Early regeneration of axons following peripheral nerve injury is enhanced if p75NTR is eliminated from the surrounding pathway.

The common neurotrophin receptor, p75NTR , has been proposed to be an inhibitor of axon regeneration after peripheral nerve injury, but whether this effect is on the regenerating axons, immune cells migrating into the injury site, or cells in the pathway surrounding the axons is not clear. Cut nerves in mice expressing fluorescent proteins in axons were repaired with grafts from non-fluorescent hosts to study axon elongation when p75NTR was eliminated separately from axons and immune cells in the proximal stump of cut nerves, from cells in the regeneration pathway, or both. Two weeks later, axons from wild type mice regenerating into grafts devoid of p75NTR had elongated more than twice as far as axons in grafts from wild type mice. No enhancement of regeneration of axons in p75NTR knockout mice was observed, whether nerves were repaired with grafts from wild type mice or from p75NTR knockout mice. To evaluate whether inhibition of p75NTR could be used to improve regeneration, nerves in wild type mice repaired without grafts were exposed to a specific inhibitor of the p75NTR receptor, LM11A-31, at the time of nerve repair. This local blockade of p75NTR resulted in successful regeneration of axons of nearly three times as many motoneurons and reinnervation of twice as many muscle fibers by regenerating motor axons as untreated controls. Expression of p75NTR surrounding regenerating axons contributes to poor regeneration during the first 2 weeks after peripheral nerve injury. Inhibition of p75NTR might be a therapeutic target for treatments of peripheral nerve injuries.

Pathways Mediating Activity-Induced Enhancement of Recovery From Peripheral Nerve Injury.

This article outlines the novel hypothesis that exercise promotes axon regeneration after peripheral nerve injury through neuronal brain-derived neurotrophic factor (BDNF), and there are three required means of promoting BDNF expression: 1) increased signaling through androgen receptors, 2) increased cAMP-responsive element-binding protein expression, and 3) increased expression of the transcription factor SRY-box containing gene 11.

Chondroitinase ABC reduces time to muscle reinnervation and improves functional recovery after sciatic nerve transection in rats.

Application of chondroitinase ABC (ChABC) to injured peripheral nerves improves axon regeneration, but it is not known whether functional recovery is also improved. Recordings of EMG activity [soleus (Sol) M response and H reflexes] evoked by nerve stimulation and of Sol and tibialis anterior (TA) EMG activity and hindlimb and foot kinematics during slope walking were made to determine whether ChABC treatment of the sciatic nerve at the time of transection improves functional recovery. Recovery of evoked EMG responses began as multiple small responses with a wide range of latencies that eventually coalesced into one or two more distinctive and consistent responses (the putative M response and the putative H reflex) in both groups. Both the initial evoked responses and the time course of their maturation returned sooner in the ChABC group than in the untreated (UT) group. The reinnervated Sol and TA were coactivated during treadmill locomotion during downslope, level, and upslope walking throughout the study period in both UT and ChABC-treated rats. By 10 wk after nerve transection and repair, locomotor activity in Sol, but not TA, had returned to its pretransection pattern. There was an increased reliance on central control of Sol activation across slopes for both groups as interpreted from elevated prestance Sol EMG activity that was no longer modulated with slope. Limb length and orientation during locomotion were similar to those observed prior to nerve injury during upslope walking only in the ChABC-treated rats. Thus treatment of cut nerves with ChABC leads to improvements in functional recovery.

Neurotrophin-4/5 is implicated in the enhancement of axon regeneration produced by treadmill training following peripheral nerve injury.

The role of neurotrophin-4/5 (NT-4/5) in the enhancement of axon regeneration in peripheral nerves produced by treadmill training was studied in mice. Common fibular nerves of animals of the H strain of thy-1-YFP mice, in which a subset of axons in peripheral nerves is marked by the presence of yellow fluorescent protein, were cut and surgically repaired using nerve grafts from non-fluorescent mice. Lengths of profiles of fluorescent regenerating axons were measured using optical sections made through whole mounts of harvested nerves. Measurements from mice that had undergone 1 h of daily treadmill training at modest speed (10 m/min) were compared with those of untrained (control) mice. Modest treadmill training resulted in fluorescent axon profiles that were nearly twice as long as controls at 1, 2 and 4 week survival times. Similar enhanced regeneration was found when cut nerves of wild type mice were repaired with grafts from NT-4/5 knockout mice or grafts made acellular by repeated freezing/thawing. No enhancement was produced by treadmill training in NT-4/5 knockout mice, irrespective of the nature of the graft used to repair the cut nerve. Much as had been observed previously for the effects of brief electrical stimulation, the effects of treadmill training on axon regeneration in cut peripheral nerves are independent of changes produced in the distal segment of the cut nerve and depend on the promotion of axon regeneration by changes in NT-4/5 expression by cells in the proximal nerve segment.

