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Introduction: Hox genes govern rostro-caudal identity along the developing spinal cord, which has a well-defined division of function between dorsal (sensory) and ventral (motor) halves. Here we exploit developmental Hoxb8 expression, normally restricted to the dorsal cord below the obex, to genetically label spinal cord-to-brain ("spinofugal") axons. Methods: We crossed two targeted (knock-in) and two non-targeted recombinase-expressing lines (Hoxb8-IRES-Cre and Hoxb8-T2AFlpO; Hoxb8- Cre and Hoxb8-FlpO, respectively) with appropriate tdtomato-expressing reporter strains. Serial sectioning, confocal and superresolution microscopy, as well as light-sheet imaging was used to reveal robust labeling of ascending axons and their terminals in expected and unexpected regions. Results: This strategy provides unprecedented anatomical detail of ascending spinal tracts anterior to the brainstem, and reveals a previously undescribed decussating tract in the ventral hypothalamus (the spinofugal hypothalamic decussating tract, or shxt). The absence of Hoxb8-suppressing elements led to multiple instances of ectopic reporter expression in Hoxb8-Cre mice (retinal ganglion and vomeronasal axons, anterior thalamic nuclei and their projections to the anterior cingulate and retrosplenial cortices and subiculum, and a population of astrocytes at the cephalic flexure) and Hoxb8-FlpO mice (Cajal--Retzius cells of the dentate gyrus, and mesenchymal cells of the choroid plexus). While targeted transgenic lines were similar in terms of known spinofugal projections, Hoxb8- IRES-Cre reporters had an additional projection to the core of the facial motor nucleus, and more abundant Hoxb8-lineage microglia scattered throughout the brain than Hoxb8-T2A-FlpO (or any other) mice, suggesting dysregulated Hoxb8- driven reporter expression in one or both lines. Discussion: This work complements structural and connectivity atlases of the mouse central nervous system, and provides a platform upon which their reactions to injury or disease can be studied. Ectopic Hoxb8-driven recombinase expression may also be a useful tool to study structure and function of other cell populations in non-targeted lines. [ABSTRACT FROM AUTHOR]

IntroductionHox genes govern rostro-caudal identity along the developing spinal cord, which has a well-defined division of function between dorsal (sensory) and ventral (motor) halves. Here we exploit developmental Hoxb8 expression, normally restricted to the dorsal cord below the obex, to genetically label spinal cord-to-brain (“spinofugal”) axons.MethodsWe crossed two targeted (knock-in) and two non-targeted recombinase-expressing lines (Hoxb8-IRES-Cre and Hoxb8-T2AFlpO; Hoxb8-Cre and Hoxb8-FlpO, respectively) with appropriate tdtomato-expressing reporter strains. Serial sectioning, confocal and superresolution microscopy, as well as light-sheet imaging was used to reveal robust labeling of ascending axons and their terminals in expected and unexpected regions.ResultsThis strategy provides unprecedented anatomical detail of ascending spinal tracts anterior to the brainstem, and reveals a previously undescribed decussating tract in the ventral hypothalamus (the spinofugal hypothalamic decussating tract, or shxt). The absence of Hoxb8-suppressing elements led to multiple instances of ectopic reporter expression in Hoxb8-Cre mice (retinal ganglion and vomeronasal axons, anterior thalamic nuclei and their projections to the anterior cingulate and retrosplenial cortices and subiculum, and a population of astrocytes at the cephalic flexure) and Hoxb8-FlpO mice (Cajal–Retzius cells of the dentate gyrus, and mesenchymal cells of the choroid plexus). While targeted transgenic lines were similar in terms of known spinofugal projections, Hoxb8-IRES-Cre reporters had an additional projection to the core of the facial motor nucleus, and more abundant Hoxb8-lineage microglia scattered throughout the brain than Hoxb8-T2A-FlpO (or any other) mice, suggesting dysregulated Hoxb8-driven reporter expression in one or both lines.DiscussionThis work complements structural and connectivity atlases of the mouse central nervous system, and provides a platform upon which their reactions to injury or disease can be studied. Ectopic Hoxb8-driven recombinase expression may also be a useful tool to study structure and function of other cell populations in non-targeted lines.

