L1 - SLEEP: THEORIES OF SLEEP FUNCTION

Question 1

energy conservation (NREM)
- JM Siegel 2005; Bringhamm H 2019

Answer 1

• inactive state = adaptive mechanism for energy conservation akin to hybernation
• sleep & torpor (metabolic & behavioural inactivity) involve phases of NREM, suggesting a related mechanism –> differ in reversability
• energy saved during sleep is redirected to restorative processes like anabolic biosynthetic reactions
• large herbivores = reduced sleep –> more time for foraging
• small herbivores = more time asleep –> high SA:BM, which increases energy costs for maintaining body temp so they need to conserve energy
• despite, animals w/ low sleep amounts do not compensate by deeper sleep
• sleep reduces exposure to danger for immature animals, with sleep decreasing as sensory-motor systems mature

Question 2

regulating core molecular & cellular processes
- JM Siegel 2005; Bringhamm H 2019

Answer 2

• faciliates key housekeeping functions –> studies show increased expression of genes required for biosynthesis & transport during sleep

1) anabolic metabolism = promotes growth, stress resistance and immune system support

2) defense against oxidative stress = protection, repair and mitigating damage
- small animals = increased metabolism = increased production of ROS by mitochondria
- sleep deprivation of rats = increased oxidative stress, particularly in supraoptic nucleus of hyppthalamus (area associated with increased protein synthesis)

3) sleep deprivation is associated w/ hormonal changes linked to metabolic syndromes & obesity

4) sleep may present a metabolic cycle, compartmentalising processes for efficiency
- eg. P of synaptic proteins (increases during wake, decreases during sleep), regualted by SIK3, implicated in lipid & sugar metabolism

5) sleep faciliates the removal of potentially toxic molecules like protein aggregates form the brain; potentially through neuronal shrinkage leading to increased interstitial fluid flux

Question 3

supporting higher brain functions

Answer 3

• role in learning & memory, supported by evidence indicating increased expression of genes involved in plasticity and protein synthesis during sleep; disturbed sleep impacts concentration & learning
• memory formation invovles synaptic changes; certain strenghtening/ weakening/ forming/ disappering
• wakefulness increases synaptic size, sleep promotes synaptic downscaling
• disconnecting neural circuits from sensory inputs during sleep may enable brain circuit restructuring, fostering novel associations

Question 4

development

Answer 4

• REM sleep levels are v. high at birth; gradually decreases –> suggest that it may play a role in development
• studies show that REM sleep deprivation during critical periods accelarated shrinkage in brain regions affected by sensory deprivation, suggesting that REM prevents pruning of unused neural connections during development

Question 5

wakefulness/ alertness

Answer 5

• REM sleep stimulates the effects of NREMS on subsequent waking behaviour, potentially conveying a selective advantage by awakening in a more alert state

Question 6

synaptic renormalisation theory

Answer 6

during the day as we engage in various activities, our brains are constantly forming & strengthening millions of synaptic connections:
- essential for encoding memories, processing information & facilitating various cognitive functions
- however, it can’t go on indefinitely w/o causing information overload or cluttering the brain w/ uneccessary connections
- so the idea of synaptic renormalization suggests that during sleep, the brain undergoes a cleaning up process & refines these synaptic connections

• when the brain is not actively engaging in processing external stimuli, it can dedicate its resources to pruning away weaker/ uneccesary synaptic connections –> helps streamline neural networks, improving efficiency, and allwoing for more effective information processing during wakefulness

Question 7

synaptic renormalisation theory
- Ascady & Harris. 2017. Science

Answer 7

sleep plays a crucial yet enigmatic role in cognitive function, w / 2 main theories suggesting its function:
- “restorative theories” = maintenance activities like repairing cellular machinery
- “information processing” = allows computational processes like memory consolidation

• recent studies shed light on synaptic changes during sleep, confirming synaptic downscaling, where synapse strength decreases
• de vivo et al. = 20% reduction in the area of axon terminals in contact w/ spines during sleep, particularly in smaller spines, indicating weaker synapses
• diering et al = decreased spine size and glutamate receptor content during sleep; noradernaline and adenosine, alternating w/ the sleep cycle, were identified as neuromodulators driving these changes
• despite these advancements, questions remain regarding the computational function of synaptic downscaling during sleep, and the specific synapses affected

Question 8

glymphatic hypothesis

Answer 8

• through innovative experiments involving fluorescent tracers injected into the CSF, researchers have observed distinct differences in CSF dynamics between wakefulness & sleep
• during wakefulness = penetration of CSF into brain appears limited
• in sleeping/ anaesthesised state = substantial increase in CSF influx into brain tissue –> suggests that sleep enhances the clearance of toxins & waste products from the brain, possibly through a mechanism analogous to the lymphatic system in other parts of the body
• it’s a particularly important process for removing amyloid-b, precursor to AD, which forms plaques
• remains unclear whether the increased penetration of CSF into the brain during sleep is due to enhanced clearance mechanism or reduced CSF outflow
• consistent w/ observations of decreased AB during sleep but unclear if its primarily due to enhanced clearance or reduced production of AB
• suggests that interventions aimed at enhancing glymphatic function (eg. certain sedatives like dexmedetodimine), may have therapeutic potential for preventing or treating neurodegenerative disorders like AD
• however, further research is needed to fully elucidate the mechanisms underlying the glymphatic system & its relevance to brain health & disease

Question 9

glymphatic hypothesis
- Xie et al. 2013. Science

Answer 9

• proteins associated w/ neurodegenerative disorders are present in the brain in the interstitial space –> the glymphatic system, involving the exchange of CSF & ISF, facilitates their removal
• studies suggest the glymphatic system’s efficiency may be linked to sleep-wake
• in vivo mice imaging = CSF influx into the brain is significantly higher during sleep than wakefulness/ anaesthesia
• arousal sharply decreases CSF influx –> suggests that the state of brain activity regulates glymphatic clearance
• influx of CSF into brain is influenced by arterial pulse waves, which propel CSF movement inward along periarterial spaces –> however, diurnal fluctuations in arterial pulsations are unlikely to account for the significant suppression of CSF fluxes during wakefulness, as arterial blood pressure is higher during physical activity
• an alternative explanation is that wakefulness is associated w/ a reduction in the volume of the interstitial space, increasing resistance to the fluid movement & suppressing CSF influx
• real time iontophoretic tetramethyl-ammonium recordings = interstitial space volume is significantly smaller in awake mice than sleep mice
• experiments w/ radiolabelled AB & inert tracer 14C-insulin showed that AB and solute clearance are more efficient during sleep & anaesthesia than wake
• noradrenergic signaling, critical for arousal, may play a role in modifying cell volume & size of interstitial space:
• administering adrenergic receptor antagonists increases CSF tracer influx in awake mice, suggesting that adrenergic signalling suppresses glymphatic solute clearance in wake state
• inhibition of adrenergic receptors in the cortex increase intersititial volume, similar to effects observed during sleep (associated w/ a shift in cortical neuron activity)