Effect of axon misdirection on recovery of electromyographic activity and kinematics after peripheral nerve injury.

In this study, patterns of activity in the soleus (Sol) and tibialis anterior (TA) muscles and hindlimb kinematics were evaluated during slope walking in rats after transection and surgical repair either of the entire sciatic nerve (Sci group) or of its two branches separately, the tibial and common fibular nerves (T/CF group). With the latter method, axons from the tibial and common fibular nerves could not reinnervate targets of the other nerve branch after injury, reducing the opportunity for misdirection. Activity in the TA shifted from the swing phase in intact rats to nearly the entire step cycle in both injured groups. Since these changes occur without misdirection of regenerating axons, they are interpreted as centrally generated. Sol activity was changed from reciprocal to that of TA in intact rats to coactivate with TA, but only in the Sci group rats. In the T/CF group rats, Sol activity was not altered from that observed in intact rats. Despite effects of injury that limited foot movements, hindlimb kinematics were conserved during downslope walking in both injury groups and during level walking in the T/CF group. During level walking in the Sci group and during upslope walking in both groups of injured rats, the ability to compensate for the effects of the nerve injury was less effective and resulted in longer limb lengths held at more acute angles throughout the step cycle. Changes in limb movements occur irrespective of axon misdirection and reflect compensatory changes in the outputs of the neural circuits that drive locomotion.

Effect of slope and sciatic nerve injury on ankle muscle recruitment and hindlimb kinematics during walking in the rat.

Slope-related differences in hindlimb movements and activation of the soleus and tibialis anterior muscles were studied during treadmill locomotion in intact rats and in rats 4 and 10 weeks following transection and surgical repair of the sciatic nerve. In intact rats, the tibialis anterior and soleus muscles were activated reciprocally at all slopes, and the overall intensity of activity in tibialis anterior and the mid-step activity in soleus increased with increasing slope. Based on the results of principal components analysis, the pattern of activation of soleus, but not of tibialis anterior, changed significantly with slope. Slope-related differences in hindlimb kinematics were found in intact rats, and these correlated well with the demands of walking up or down slopes. Following recovery from sciatic nerve injury, the soleus and tibialis anterior were co-activated throughout much of the step cycle and there was no difference in intensity or pattern of activation with slope for either muscle. Unlike intact rats, these animals walked with their feet flat on the treadmill belt through most of the stance phase. Even so, during downslope walking limb length and limb orientation throughout the step cycle were not significantly changed from values found in intact rats. This conservation of hindlimb kinematics was not observed during level or upslope walking. These findings are interpreted as evidence that the recovering animals adopt a novel locomotor strategy that involves stiffening of the ankle joint by antagonist co-activation and compensation at more proximal joints. Their movements are most suitable to the requirements of downslope walking but the recovering rats lack the ability to adapt to the demands of level or upslope walking.

Femoral artery diameter and arteriogenic cytokines in healthy women.

Animal studies have identified monocyte chemoattractive protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) as critical mediators of arterial diameter enlargement in response to chronic increases in blood flow (arteriogenesis). Furthermore, cellular studies have shown that the shear stresses resulting from increased blood flow stimulate synthesis of MCP-1, which in turn stimulates synthesis of VEGF. The purpose of this study was to determine if these mechanisms are evident in healthy women. Resting femoral artery diameter and blood flow, lean leg mass, MCP-1 and VEGF concentrations, and aerobic capacity were measured in 34 healthy women along with plasma concentrations of lipids associated with cardiovascular disease risk. Femoral artery diameter was independently related to metabolically active (lean) leg mass (b=0.41, P=0.008) and aerobic capacity (b=0.45, P=0.004). Plasma MCP-1 correlated negatively with the ratio of femoral artery diameter to lean leg mass (b=-0.42, P=0.009) and positively with serum triglycerides (b=0.46, P=0.005). Plasma VEGF exhibited similar correlations and strongly correlated with MCP-1 (R=0.92, P<0.0001). The results indicate that circulating MCP-1 and VEGF concentrations are associated with both arteriogenic and atherogenic stimuli in healthy women.

