Chemogenetic modulation of sensory afferents induces locomotor changes and plasticity after spinal cord injury
Neuromodulatory therapies for spinal cord injury (SCI) such as electrical epidural stimulation (EES) are increasingly effective at improving patient outcomes. These improvements are thought to be due, at least in part, to plasticity in neuronal circuits. Precisely which circuits are influenced and w...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.872634/full |
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| author | Jaclyn T. Eisdorfer Jaclyn T. Eisdorfer Hannah Sobotka-Briner Susan Schramfield George Moukarzel Jie Chen Thomas J. Campion Rupert Smit Bradley C. Rauscher Michel A. Lemay George M. Smith Andrew J. Spence |
| author_facet | Jaclyn T. Eisdorfer Jaclyn T. Eisdorfer Hannah Sobotka-Briner Susan Schramfield George Moukarzel Jie Chen Thomas J. Campion Rupert Smit Bradley C. Rauscher Michel A. Lemay George M. Smith Andrew J. Spence |
| author_sort | Jaclyn T. Eisdorfer |
| collection | DOAJ |
| description | Neuromodulatory therapies for spinal cord injury (SCI) such as electrical epidural stimulation (EES) are increasingly effective at improving patient outcomes. These improvements are thought to be due, at least in part, to plasticity in neuronal circuits. Precisely which circuits are influenced and which afferent classes are most effective in stimulating change remain important open questions. Genetic tools, such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), support targeted and reversible neuromodulation as well as histological characterization of manipulated neurons. We therefore transduced and activated lumbar large diameter peripheral afferents with excitatory (hM3Dq) DREADDs, in a manner analogous to EES, in a rat hemisection model, to begin to trace plasticity and observe concomitant locomotor changes. Chronic DREADDs activation, coupled with thrice weekly treadmill training, was observed to increase afferent fluorescent labeling within motor pools and Clarke's column when compared to control animals. This plasticity may underlie kinematic differences that we observed across stages of recovery, including an increased and less variable hindquarters height in DREADDs animals, shorter step durations, a more flexed ankle joint early in recovery, a less variable ankle joint angle in swing phase, but a more variable hip joint angle. Withdrawal of DREADDs agonist, clozapine-N-oxide (CNO) left these kinematic differences largely unaffected; suggesting that DREADDs activation is not necessary for them later in recovery. However, we observed an intermittent “buckling” phenomenon in DREADDs animals without CNO activation, that did not occur with CNO re-administration. Future studies could use more refined genetic targeted of specific afferent classes, and utilize muscle recordings to find where afferent modulation is most influential in altering motor output. |
| first_indexed | 2024-04-14T03:16:49Z |
| format | Article |
| id | doaj.art-4613ac1f1eeb4f8b888449cf218de61d |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-14T03:16:49Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-4613ac1f1eeb4f8b888449cf218de61d2022-12-22T02:15:26ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992022-08-011510.3389/fnmol.2022.872634872634Chemogenetic modulation of sensory afferents induces locomotor changes and plasticity after spinal cord injuryJaclyn T. Eisdorfer0Jaclyn T. Eisdorfer1Hannah Sobotka-Briner2Susan Schramfield3George Moukarzel4Jie Chen5Thomas J. Campion6Rupert Smit7Bradley C. Rauscher8Michel A. Lemay9George M. Smith10Andrew J. Spence11Department of Bioengineering, College of Engineering, Temple University, Philadelphia, PA, United StatesDepartment of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United StatesDepartment of Bioengineering, College of Engineering, Temple University, Philadelphia, PA, United StatesDepartment of Bioengineering, College of Engineering, Temple University, Philadelphia, PA, United StatesDepartment of Bioengineering, College of Engineering, Temple University, Philadelphia, PA, United StatesDepartment of Neuroscience, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United StatesDepartment of Neuroscience, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United StatesDepartment of Neuroscience, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United StatesDepartment of Bioengineering, College of Engineering, Temple University, Philadelphia, PA, United StatesDepartment of Bioengineering, College of Engineering, Temple University, Philadelphia, PA, United StatesDepartment of Neuroscience, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United StatesDepartment of Bioengineering, College of Engineering, Temple University, Philadelphia, PA, United StatesNeuromodulatory therapies for spinal cord injury (SCI) such as electrical epidural stimulation (EES) are increasingly effective at improving patient outcomes. These improvements are thought to be due, at least in part, to plasticity in neuronal circuits. Precisely which circuits are influenced and which afferent classes are most effective in stimulating change remain important open questions. Genetic tools, such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), support targeted and reversible neuromodulation as well as histological characterization of manipulated neurons. We therefore transduced and activated lumbar large diameter peripheral afferents with excitatory (hM3Dq) DREADDs, in a manner analogous to EES, in a rat hemisection model, to begin to trace plasticity and observe concomitant locomotor changes. Chronic DREADDs activation, coupled with thrice weekly treadmill training, was observed to increase afferent fluorescent labeling within motor pools and Clarke's column when compared to control animals. This plasticity may underlie kinematic differences that we observed across stages of recovery, including an increased and less variable hindquarters height in DREADDs animals, shorter step durations, a more flexed ankle joint early in recovery, a less variable ankle joint angle in swing phase, but a more variable hip joint angle. Withdrawal of DREADDs agonist, clozapine-N-oxide (CNO) left these kinematic differences largely unaffected; suggesting that DREADDs activation is not necessary for them later in recovery. However, we observed an intermittent “buckling” phenomenon in DREADDs animals without CNO activation, that did not occur with CNO re-administration. Future studies could use more refined genetic targeted of specific afferent classes, and utilize muscle recordings to find where afferent modulation is most influential in altering motor output.https://www.frontiersin.org/articles/10.3389/fnmol.2022.872634/fullspinal cord injuryclozapine-N-oxideDREADDs or chemogeneticsDesigner Receptors Exclusively Activated by Designer Drugskinematicsfunctional recovery after SCI |
| spellingShingle | Jaclyn T. Eisdorfer Jaclyn T. Eisdorfer Hannah Sobotka-Briner Susan Schramfield George Moukarzel Jie Chen Thomas J. Campion Rupert Smit Bradley C. Rauscher Michel A. Lemay George M. Smith Andrew J. Spence Chemogenetic modulation of sensory afferents induces locomotor changes and plasticity after spinal cord injury Frontiers in Molecular Neuroscience spinal cord injury clozapine-N-oxide DREADDs or chemogenetics Designer Receptors Exclusively Activated by Designer Drugs kinematics functional recovery after SCI |
| title | Chemogenetic modulation of sensory afferents induces locomotor changes and plasticity after spinal cord injury |
| title_full | Chemogenetic modulation of sensory afferents induces locomotor changes and plasticity after spinal cord injury |
| title_fullStr | Chemogenetic modulation of sensory afferents induces locomotor changes and plasticity after spinal cord injury |
| title_full_unstemmed | Chemogenetic modulation of sensory afferents induces locomotor changes and plasticity after spinal cord injury |
| title_short | Chemogenetic modulation of sensory afferents induces locomotor changes and plasticity after spinal cord injury |
| title_sort | chemogenetic modulation of sensory afferents induces locomotor changes and plasticity after spinal cord injury |
| topic | spinal cord injury clozapine-N-oxide DREADDs or chemogenetics Designer Receptors Exclusively Activated by Designer Drugs kinematics functional recovery after SCI |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.872634/full |
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