@article {4094, title = {Why New Spinal Cord Plasticity Does Not Disrupt Old Motor Behaviors}, journal = {The Journal of Neuroscience}, volume = {37}, year = {2017}, month = {July}, pages = {8198-8206}, abstract = {When new motor learning changes the spinal cord, old behaviors are not impaired; their key features are preserved by additional compensatory plasticity. To explore the mechanisms responsible for this compensatory plasticity, we transected the spinal dorsal ascending tract before or after female rats acquired a new behavior{\textemdash}operantly conditioned increase or decrease in the right soleus H-reflex{\textemdash}and examined an old behavior{\textemdash}locomotion. Neither spinal dorsal ascending tract transection nor H-reflex conditioning alone impaired locomotion. Nevertheless, when spinal dorsal ascending tract transection and H-reflex conditioning were combined, the rats developed a limp and a tilted posture that correlated in direction and magnitude with the H-reflex change. When the right H-reflex was increased by conditioning, the right step lasted longer than the left and the right hip was higher than the left; when the right H-reflex was decreased by conditioning, the opposite occurred. These results indicate that ascending sensory input guides the compensatory plasticity that normally prevents the plasticity underlying H-reflex change from impairing locomotion. They support the concept of the state of the spinal cord as a negotiated equilibrium that reflects the concurrent influences of all the behaviors in an individual{\textquoteright}s repertoire; and they support the new therapeutic strategies this concept introduces.}, keywords = {H-Reflex, motor learning, operant conditioning, plasticity, Rehabilitation, Spinal Cord}, doi = {10.1523/JNEUROSCI.0767-17.2017}, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566867/}, author = {Chen, Yi and Chen, Lu and Wang, Yu and Chen, Xiang Yang and Jonathan Wolpaw} } @article {3565, title = {Ablation of the inferior olive prevents H-reflex down-conditioning in rats.}, journal = {Journal of neurophysiology}, volume = {115}, year = {2016}, month = {Mar}, pages = {1630{\textendash}1636}, abstract = {We evaluated the role of the inferior olive (IO) in acquisition of the spinal cord plasticity that underlies H-reflex down-conditioning, a simple motor skill. The IO was chemically ablated before a 50-day exposure to an operant conditioning protocol that rewarded a smaller soleus H-reflex. In normal rats, down-conditioning succeeds (i.e., H-reflex size decreases at least 20\%) in 80\% of animals. Down-conditioning failed in every IO-ablated rat (P< 0.001 vs. normal rats). IO ablation itself had no long-term effect on H-reflex size. These results indicate that the IO is essential for acquisition of a down-conditioned H-reflex. With previous data, they support the hypothesis that IO and cortical inputs to cerebellum enable the cerebellum to guide sensorimotor cortex plasticity that produces and maintains the spinal cord plasticity that underlies the down-conditioned H-reflex. They help to further define H-reflex conditioning as a model for understanding motor learning and as a new approach to enhancing functional recovery after trauma or disease.}, keywords = {Spinal Cord}, issn = {1522-1598}, doi = {10.1152/jn.01069.2015}, url = {http://www.ncbi.nlm.nih.gov/pubmed/26792888}, author = {Xiang Yang Chen and Wang, Yu and Yi Chen and Chen, Lu and Jonathan Wolpaw} } @article {3566, title = {The inferior olive is essential for long-term maintenance of a simple motor skill.}, journal = {Journal of neurophysiology}, volume = {116}, year = {2016}, month = {Oct}, pages = {1946{\textendash}1955}, abstract = {The inferior olive (IO) is essential for operant down-conditioning of the rat soleus H-reflex, a simple motor skill. To evaluate the role of the IO in long-term maintenance of this skill, the H-reflex was down-conditioned over 50 days, the IO was chemically ablated, and down-conditioning continued for up to 102 more days. H-reflex size just before IO ablation averaged 62({\textpm}2 SE)\% of its initial value (P < 0.001 vs. initial). After IO ablation, H-reflex size rose to 75-80\% over ?10 days, remained there for ?30 days, rose over 