Effects of downslope walking on Soleus H-reflexes and walking function in individuals with multiple sclerosis: A preliminary study.

BACKGROUND: Downslope walking (DSW) is an eccentric-based exercise intervention that promotes neuroplasticity of spinal reflex circuitry by inducing depression of Soleus Hoffman (H)-reflexes in young, neurologically unimpaired adults. OBJECTIVE: The objective of the study was to evaluate the effects of DSW on spinal excitability (SE) and walking function (WF) in people with multiple sclerosis (PwMS). METHODS: Our study comprised two experiments on 12 PwMS (11 women; 45.3±11.8 years). Experiment 1 evaluated acute effects of a single 20-minute session of treadmill walking at three different walking grades on SE, 0% or level walking (LW), - 7.5% DSW, and - 15% DSW. Experiment 2 evaluated the effects of 6 sessions of DSW, at - 7.5% DSW (with second session being - 15% DSW) on SE and WF. RESULTS: Experiment 1 showed significantly greater acute % H-reflex depression following - 15% DSW compared to LW (p = 0.02) and - 7.5% DSW (p = 0.05). Experiment 2 demonstrated significant improvements in WF. PwMS who showed greater acute H-reflex depression during the - 15% DSW session also demonstrated greater physical activity, long-distance WF, and the ability to have greater H-reflex depression after DSW training. Significant changes were not observed in regards to SE. CONCLUSIONS: Though significant changes were not observed in SE after DSW training, we observed an improvement in WF which merits further investigation of DSW in PwMS.

Femoral artery remodeling after aerobic exercise training without weight loss in women.

BACKGROUND: It is currently unclear whether reductions in adiposity mediate the improvements in vascular health that occur with aerobic exercise. The purpose of this longitudinal study of 13 healthy women (33 +/- 4 years old) was to determine whether 14 weeks of aerobic exercise would alter functional measures of vascular health, namely resting aortic pulse wave velocity (aPWV, an index of arterial stiffness), femoral artery diameter (D(FA)), and femoral artery blood flow (BF(FA)) independent of changes in adiposity. METHODS: Aerobic fitness was assessed as VO2peak normalized to fat-free mass, and adiposity (percent body fat) was determined by dual energy x-ray absorptiometry. Serum concentrations of proteins associated with risk for cardiovascular disease, including C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), and leptin, were also measured. Subjects cycled for 50 minutes, 3 times per week. RESULTS: Aerobic fitness normalized to fat-free mass increased 6% (P = 0.03) whereas adiposity did not change. Resting D(FA) increased 12% (P < 0.001) and resting shear rate decreased 28% (P = 0.007). Aortic PWV, and serum sICAM-1, CRP and leptin did not change with training. CONCLUSION: Significant reductions in adiposity were not necessary for aerobic exercise training to bring about improvements in aerobic fitness and arterial remodeling. Peripheral arterial remodeling occurred without changes in central arterial stiffness or markers of inflammation.

The Short-Term Effect of Slope Walking on Soleus H-Reflexes in People with Multiple Sclerosis.

Downslope walking (DSW) causes H-reflex depression in healthy adults, and thus may hold promise for inducing spinal reflex plasticity in people with Multiple Sclerosis (PwMS). The study purpose was to test the hypothesis that DSW will cause acute depression of spinal excitability in PwMS. Soleus H-reflexes were measured in PwMS (n = 18) before and after 20 min of treadmill walking during three visits. Participants walked on a different slope each visit [level: 0% level walking (LW), upslope: +7.5% treadmill walking with an upslope (USW) or downslope: -7.5% (DSW)]. The soleus Hmax/Mmax ratio was used to measure spinal excitability. Heart rate and ratings of perceived exertion (RPE) were measured during walking. DSW induced the largest change in spinal excitability (a 26.7% reduction in soleus Hmax/Mmax (p = 0.001)), although LW also reduced Hmax/Mmax (-5.3%, p = 0.05). Heart rate (p < 0.001) was lowest for DSW, and RPE for DSW did not exceed "Fairly light". DSW evokes short-term spinal plasticity in PwMS, while requiring no greater effort than LW. Our results suggest that PwMS retain the capacity for DSW-induced short-term spinal reflex modulation previously found in healthy adults. These results may provide a foundation for further investigation of long-term effects of DSW on spinal reflex plasticity and functional ability in PwMS.

