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Clocks, Sleep & Rhythms Of Life > Lectures 10-12 > Flashcards

Lectures 10-12 Flashcards

1
Q

What are the two main definitions of sleep?

A

Behavioural: A normal absence of consciousness.

Electrophysiological: A pattern of specific brain wave activity.

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2
Q

What is the transition from waking to ‘sleep’ associated with?

A

An overall decrease in neuronal activity.

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3
Q

Why is sleep NOT a global ‘turning down’ of brain activity?

A

It’s a deliberate and active process:

Sleep is a series of precisely controlled brain states and the sequence is determined by activity of specific brain nuclei.

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4
Q

Why do we sleep?

A

Sleep is a basic homeostatic function that occurs in some fashion in all multicell organisms.

The requirement for sleep increases with the time spent awake.

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5
Q

What is the relationship between sleep duration and organism size?

A

The duration of sleep appears to increase with organism size.

Smaller organisms tend to alternate between short bouts of sleeping/waking - suggested due to reduced capacity for wakefulness or as a requirement for increased vigilance

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6
Q

Describe the general trend of sleep duration in humans as they age.

A

From when you are born, there is a downwards trend from ~16 hours of sleep to ~6-7 hours per night.

This goes from 16 -> 12 hours in the first year, then 12 -> 10 hours when you are 10 years old, and sloping down from 10 -> 8 and below once you’re 20 years old.

It’s also not just the amount of time that you sleep for that changes, it’s also the patterns of sleep (when a child it’s more sporadic, adults it’s more consistent).

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7
Q

Why do you need to sleep?

A

Across all organisms, we know that sleep is critical for the maintenance of cognitive function - without sleep you will die.

STUDY: used electrophysiological recordings in rats and just as they were showing that they were about to sleep, they would then shake the cage keeping them in perpetual sleep deprivation.

After 2 weeks, the rats would die. This is impressive given their relative lifespan.

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8
Q

What is the main methodology to measure sleep?

A

Electroencephalography (EEG).

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9
Q

What are the main advantages of using EEG in sleep research?

A

It provides a continuous recording of brain activity.

It’s cheap and non-invasive - it can be taken home to be worn during sleep.

It allows a quantitative measure of whether someone is actually asleep or not.

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10
Q

What is ECoG?

A

Electrocorticogram - it’s when the cortex is exposed and the electrodes are placed directly on its surface.

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11
Q

What are the two main measurements in which EEG waveforms are measured?

A

According to their amplitude and frequency.

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12
Q

What is the general rule about the brain waves waveform as you fall asleep?

A

The amplitude gets bigger and the frequency gets slower as you get into deeper sleep.

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13
Q

Provide an overview of EEG sleep stages.

A

EEG Sleep Stages Overview

  • NREM Sleep:
    • Stage 1: Alpha → theta waves; light sleep, easy to wake.
    • Stage 2: Theta waves with sleep spindles & K-complexes; stable sleep.
    • Stage 3: Delta waves; deep sleep, hard to wake, essential for recovery.
  • REM Sleep:
    • EEG resembles wakefulness (low amplitude, mixed frequency).
    • Rapid eye movements, muscle paralysis, vivid dreams.
  • Sleep Cycles: ~90 min; more deep sleep early, more REM later.
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14
Q

Outline the key details of alpha waves

A
  • Frequency: 8-13 Hz
  • Associated with: Relaxed wakefulness, calm focus (e.g., eyes closed but awake).
  • Common location: Occipital and parietal regions.
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15
Q

Outline the key details of beta waves

A
  • Frequency: 13-30 Hz
  • Associated with: Active thinking, problem-solving, and alertness.
  • Common location: Frontal and central regions.
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16
Q

Outline the key details of theta waves

A
  • Frequency: 4-8 Hz
  • Associated with: Light sleep, deep relaxation, and drowsiness.
  • Common location: Temporal and parietal regions.
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17
Q

Outline the key details of delta waves

A
  • Frequency: 0.5-4 Hz
  • Associated with: Deep sleep (Stage 3 NREM), restorative processes.
  • Common location: Frontal regions during deep sleep.
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18
Q

Outline the key details of gamma waves

A
  • Frequency: 30-100 Hz
  • Associated with: High-level cognition, attention, and memory binding.
  • Common location: Distributed across the brain.
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19
Q

What did Kleitman and Aserinsky show about sleep in 1953?

A

Using EEG recordings they showed that sleep consists of a number of ages that occur in a characteristic sequence.

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20
Q

What is the average amount of sleep cycles per night and what type of chart would show you this?

A

Average of 5 sleep cycles/night.

A hypnogram.

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21
Q

What are the unique characteristics of REM/SWS and deep sleep as a person goes through all the sleep cycles?

A

REM duration increases/SWS decreases throughout the sleep bout.

