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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]

The oxygen-sensing prolyl hydroxylase domain proteins (PHDs) regulate cellular metabolism, but their role in neuronal metabolism during stroke is unknown. Here we report that PHD1 deficiency provides neuroprotection in a murine model of permanent brain ischemia. This was not due to an increased collateral vessel network. Instead, PHD1(-/-) neurons were protected against oxygen-nutrient deprivation by reprogramming glucose metabolism. Indeed, PHD1(-/-) neurons enhanced glucose flux through the oxidative pentose phosphate pathway by diverting glucose away from glycolysis. As a result, PHD1(-/-) neurons increased their redox buffering capacity to scavenge oxygen radicals in ischemia. Intracerebroventricular injection of PHD1-antisense oligonucleotides reduced the cerebral infarct size and neurological deficits following stroke. These data identify PHD1 as a regulator of neuronal metabolism and a potential therapeutic target in ischemic stroke.

One avenue of research for partial restoration of function following spinal cord injury is the use of neural prostheses, an example of which is functional electrical stimulation (FES) devices for motor functions. Neural prostheses may also be useful for the extraction of sensory information directly from the nervous system. We suggest the spinal cord as a possible site for the detection of peripheral sensory information from neural activity alone. Acute multichannel extracellular recordings were used to extract neural spike activity elicited from peripheral sensations from the spinal cords of rats. To test the recording method and classification potential, eight classes of sensory events were recorded consisting of electricai stimulation of seven locations on rat forepaws, and another class of data during which no stimulus was present. A dual-stage classification scheme using principal component analysis and k-Means clustering was devised to classify the sensory events during single trials. The eight tasks were correctly identified at a mean accuracy of 96%. Thus, we have shown the methodology to detect and classify peripheral sensory information from multichannel recordings of the spinal cord. These methods may be useful, for example, in a closed-loop FES for restoration of hand grasp. Index Terms--Brain interface, functional electrical stimulation, neural prosthesis, spinal cord injury.

Author(s): Matt S. Ramer (corresponding author) [1]; John V. Priestley [2]; Stephen B. McMahon [1] The arrest of dorsal root axonal regeneration at the transitional zone between the peripheral and [...]

Abstract In this review, we first provide a brief historical perspective, discussing how peripheral nerve injury (PNI) may have caused World War I. We then consider the initiation, progression, and resolution of the cellular inflammatory response after PNI, before comparing the PNI inflammatory response with that induced by spinal cord injury (SCI). In contrast with central nervous system (CNS) axons, those in the periphery have the remarkable ability to regenerate after injury. Nevertheless, peripheral nervous system (PNS) axon regrowth is hampered by nerve gaps created by injury. In addition, the growth-supportive milieu of PNS axons is not sustained over time, precluding long-distance regeneration. Therefore, studying PNI could be instructive for both improving PNS regeneration and recovery after CNS injury. In addition to requiring a robust regenerative response from the injured neuron itself, successful axon regeneration is dependent on the coordinated efforts of non-neuronal cells which release extracellular matrix molecules, cytokines, and growth factors that support axon regrowth. The inflammatory response is initiated by axonal disintegration in the distal nerve stump: this causes blood-nerve barrier permeabilization and activates nearby Schwann cells and resident macrophages via receptors sensitive to tissue damage. Denervated Schwann cells respond to injury by shedding myelin, proliferating, phagocytosing debris, and releasing cytokines that recruit blood-borne monocytes/macrophages. Macrophages take over the bulk of phagocytosis within days of PNI, before exiting the nerve by the circulation once remyelination has occurred. The efficacy of the PNS inflammatory response (although transient) stands in stark contrast with that of the CNS, where the response of nearby cells is associated with inhibitory scar formation, quiescence, and degeneration/apoptosis. Rather than efficiently removing debris before resolving the inflammatory response as in other tissues, macrophages infiltrating the CNS exacerbate cell death and damage by releasing toxic pro-inflammatory mediators over an extended period of time. Future research will help determine how to manipulate PNS and CNS inflammatory responses in order to improve tissue repair and functional recovery.

Adult neurones fail to regenerate when injured in the CNS, which leads to severe and irreversible functional deficits. Several important advances in understanding the reasons for this failure have been gained from the use of primary sensory neurones as a model system. The peripherally and centrally projecting branches of sensory neurones are differentially capable of regeneration, which is why these cells are ideally situated to elucidate the mechanisms that underlie regeneration failure. Such mechanisms include both a hostile environment within the spinal cord and a poor growth response following injury. For successful functional regeneration to occur, it is likely that both of these barriers will have to be surmounted, along with the challenge of guiding regrowing axons to appropriate postsynaptic targets. The contribution that the study of primary sensory neurones has made to the attainment of this goal will be reviewed.