Longer Duration of Downslope Treadmill Walking Induces Depression of H-Reflexes Measured during Standing and Walking.

OBJECTIVES: The Hoffman-reflex (H-reflex) is an electrophysiological technique used to evaluate the excitability of the monosynaptic spinal reflex arc. In individuals with upper motor neuron lesions who show elevated spinal excitability, a depression of spinal excitability may indicate adaptive spinal plasticity. Downslope walking (DSW), an exercise intervention comprising repetitive eccentric muscle activity, has been shown to induce depression of soleus H-reflex amplitudes while seated, however, the dose-response time-course of H-reflex modulation during DSW has not been characterized. The objectives of this study were twofold: (1) to evaluate DSW-induced soleus H-reflex depression in the standing posture and during walking, and (2) to investigate the effect of walking duration (20 minutes and 40 minutes) of DSW (-15% decline) on soleus H-reflexes, (with level walking (LW) as a control intervention). METHODS: Soleus H-reflexes were collected Pre, Post-20 minutes, and Post-40 minutes of walking in the standing position; and H-reflexes were also measured at 4 different time points during the terminal stance phase of walking. RESULTS: Our results showed that soleus H-reflexes evaluated in standing showed a greater % depression after DSW compared to LW, with a statistical trend for greater depression with longer durations (40-minutes). H-reflexes measured during walking showed greater depression after 40 minutes of walking compared to 20- or 30-minutes for both DSW and LW. CONCLUSIONS: Longer duration treadmill walking (40-minutes) may induce a greater acute depressive effect on soleus H-reflex excitability compared to shorter durations (20-minutes) of treadmill walking. Future work will investigate the potential for DSW as a gait training intervention in people with upper motor neuron lesions such as multiple sclerosis and stroke.

Walking duration and slope steepness determine the effect of downslope walking on the soleus H-reflex pathway.

The purpose of this study was to determine if the effect of downslope walking (DSW) on spinal excitability depends on walking duration and slope steepness, and if findings from the soleus (Sol) generalize to the tibialis anterior (TA). Sol and TA Hmax and Mmax were measured before and after four DSW doses (time/slope, min/%) on separate days (10/-15, 20/-15, 10/-25, 20/-25, n=14), and one 20-min bout of level walking (LW, n=12), always at 2.5 mph. Heart rate (HR) and ratings of perceived exertion (RPE) were measured during walking. DSW for all doses except 10/-15 caused greater Sol Hmax/Mmax depression than LW (p≤0.02), and 20/-25 caused greater Hmax/Mmax depression than 10/-15 (p≤0.01). TA H-reflex curves were substantially smaller than Sol H-reflex curves, and this study was unable to detect an effect of LW or DSW on TA Hmax/Mmax. Although HR and RPE were significantly higher during DSW at -25% than at -15% slope, group HR and RPE nevertheless peaked at relatively low values of 101.4±14.2 bpm and 12.6±2.3, respectively. In conclusion, DSW duration and slope steepness interact to determine the magnitude of Sol H-reflex depression, but these effects do not generalize to the TA.

Upper vs lower extremity arterial function after spinal cord injury.

