Molecular machinery and cell biology of sleep control
<p>Sleep is vital and universal, yet its essential biological functions remain elusive.</p> <p>The sleep homeostat tracks an internal process that generates sleep pressure during waking, which is then periodically discharged by initiating sleep. Understanding the molecular nature...
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| Format: | Thesis |
| Language: | English |
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2022
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| _version_ | 1817932037600837632 |
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| author | Sarnataro, R |
| author2 | Miesenboeck, G |
| author_facet | Miesenboeck, G Sarnataro, R |
| author_sort | Sarnataro, R |
| collection | OXFORD |
| description | <p>Sleep is vital and universal, yet its essential biological functions remain elusive.</p>
<p>The sleep homeostat tracks an internal process that generates sleep pressure during waking, which is then periodically discharged by initiating sleep. Understanding the molecular nature of sleep pressure and its regulation by the homeostat will help to elucidate the physiological variables linked to the essential function of sleep.</p>
<p>In Drosophila, rising sleep pressure increases the activity of sleep-control neurons projecting to the dorsal fan-shaped body (dFB). Sleep need is encoded in the intrinsic excitability of these neurons, which fluctuates because two potassium conductances, voltage-gated Shaker and the leak channel Sandman, are modulated antagonistically. Signalling cascades transducing sleep pressure into sleep must thus converge on the regulation of currents flowing through these two ion channels.</p>
<p>To obtain a comprehensive view of the molecular machinery operating within dFB neurons, I have characterised transcriptomes of single cells isolated from dissociated brains of rested and sleep-deprived flies.
These studies revealed a mechanism of bidirectional control of mitochondrial dynamics and sleep in dFB neurons. Sleep loss selectively upregulates genes encoding mitochondrial proteins and alters mitochondrial dynamics in these neurons. Conversely, manipulating mitochondrial fission and fusion in dFB neurons affects sleep in opposing ways. Since mitochondrial dynamics reflect and influence ATP synthesis and ROS production, they suggest a causal link to cellular oxidative stress, which is recorded by Shaker's redox-sensitive β-subunit and converted to heightened neuronal excitability driving sleep.</p>
<p>At the synaptic level, sleep deprivation decreases the strength of dFB neuron output synapses, which release the (in the Drosophila CNS inhibitory) transmitter glutamate. The neurons are heterogeneous in the expression of an octopamine receptor, whose cognate monoamine calibrates sleep.</p>
<p>These studies, based on the first single-cell transcriptome of an animal’s sleep-control neurons in different conditions of sleep pressure, advance our understanding of how sleep-control is implemented in the brain.</p> |
| first_indexed | 2024-03-07T07:31:23Z |
| format | Thesis |
| id | oxford-uuid:16a70d1b-caac-498d-a847-9c259adc1cd3 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:31:33Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | oxford-uuid:16a70d1b-caac-498d-a847-9c259adc1cd32024-12-01T14:55:09ZMolecular machinery and cell biology of sleep controlThesishttp://purl.org/coar/resource_type/c_db06uuid:16a70d1b-caac-498d-a847-9c259adc1cd3Molecular biologySleepNeurosciencesDoctor of philosophy degreeCytologyMitochondriaPhysiologyEnglishHyrax Deposit2022Sarnataro, RMiesenboeck, G<p>Sleep is vital and universal, yet its essential biological functions remain elusive.</p> <p>The sleep homeostat tracks an internal process that generates sleep pressure during waking, which is then periodically discharged by initiating sleep. Understanding the molecular nature of sleep pressure and its regulation by the homeostat will help to elucidate the physiological variables linked to the essential function of sleep.</p> <p>In Drosophila, rising sleep pressure increases the activity of sleep-control neurons projecting to the dorsal fan-shaped body (dFB). Sleep need is encoded in the intrinsic excitability of these neurons, which fluctuates because two potassium conductances, voltage-gated Shaker and the leak channel Sandman, are modulated antagonistically. Signalling cascades transducing sleep pressure into sleep must thus converge on the regulation of currents flowing through these two ion channels.</p> <p>To obtain a comprehensive view of the molecular machinery operating within dFB neurons, I have characterised transcriptomes of single cells isolated from dissociated brains of rested and sleep-deprived flies. These studies revealed a mechanism of bidirectional control of mitochondrial dynamics and sleep in dFB neurons. Sleep loss selectively upregulates genes encoding mitochondrial proteins and alters mitochondrial dynamics in these neurons. Conversely, manipulating mitochondrial fission and fusion in dFB neurons affects sleep in opposing ways. Since mitochondrial dynamics reflect and influence ATP synthesis and ROS production, they suggest a causal link to cellular oxidative stress, which is recorded by Shaker's redox-sensitive β-subunit and converted to heightened neuronal excitability driving sleep.</p> <p>At the synaptic level, sleep deprivation decreases the strength of dFB neuron output synapses, which release the (in the Drosophila CNS inhibitory) transmitter glutamate. The neurons are heterogeneous in the expression of an octopamine receptor, whose cognate monoamine calibrates sleep.</p> <p>These studies, based on the first single-cell transcriptome of an animal’s sleep-control neurons in different conditions of sleep pressure, advance our understanding of how sleep-control is implemented in the brain.</p> |
| spellingShingle | Molecular biology Sleep Neurosciences Doctor of philosophy degree Cytology Mitochondria Physiology Sarnataro, R Molecular machinery and cell biology of sleep control |
| title | Molecular machinery and cell biology of sleep control |
| title_full | Molecular machinery and cell biology of sleep control |
| title_fullStr | Molecular machinery and cell biology of sleep control |
| title_full_unstemmed | Molecular machinery and cell biology of sleep control |
| title_short | Molecular machinery and cell biology of sleep control |
| title_sort | molecular machinery and cell biology of sleep control |
| topic | Molecular biology Sleep Neurosciences Doctor of philosophy degree Cytology Mitochondria Physiology |
| work_keys_str_mv | AT sarnataror molecularmachineryandcellbiologyofsleepcontrol |