Semaphorin 7A restricts serotonergic innervation and ensures recovery after spinal cord injury

Descending serotonergic (5-HT) projections originating from the raphe nuclei form an important input to the spinal cord that control basic locomotion. The molecular signals that control this projection pattern are currently unknown. Here, we identify Semaphorin7A (Sema7A) as a critical cue that restricts serotonergic innervation in the spinal cord. Sema7A deficient mice show a marked increase in serotonergic fiber density in all layers of the spinal cord while the density of neurons expressing the corresponding 5-HTR2α receptor remains unchanged. These alterations appear to be successfully compensated as no obvious changes in rhythmic locomotion and skilled stepping are observed in adult mice. When the system is challenged with a spinal lesion, serotonergic innervation patterns in both Sema7A-deficient and -competent mice evolve over time with excessive innervation becoming most pronounced in the dorsal horn of Sema7A-deficient mice. These altered serotonergic innervation patterns correlate with diminished functional recovery that predominantly affects rhythmic locomotion. Our findings identify Sema7A as a critical regulator of serotonergic circuit formation in the injured spinal cord

Imaging corticospinal tract connectivity in injured rat spinal cord using manganese-enhanced MRI

BACKGROUND: Manganese-enhanced MRI (MEI) offers a novel neuroimaging modality to trace corticospinal tract (CST) in live animals. This paper expands this capability further and tests the utility of MEI to image axonal fiber connectivity in CST of injured spinal cord (SC). METHODS: A rat was injured at the thoracic T4 level of the SC. The CST was labeled with manganese (Mn) injected intracortically at two weeks post injury. Next day, the injured SC was imaged using MEI and diffusion tensor imaging (DTI) modalities. RESULTS: In vivo MEI data obtained from cervical SC confirmed that CST was successfully labeled with Mn. Ex vivo MEI data obtained from excised SC depicted Mn labeling of the CST in SC sections caudal to the lesion, which meant that Mn was transported through the injury, possibly mediated by viable CST fibers present at the injury site. Examining the ex vivo data from the injury epicenter closely revealed a thin strip of signal enhancement located ventrally between the dorsal horns. This enhancement was presumably associated with the Mn accumulation in these intact fibers projecting caudally as part of the CST. Additional measurements with DTI supported this view. CONCLUSION: Combining these preliminary results collectively demonstrated the feasibility of imaging fiber connectivity in experimentally injured SC using MEI. This approach may play important role in future investigations aimed at understanding the neuroplasticity in experimental SCI research

FGF22 signaling regulates synapse formation during post‐injury remodeling of the spinal cord

The remodeling of axonal circuits after injury requires the formation of new synaptic contacts to enable functional recovery. Which molecular signals initiate such axonal and synaptic reorganisation in the adult central nervous system is currently unknown. Here, we identify FGF22 as a key regulator of circuit remodeling in the injured spinal cord. We show that FGF22 is produced by spinal relay neurons, while its main receptors FGFR1 and FGFR2 are expressed by cortical projection neurons. FGF22 deficiency or the targeted deletion of FGFR1 and FGFR2 in the hindlimb motor cortex limits the formation of new synapses between corticospinal collaterals and relay neurons, delays their molecular maturation, and impedes functional recovery in a mouse model of spinal cord injury. These results establish FGF22 as a synaptogenic mediator in the adult nervous system and a crucial regulator of synapse formation and maturation during post‐injury remodeling in the spinal cord.SynopsisFollowing spinal cord injury, transected projections form detour circuits that circumvent the lesion and contribute to functional recovery. The formation of new synaptic contacts is a crucial step of the process, but its molecular regulation is currently not understood. Members of the FGF family can promote synapse formation during nervous system development, suggesting that they might have a similar function in the injured adult CNS. Here, we show that:FGF22 and FGF22 receptors are expressed in the adult nervous system.FGF22 deficiency or deletion of FGF22 receptors restricts the formation and maturation of new synapses in the injured spinal cord.Genetic disruption of FGF22 signaling impedes spontaneous functional recovery following spinal cord injury.FGF22 is a synaptogenic mediator in the adult nervous system and promotes synaptic plasticity and circuit remodeling in a mouse model of spinal cord injury.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111756/1/embj201490578-sup-0001-Suppl_Info.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/111756/2/embj201490578.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/111756/3/embj201490578.reviewer_comments.pd

Remodeling of Axonal Connections Contributes to Recovery in an Animal Model of Multiple Sclerosis

In multiple sclerosis (MS), inflammation in the central nervous system (CNS) leads to damage of axons and myelin. Early during the clinical course, patients can compensate this damage, but little is known about the changes that underlie this improvement of neurological function. To study axonal changes that may contribute to recovery, we made use of an animal model of MS, which allows us to target inflammatory lesions to the corticospinal tract (CST), a major descending motor pathway. We demonstrate that axons remodel at multiple levels in response to a single neuroinflammatory lesion as follows: (a) surrounding the lesion, local interneurons show regenerative sprouting; (b) above the lesion, descending CST axons extend new collaterals that establish a “detour” circuit to the lumbar target area, whereas below the lesion, spared CST axons increase their terminal branching; and (c) in the motor cortex, the distribution of projection neurons is remodeled, and new neurons are recruited to the cortical motor pool. Behavioral tests directly show the importance of these changes for recovery. This paper provides evidence for a highly plastic response of the motor system to a single neuroinflammatory lesion. This framework will help to understand the endogenous repair capacity of the CNS and to develop therapeutic strategies to support it

