Investigating the genetic basis of sleep using forward genetics
<p>The alternation between waking and sleep is regulated by the internal circadian clock and sleep-wake history, and is also influenced by the external environment. Although our understanding of the circadian aspect of sleep regulation has increased, the mechanisms underlying sleep homeostasis...
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| Format: | Thèse |
| Langue: | English |
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2018
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| _version_ | 1826315682270150656 |
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| author | Guillaumin, M |
| author2 | Peirson, S |
| author_facet | Peirson, S Guillaumin, M |
| author_sort | Guillaumin, M |
| collection | OXFORD |
| description | <p>The alternation between waking and sleep is regulated by the internal circadian clock and sleep-wake history, and is also influenced by the external environment. Although our understanding of the circadian aspect of sleep regulation has increased, the mechanisms underlying sleep homeostasis are still largely unknown. Independent of the circadian clock, only a limited number of genes have been associated with specific sleep-wake properties. Forward genetics provides an unbiased approach, which seeks to identify genes involved in specific biological processes. This project has focused on the Sleepy6 mouse line which was obtained via a forward genetics sleep screen. This model has a mutation in synaptobrevin 2, which results in a decreased sleep duration. We aimed to further characterise the sleep phenotype of this line, at a molecular and behavioural level, to gain novel insights into the regulation of sleep. Using molecular techniques to evaluate neurotransmitter levels and gene expression, we found no significant differences in the neurotransmitter pathways investigated. Behavioural assays highlighted hyperactivity, with a mild learning deficit. Electrophysiology recordings from the motor (M1) and visual (V1) cortical areas revealed that Sleepy6 homozygous mice have reduced amounts of rapid-eye movement sleep (REMS) and a strong decrease in the amplitude of electroencephalography (EEG) and local field potential (LFP) signals, especially during non-REMS when traces are reminiscent of the burst suppression patterns often observed during anaesthesia, rather than natural sleep. At a local level, neuronal firing in Sleepy6 homozygotes ceased for seconds at a time during non-REMS, coinciding with very low-amplitude EEG and LFP traces. Sleepy6 homozygous mice also displayed a longer latency to switch between vigilance states. Finally, the successful adaption of an elaborated version of the “two-process” model of sleep regulation to recordings performed in mice suggests that sleep pressure decreases at a slower rate in Sleepy6 homozygotes. This result should be interpreted in light of the above findings, as the model relies on power in the slow-wave (0.5-4 Hz) range during non-REMS, which is affected by the very low-amplitude oscillations observed in this state in Sleepy6 homozygotes. This combination of in vivo and computational work using the Sleepy6 line provides new insights into the mechanisms that underlie sleep architecture and the alternation between vigilance states. It also has the potential to further our understanding of the mechanisms underpinning the generation of slow-waves and anaesthesia.</p> |
| first_indexed | 2024-03-06T18:57:46Z |
| format | Thesis |
| id | oxford-uuid:126e9ed6-d0f8-4100-9f09-a39c2add9d4f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:30:32Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | oxford-uuid:126e9ed6-d0f8-4100-9f09-a39c2add9d4f2024-12-01T13:53:47ZInvestigating the genetic basis of sleep using forward geneticsThesishttp://purl.org/coar/resource_type/c_db06uuid:126e9ed6-d0f8-4100-9f09-a39c2add9d4fSleepNeurosciencesEnglishORA Deposit2018Guillaumin, MPeirson, SVyazovskiy, V<p>The alternation between waking and sleep is regulated by the internal circadian clock and sleep-wake history, and is also influenced by the external environment. Although our understanding of the circadian aspect of sleep regulation has increased, the mechanisms underlying sleep homeostasis are still largely unknown. Independent of the circadian clock, only a limited number of genes have been associated with specific sleep-wake properties. Forward genetics provides an unbiased approach, which seeks to identify genes involved in specific biological processes. This project has focused on the Sleepy6 mouse line which was obtained via a forward genetics sleep screen. This model has a mutation in synaptobrevin 2, which results in a decreased sleep duration. We aimed to further characterise the sleep phenotype of this line, at a molecular and behavioural level, to gain novel insights into the regulation of sleep. Using molecular techniques to evaluate neurotransmitter levels and gene expression, we found no significant differences in the neurotransmitter pathways investigated. Behavioural assays highlighted hyperactivity, with a mild learning deficit. Electrophysiology recordings from the motor (M1) and visual (V1) cortical areas revealed that Sleepy6 homozygous mice have reduced amounts of rapid-eye movement sleep (REMS) and a strong decrease in the amplitude of electroencephalography (EEG) and local field potential (LFP) signals, especially during non-REMS when traces are reminiscent of the burst suppression patterns often observed during anaesthesia, rather than natural sleep. At a local level, neuronal firing in Sleepy6 homozygotes ceased for seconds at a time during non-REMS, coinciding with very low-amplitude EEG and LFP traces. Sleepy6 homozygous mice also displayed a longer latency to switch between vigilance states. Finally, the successful adaption of an elaborated version of the “two-process” model of sleep regulation to recordings performed in mice suggests that sleep pressure decreases at a slower rate in Sleepy6 homozygotes. This result should be interpreted in light of the above findings, as the model relies on power in the slow-wave (0.5-4 Hz) range during non-REMS, which is affected by the very low-amplitude oscillations observed in this state in Sleepy6 homozygotes. This combination of in vivo and computational work using the Sleepy6 line provides new insights into the mechanisms that underlie sleep architecture and the alternation between vigilance states. It also has the potential to further our understanding of the mechanisms underpinning the generation of slow-waves and anaesthesia.</p> |
| spellingShingle | Sleep Neurosciences Guillaumin, M Investigating the genetic basis of sleep using forward genetics |
| title | Investigating the genetic basis of sleep using forward genetics |
| title_full | Investigating the genetic basis of sleep using forward genetics |
| title_fullStr | Investigating the genetic basis of sleep using forward genetics |
| title_full_unstemmed | Investigating the genetic basis of sleep using forward genetics |
| title_short | Investigating the genetic basis of sleep using forward genetics |
| title_sort | investigating the genetic basis of sleep using forward genetics |
| topic | Sleep Neurosciences |
| work_keys_str_mv | AT guillauminm investigatingthegeneticbasisofsleepusingforwardgenetics |