Browsing by Subject "locomotion"

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    Dopaminergic signaling in the spinal cord suppresses locomotion in larval zebrafish development
    (2024-03) Walters, Deborah, L
    The significance of dopamine (DA) and its multifaceted role as a neurotransmitter in the central nervous system has undergone extensive investigation. The research focus of my project centers on dopamine’s role in modulating spinal locomotor circuits in larvae zebrafish. Previous research from our lab showed that larval zebrafish swimming patterns change during development from long episodes durations at 3 days post fertilization (dpf) to short episode durations at 4 dpf and coincides with gross to fine motor control. Dopamine receptor D4 signaling in the spinal cord is necessary in facilitating this switch, likely by modulating dopamine signaling and regulating the activity of motor neurons involved in generating locomotor patterns. We demonstrated that antagonism of D4R signaling starting at 3 dpf prevents the switch from long to short episode durations, while D4R antagonism at 4 dpf reverses the switch from short to long episode durations. We hypothesized that 3 dpf larvae possess sufficient dopaminergic receptors in the spinal cord to bind to DA, enabling the advancement of the developmental switch from immature, long swim patterns to a mature state resembling 4 dpf larvae by exposing larvae at 3 dpf to exogenous DA. To test this, we used transgenic zebrafish that expressed Channelrhodopsin (ChR) in glutamatergic neurons within the spinal cord, allowing for the activation of these neurons using blue-light stimulation. Fictive swimming was measured using peripheral nerve recordings in different conditions, of a baseline (t0), treatment of dopamine (t1), and washout (saline) (t2). Control (untreated) preparations exhibited no significant changes between conditions, indicating that repeated optogenetic stimulation by itself did not induce notable changes in locomotor activity. Dopamine application significantly decreased the number of bursts and episode duration during optogenetic stimulation locomotor activity without affecting number of episodes, burst duration, or inter-burst intervals. These results suggest that exogenous DA affected swim patterns in 3 dpf larvae to resemble their 5 dpf counterparts, indicating a sufficient expression level of dopamine receptors in spinal locomotor networks of 3 dpf larvae to prematurely advance the developmental switch. These results could elucidate how neurodegenerative and motor disorders develop and progress, and shed light on the mechanisms underlying spinal cord injury. These findings could potentially inform translational medical approaches creating novel therapeutic interventions for treating neurodegenerative diseases.
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    Dynamic cortical networks in spontaneous and externally-driven locomotion
    (2022-11) West, Sarah
    Locomotion requires extensive computations carried out across motor and sensory cortical regions to ensure safe and accurate navigation through the external environment. Motor cortical regions utilize sensory stimuli to adjust gait to avoid obstacles, while sensory cortical areas use internally-generated motor signals to predict corresponding sensory inputs. Despite the extensive cortical activation during locomotion, it is unclear how sensory and motor information are exchanged between areas or if they are organized via cortical-cortical mechanisms. To investigate these questions, wide-field Ca2+ imaging of the dorsal cerebral cortex was performed in mice during locomotion and the functional connectivity network formed by cortical areas was determined. The first hypothesis tested by this thesis was whether the cortical connectivity network forms a distinct structure during spontaneous locomotion than at rest, which would reveal an organizing mechanism of cortex-wide sensory-motor exchange. During locomotion, the correlations between most regions decrease, even as activity increases. However, connectivity between the secondary motor cortex (M2) and the rest of the cortex increased. These changes are independent of overall activity level and the step cycle, and causality analysis suggests information flows from M2 to other cortical regions. Combined with evidence from the literature, this suggests cortical activity during locomotion is organized by top-down signaling from M2 to each region. M2 and other upstream motor control areas are associated with the initiation of internally-driven movements, as opposed to externally-driven movements in response to external stimuli. Furthermore, little cortical input is required to generate simple gait patterns when an animal walks on a motorized treadmill. Therefore, we hypothesized that the organizing M2 connectivity structure would be diminished during motorized treadmill locomotion. To test this hypothesis, wide-field Ca2+ imaging was performed as mice walked spontaneously and on a motorized treadmill. M2 connectivity is indeed reduced during motorized treadmill locomotion compared to spontaneous, especially at locomotion onset and offset. Moreover, M2 connectivity is lower during deceleration of the treadmill than acceleration, and the spontaneous and motorized treadmill conditions induce different connectivity patterns in the periods immediately before and after walking. Together these results demonstrate that M2 organizing connectivity is engaged less in externally-driven movement, and that the differences between internally- and externally-driven locomotion control are evident at the level of the cortical functional network. This work has implications for locomotion pathologies, such as freezing-of-gait (FOG), that are linked to the internal generation of movement and the dysregulation of activity and connectivity of upstream motor cortical regions homologous to M2.