 5 µm, and staining with hematoxylin and eosin) since these preparations are traditionally applied to study materials produced during most animal toxicity studies. A few images are of tissues processed using special procedures (ie, immersion or perfusion fixation using methanol-free 4% formaldehyde, postfixation in glutaraldehyde and osmium, embedding in hard plastic resin, sectioning at 1 µm, and staining with toluidine blue), since these preparations promote better stabilization of lipids and thus optimal resolution of myelin sheaths. Together, this compilation provides a useful resource for discriminating among normal structures, procedure- and processing-related artifacts, incidental background changes, and treatment-induced findings that may be seen in PNS tissues of laboratory animals.
Asunto(s)
Sistema Nervioso Periférico/patología , Pruebas de Toxicidad , Animales , Animales de Laboratorio , Vaina de Mielina , Síndromes de Neurotoxicidad , Adhesión en Parafina , Coloración y EtiquetadoRESUMEN
Nerve fiber teasing is a sensitive technique utilized in diagnostic neuropathology practice, laboratory research, and animal toxicity studies for characterizing changes in single myelinated nerve fibers over extended distances. In animal toxicity studies, a nerve portion (approximately 10 mm in length) is stained with Sudan black for 24 to 48 hours and then transferred into a drop of viscous medium (eg, glycerin) mounted on an adhesive-coated glass slide, positioning it such that the proximodistal orientation is known. Individual fibers are removed using fine forceps while the sample is viewed under a stereomicroscope. In general, lesions can be identified during teasing, but more detailed characterization and photodocumentation is undertaken once nerve fibers have been dried and coverslipped. Nerve fiber teasing is particularly useful for distinguishing early stages of axonal degeneration (which presents as ovoid fiber fragments in the midinternodal region) from segmental demyelination (which presents as loss of original myelin segments and their replacement by thinner, shorter segments in the absence of axonal damage). The slow, laborious nature of nerve fiber teasing dictates that the technique will be employed on a few samples as an auxiliary method to better define the pathogenesis of nerve lesions first identified by conventional histopathologic assessment.
Asunto(s)
Fibras Nerviosas Mielínicas/patología , Pruebas de Toxicidad , Animales , Vaina de Mielina/patología , PatologíaRESUMEN
Two beagle dog strains were used in a 14-day intrathecal infusion study for a small molecule test article. A moderate number of Renaut bodies (RBs) were observed in the sciatic nerves of control and test article-treated adult animals as early as 1 day after test article infusion (ie, 5 days after catheter implantation in the lumbar cistern). In most cases, the sciatic nerve was affected unilaterally, apparently in association with extended lateral recumbency on one side. The lighter beagle strain (Marshall), and especially the females (which weighed less than age-matched Marshall males), developed more RBs. In contrast, neither females nor males of the larger strain (Harlan) developed any nerve lesions. These data support the hypothesis that RBs develop following mechanical stress to sciatic nerves, suggest that this change may develop fairly quickly following an insult, and demonstrate that different dog strains exhibit strain-specific nerve changes.
Asunto(s)
Nervio Ciático/patología , Animales , Perros , Femenino , Inyecciones Espinales , MasculinoRESUMEN
Chemotherapy-induced peripheral neuropathy (CiPN) is a serious adverse effect in the clinic, but nonclinical assessment methods in animal studies are limited to labor intensive behavioral tests or semi-quantitative microscopic evaluation. Hence, microRNA (miRNA) biomarkers and automated in-life behavioral tracking were assessed for their utility as non-invasive methods. To address the lack of diagnostic biomarkers, we explored miR-124, miR-183 and miR-338 in a CiPN model induced by paclitaxel, a well-known neurotoxic agent. In addition, conventional and Vium's innovative Digital Vivarium technology-based in-life behavioral tests and postmortem microscopic examination of the dorsal root ganglion (DRG) and the sciatic nerve were performed. Terminal blood was collected on days 8 or 16, after 20 mg/kg paclitaxel was administered every other day for total of 4 or 7 doses, respectively, for plasma miRNA quantification by RT-qPCR. DRG and sciatic nerve samples were collected from mice sacrificed on day 16 for miRNA quantification. Among the three miRNAs analyzed, only miR-124 was statistically significantly increased (5 fold and 10 fold on day 8 and day 16, respectively). The increase in circulating miR-124 correlated with cold allodynia and axonal degeneration in both DRG and sciatic nerve. Automated home cage motion analysis revealed for the first time that nighttime motion was significantly decreased (P < 0.05) in paclitaxel-dosed animals. Although both increase in circulating miR-124 and decrease in nighttime motion are compelling, our results provide positive evidence warranting further testing using additional peripheral nerve toxicants and diverse experimental CiPN models.