Heterotopic Transcallosal Projections Are Present throughout the Mouse Cortex

Transcallosal projection neurons are a population of pyramidal excitatory neurons located in layers II/III and to a lesser extent layer V of the cortex. Their axons form the corpus callosum thereby providing an inter-hemispheric connection in the brain. While transcallosal projection neurons have been described in some detail before, it is so far unclear whether they are uniformly organized throughout the cortex or whether different functional regions of the cortex contain distinct adaptations of their transcallosal connectivity. To address this question, we have therefore conducted a systematic analysis of transcallosal projection neurons and their axons across six distinct stereotactic coordinates in the mouse cortex that cover different areas of the motor and somatosensory cortices. Using anterograde and retrograde tracing techniques, we found that in agreement with previous studies, most of the transcallosal projections show a precise homotopic organization. The somata of these neurons are predominantly located in layer II/III and layer V but notably smaller numbers of these cells are also found in layer IV and layer VI. In addition, regional differences in the distribution of their somata and the precision of their projections exist indicating that while transcallosal neurons show a uniform organization throughout the mouse cortex, there is a sizeable fraction of these connections that are heterotopic. Our study thus provides a comprehensive characterization of transcallosal connectivity in different cortical areas that can serve as the basis for further investigations of the establishment of inter-hemispheric projections in development and their alterations in disease

Formation of somatosensory detour circuits mediates functional recovery following dorsal column injury

Anatomically incomplete spinal cord injuries can be followed by functional recovery mediated, in part, by the formation of intraspinal detour circuits. Here, we show that adult mice recover tactile and proprioceptive function following a unilateral dorsal column lesion. We therefore investigated the basis of this recovery and focused on the plasticity of the dorsal column-medial lemniscus pathway. We show that ascending dorsal root ganglion (DRG) axons branch in the spinal grey matter and substantially increase the number of these collaterals following injury. These sensory fibers exhibit synapsin-positive varicosities, indicating their integration into spinal networks. Using a monosynaptic circuit tracing with rabies viruses injected into the cuneate nucleus, we show the presence of spinal cord neurons that provide a detour pathway to the original target area of DRG axons. Notably the number of contacts between DRG collaterals and those spinal neurons increases by more than 300% after injury. We then characterized these interneurons and showed that the lesion triggers a remodeling of the connectivity pattern. Finally, using re-lesion experiments after initial remodeling of connections, we show that these detour circuits are responsible for the recovery of tactile and proprioceptive function. Taken together our study reveals that detour circuits represent a common blueprint for axonal rewiring after injury

EROS Variable Stars : Discovery of Beat Cepheids in the Small Magellanic Cloud and the effect of metallicity on pulsation

We report the discovery of eleven beat Cepheids in the Small Magellanic Cloud, using data obtained by the EROS microlensing survey. Four stars are beating in the fundamental and first overtone mode (F/1OT), seven are beating in the first and second overtone (1OT/2OT). The SMC F/1OT ratio is systematically higher than the LMC F/1OT, while the 1OT/2OT period ratio in the SMC Cepheids is the same as the LMC one.Comment: 4 pages, Latex file with 4 .ps figures. accepted for publication in A A Letter

The effect of metallicity on the Cepheid distance scale and its implications for the Hubble constant (H0H_0) determination

Recent HST determinations of the expansion's rate of the Universe (the Hubble constant, H_0) assumed that the Cepheid Period-Luminosity relation at V and I are independent of metallicity (Freedman, et al., 1996, Saha et al., 1996, Tanvir et al., 1995). The three groups obtain different vales for H_0. We note that most of this discrepancy stems from the asumption (by both groups) that the Period-Luminosity relation is independent of metallicity. We come to this conclusion as a result of our study of the Period-Luminosity relation of 481 Cepheids with 3 millions two colour measurements in the Large Magellanic Cloud and the Small Magellanic Cloud obtained as a by-product of the EROS microlensing survey. We find that the derived interstellar absorption corrections are particularly sensitive to the metallicity and when our result is applied to recent estimates based on HST Cepheids observations it makes the low-H_0 values higher and the high-H_0 value lower, bringing those discrepant estimates into agrement around $H_0 \approx 70 km/s Mpc^{-1}$.Comment: 4 pages, Latex, with 2 .ps accepted for publication astronomy and astrophysics Letter

Search for a periodic signal from Cygnus X-3 usingmuons observed underground in the Frejus detector (4800 mwe)

Periodic signals from Cygnus X-3 in the ultra high energy range were recently reported by air shower arrays and attributed to gamma rays. Although gamma rays are expected to produce muon-poor showers, the preceding observations have stimulated similar studies based on underground muons. Two groups have claimed a significant underground signal coming from Cygnus X-3. The results are, however, extremely difficult to explain in the present framework of particle physics, and clearly need confirmation. The preliminary results obtained from the Frejus underground detector during its first 16 months of operation (March 1984 to June 1985) are presented