Deep sleep is only present in the first two cycles.

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22
Q

What is an EOG?

A

Electrooculogram

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23
Q

What is an EMG?

A

Electromyogram

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24
Q

What does a hypnogram show?

A

The proportion of time spent in different sleep stages

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25
Q

What do EOGs reveal about sleep?

A

That eye movement is most active during REM.

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26
Q

What do EMGs reveal about sleep?

A

Neck movement is most prominent at waking and REM transitions.

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27
Q

What happens to heart rate and respiration levels during REM?

A

They peak to waking levels.

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28
Q

What are the three interacting neural systems that actively control sleep (at least)?

A

Forebrain System - can independently support SWS.

Brainstem System - activates the forebrain into waking.

System in the Pons - triggers REM sleep.

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29
Q

What studies were critical for identifying the 3 interacting neural systems that actively control sleep?

A

Frederic Bremer nerve transection studies performed in Cats.

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30
Q

What is the role of the forebrain in actively controlling sleep?

A

It can independently support SWS.

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31
Q

What is the role of the brainstem in actively controlling sleep?

A

It activates the forebrain into waking.

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32
Q

What is the role of the system in the Pons in actively controlling sleep?

A

It triggers REM sleep.

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33
Q

Outline the Encephale Isole study by Frederic Bremer (1935).

A

METHODS:
- Used cats and performed a transection between the medulla and the spinal cord.
- This left the brain fully isolated and would highlight the role of the spinal input.

RESULTS:
- The brain went through all the stages of sleep.
- This showed that Spinal Input is not required for waking.

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34
Q

Outline the Cerveau Isole study by Frederic Bremer (1935).

A

METHODS:
- He performed a transection between the brainstem and the midbrain so that only the forebrain was present.
- Looked to see what happened to sleep.

RESULTS:
- He found that the brain was stuck in a constant state of SWS.
- This showed that there was a region in the forebrain that was causing SWS (later found to be the VLPO).

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35
Q

What is known about the VLPOs role in sleep?

A

Frederic Bremer first showed that isolating the forebrain meant that the brain was stuck in SWS, showing the presence of it’s production here.

Later, studies showed that if you stimulated the VLPO you can make animals fall asleep and that lesions would abolish this type of sleep.

Thus, it seems to be a crucial site for SWS initiation.

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36
Q

Provide a general overview as to how the VLPO in involved in sleep.

A

Neurons in the VLPO become active at sleep onset.

It’s neurons are inhibitory (GABAergic) and project widely across the brain.

Their stimulation/activation induces SWS.

VLPO neurons are inhibited by neurochemicals associated with arousal (Noradrenaline, ACh, Histamine and 5HT).

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37
Q

If an isolated Forebrain leads to a brain stuck in SWS, what can be inferred about the rest of the brains role in sleep?

A

Forebrain = SWS only.

Brainstem & Forebrain = Can shift between all sleep stages.

Thus, the parts controlling waking and REM must be controlled in the brainstem.

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38
Q

What is the ARAS?

A

Ascending Reticular Activation System.

It’s a set of major brainstem arousal pathways that plays a major role in generating waking and REM sleep.

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39
Q

Describe in detail the Flip-flop model by Saper et al., (2005).

A

This is the current conceptual model about how the control between sleep and wake works.

There are two sets of mutually antagonistic/opposing cells.

VLPO is sleep promoting and inhibits the wake-promoting cells via Galanin/GABA.

Inputting the following wake-promoting regions:
- TMN - Tuberomammillary Nucleus (Hypothalamus)
- DR - Dorsal Raphe (Brainstem)
- LC - Locus Coeruleus (Brainstem)
- LDT/PPT - Laterodorsal tegmental/pedunculopontine tegmental (Brainstem).

The reverse is true too; the wake-promoting regions input the VLPO and inhibit it using the following neurotransmitters:

  • TMN - GABA/Histamine
  • DR - Serotonin
  • LC - Noradrenaline
  • LDT/PPT - Acetylcholine.

*These connections between cell groups are not necessarily direct.

Via interneurons their signals can be flipped.

So as this stands, everyone is inhibiting everyone.

For the model to work, you need something to come tip the ‘balance’ between wake and sleep.

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40
Q

What are the wake promoting areas in the Flip-Flop model? (4)

A
  • TMN - Tuberomammillary Nucleus (Hypothalamus)
  • DR - Dorsal Raphe (Brainstem)
  • LC - Locus Coeruleus (Brainstem)
  • LDT/PPT - Laterodorsal tegmental/pedunculopontine tegmental (Brainstem)
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41
Q

What is the neurotransmitter used by the Tuberomamillary Nucleus in the Flip-Flop model? What does it do?

A

GABA/Histamine - Inhibit the sleep-promoting VLPO.