This report describes 2 events of degenerative myelopathy in 4- to 27-day-old piglets, with mortality rates reaching 40%. Sows were fed rations containing low levels of pantothenic acid. Piglets presented with severe depression, weakness, ataxia, and paresis, which were more pronounced in the pelvic limbs. No significant gross lesions were observed. Histologically, there were degeneration and necrosis of neurons in the spinal cord, primarily in the thoracic nucleus in the thoracic and lumbar segments, and motor neurons in nucleus IX of the ventral horn in the cervical and lumbar intumescence. Minimal-to-moderate axonal and myelin degeneration was observed in the dorsal funiculus of the spinal cord and in the dorsal and ventral nerve roots. Immunohistochemistry demonstrated depletion of acetylcholine neurotransmitters in motor neurons and accumulation of neurofilaments in the perikaryon of neurons in the thoracic nucleus and motor neurons. Ultrastructurally, the thoracic nucleus neurons and motor neurons showed dissolution of Nissl granulation. The topographical distribution of the lesions indicates damage to the second-order neurons of the spinocerebellar tract, first-order axon cuneocerebellar tract, and dorsal column-medial lemniscus pathway as the cause of the conscious and unconscious proprioceptive deficit, and damage to the alpha motor neuron as the cause of the motor deficit. Clinical signs reversed and no new cases occurred after pantothenic acid levels were corrected in the ration, and piglets received parenteral administration of pantothenic acid. This study highlights the important and practical use of detailed neuropathological analysis to refine differential diagnosis. [ABSTRACT FROM AUTHOR]

Peripheral and intraspinal feedback is required to shape and update the output of spinal networks that execute motor behavior. We report that lumbar dI2 spinal interneurons in chicks receive synaptic input from afferents and premotor neurons. These interneurons innervate contralateral premotor networks in the lumbar and brachial spinal cord, and their ascending projections innervate the cerebellum. These findings suggest that dI2 neurons function as interneurons in local lumbar circuits, are involved in lumbo-brachial coupling, and that part of them deliver peripheral and intraspinal feedback to the cerebellum. Silencing of dI2 neurons leads to destabilized stepping in posthatching day 8 hatchlings, with occasional collapses, variable step profiles, and a wide-base walking gait, suggesting that dI2 neurons may contribute to the stabilization of the bipedal gait.

Muscle kinematics and kinetics are nonlinearly encoded by proprioceptors, and the changes in muscle length and velocity are integrated into Ia afferent. Besides, proprioceptive signals from multiple muscles are probably mixed in afferent pathways, which all lead to difficulties in proprioceptive recognition for the cerebellum. In this study, the artificial neural networks, whose organizations are biologically based on the spinocerebellar tract and cerebellum, are utilized to decode the proprioceptive signals. Consistent with the controversy of the proprioceptive division in the dorsal spinocerebellar tract, the spinocerebellar tract networks incorporated two distinct inferences, (1) the centralized networks, which mixed Ia, II, and Ib and processed them together; (2) the decentralized networks, which processed Ia, II, and Ib afferents separately. The cerebellar networks were based on the Marr–Albus model to recognize the kinematic states. The networks were trained by a specific movement, and the trained networks were subsequently required to predict kinematic states of six movements. The results demonstrated that the centralized networks, which were more consistent with the physiological findings in recent years, had better recognition accuracy than the decentralized networks, and the networks were still effective even when proprioceptive afferents from multiple muscles were integrated. [ABSTRACT FROM AUTHOR]

Abstract: Background: In the current study, as a first step to develop a monitoring method of cerebellar functions, we tried to record evoked potentials on the cerebellar cortex by electrical stimulation of the rat SCT, which is located in the Inf-CPed. Methods: The experimental study was performed on rats. Unilateral muscular contractions of quadriceps femoris muscle were elicited by electrical stimulation. The evoked potentials were recorded from the surface of the ipsilateral cerebellum and the contralateral primary sensory cortex. Results: The highly reproducible potentials obtained from the ipsilateral cerebellar hemisphere were named SCEP. The SCEP exhibited one negative peak with a latency of 11.7 ± 0.3 milliseconds (N11). Short-latency somatosensory evoked potential was recorded from the contralateral primary sensory cortex with a latency of 19.1 ± 0.6 milliseconds. Coagulation of the ipsilateral Inf-CPed caused disappearance or marked reduction of the SCEP N11, but it did not change the SSEP. On the other hand, sectioning of the ipsilateral dorsal column resulted in the disappearance of the SSEP, but it did not affect the SCEP N11. Conclusions: Reproducible SCEP was recorded from the rat cerebellar hemisphere by electrical stimulation of the quadriceps femoris muscle. We posit that the SCEP differs from the SSEP, which ascends via the dorsal column, and that it is conducted by the dorsal SCT located in the Inf-CPed. Our results suggest that it may be possible to detect the dysfunction of the Inf-CPed electrophysiologically by using SCEP. [Copyright &y& Elsevier]