BACKGROUND/OBJECTIVE: The purpose of the study was to determine whether arterial diameter, flow-mediated dilatation (FMD), and arterial range are affected by spinal cord injury (SCI). We assessed arm (radial) and leg (posterior-tibial) arteries that are comparable in size and function to determine whether (a) arterial function is reduced in individuals with SCI vs nondisabled subjects and (b) decrements to SCI arterial function are greater in the legs vs arms. PARTICIPANTS: Eighteen men with chronic (9.8 +/- 6.3 years) SCI (T2 to T11; American Spinal Injury Association A) and 13 nondisabled subjects matched for age (33.1 +/- 4.8 vs 29.8 +/- 8.2 years old, respectively), height, and weight (BMI = 25.3 +/- 5.8 vs 26.6 +/- 5.5 kg/m2, respectively). METHODS: Radial and posterior tibial artery B-mode ultrasound images were continuously captured to measure resting diameter, occluded diameter, and postischemic diameters. Hierarchical linear modeling accounted for the nested experimental design. RESULTS: Individuals with SCI have lower systemic (arm + leg) FMD than nondisabled subjects (9.3% vs 12.3%, respectively; P= 0.035), primarily because of reduced leg FMD (11.5 +/- 3.1% vs 7.0 +/- 2.8% for SCI arms vs legs, respectively; P = 0.010). Persons with SCI also had lower arterial range than nondisabled subjects (0.79 vs 1.00 mm, respectively; P = 0.043), primarily because of the legs (0.81 +/- 0.09 vs 0.56 +/- 0.11 mm for SCI arms vs legs, respectively; P = 0.030). CONCLUSION: Leg arterial function seems to deteriorate at greater rates compared to the arms for individuals with SCI. Interventions to improve cardiovascular health should include measurements taken in the legs.

Slope walking causes short-term changes in soleus H-reflex excitability.

The purpose of this study was to test the hypothesis that downslope treadmill walking decreases spinal excitability. Soleus H-reflexes were measured in sixteen adults on 3 days. Measurements were taken before and twice after 20 min of treadmill walking at 2.5 mph (starting at 10 and 45 min post). Participants walked on a different slope each day [level (Lv), upslope (Us) or downslope (Ds)]. The tibial nerve was electrically stimulated with a range of intensities to construct the M-response and H-reflex curves. Maximum evoked responses (Hmax and Mmax) and slopes of the ascending limbs (Hslp and Mslp) of the curves were evaluated. Rate-dependent depression (RDD) was measured as the % depression of the H-reflex when measured at a rate of 1.0 Hz versus 0.1 Hz. Heart rate (HR), blood pressure (BP), and ratings of perceived exertion (RPE) were measured during walking. Ds and Lv walking reduced the Hmax/Mmax ratio (P = 0.001 & P = 0.02), although the reduction was larger for Ds walking (29.3 ± 6.2% vs. 6.8 ± 5.2%, P = 0.02). The reduction associated with Ds walking was correlated with physical activity level as measured via questionnaire (r = -0.52, P = 0.04). Us walking caused an increase in the Hslp/Mslp ratio (P = 0.03) and a decrease in RDD (P = 0.04). These changes recovered by 45 min. Exercise HR and BP were highest during Us walking. RPE was greater during Ds and Us walking compared to Lv walking, but did not exceed "Fairly light" for Ds walking. In conclusion, in healthy adults treadmill walking has a short-term effect on soleus H-reflex excitability that is determined by the slope of the treadmill surface.

Relationship between blood velocity and conduit artery diameter and the effects of smoking on vascular responsiveness.

Transient changes in arterial diameter in response to transient ischemia-induced changes in arterial blood velocity have been used as an index of vascular health. The purpose of this study was to determine the relationship between blood velocity and diameter in the brachial artery by different methods of increasing blood velocity. Acute cigarette smoking was used with otherwise healthy young occasional smokers to determine the influence of endothelial-nitric oxide pathways on the arterial diameter-blood velocity relationship. Nine nonsmokers and 12 occasional smokers (<1 pack/wk) were tested. Blood flow to the forearm was manipulated to indirectly investigate the relationship between blood velocity and diameter in the brachial artery. Blood flow to forearm was manipulated through the use of 1) 5-min ischemia; 2) handgrip exercise; 3) indirect local heating; and 4) 5-min ischemia plus indirect local heating. A strong relationship was observed between blood velocity and diameter independent of the method used to increase blood velocity (R(2) = 0.89). The mean slope of the velocity-diameter relationship was not different between nonsmokers and occasional smokers who abstained from smoking at least 2 days. Acute smoking did not alter the slope of the velocity-diameter relationship although the mean intercept was decreased as a result of consistent vasoconstriction (7-10%). The mechanisms by which smoking impairs vascular health are largely unknown. These findings differ from previous smoking studies that used chronic and/or heavier smokers. The velocity-diameter relationship appears independent of the method for increasing velocity. Acute smoking in occasional smokers results in vasoconstriction without altering vascular responsiveness. The velocity-diameter relationship may be a useful measure of the progression of vascular disease.

Use of ultrasound for non-invasive assessment of flow-mediated dilation.