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42
Q

What is the neurotransmitter used by the Dorsal Raphe in the Flip-Flop model? What does it do?

A

Serotonin - Inhibit the sleep-promoting VLPO.

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43
Q

What is the neurotransmitter used by the Locus Coeruleus in the Flip-Flop Model? What does it do?

A

Noradrenaline - Inhibit the sleep-promoting VLPO.

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44
Q

What is the neurotransmitter used by the Laterodorsal Tegmental/Pedunculopontine Tegmental in the Flip-Flop model? What does it do?

A

Acetylcholine - Inhibit the sleep-promoting VLPO.

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45
Q

What is the neurotransmitter used by the Ventral Lateral Preoptic Area in the Flip-Flop Model? What does it do?

A

Galanin/GABA - inhibits the wake-promoting areas.

  • TMN - Tuberomammillary Nucleus (Hypothalamus)
  • DR - Dorsal Raphe (Brainstem)
  • LC - Locus Coeruleus (Brainstem)
  • LDT/PPT - Laterodorsal tegmental/pedunculopontine tegmental (Brainstem)
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46
Q

What seems to be the neurotransmitter that provides excitatory input to wake-promoting neurons in the Flip-Flop model?

A

Orexin/Hypocretin.

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47
Q

What seems to be the neurotransmitter that provides excitatory input to sleep-promoting neurons in the Flip-Flop model?

A

Adenosine seems to be a likely candidate.

It’s not agreed upon yet…

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48
Q

Outline the potential reason for Adenosine to be a sleep regulator.

A

Adenosine is a by product of energy metabolism.

During intense neural activity, it will build up in the extracellular space.

So, the longer you’re awake, the more of it you have in your brain - whilst you sleep it will be cleared.

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49
Q

What are 4 major pieces of evidence as to why Adenosine might be a sleep regulator?

A

Adenosine levels increase during waking and decrease during sleep.

Adenosine agonists increase sleep.

Adenosine receptor antagonists (e.g., caffeine) inhibit sleep

Adenosine activates the VLPO (sleep promoting) neurons.

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50
Q

What are the two pathways of the Ascending Reticular Activating System (ARAS)?

A

Dorsal and Ventral.

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51
Q

What is the dorsal pathway of the ARAS? Include its route, neurotransmitters, and roles in wakefulness and sleep.

A

Route: Brainstem → Thalamus → Cerebral Cortex

Neurotransmitters: Acetylcholine (ACh)

Role in Wakefulness: Maintains arousal by enhancing sensory relay through the thalamus.

Role in Sleep: Active during REM sleep, facilitating sensory experiences in dreams.

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52
Q

What is the ventral pathway of the ARAS? Include its route, neurotransmitters, and roles in wakefulness and sleep.

A

Route: Brainstem → Hypothalamus → Basal Forebrain → Cerebral Cortex

Neurotransmitters: Monoamines (Norepinephrine, Serotonin, Histamine, Dopamine), Orexin

Role in Wakefulness: Stabilizes wakefulness by promoting cortical activation and preventing transitions to sleep.

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53
Q

What is the source and role of noradrenaline in arousal and wakefulness?

A

Source: Locus Coeruleus

Role: Promotes wakefulness

Targets: Neocortex, Hippocampus, Thalamus, Hypothalamus, Cerebellum, Brainstem

Drugs: Amphetamines (+) arousal/wakefulness

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54
Q

What is the source and role of serotonin in arousal and wakefulness?

A

Source: Raphe Nuclei

Role: Promotes wakefulness

Targets: Neocortex, Hippocampus, Thalamus, Basal Ganglia, Hypothalamus

Drugs: MDMA (+) arousal/wakefulness

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55
Q

What is the source and role of histamine in arousal and wakefulness?

A

Source: Tuberomammillary Nucleus

Role: Promotes wakefulness

Targets: Neocortex, Hippocampus, Thalamus, Basal Ganglia, Hypothalamus

Drugs: Antihistamines (-) drowsiness/sleep (Note: newer versions that do not cross the blood-brain barrier lack this effect)

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56
Q

Describe the relationship between the spikes/second of Noradrenaline cells and the sleep/wake of a rat.

A

The activity in the cell is high when the animal is awake and then it declines.

As the cell starts to switch off, it begins to shift into SWS.

It continues to taper off until REM sleep where there is almost NO activity.

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57
Q

What is the source and role of acetylcholine in arousal and wakefulness?

A

Source: Pedunculopontine Tegmental Nucleus (PPTN) and Laterodorsal Tegmental Nucleus (LDTN)

Role: Promotes wakefulness

Targets: Thalamus, Cortex, Basal Ganglia, and Basal Forebrain

Drugs:
Cholinesterase inhibitors (+): Enhance ACh availability (used in Alzheimer’s to improve cognition).