Abstract: The paths of embryonic chick spinal commissural neurons originating from the lumbosacral (LS) 2 spinal segment and born around Hamburger-Hamilton stage (HH) 18 were observed by labeling the axons with an in ovo electroporation method designed to limit the electroporated area to ~one somite length. After crossing the floor plate, these axons followed two major paths, one ventral and one dorsal, and a minor path running between the major ones. These axons reached the brachial region by HH28, passed through the cervical region at HH29, and entered the medullary area by HH30. The dorsal axons entered the developing cerebellum by HH33, crossed the midline again, and spread into the rostral–ipsilateral area of the developing cerebellum so that most of them were confined to lobules II–III by HH39. A small population of ventrally running axons turned to enter the cerebellum, and the rest entered the superior medullary velum between the cerebellum and the midbrain. The LS2-originating axons that ascended ipsilaterally into the cerebellum followed a single path, and their extension was delayed compared with that of the commissural axons. Some of the ipsilateral axons innervated the cerebellum; the rest entered the superior medullary velum. These direct observations of the formation of part of the spinocerebellar projections in chick will be a useful reference for future analyses of the underlying mechanisms. [Copyright &y& Elsevier]

Abstract: We describe a 39-year-old Japanese woman with familial amyotrophic lateral sclerosis (FALS) in whom we identified a missense mutation (Gly93→Ser) in exon 4 of the Cu/Zn superoxidase dismutase-1 (SOD1) gene in which no pathological data have been available. The disease duration was 16 years, and she died of respiratory failure. The initial sign was weakness of the lower limbs. She had no clear upper motor neuron involvement. Respiratory muscle weakness had developed 1 year before her death. Neuropathological examinations showed simultaneous involvement of the pyramidal tract and lower motor neurons as well as degeneration in the Clarke''s nucleus, the spinocerebellar tract, the posterior column, the dentatorubral system, and anterolateral columns of the spinal cord. However, the patient has no Lewy body-like hyaline inclusions (LBHIs), which are characteristic features of mutant SOD1-related FALS with posterior column involvement. Based on clinical, genetic and pathological findings with a review of the literature, we suggest that degeneration of the dentatorubral system and the absence of LBHIs in our case are pathological features in FALS with the Gly93Ser mutation. [Copyright &y& Elsevier]

The dorsal spinocerebellar tract (DSCT) provides a major mossy fiber input to the spinocerebellum, which plays a significant role in the control of posture and locomotion. Recent work from our laboratory has provided evidence that DSCT neurons encode a global representation of hindlimb mechanics during passive limb movements. The framework that most successfully accounts for passive DSCT behavior is kinematics-based having the coordinates of the limb axis, limb-axis length and orientation. Here we examined the responses of DSCT neurons in decerebrate cats as they walked on a moving treadmill and compared them with the responses passive step-like movements of the hindlimb produced manually. We found that DSCT responses to active locomotion were quantitatively different from the responses to kinematically similar passive limb movements on the treadmill. The differences could not be simply accounted for by the difference in limb-axis kinematics in the two conditions, nor could they be accounted for by new or different response components. Instead, differences could be attributed to an increased relative prominence of specific response components occurring during the stance phase of active stepping, which may reflect a difference in the behavior of the sensory receptors and/or of the DSCT circuitry during active stepping. We propose from these results that DSCT neurons encode two global aspects of limb mechanics that are also important in controlling locomotion at the spinal level, namely the orientation angle of the limb axis and limb loading. Although limb-axis length seemed to be an independent predictor of DSCT activity during passive limb movements, we argue that it is not independent of limb loading, which is likely to be proportional to limb length under passive conditions. [ABSTRACT FROM AUTHOR]

We examined the characteristic clinical features of one family of familial amyotrophic lateral sclerosis (FALS) with a His46Arg mutation in the enzyme Cu/Zn superoxide dismutase-1 (SOD1). The disease duration for this family was 18.1±13.2 (mean±S.D.) years, with the age at onset being 39.7±10.5 years old (mean±S.D.). The initial sign was distal weakness of the unilateral lower limb, extending to the lower limb of the other side. A wheel chair became necessary at 9.8±3.2 years after the onset. Upper limb weakness started at 15.5±8.9 years following from the onset. An autopsy was performed on a 71-year-old woman of the family with the mutation. Her disease duration was 47 years, and she died of pneumonia. She had no clear upper motor neuron involvement. Bulbar sign and respiratory muscle weakness had developed 2 years before her death. Neuropathological findings showed degeneration of corticospinal tracts, anterior/posterior spinocerebellar tracts, posterior columns, and Clarke''s columns. There were few anterior horn cells in the lumbar spinal cord and no Lewy body-like hyaline inclusion bodies in these remaining anterior horn neurons. This is the first autopsy report of FALS with a His46Arg mutation in the SOD1 enzyme. [Copyright &y& Elsevier]

