Illuminating and sculpting the structure and function of mitochondria in sleep-control neurons
<p>In <em>Drosophila</em>, sleep deprivation leads to the accumulation of reactive oxygen species (ROS) in the mitochondria of sleep-control neurons projecting to the dorsal fan-shaped body (dFB)(Kempf et al., 2019). ROS levels provide an internal representation of sleep need by ac...
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| Format: | Thesis |
| Language: | English |
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2023
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| _version_ | 1811139888612900864 |
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| author | Monaco, N |
| author2 | Miesenböck, G |
| author_facet | Miesenböck, G Monaco, N |
| author_sort | Monaco, N |
| collection | OXFORD |
| description | <p>In <em>Drosophila</em>, sleep deprivation leads to the accumulation of reactive oxygen species (ROS) in the mitochondria of sleep-control neurons projecting to the dorsal fan-shaped body (dFB)(Kempf et al., 2019). ROS levels provide an internal representation of sleep need by activating sleep via the redox-sensitive β-subunit of the voltage-gated potassium channel Shaker (Kempf et al., 2019). Shaker regulates the excitability of sleep-promoting cells via the oxidation state of a stably bound nicotinamide cofactor (Donlea, Pimentel, & Miesenböck, 2014b; Pimentel et al., 2016).</p>
<p>Unpublished data (Sarnataro, 2022) has examined the changes in dorsal fan body neurons (dFBNs) after sleep deprivation. Transcriptomes of single cells isolated from the brains of rested and sleep-deprived flies showed genes upregulated in dFBNs, primarily encoding proteins with roles in mitochondrial respiration and ATP synthesis. Whereas morphological observation of mitochondria in dFBNs after sleep deprivation showed changes in mitochondrial structure with increased fragmentation.</p>
<p>This thesis builds on this evidence and focuses on the flexible and bidirectional dynamics of mitochondria in sleep control neurons and how they change sleep and are changed by sleep. This approach is split into two strategies: observing mitochondrially related cell changes after sleep deprivation and directly manipulating mitochondria, then observing changes in sleep.</p>
<p>Specifically, I showed gene expression changes were accompanied by mitochondrial fragmentation, enhanced mitophagy, and increased mitochondrial fission. The morphological changes were reversible after recovery from sleep, and directly manipulating mitochondrial dynamics affected sleep behaviour.</p>
<p>To further delineate mitochondrial changes in the dFB neurons after sleep, I developed and designed a genetically encoded voltage indicator for the mitochondrial membrane. Upon validation, this tool should allow in-vivo imaging of mitochondrial membrane potential over more extended time frames and provide a readout of mitochondrial dysfunction.</p> |
| first_indexed | 2024-09-25T04:13:15Z |
| format | Thesis |
| id | oxford-uuid:06af9052-f9ee-4394-be85-a08c03caa074 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:13:15Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | oxford-uuid:06af9052-f9ee-4394-be85-a08c03caa0742024-07-12T08:54:09ZIlluminating and sculpting the structure and function of mitochondria in sleep-control neuronsThesishttp://purl.org/coar/resource_type/c_bdccuuid:06af9052-f9ee-4394-be85-a08c03caa074NeuroscienceEnglishHyrax Deposit2023Monaco, NMiesenböck, GGoodwin, S<p>In <em>Drosophila</em>, sleep deprivation leads to the accumulation of reactive oxygen species (ROS) in the mitochondria of sleep-control neurons projecting to the dorsal fan-shaped body (dFB)(Kempf et al., 2019). ROS levels provide an internal representation of sleep need by activating sleep via the redox-sensitive β-subunit of the voltage-gated potassium channel Shaker (Kempf et al., 2019). Shaker regulates the excitability of sleep-promoting cells via the oxidation state of a stably bound nicotinamide cofactor (Donlea, Pimentel, & Miesenböck, 2014b; Pimentel et al., 2016).</p> <p>Unpublished data (Sarnataro, 2022) has examined the changes in dorsal fan body neurons (dFBNs) after sleep deprivation. Transcriptomes of single cells isolated from the brains of rested and sleep-deprived flies showed genes upregulated in dFBNs, primarily encoding proteins with roles in mitochondrial respiration and ATP synthesis. Whereas morphological observation of mitochondria in dFBNs after sleep deprivation showed changes in mitochondrial structure with increased fragmentation.</p> <p>This thesis builds on this evidence and focuses on the flexible and bidirectional dynamics of mitochondria in sleep control neurons and how they change sleep and are changed by sleep. This approach is split into two strategies: observing mitochondrially related cell changes after sleep deprivation and directly manipulating mitochondria, then observing changes in sleep.</p> <p>Specifically, I showed gene expression changes were accompanied by mitochondrial fragmentation, enhanced mitophagy, and increased mitochondrial fission. The morphological changes were reversible after recovery from sleep, and directly manipulating mitochondrial dynamics affected sleep behaviour.</p> <p>To further delineate mitochondrial changes in the dFB neurons after sleep, I developed and designed a genetically encoded voltage indicator for the mitochondrial membrane. Upon validation, this tool should allow in-vivo imaging of mitochondrial membrane potential over more extended time frames and provide a readout of mitochondrial dysfunction.</p> |
| spellingShingle | Neuroscience Monaco, N Illuminating and sculpting the structure and function of mitochondria in sleep-control neurons |
| title | Illuminating and sculpting the structure and function of mitochondria in sleep-control neurons |
| title_full | Illuminating and sculpting the structure and function of mitochondria in sleep-control neurons |
| title_fullStr | Illuminating and sculpting the structure and function of mitochondria in sleep-control neurons |
| title_full_unstemmed | Illuminating and sculpting the structure and function of mitochondria in sleep-control neurons |
| title_short | Illuminating and sculpting the structure and function of mitochondria in sleep-control neurons |
| title_sort | illuminating and sculpting the structure and function of mitochondria in sleep control neurons |
| topic | Neuroscience |
| work_keys_str_mv | AT monacon illuminatingandsculptingthestructureandfunctionofmitochondriainsleepcontrolneurons |