Anticholinergics (-): Reduce ACh activity (cause sedation or impair wakefulness).

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58
Q

What happens if you stimulate cholinergic neurons in the ascending reticular activating system?

A

It produces arousal and wakes the animal up (if it was sleeping ofc).

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59
Q

What is the relation to ACh cells and wake, REM and SWS?

A

High firing during wake and REM

Low firing during SWS.

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60
Q

What causes changes in mental states revealed by EEG during sleep?

A

Changes in mental states revealed by EEG result from changes in communication between the thalamus and cortex.

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61
Q

What brainstem inputs do thalamocortical cells receive?

A

Thalamocortical cells receive brainstem inputs from:

Locus coeruleus (noradrenaline)
Raphe nuclei (serotonin)
Pontine nuclei (cholinergic)

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62
Q

What happens when activity in brainstem afferents decreases?

A

When activity in brainstem afferents decreases:

Thalamic rhythmic bursting occurs.
There is increased synchrony of cortical targets.

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63
Q

What does EEG show during sleep (stage 4) and wakefulness?

A

During sleep (Stage 4):

Synchronous activity of many thalamic and cortical neurons.

Appears as high amplitude slow waves (delta activity).

During wakefulness:

Asynchronous activity across thalamic and cortical neurons.

Appears as alpha and beta activity.

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64
Q

What does EEG measure (during sleep research) and how does it differ during sleep and wakefulness?

A

EEG measures: Communication from the thalamus to the cortex, recording groups of cortical cells switching on or off.

During sleep: Thalamic cells rhythmically switch on and off, creating synchronous slow waves.

During wakefulness: Thalamic cells stop rhythmic switching and instead respond to sensory information they are tuned to, resulting in asynchronous activity.

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65
Q

What are the three main types of neurons involved in the interactions between the cortex and thalamus during SWS?

A

Corticothalamic (CT) neurons.

Thalamocortical (TC) neurons.

Thalamic Reticular (RE) neurons.

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66
Q

In the Thalamic SWS Circuit, name the following neurons and whether they are excitatory or inhibitory and what neurotransmitter they use: CT, TC, RE.

A

CT = Corticothalamic Neurons, Excitatory, Glutamate.

TC = Thalamocortical Neurons, Excitatory, Glutamate.

RE + Thalamic Reticular Neurons, Inhibitory, GABA

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67
Q

Briefly explain the inputs and output between the three main neuron types in the Thalamic SWS Circuit.

What does this structure optimise for?

A

CT and TC are excitatory and excite each other.

RE cells are inhibitory and have excitatory inputs from CT and TC cells.

RE cells only have an inhibitory input to TC cells.

This structure is optimised for rhythmic activity

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68
Q

What is the typical activity of thalamocortical cells?

A

They show very rhythmic activity in membrane potential and firing.

This is an intrinsic property of TC cells; they do it automatically.

69
Q

Outline the proof that thalamocortical neurons exhibit intrinsic oscillations.

A

Used TTX which blocks Na+ channels so there are no APs and the cells cannot communicate with each other.

Despite this, the TC’s still have this rhythm, showing it’s intrinsic.

If you look at the CT and RE cells under TTX as well, they still have sustained rhythms but they are out of sync.

So the firing of APs keeps them synchronised together.

70
Q

What do Reticular neurons do to the oscillations in TC cells? What feature of them allows them to do this?

A

They synchronise them.

RE cells have dendro-dendritic synapses with other RE cells which allow them to synchronise rhythmic firing in TC cells.

(Dendrites communicate with Dendrites).

This is what allows slow wave sleep as it’s causes a rhythmic bursting.

71
Q

What effect do Brainstem inputs have on RE cells and the following cascades?

A

They switch off the RE cells and stimulate TC cells promoting asynchronous tonic TC cell firing.

72
Q

What do Brainstem inputs promote during SWS?

A

Wakefulness due to switching off the RE cells that stimulate TC cells promoting asynchronous tonic TC cell firing.

(SWS is rhythmic firing of TC cells… so promoting it to desynchronised tonic firing will wake you up).

73
Q

Briefly outline how the effect/role of Brainstem input during SWS was discovered.

A

If you depolarise the oscillating TC cells in different stages of its oscillation, you will get different results (think hyperpolarisation, peak AP, half way between).

This will ‘kick it out’ of its oscillation pattern into an intermediate level where it can no longer generate the AP.

So either it will fire a burst of spikes or not fire.

THEY ALSO switch off the cells in the Reticular nucleus - this stops individual TC cells from synching to each other so that they can only activate when sensory information comes in to activate them.

74
Q

What is the brains ‘default’ state and what does it require to kick it out of this state?

A

Slow wave activity - it requires external stimuli to kick it out of this state.

75
Q

If the brain isn’t “switched off” during sleep, what is it?