10 days to above its initial value, and averaged 140({\textpm}14)\% for the final 10 days of study (P < 0.01 vs. initial). This two-stage loss of down-conditioning maintenance correlated with IO neuronal loss (r = 0.75, P < 0.01) and was similar to the loss of down-conditioning that follows ablation of the cerebellar output nuclei dentate and interpositus. In control (i.e., unconditioned) rats, IO ablation has no long-term effect on H-reflex size. These results indicate that the IO is essential for long-term maintenance of a down-conditioned H-reflex. With previous data, they support the hypothesis that IO and cortical inputs to cerebellum combine to produce cerebellar plasticity that produces sensorimotor cortex plasticity that produces spinal cord plasticity that produces the smaller H-reflex. H-reflex down-conditioning appears to depend on a hierarchy of plasticity that may be guided by the IO and begin in the cerebellum. Similar hierarchies may underlie other motor learning.}, issn = {1522-1598}, doi = {10.1152/jn.00085.2016}, url = {http://www.ncbi.nlm.nih.gov/pubmed/27535367}, author = {Xiang Yang Chen and Wang, Yu and Yi Chen and Chen, Lu and Jonathan Wolpaw} } @article {3390, title = {Locomotor impact of beneficial or nonbeneficial H-reflex conditioning after spinal cord injury.}, journal = {J Neurophysiol}, volume = {111}, year = {2014}, month = {03/2014}, pages = {1249-58}, abstract = {When new motor learning changes neurons and synapses in the spinal cord, it may affect previously learned behaviors that depend on the same spinal neurons and synapses. To explore these effects, we used operant conditioning to strengthen or weaken the right soleus H-reflex pathway in rats in which a right spinal cord contusion had impaired locomotion. When up-conditioning increased the H-reflex, locomotion improved. Steps became longer, and step-cycle asymmetry (i.e., limping) disappeared. In contrast, when down-conditioning decreased the H-reflex, locomotion did not worsen. Steps did not become shorter, and asymmetry did not increase. Electromyographic and kinematic analyses explained how H-reflex increase improved locomotion and why H-reflex decrease did not further impair it. Although the impact of up-conditioning or down-conditioning on the H-reflex pathway was still present during locomotion, only up-conditioning affected the soleus locomotor burst. Additionally, compensatory plasticity apparently prevented the weaker H-reflex pathway caused by down-conditioning from weakening the locomotor burst and further impairing locomotion. The results support the hypothesis that the state of the spinal cord is a "negotiated equilibrium" that serves all the behaviors that depend on it. When new learning changes the spinal cord, old behaviors undergo concurrent relearning that preserves or improves their key features. Thus, if an old behavior has been impaired by trauma or disease, spinal reflex conditioning, by changing a specific pathway and triggering a new negotiation, may enable recovery beyond that achieved simply by practicing the old behavior. Spinal reflex conditioning protocols might complement other neurorehabilitation methods and enhance recovery.}, keywords = {Animals, Conditioning, Operant, Female, H-Reflex, Learning, Locomotion, Male, Rats, Rats, Sprague-Dawley, Spinal Cord Injuries}, issn = {1522-1598}, doi = {10.1152/jn.00756.2013}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24371288}, author = {Yi Chen and Lu Chen and Liu, Rongliang and Wang, Yu and Xiang Yang Chen and Jonathan Wolpaw} } @article {3383, title = {Persistent beneficial impact of H-reflex conditioning in spinal cord-injured rats.}, journal = {J Neurophysiol}, volume = {112}, year = {2014}, month = {11/2014}, pages = {2374-81}, abstract = {

