Publication Date
2018
Document Type
Dissertation
Committee Members
Sherif Elbasiouny, Ph.D. (Advisor); Mark Rich, M.D., Ph.D. (Committee Member); Mill Miller, Ph.D. (Committee Member); David Ladle, Ph.D. (Committee Member); Lynn Hartzler, Ph.D. (Committee Member)
Degree Name
Doctor of Philosophy (PhD)
Abstract
Spinal motoneurons are the final common path for motor signals. Thus, the firing activity recorded from spinal motoneurons or their axons in the ventral roots represents the motor output of the nervous system. This dissertation investigates two major phenomena that help generate and shape the neuronal motor output. Specialized groups of spinal neurons called central pattern generators (CPGs) are capable of orchestrating rhythmic bursting activity without involvement of the brain. This activity underlies stereotyped movements such as locomotion. If known, the ionic mechanisms responsible for generating this activity can offer new pharmacological interventions to restore walking in paralyzed patients with intact spinal circuits. In part-I of this dissertation, we examined the role of the small conductance Ca⁺²-activated potassium (SK) channels in the generation of rhythmic activity. SK channels represent a strong candidate for controlling bursting behaviors because they have a dual regulatory function on both the synaptic inputs and the firing output of spinal neurons. Rhythmic activity was studied in murine spinal cord preparations in vitro using intracellular and extracellular electrophysiological recordings. The data showed that inhibition of SK channels -using multiple approaches- facilitates the initiation of rhythmic motor outputs. Additionally, graded pharmacological modulation of SK channels determined the amplitude of the motor bursts in a dose-dependent manner. Similar manipulations of other types of ion channels did not replicate these effects. The autonomous activity of the spinal CPGs can continue for long periods of time without extrinsic inputs. However, to meet the demands of the environment, the locomotor activity has to undergo continuous modulation by peripheral sensory inputs and descending supraspinal inputs (sensorimotor integration). These synaptic inputs exhibit use-dependent plasticity at physiological firing frequencies (either facilitation or depression). Using a combination of intracellular and extracellular recordings, part-II of this dissertation investigated how variable sensory and descending inputs of different frequencies, amplitudes, and neuromodulatory states generate a steady motor output at the cellular and system levels. The data indicated that integration of multiple, despite adapting, excitatory inputs help generate a stable motor output by maintaining the synaptic potentials above the firing threshold, which was more readily achievable at higher neuromodulatory states.
Page Count
168
Department or Program
Biomedical Sciences
Year Degree Awarded
2018
Copyright
Copyright 2018, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0000-0001-9027-1960