A

It’s where thalamocortical neurons revert to their default mode.

76
Q

What are the phenotypic characteristics of REM sleep?

A

Desynchronised EEG (more like waking).

Paralysis (preventing physical activity).

Rapid Eye Movements (Hence REM).

77
Q

What is the onset of REM sleep characterised by?

A

PGO waves.

Pons (Brainstem) -> Geniculate (Lateral Geniculate - visual part of thalamus) -> Occipital (visual cortex).

78
Q

What is PGO and why is it relevant?

A

It’s activity that spreads from the Pons, to the Geniculate and to the occipital.

It’s relevant because this is what characterises the onset of REM sleep.

79
Q

What type of cells control REM sleep?

A

Cholinergic Cells.

80
Q

Where are the cells and what type are they that control the origins of REM sleep?

A

Cholinergic cells in the pons.

81
Q

Where is the peribrachial area and what does it contain?

A

It’s an area in the pons that contains the Pedunculopontine Nucleus (PPN) and the Laterodorsal Tegmental Nucleus (LDT).

82
Q

What are the two main structures in the peribrachial area and what is their relevance to sleep?

A

Pedunculopontine Nucleus (PPT) and the Laterodorsal Tegmental Nucleus (LDT); they are cholinergic and fire at a high rate during REM sleep.

83
Q

What are REM-ON cells?

A

Cells that fire at a high rate during REM only.

84
Q

Outline the activity of REM-ON cells during waking, slow-wave sleep and REM sleep.

A

During waking they are next to silent, slow wave sleep they are next to silent.

They begin to fire during Pre-REM and fire highly during REM sleep.

85
Q

What are the primary features of REM sleep controlled by neural circuits?

A

Cortical activation/EEG desynchronisation

PGO waves (ponto-geniculo-occipital waves)

Rapid eye movements

Muscular paralysis

86
Q

Which brain areas are responsible for cortical activation and EEG desynchronisation during REM sleep?

A

The thalamus (LGN) and the cortex play key roles, driven by input from the basal forebrain and projections from the pontine reticular formation.

87
Q

What is the role of the peribrachial area in driving the characteristic features of REM sleep?

A

The peribrachial area drives all the characteristic features of REM sleep by projecting to:

  • The thalamus (LGN) for cortical activation and PGO waves.
  • The tectum for rapid eye movements.
  • The subcoerulear nucleus for muscular paralysis.
88
Q

What neural structures control muscular paralysis during REM sleep?

A

The subcoerulear nucleus, influenced by the peribrachial area, sends signals to the medulla, which inhibits motor activity and causes muscular paralysis.

89
Q

How are rapid eye movements (REMs) generated during REM sleep?

A

The peribrachial area projects to the tectum, which controls the rapid eye movements characteristic of REM sleep.

90
Q

Summarise the role of the pontine reticular formation in REM sleep.

A

The pontine reticular formation is a key relay point that coordinates signals from the basal forebrain and peribrachial area to promote cortical activation and EEG desynchronisation.

91
Q

What is the role of the medulla in REM sleep?

A

The medulla, activated by the subcoerulear nucleus, inhibits motor neurons to enforce muscular paralysis during REM sleep.

92
Q

What is the overall role of cholinergic cells in REM sleep?

A

Cholinergic cells, particularly in the peribrachial area, orchestrate all major REM sleep features by projecting to:

The thalamus (cortical activation and PGO waves).
The tectum (rapid eye movements).
The subcoerulear nucleus and medulla (muscular paralysis).

93
Q

What two types of cell activity from what area seem to suppress REM sleep? How?

A

5HT and NA (noradrenaline) inputs from the Raphe have inhibitory input to the peribrachial area, in turn, inhibiting the REM-ON cells.

94
Q

Which two areas switch off in SWS?

A

The Raphe and the LC.

95
Q

During SWS, Decreased ___ and ___ input allows _________ to become active and ____ to start.

A

During SWS, Decreased 5HT and NA input allows Peribrachium to become active and REM to start.

96
Q

Outline the relationship between REM-off and REM-on cells and the areas/neurotransmitters involved.

A

REM-OFF:
- Noradrenaline (Locus Coeruleus).
- 5-HT (Raphe).

REM-ON:
- Acetylcholine (Pontine Nucleus).

When REM-OFF cells are active, the REM-ON cells are massively suppressed and inactive, as the NA and 5-HT from the LC and Raphe inhibit the REM-ON cells.

As their activity declines, the REM-ON cells can become active. There is a point at which the REM-OFF cells activity reaches a low enough point that there can be a quick and steep inflection in the activity of REM-ON cells - this is where REM-ON commences.

97
Q

Who first discovered that we have precise sleep rhythms using ECG recordings?

A

Nathaniel Kleitman.

98
Q

Why was the idea of an internal clock driving behaviour and physiology initially dismissed?