Operant conditioning of a spinal cord reflex can improve locomotion in rats and humans with incomplete spinal cord injury. This study examined the persistence of its beneficial effects. In rats in which a right lateral column contusion injury had produced asymmetric locomotion, up-conditioning of the right soleus H-reflex eliminated the asymmetry while down-conditioning had no effect. After the 50-day conditioning period ended, the H-reflex was monitored for 100 [{\textpm}9 (SD)] (range 79-108) more days and locomotion was then reevaluated. After conditioning ended in up-conditioned rats, the H-reflex continued to increase, and locomotion continued to improve. In down-conditioned rats, the H-reflex decrease gradually disappeared after conditioning ended, and locomotion at the end of data collection remained as impaired as it had been before and immediately after down-conditioning. The persistence (and further progression) of H-reflex increase but not H-reflex decrease in these spinal cord-injured rats is consistent with the fact that up-conditioning improved their locomotion while down-conditioning did not. That is, even after up-conditioning ended, the up-conditioned H-reflex pathway remained adaptive because it improved locomotion. The persistence and further enhancement of the locomotor improvement indicates that spinal reflex conditioning protocols might supplement current therapies and enhance neurorehabilitation. They may be especially useful when significant spinal cord regeneration becomes possible and precise methods for retraining the regenerated spinal cord are needed.

}, keywords = {H-reflex conditioning, Learning, Locomotion, Memory, Motor control, Rehabilitation, spinal cord injury, spinal cord plasticity}, issn = {1522-1598}, doi = {10.1152/jn.00422.2014}, url = {http://www.ncbi.nlm.nih.gov/pubmed/25143542}, author = {Yi Chen and Lu Chen and Wang, Yu and Jonathan Wolpaw and Xiang Yang Chen} } @article {3084, title = {Cortical stimulation causes long-term changes in H-reflexes and spinal motoneuron GABA receptors.}, journal = {Journal of neurophysiology}, volume = {108}, year = {2012}, month = {11/2012}, pages = {2668{\textendash}2678}, abstract = {The cortex gradually modifies the spinal cord during development, throughout later life, and in response to trauma or disease. The mechanisms of this essential function are not well understood. In this study, weak electrical stimulation of rat sensorimotor cortex increased the soleus H-reflex, increased the numbers and sizes of GABAergic spinal interneurons and GABAergic terminals on soleus motoneurons, and decreased GABA(A) and GABA(B) receptor labeling in these motoneurons. Several months after the stimulation ended the interneuron and terminal increases had disappeared, but the H-reflex increase and the receptor decreases remained. The changes in GABAergic terminals and GABA(B) receptors accurately predicted the changes in H-reflex size. The results reveal a new long-term dimension to cortical-spinal interactions and raise new therapeutic possibilities.}, keywords = {Spinal Cord}, issn = {1522-1598}, doi = {10.1152/jn.00516.2012}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22933718}, author = {Wang, Yu and Yi Chen and Lu Chen and Jonathan Wolpaw and Xiang Yang Chen} } @article {3090, title = {Operant conditioning of rat soleus H-reflex oppositely affects another H-reflex and changes locomotor kinematics.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {31}, year = {2011}, month = {08/2011}, pages = {11370{\textendash}11375}, abstract = {H-reflex conditioning is a model for studying the plasticity associated with a new motor skill. We are exploring its effects on other reflexes and on locomotion. Rats were implanted with EMG electrodes in both solei (SOL(R) and SOL(L)) and right quadriceps (QD(R)), and stimulating cuffs on both posterior tibial (PT) nerves and right posterior femoral nerve. When SOL(R) EMG remained in a defined range, PT(R) stimulation just above M-response threshold elicited the SOL(R) H-reflex. Analogous procedures elicited the QD(R) and SOL(L) H-reflexes. After a control period, each rat was exposed for 50 d to a protocol that rewarded SOL(R) H-reflexes that were above (HRup rats) or below (HRdown rats) a criterion. HRup conditioning increased the SOL(R) H-reflex to 214 {\textpm} 37\% (mean {\textpm} SEM) of control (p = 0.02) and decreased the QD(R) H-reflex to 71 {\textpm} 26\% (p = 0.06). HRdown conditioning decreased the SOL(R) H-reflex to 69 {\textpm} 2\% (p < 0.001) and increased the QD(R) H-reflex to 121 {\textpm} 7\% (p = 0.02). These changes remained during locomotion. The SOL(L) H-reflex did not change. During the stance phase of locomotion, ankle plantarflexion increased in HRup rats and decreased in HRdown rats, hip extension did the opposite, and hip height did not change. The plasticity that changes the QD(R) H-reflex and locomotor kinematics may be inevitable (i.e., reactive) due to the ubiquity of activity-dependent CNS plasticity, and/or necessary (i.e., compensatory) to preserve other behaviors (e.g., locomotion) that would otherwise be disturbed by the change in the SOL(R) H-reflex pathway. The changes in joint angles, coupled with the preservation of hip height, suggest that compensatory plasticity did occur.