Extensive regeneration of sensory axons into the spinal cord can be achieved experimentally after dorsal root injury, but no effort has been made to target regenerating axons and restore a normal lamina-specific projection pattern. Ectopic axon growth is potentially associated with functional disorders such as chronic pain and autonomic dysreflexia. This study was designed to target regenerating axons to normal synaptic locations in the spinal cord by combining positive and negative guidance molecules. Previously, we observed that, after dorsal rhizotomy, overexpression of NGF leads to robust regeneration and sprouting of calcitonin gene-related peptide (CGRP)-positive nociceptive axons throughout dorsal horn and ventral horns. To restrict these axons within superficial laminas, adenovirus expressing semaphorin 3A was injected into the ventral spinal cord 3 d after NGF virus injection. Semaphorin 3A expression was observed in deep dorsal and ventral cord regions and limited axon growth to laminas I and II, shaping axonal regeneration toward the normal distribution pattern. NGF and semaphorin 3A treatment also targeted the regeneration of substance P-positive nociceptive axons but had no effect on injured isolectin B4-binding nociceptive axons. Axon regeneration led to functional restoration of nociception in both NGF-and NGF/semaphorin 3A-treated rats. Although no significant difference in behavior was found between these two groups, confocal microscopy illustrated ectopic synaptic formations in deeper laminas in NGF/green fluorescent protein-treated rats. The results suggested that antagonistic guidance cues can be used to induce and refine regeneration within the CNS, which is important for longterm, optimal functional recovery.

Activity-dependent survival of olfactory sensory neurons (OSNs) may allow animals to tune their olfactory systems to match their odor environment. Activity-dependent genes should play important roles in this process, motivating experiments to identify them. Both unilateral naris occlusion of mice for 6 days and genetic silencing of OSNs decreased S100A5, Lrrc3b, Kirrel2, Slc17a6, Rasgrp4, Pcp4l1, Plcxd3, and Kcnn2 while increasing Kirrel3. Naris occlusion also decreased Eml5, Ptprn, and Nphs1. OSN number was unchanged and stress-response mRNAs were unaffected after 6 days of naris occlusion. This leaves odor stimulation as the most likely cause of differential abundance of these mRNAs, but through a mechanism that is slow or indirect for most because 30-40 min of odor stimulation increased only 3 of 11 mRNAs decreased by naris occlusion: S100A5, Lrrc3b, and Kirrel2. Odorant receptor (OR) mRNAs were significantly more variable than the average mRNA, consistent with difficulty in reliably detecting changes in these mRNAs after 6 days of naris occlusion. One OR mRNA, Olfr855, was consistently decreased, however. These results suggest that the latency from the cessation of odor stimulation to effects on activity-dependent OSN survival must be a week or more in juvenile mice.

Purpose of review The bioactive lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1 phosphate (S1P) have potent effects on blood and vascular cells. This review focuses their potential contributions to the development of atherosclerosis, acute complications, such as acute myocardial infarction, and chronic ischemic cardiac damage. Recent findings Exciting recent developments have provided insight into the molecular underpinnings of LPA and S1P receptor signaling. New lines of evidence suggest roles for these pathways in the development of atherosclerosis. In experimental animal models, the production, signaling and metabolism of LPA may be influenced by environmental factors in the diet that synergize to promote the progression of atherosclerotic vascular disease. This is supported by observations of human polymorphisms in the lysophospholipid metabolizing enzyme, PPAP2B, that are associated with risk of coronary artery disease and myocardial infarction. S1P signaling protects from myocardial damage that follows acute and chronic ischemia both by direct effects on cardiomyocytes and through stem cell recruitment to ischemic tissue. Summary This review will suggest novel strategies to prevent the complications of coronary artery disease by targeting LPA production and signaling. Additionally, ways in which S1P signaling pathways may be harnessed to attenuate ischemia-induced cardiac dysfunction will be explored.

Successful regeneration after injury requires either the direct reformation of the circuit or the formation of a bridge circuit to provide partial functional return through a more indirect route. Presently, little is known about the specificity of how regenerating axons reconnect or reconstruct functional circuits. We have established an in vivo dorsal root entry zone model, which in the presence of NGF, shows very robust regeneration of peptidergic nociceptive axons, but not other sensory axons. Expression of NGF in normal, non-injured animals leads to robust sprouting of only the peptidergic nociceptive axons. Interestingly, NGF-induced sprouting of these axons leads to severe chronic pain, whereas, regeneration leads to protective like pain without chronic pain. Using this model we set out to compare differences in behavioral outcomes and circuit features between these two groups. In this study, we examined pre-synaptic and post-synaptic markers to evaluate the relationship between synaptic connections and behavioral responses. NGF-induced sprouting of CGRP axons resulted in a significant redistribution of synapses and cFos expression into the deeper dorsal horn. Regeneration of only the CGRP axons showed a general reduction in synapses and cFos expression within laminae I and II; however, inflammation of the hindpaw induced peripheral sensitization. This data shows that although NGF-induced sprouting of peptidergic axons induces robust chronic pain and cFos expression throughout the entire dorsal horn, regeneration of the same axons resulted in normal protective pain with a synaptic and cFos distribution similar, albeit significantly less than that shown by the sprouting of CGRP axons.

BackgroundAdult neurogenesis, fundamental for cellular homeostasis in the mammalian olfactory epithelium, requires major shifts in gene expression to produce mature olfactory sensory neurons (OSNs) from multipotent progenitor cells. To understand these dynamic events requires identifying not only the genes involved but also the cell types that express each gene. Only then can the interrelationships of the encoded proteins reveal the sequences of molecular events that control the plasticity of the adult olfactory epithelium.ResultsOf 4,057 differentially abundant mRNAs at 5 days after lesion-induced OSN replacement in adult mice, 2,334 were decreased mRNAs expressed by mature OSNs. Of the 1,723 increased mRNAs, many were expressed by cell types other than OSNs and encoded proteins involved in cell proliferation and transcriptional regulation, consistent with increased basal cell proliferation. Others encoded fatty acid metabolism and lysosomal proteins expressed by infiltrating macrophages that help scavenge debris from the apoptosis of mature OSNs. The mRNAs of immature OSNs behaved dichotomously, increasing if they supported early events in OSN differentiation (axon initiation, vesicular trafficking, cytoskeletal organization and focal adhesions) but decreasing if they supported homeostatic processes that carry over into mature OSNs (energy production, axon maintenance and protein catabolism). The complexity of shifts in gene expression responsible for converting basal cells into neurons was evident in the increased abundance of 203 transcriptional regulators expressed by basal cells and immature OSNs.ConclusionsMany of the molecular changes evoked during adult neurogenesis can now be ascribed to specific cellular events in the OSN cell lineage, thereby defining new stages in the development of these neurons. Most notably, the patterns of gene expression in immature OSNs changed in a characteristic fashion as these neurons differentiated. Initial patterns were consistent with the transition into a neuronal morphology (neuritogenesis) and later patterns with neuronal homeostasis. Overall, gene expression patterns during adult olfactory neurogenesis showed substantial similarity to those of embryonic brain.

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