The pathological complications of atherosclerosis, namely heart attacks and strokes, remain the leading cause of mortality in the Western world. Preceding atherosclerosis is endothelial dysfunction. There is therefore interest in the application of non-invasive clinical tools to assess endothelial function. The flow-mediated dilation (FMD) test is the standard tool used to assess endothelial function. Reduced FMD is an early marker of atherosclerosis and has been noted for its capacity to predict future cardiovascular disease events. This review discusses the measurement of endothelial function using ultrasound, with a focus on the FMD technique.

The importance of velocity acceleration to flow-mediated dilation.

The validity of the flow-mediated dilation test has been questioned due to the lack of normalization to the primary stimulus, shear stress. Shear stress can be calculated using Poiseuille's law. However, little attention has been given to the most appropriate blood velocity parameter(s) for calculating shear stress. The pulsatile nature of blood flow exposes the endothelial cells to two distinct shear stimuli during the cardiac cycle: a large rate of change in shear at the onset of flow (velocity acceleration), followed by a steady component. The parameter typically entered into the Poiseuille's law equation to determine shear stress is time-averaged blood velocity, with no regard for flow pulsatility. This paper will discuss (1) the limitations of using Posieuille's law to estimate shear stress and (2) the importance of the velocity profile-with emphasis on velocity acceleration-to endothelial function and vascular tone.

There's more to flow-mediated dilation than nitric oxide.

Flow-mediated dilation (FMD) is the standard tool used to assess endothelial function. The premise behind the standard FMD test is that it serves as an endothelial-dependant nitric oxide bioassay; however, the endothelium may release additional dilatory molecules which contribute to FMD, most notably prostacyclin and endothelial-derived hyperpolarizing factor. The relative importance of these molecules to the dilatory response may vary substantially among individuals, particularly in response to a number of diseased states. This review discusses how each of these molecules may contribute to vasodilation, and considers the circumstances in which they may vary.

Sex differences in the effectiveness of treadmill training in enhancing axon regeneration in injured peripheral nerves.

Exercise in the form of daily treadmill training results in significant enhancement of axon regeneration following peripheral nerve injury. Because androgens are also linked to enhanced axon regeneration, we wanted to investigate whether sex differences in the effect of treadmill training might exist. The common fibular nerves of thy-1-YFP-H mice were cut and repaired with a graft of the same nerve from a strain-matched wild-type donor mouse. Animals were treated with one of two daily treadmill training paradigms: slow continuous walking for 1 h or four higher intensity intervals of 2 min duration separated by 5-min rest periods. Training was begun on the third day following nerve injury and continued 5 days per week for 2 weeks. Effects on regeneration were evaluated by measuring regenerating axon profile lengths in optical sections through the repair sites and grafts at the end of the training period. No sex differences were found in untrained control mice. Continuous training resulted in significant enhancement of axon regeneration only in males. No effect was found in females or in castrated males. Interval training was effective in enhancing axon regeneration only in females and not in intact males or castrated males. Untrained females treated with the aromatase inhibitor, anastrozole, had significant enhancement of axon regeneration without increasing serum testosterone levels. Two different mechanisms exist to promote axon regeneration in a sex-dependent manner. In males treadmill training uses testicular androgens. In females, a different cellular mechanism for the effect of treadmill training must exist.

Enhancing recovery from peripheral nerve injury using treadmill training.

Full functional recovery after traumatic peripheral nerve injury is rare. We postulate three reasons for the poor functional outcome measures observed. Axon regeneration is slow and not all axons participate. Significant misdirection of regenerating axons to reinnervate inappropriate targets occurs. Seemingly permanent changes in neural circuitry in the central nervous system are found to accompany axotomy of peripheral axons. Exercise in the form of modest daily treadmill training impacts all three of these areas. Compared to untrained controls, regenerating axons elongate considerably farther in treadmill trained animals and do so via an autocrine/paracrine neurotrophin signaling pathway. This enhancement of axon regeneration takes place without an increase in the amount of misdirection of regenerating axons found without training. The enhancement also occurs in a sex-dependent manner. Slow continuous training is effective only in males, while more intense interval training is effective only in females. In treadmill trained, but not untrained mice the extent of coverage of axotomized motoneurons is maintained, thus preserving important elements of the spinal circuitry.