}, keywords = {Rats, Sprague-Dawley}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.1526-11.2011}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21813696}, author = {Yi Chen and Lu Chen and Wang, Yu and Jonathan Wolpaw and Xiang Yang Chen} } @article {3186, title = {WITHDRAWN: H-reflex up-conditioning after sciatic nerve transection and regeneration may increase VGLUT-1 terminals and GluR2/3 immunoreactivity in spinal motoneurons.}, journal = {Neuroscience letters}, year = {2011}, month = {12/2011}, abstract = {This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.}, issn = {1872-7972}, doi = {10.1016/j.neulet.2011.12.011}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22198372}, author = {Sun, Chenyou and Wang, Yu and Xiang Yang Chen} } @article {3095, title = {H-reflex up-conditioning encourages recovery of EMG activity and H-reflexes after sciatic nerve transection and repair in rats.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {30}, year = {2010}, month = {12/2010}, pages = {16128{\textendash}16136}, abstract = {Operant conditioning of the spinal stretch reflex or its electrical analog, the H-reflex, produces spinal cord plasticity and can thereby affect motoneuron responses to primary afferent input. To explore whether this conditioning can affect the functional outcome after peripheral nerve injury, we assessed the effect of up-conditioning soleus (SOL) H-reflex on SOL and tibialis anterior (TA) function after sciatic nerve transection and repair. Sprague Dawley rats were implanted with EMG electrodes in SOL and TA and stimulating cuffs on the posterior tibial nerve. After control data collection, the sciatic nerve was transected and repaired and the rat was exposed for 120 d to continued control data collection (TC rats) or SOL H-reflex up-conditioning (TU rats). At the end of data collection, motoneurons that had reinnervated SOL and TA were labeled retrogradely. Putative primary afferent terminals [i.e., terminals containing vesicular glutamate transporter-1 (VGLUT1)] on SOL motoneurons were studied immunohistochemically. SOL (and probably TA) background EMG activity recovered faster in TU rats than in TC rats, and the final recovered SOL H-reflex was significantly larger in TU than in TC rats. TU and TC rats had significantly fewer labeled motoneurons and higher proportions of double-labeled motoneurons than untransected rats. VGLUT1 terminals were significantly more numerous on SOL motoneurons of TU than TC rats. Combined with the larger H-reflexes in TU rats, this anatomical finding supports the hypothesis that SOL H-reflex up-conditioning strengthened primary afferent reinnervation of SOL motoneurons. These results suggest that H-reflex up-conditioning may improve functional recovery after nerve injury and repair.}, keywords = {conditioning, peripheral nerve, plasticity, Reflex, regeneration, Spinal Cord}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.4578-10.2010}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21123559}, author = {Yi Chen and Wang, Yu and Lu Chen and Sun, Chenyou and English, Arthur W. and Jonathan Wolpaw and Xiang Yang Chen} } @article {3100, title = {Reflex conditioning: a new strategy for improving motor function after spinal cord injury.}, journal = {Annals of the New York Academy of Sciences}, volume = {1198 Suppl 1}, year = {2010}, month = {06/2010}, pages = {E12{\textendash}E21}, abstract = {Spinal reflex conditioning changes reflex size, induces spinal cord plasticity, and modifies locomotion. Appropriate reflex conditioning can improve walking in rats after spinal cord injury (SCI). Reflex conditioning offers a new therapeutic strategy for restoring function in people with SCI. This approach can address the specific deficits of individuals with SCI by targeting specific reflex pathways for increased or decreased responsiveness. In addition, once clinically significant regeneration can be achieved, reflex conditioning could provide a means of reeducating the newly (and probably imperfectly) reconnected spinal cord.