A

At the time, the concept of an internal clock was not widely accepted or considered realistic.

99
Q

What hypothesis did Kleitman have about the human sleep-wake cycle?

A

He believed we naturally follow a 24-hour cycle because of the world we live in but he speculated that a 30-hour day cycle might be more efficient.

100
Q

What was Nathaniel Kleitman’s Mammoth Cave experiment and what did it reveal?

A

Kleitman and his assistant lived in Mammoth Cave for a month, trying to follow a 28-hour day (9 hours sleep, 9 hours work, 9 hours rest) without external cues.

The assistant adapted, but Kleitman could not, suggesting a biological limitation to non-24-hour cycles.

101
Q

What were Jurgen Aschoff’s bunker experiments and what did they reveal?

A

Aschoff placed participants in a WW2 bunker without external timing cues. Most people adopted a natural circadian cycle slightly longer than 24 hours (~24.2–25), but some had much longer cycles (e.g., 50 hours), showing individual variations in the circadian clock.

102
Q

How did Kleitman’s and Aschoff’s studies contribute to circadian rhythm research?

A

Kleitman showed that humans struggle to adapt to cycles outside ~24 hours, while Aschoff demonstrated that, in the absence of external cues, the internal clock runs slightly longer than 24 hours, establishing the concept of free-running rhythms.

103
Q

What is the Opponent Process Model?

(*AKA Two Process Model)

A

It’s a model that represents the relationship between sleep load and the circadian promotion of wakefulness.

The first is a homeostatic mechanism; the longer you are awake, the more tired you become.

Once you sleep, you repay this ‘sleep debt’ and wake up less tired.

This is odd for a homeostatic system because it’s supposed to keep things balanced, so why does it build up a sleep debt instead of keeping it low?

The circadian system is the reason.

As you build up sleep ‘load’ the circadian drive for wakefulness increases.

When it decreases as night sets in, the sleep debt is no longer inhibited and you sleep and pay off the ‘debt’.

Once the drive for circadian wakefulness comes back in, you wake up and repeat the process - the debt has been paid off.

104
Q

What is the Mistlberger (2005) definition of the Opponent Process Model?

A

An SCN-dependent process that actively facilitates the initiation and maintenance of wakefulness, opposing a homeostatic sleep tendency that builds up while we are awake.

105
Q

Outline the study into circadian rhythms where ps ignore the sleep homeostat.

A

METHODS:
- Asked participants to go a period of 72 hours without sleeping.
- Asked for their subjective experience of tiredness.

RESULTS:
- There is an uptrend of how tired they get over the 3 days of the experiment.
- Also, there is a rhythm (surprising) in how tired they are.
- The tiredness on the first night is a lot higher than that of the third day.

Seems that the circadian drive for wakefulness is having a very large impact on how tired they feel - more than the feeling of tiredness.

106
Q

Outline the SCN lesion study in day-active squirrel monkeys.

A

METHODS:
- Compared SCN intact vs SCN lesioned squirrel monkeys.
- Used EEG to see if they were asleep or awake and measured body temperature.
- Kept the monkeys in constant dim light to see the rhythms free run.

RESULTS:
- In constant dim light there is a rhythm of ~25 hours in body temp.
- They also has a rhythm in sleep and wake that is aligned with that: lowest body temp = sleeping, highest body temp = peak awake.
- These rhythms are in anti-phase with each other.
- In SCN lesion you lose rhythms in sleep and body temp.
- You also lose any consistent sleep in the animal.

107
Q

What occurs if the circadian drive for wake is not present?

A

The homeostat maintains a low sleep load by constantly repaying the sleep debt.

This is shown phenotypically by a constant high frequency oscillation between sleep and wake (e.g., Up for 20 mins, sleep for 20 mins, up for 20 mins… etc).

108
Q

Outline the study into forced desynchrony to a 28 hour rhythm.

A

METHODS:
- Start by putting people in 8 hours of enforced darkness and 16 hours of dim light where they cannot sleep (to eliminate individual variation).
- After a few days, they go into 40 hours of dim light to check what their internal rhythm now is.
- Then they go into a 28 hour cycle; 9.5 hours of darkness, rest is dim light and sleep is prohibited.
- Measured rhythms of body temperature.

RESULTS:
- In T=28, the body temp rhythm free runs and doesn’t entrain to the 28 hour day.
- When you have a cycle that the system cannot entrain to, the clock will free run.

109
Q

How does circadian time and sleep schedule affect the likelihood of being awake during a sleep bout?

A

At the start of a sleep bout, there is nearly a 100% chance of being asleep, especially within the first 1.5 hours, as the body prioritises deep sleep to repay accumulated sleep debt.

