Chemogenetic stimulation of grafted neurons and changes in spinal afferent input in paraplegic rats

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dc.contributor.authorNazzal, Mona
dc.contributor.examiningcommitteeCowley, Kristine (Physiology and Pathophysiology)
dc.contributor.examiningcommitteeJackson, Michael (Pharmacology and Therapeutics)
dc.contributor.examiningcommitteeKirouac, Gilbert (Oral Biology)
dc.contributor.examiningcommitteeBui, Tuan (University of Ottawa)
dc.contributor.supervisorStecina, Katinka
dc.date.accessioned2024-01-08T19:54:36Z
dc.date.available2024-01-08T19:54:36Z
dc.date.issued2023-12-19
dc.date.submitted2023-12-24T19:08:26Zen_US
dc.degree.disciplinePhysiology and Pathophysiologyen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)
dc.description.abstractOver 2,000 yearly new cases of spinal cord injury (SCI) in Canada leave many people with reduced motor function that leads to secondary health complications. Increasing one’s ability to walk can significantly curtail these complications but there is currently no treatment for recovering locomotor function after SCI in humans. Preclinical research with rodent models was used for my studies described in this dissertation to seek a better understanding of mechanisms underlying the recovery of walking. The purpose of the first study was to examine changes in networks transmitting sensory input to motoneurons between the first and the fifth week after a complete SCI. The hypothesis that afferent input from the tibial nerve (TIB) in the lumbar segments is distributed differently after SCI was examined. A complete spinal transection injury in rats and in vivo electrophysiological measurements of evoked potentials following TIB stimulation were used. TIB afferents evoked intraspinal field potentials in the dorsal horn that showed a significant reduction in amplitude at one-week post-SCI. By five weeks post-SCI, however, TIB afferent transmission efficacy in these pathways was similar in rats without SCI. These findings suggest that TIB afferent input combined with dorsal horn neural excitability of spinal interneurons drives the reorganization needed for recovery of some walking capacity. My second study utilized a genetically modified rat model in which neurons producing serotonin (5-HT) could be activated to escalate locomotor recovery. By using grafting of embryonic 5-HT neurons below the level of SCI, we tested the hypothesis that activation of grafted 5-HT neurons by chemogenetic means in paraplegic rats improves locomotor activity (compared to rats in which only grafting was done). Behavioral analysis by kinematic and hindlimb EMG assessments during treadmill walking were performed before and after chemogenetic stimulation of grafted 5-HT cells and immunohistochemistry on spinal tissue was used to verify the targets of this stimulation. We found that locomotor cycle regularity and left-right coordination were altered. The findings suggest that selective targeting of neural subpopulations may be a better strategy for improving recovery of walking after complete SCI.
dc.description.noteFebruary 2024
dc.identifier.urihttp://hdl.handle.net/1993/37954
dc.language.isoeng
dc.rightsopen accessen_US
dc.subjectgroup II afferents
dc.subjectSpinal cord injury (SCI)
dc.subjectserotonin
dc.subjectlocomotion
dc.subjectchemogenetics
dc.subjectCentral pattern generator (CPG)
dc.subjectCord dorsum potential (CDP)
dc.subjectLocal field potential
dc.subjectgrafts
dc.subjectTibial nerve
dc.subjectinterneurons
dc.subjectDREADDs
dc.subjectCompound 21 (C21)
dc.subjectElectromyography (EMG)
dc.subjectkinematics
dc.subject5-HT
dc.subjectafferent
dc.titleChemogenetic stimulation of grafted neurons and changes in spinal afferent input in paraplegic rats
dc.typedoctoral thesisen_US
local.subject.manitobano
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