}, keywords = {H-Reflex, learning and memory, Locomotion, plasticity, reflex conditioning, Rehabilitation, spinal cord injury}, issn = {1749-6632}, doi = {10.1111/j.1749-6632.2010.05565.x}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20590534}, author = {Xiang Yang Chen and Yi Chen and Wang, Yu and Thompson, Aiko and Jonathan S. Carp and Segal, Richard L. and Jonathan Wolpaw} } @article {3110, title = {H-reflex down-conditioning greatly increases the number of identifiable GABAergic interneurons in rat ventral horn.}, journal = {Neuroscience letters}, volume = {452}, year = {2009}, month = {03/2009}, pages = {124{\textendash}129}, abstract = {H-reflex down-conditioning increases GABAergic terminals on spinal cord motoneurons. To explore the origins of these terminals, we studied the numbers and distributions of spinal cord GABAergic interneurons. The number of identifiable GABAergic interneurons in the ventral horn was 78\% greater in rats in which down-conditioning was successful than in naive rats or rats in which down-conditioning failed. No increase occurred in other spinal lamina or on the contralateral side. This finding supports the hypothesis that the corticospinal tract influence that induces the motoneuron plasticity underlying down-conditioning reaches the motoneuron through GABAergic interneurons in the ventral horn.}, keywords = {activity-dependent plasticity, GABAergic interneurons, H-reflex conditioning, learning and memory, Motor control, Spinal Cord}, issn = {0304-3940}, doi = {10.1016/j.neulet.2009.01.054}, url = {http://www.ncbi.nlm.nih.gov/pubmed/19383426}, author = {Wang, Yu and Pillai, Shreejith and Jonathan Wolpaw and Xiang Yang Chen} } @article {3188, title = {Effects of H-reflex up-conditioning on GABAergic terminals on rat soleus motoneurons.}, journal = {The European journal of neuroscience}, volume = {28}, year = {2008}, month = {08/2008}, pages = {668{\textendash}674}, abstract = {To explore the role of spinal cord plasticity in motor learning, we evaluated the effects of H-reflex operant conditioning on GABAergic input to rat spinal motoneurons. Previous work indicated that down-conditioning of soleus H-reflex increases GABAergic input to soleus motoneurons. This study explored the effect of H-reflex up-conditioning on GABAergic input. Of nine rats exposed to H-reflex up-conditioning, up-conditioning was successful (H-reflex increase >or= 20\%) in seven and failed (change < 20\%) in two. These rats and eight naive control (i.e. unconditioned) rats were injected with cholera toxin subunit B-conjugated Alexa fluor 488 into the soleus muscle to retrogradely label soleus motoneurons. Sections containing soleus motoneurons were processed for GAD(67) [one of the two principal forms of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD)] with an ABC-peroxidase system. Two blinded independent raters counted and measured GABAergic terminals on these motoneurons. Unlike successful down-conditioning, which greatly increased the number of identifiable GABAergic terminals on the motoneurons, up-conditioning did not significantly change GABAergic terminal number. Successful up-conditioning did produce slight but statistically significant increases in GABAergic terminal diameter and soma coverage. These results are consistent with other data indicating that up- and down-conditioning are not mirror images of each other, but rather have different mechanisms. Although the marked changes in GABAergic terminals with down-conditioning probably contribute to H-reflex decrease, the modest changes in GABAergic terminals associated with up-conditioning may be compensatory or reactive plasticity, rather than the plasticity responsible for H-reflex increase. As a variety of spinal and supraspinal GABAergic neurons innervate motoneurons, the changes found with up-conditioning may be in terminals other than those affected in successful down-conditioning.