As the sleep bout progresses, the likelihood of being awake increases due to:
- Reduced sleep pressure (less need for sleep as debt is repaid).
- The influence of the circadian rhythm, which promotes wakefulness during specific times, even during scheduled sleep.
- The relationship depends on circadian alignment:
- If the sleep bout coincides with a low circadian wake drive, sleep is more consolidated.
- If the bout occurs closer to the circadian wake peak (e.g., late sleep schedules), awakenings are more likely.

110
Q

What does the resulting graph of plotting circadian and homeostatic processes interacting show to us about determining sleep duration?

A

If you’re at circadian phase 0, there is almost no chance that you are awake.

If you are at circadian phase 180, the longer you’ve been asleep, the more likely you are to wake up.

Consolidate 8h sleep is only possible if you go to bed between 22:00 and 23:00.

111
Q

Why in sleep experiments do some participants have rhythms much longer than 24 hours?

A

Often, they will be in a small room or confined to a bed (to reduce confounds).

When there is little activity, there is little sleep debt (sometimes) and they don’t know the day so they can stay awake through ‘night’ and stay up for a much more extended period.

Thus, people have a normal cycle it’s merely the situation that isn’t normal.

112
Q

Outline the van Someren et al (1997) study into sleep rhythms in dementia patients.

A

METHODS:
- Standard care home lighting is ~400 lux and those staying here show quite irregular and weaker circadian rhythms, as well as not sleeping as much.
- In this study, the researchers introduced enhanced lighting of ~1200 lux, 3x brighter than the standard, and looked to see the result.

RESULTS:
- Gave them a much more robust rhythm and even started to improve their cognitive function to some degree.

113
Q

What is the problem with night-shift work in relation to circadian rhythms?

A

A big issue in particular in night shift is that the light they get at the work is a lot dimmer than the sun AND they see the sun before and after work.

This makes it very hard to entrain to the work schedule.

Instead, staying synchronised to the day.

You go to sleep after a long shift but after you go to sleep, the circadian drive for wakefulness begins to kick in and wake you up - not allowing full restful asleep.

114
Q

Outline the statistics of night-shift workers in a nuclear power plant.

A

60% of workers fall asleep 1/week
25% of workers fall asleep 4-5/week
15% of workers fall asleep 10/week

33% of workers admitted that falling asleep had caused a significant error or near-miss once/year.

In a small study, all 5 controllers were found asleep and they refused to accept that they had.

115
Q

What is a problem in the difference in sleep duration as you get older when external cues are factored in? (Roenneberg et al., 2003)

A

When looking at the sleep duration of humans, you’ll see that there is a hockey stick shape (starting top left and ending bottom right).

However, if you ask free days vs work days to separate them, you see that sleep duration has a much slower gradient.

Thus, one of the problems is the huge mismatch between free and work days.

Especially for younger people.

116
Q

What is a problem with having a chronotype different to your society?

A

You won’t function to your max due to not accruing enough quality sleep that your body needs.

117
Q

What makes social jet lag worse?

A

Having a later chronotype; the later your chronotype, the less sleep you get on work days and the more sleep on weekends.

118
Q

Outline the results from the study in Germany looking at where you live and its effect on chronotype.

A

People who live in the east have an earlier chronotype than those in the west, this is due to sun rising in the east.

Also, people from the countryside’s chronotype tracks the sun a lot better as their is a relationship between relative chronotypes and sunlight availability (earlier in east, later in west).

Whereas in large cities and towns this still occurs but it is more offset from dawn (could be occupational difference).

119
Q

What did a SCN intact vs SCN lesion rat study show about light entrainment on sleep?

A

EEG recordings from a rat quantifying the amount of SWS of minutes per hour as a function of time of day.

Shows more sleep more during the light than it does in the dark.

*It’s not always asleep in the light but more than the dark.

If you lesion the SCN, the amplitude of the cycle goes down but there is still the rhythm,

Thus there is some mechanism in which light is controlling sleep in another way.

120
Q

Outline the Chellappa et al. (2011) study into bright light and its effect on sleep.

A

METHODS:
- Used carefully controlled conditions, had people sitting in a dark room at varying times of day.
- Would have a box which had a light on or off - providing light cue or not.

RESULTS:
- Found that independent of time of day, the light made people more alert.

*We don’t know the mechanism in humans but we know better in rodents.

121
Q

Outline the Lupi et al (2008) study into lights effect on rodent sleep.

A

METHODS:
EEG Recordings:
- Researchers recorded brain activity in mice using EEG.
Light Pulse During Active Phase:
- A light pulse was administered during the mice’s active phase (night) to assess its impact on sleep (SWS or REM).
Mouse Models Used:
- Normal mice: With functional rods, cones, and melanopsin.
Rod/coneless mice: Lacking rods and cones but retaining melanopsin.
- Melanopsin Knockout (KO) mice: Lacking melanopsin but with functional rods and cones.