• Cervical, brachial, thoracic, and lumbar ascending tract formation are visualized. • The ascending tracts originating in different spinal segments develop similar paths. • However, their elongation and cerebellar projection profiles are different. The present study aimed to assess spinal tract formation in neurons originating from cervical (C7), brachial (C14), and thoracic (T4) regions, with the lumbar (LS2) region as a reference, in a chick embryo. For the assessment of the spinal tracts, we introduced a vector expressing human placental alkaline phosphatase into progenitor cells generated after neural tube closure and belonging to the above segments, using in ovo electroporation. The ascending axons took primarily similar paths: dorsal commissural, ventral commissural, and dorsal non-commissural paths, with some variance depending on their originating segments. Some populations of non-commissural neurons later extended their axons following a ventral path. The elongation rates of these axons are primarily constant and tended to increase over time; however, some variations depending on the originating segments were also observed. Some of the dorsally ascending axons entered into the developing cerebellum, and spinocerebellar neurons originating from T4 projected their axons into the cortex of the cerebellum differently from those from LS2. These results unveil an overall picture of early ascending spinal tract formation. [ABSTRACT FROM AUTHOR]

Extracellular and intracellular recordings were made from spinocerebellar tract neurones of the central cervical nucleus (CCN) in C1-C3 segments of the anaesthetized cat. These neurones were identified by antidromic activation from the cerebellar peduncle. Stimulation of the ipsilateral dorsal root elicited extracellular spikes or EPSPs with a monosynaptic latency in almost all CCN neurones in the same segment (segmental input). Late excitatory effects were also observed in about one third of CCN neurones. The monosynaptic EPSP was occasionally followed by an IPSP. The excitatory input from the dorsal root to CCN neurones was extended over several segments for some CCN neurons (extrasegmental input). Monosynaptic excitation was evoked in CCN neurones after stimulation of dorsal neck muscle nerves as well; i.e. splenius (SPL), biventer cervicis and complexus (BCC), rectus capitus dorsalis, and obliquus capitus caudalis. Thresholds for this excitation were near the threshold of the nerve, suggesting that it originated from group I fibres. The component of excitation added after strong stimulation of neck muscle nerves would be attributed to group II fibres. When a CCN neurone received excitatory input from the nerve of one muscle, it was generally not affected by stimulation of other nerves in the same segment. Such muscle specificity of segmental input was the principal pattern of connexion of neck muscle afferents with CCN neurones. In some cases, however, excitatory convergence from SPL and BCC nerves onto single CCN neurones or excitation from the SPL nerve and inhibition from the BCC nerve were also observed. Nearly half of the CCN neurones received input from one muscle nerve of the same segment and not from the afferent of the same muscle of different segments, indicating a segment specificity of input. In the remaining CCN neurones, weaker excitatory effects were induced from afferents of different segments as well. In such extrasegmental effects, inputs to CCN neurones from caudal segments predominated in frequency over those from rostral segments. The origin of extrasegmental input was generally confined to the same muscle. Low threshold muscle afferents from the SPL and BCC were intraaxonally stained with HRP. The collaterals of the stained fibre distributed branchlets and terminals to the CCN, laminae VII, VIII, and motor nuclei. Two fibres responding to local muscle prodding or stretch showed a similar morphology. The findings indicated that muscle spindle afferents from primary endings projected to the CCN. [ABSTRACT FROM AUTHOR]

Spinocerebellar tract (SCT) neurones in and around the central cervical nucleus (CCN) were physiologically identified by antidromic activation of these cells on stimulation of the cerebellum. Among the Spinocerebellar tract cells thus identified, those ascending the contralateral spinal funiculi were found in the CCN and ventralwards, whereas those ascending the ipsilateral funiculi existed mostly dorsal to the CCN partly overlapping with crossed cells in the nucleus. Mapping sites from which CCN cells were antidromically activated showed that axons of the CCN-SCT cross at the same segment, ascend the ventral funiculus initially, the lateral funiculus at rostral C and the lateral border of the medulla to reach the cerebellar peduncle, enter the cerebellum mainly via the restiform body but possibly also via the superior peduncle. Systematic mapping of stimulation within the cerebellum indicated that the CCNSCT projects to the medial part of the anterior lobe and the posterior lobe bilaterally. Projection to lobules I-II was found in almost all CCN-SCT cells examined. Three fourths of CCN-SCT cells projected to the posterior lobe, as revealed by less extensive mapping. Mapping of axonal regions of the same single CCN-SCT cells showed that they project multifocally in the cerebellum, where projection to lobules I-II was common and that to other areas varied with individual cells. Conduction velocites decreased within the cerebellum probably as the result of repeated branching. Mossy fibre responses evoked on stimulation of the C dorsal root in cats with the transected dorsal funiculi were shown to be mediated mostly via the CCN-SCT. Mapping the field potential showed that the response was by far the largest in lobules I-II. This suggested that the terminals provided by the CCN-SCT are the densest in these lobules. [ABSTRACT FROM AUTHOR]