Sleep is an essential process for physical and cognitive health, and plays an important
role in cognitive processes such as learning and memory. Impairments to the sleepwake cycle, including reductions in rapid eye movement (REM) sleep occur alongside
cognitive deficits in many neurodegenerative diseases, such as Alzheimer’s Disease
(AD). However, many aspects of sleep regulation, particularly for REM sleep remain
to be fully characterised. Across the sleep-wake cycle, astrocytic intracellular Ca2+
levels fluctuate, with distinct changes occurring across different brain regions.
Conflicting results have been reported regarding astrocytes in the pons, a region which
is known to be involved in regulating REM sleep, with both reduced and relatively high
Ca2+ signals upon REM sleep induction being reported. Thus, how pontine astrocytes
contribute to REM sleep regulation remains unclear. Bridging the gap in this
knowledge would benefit our understanding of REM sleep regulation, and provide
valuable insight for disorders in which REM sleep is altered.
In this project, we hypothesised that manipulating pontine astrocyte activity would
modulate REM sleep regulation. To test this, we virally induced hM3Dq receptor
expression in pontine astrocytes, under the control of a gfaABC1D promotor, and
monitored electroencephalography (EEG) and electromyography (EMG) activity to
classify sleep states. We found that activating pontine astrocytes causes a significant
reduction in the total percent of REM sleep and the number of REM sleep episodes
across six hours in a dose-dependent manner (1, 5, and 10 mg/kg clozapine-N-oxide
(CNO)) compared to controls. We also show that rebound REM sleep in the hours
following this effect did not occur.
We next hypothesised that the reductions in REM sleep caused by chemogenetic
manipulations of astrocytes would have a detrimental effect on spatial memory. We
found a trend for reduced spatial memory, but not object recognition memory, in
chemogenetically modified mice.
Finally, we conducted a pilot study to determine if astrocytic Ca2+ levels were increased
following CNO administration. We observed some state-dependent changes in
v
exemplar data but were not able to confirm this trend across animals due to technical
limitations.
Overall, our study shows that REM sleep is reduced following chemogenetic activation
of pontine astrocytes. We included appropriate negative controls to validate our
findings. For the first time, we show that this effect is dose dependent, does not induce
rebound REM sleep, and has a tendency to impair spatial memory. Thus, in summary,
our results suggest a causal role of pontine astrocytes in REM sleep induction, which
is an important finding for our understanding of REM sleep regulation.
| Date of Award | 29 Nov 2024 |
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| Original language | English |
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| Awarding Institution | - University Of Strathclyde
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| Sponsors | University of Strathclyde |
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| Supervisor | Shuzo Sakata (Supervisor) & Keith Mathieson (Supervisor) |
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