}, keywords = {activity-dependent plasticity, Learning, Memory, Motor control, Spinal Cord}, issn = {1460-9568}, doi = {10.1111/j.1460-9568.2008.06370.x}, url = {http://www.ncbi.nlm.nih.gov/pubmed/18657184}, author = {Pillai, Shreejith and Wang, Yu and Jonathan Wolpaw and Xiang Yang Chen} } @article {3150, title = {Spinal and supraspinal effects of long-term stimulation of sensorimotor cortex in rats.}, journal = {Journal of neurophysiology}, volume = {98}, year = {2007}, month = {08/2007}, pages = {878{\textendash}887}, abstract = {Sensorimotor cortex (SMC) modifies spinal cord reflex function throughout life and is essential for operant conditioning of the H-reflex. To further explore this long-term SMC influence over spinal cord function and its possible clinical uses, we assessed the effect of long-term SMC stimulation on the soleus H-reflex. In freely moving rats, the soleus H-reflex was measured 24 h/day for 12 wk. The soleus background EMG and M response associated with H-reflex elicitation were kept stable throughout. SMC stimulation was delivered in a 20-day-on/20-day-off/20-day-on protocol in which a train of biphasic 1-ms pulses at 25 Hz for 1 s was delivered every 10 s for the on-days. The SMC stimulus was automatically adjusted to maintain a constant descending volley. H-reflex size gradually increased during the 20 on-days, stayed high during the 20 off-days, and rose further during the next 20 on-days. In addition, the SMC stimulus needed to maintain a stable descending volley rose steadily over days. It fell during the 20 off-days and rose again when stimulation resumed. These results suggest that SMC stimulation, like H-reflex operant conditioning, induces activity-dependent plasticity in both the brain and the spinal cord and that the plasticity responsible for the H-reflex increase persists longer after the end of SMC stimulation than that underlying the change in the SMC response to stimulation.}, keywords = {Time Factors}, issn = {0022-3077}, doi = {10.1152/jn.00283.2007}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17522179}, author = {Xiang Yang Chen and Pillai, Shreejith and Yi Chen and Wang, Yu and Lu Chen and Jonathan S. Carp and Jonathan Wolpaw} } @article {3193, title = {Motor learning changes GABAergic terminals on spinal motoneurons in normal rats.}, journal = {The European journal of neuroscience}, volume = {23}, year = {2006}, month = {01/2006}, pages = {141{\textendash}150}, abstract = {The role of spinal cord plasticity in motor learning is largely unknown. This study explored the effects of H-reflex operant conditioning, a simple model of motor learning, on GABAergic input to spinal motoneurons in rats. Soleus motoneurons were labeled by retrograde transport of a fluorescent tracer and GABAergic terminals on them were identified by glutamic acid decarboxylase (GAD)67 immunoreactivity. Three groups were studied: (i) rats in which down-conditioning had reduced the H-reflex (successful HRdown rats); (ii) rats in which down-conditioning had not reduced the H-reflex (unsuccessful HRdown rats) and (iii) unconditioned (naive) rats. The number, size and GAD density of GABAergic terminals, and their coverage of the motoneuron, were significantly greater in successful HRdown rats than in unsuccessful HRdown or naive rats. It is likely that these differences are due to modifications in terminals from spinal interneurons in lamina VI-VII and that the increased terminal number, size, GAD density and coverage in successful HRdown rats reflect and convey a corticospinal tract influence that changes motoneuron firing threshold and thereby decreases the H-reflex. GABAergic terminals in spinal cord change after spinal cord transection. The present results demonstrate that such spinal cord plasticity also occurs in intact rats in the course of motor learning and suggest that this plasticity contributes to skill acquisition.}, keywords = {activity-dependent plasticity, GABA, H-Reflex, Memory, Motor control, Spinal Cord}, issn = {0953-816X}, doi = {10.1111/j.1460-9568.2005.04547.x}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16420424}, author = {Wang, Yu and Pillai, Shreejith and Jonathan Wolpaw and Xiang Yang Chen} }