RESULTS:
Normal Mice:
- Light pulses successfully induced sleep (SWS or REM).
Rod/Cone-Less Mice:
- These mice still entered sleep following light pulses, showing that melanopsin was sufficient to mediate this response.

Melanopsin KO Mice:
- Light pulses did NOT induce sleep in these mice, even though rods and cones were present.

Conclusion:
- Melanopsin is required for light-induced sleep responses, as its absence prevents the effect despite the presence of other photoreceptors.

122
Q

What are the two main regions that ipRGCs project to?

A

The Suprachiasmatic Nucleus (SCN) and the Ventro-Lateral Pre-Optic Area (VLPO)

123
Q

Why could the VLPO be a candidate for photoentrainment outside of the SCN?

A

Because it’s in the thalamus that controls SWS and receives direct input from the retina.

124
Q

Outline the c-Fos expression study into the VLPO and what it found.

A

METHODS:
- Use c-Fos as a marker of neuronal activity.
- Looked at WT and Melanopsin KO mice.
- Introduce a light pulse in the middle of night

RESULTS:
- In WT you see a big increase of c-Fos in the VLPO in response to light pulse.
- If you do the same thing in melanopsin KO mice, this effect is gone (no c-Fos) giving evidence towards melanopsin projecting to VLPO as a mechanism for light directly influencing sleep.

125
Q

Provide an overview of Narcolepsy.

A

It’s a neurological disorder characterised by chronic sleepiness.

It’s a very rare brain disorder: 1 in 2000 people suffer (30,000 in UK).

Usually appears between the ages of 15-35 years old.

Two types:
- Narcolepsy type 1 (NT-1): classic or typical
- Narcolepsy type 2 (NT-2): less known.

126
Q

What are the 4 main symptoms of narcolepsy?

A

Excessive daytime sleepiness.

Cataplexy.

Sleep Paralysis.

Hypnagogic Hallucinations.

127
Q

What is cataplexy?

A

Brief episodes of muscle weakness/paralysis precipitated by strong emotions such as laughter or surprise.

It’s where the person loses muscle tone - EMG recordings show this.

128
Q

Define sleep paralysis.

A

Abnormal episodes of REM sleep atonia.

129
Q

Define hypnagogic hallucinations.

A

Hypnagogic hallucinations are vivid, sensory experiences that occur during the transition from wakefulness to sleep. They can involve visual, auditory, or tactile sensations and are typically associated with sleep onset.

130
Q

What is thought to be the neurobiological basis narcolepsy?

A

Hypocretins/Orexins.

131
Q

What are the names of the Hypocretins/Orexins?

A

Orexin A and Orexin B; Hcrt-1 and Hcrt-2

(Same thing, different names respectively).

132
Q

Define the structure of the Hypocretins/Orexins.

A

Two carboxy-terminally amidated neuropeptides of related sequence.

133
Q

How do Hypocretins/Orexins function?

A

Via two G-protein-couple receptors (GPCRs) differentially distributed throughout the brain.

134
Q

Provide evidence for Hypocretins/Orexins being strongly conserved peptides.

A

Genes encoding prepro-orexin found in puffer fish and various frog species.

This indicates that the gene arose early in chordate lineage.

135
Q

What are the two types of orexin and how do they differ in receptor binding?

A

Orexin Types:
- Derived from prepro-orexin, which is cleaved into Orexin A and Orexin B.

Receptor Binding:
- Orexin A binds to both OX1R and OX2R with equal affinity.
- Orexin B binds to OX2R with higher affinity.

136
Q

Which region in the brain is the origin of orexin?

A

The Lateral Hypothalamus contains a few 1000 cells that synthesise it.

137
Q

What are the areas that Orexins project to that are involved in sleep regulation?

A

Dorsal Raphe (DR), Locus Coeruleus (LC), Lateral Dorsal Tegmental Nucleus (LDT) and Pedunculopontine Tegmental Nucleus (PPT)

138
Q

What are some of the functions of brain areas that the fibres containing Orexins innervate?

A

Control of cardiovascular system.

Ingestive Behaviour.

Reward.

Sleep-Wake Cycles.

139
Q

Are Orexin peptides excitatory or inhibitory? What are some of their primary roles?

A

Excitatory.

Stimulates food intake, blood pressure, locomotor activity.

Increases wakefulness

Supresses REM sleep.

140
Q

What happens when an orexin cell is stimulated?

A

It will release orexin that activates OXR GPCRs and causes downstream cascades.

141
Q

Outline the Sakurai et al., (1998) study into Orexin.

A

METHODS:
- Orexin A and Orexin B were injected into the brain (too large to - cross the BBB naturally).
- Food consumption was measured after injection.
- Next, the effect of feeding states was studied by comparing orexin - levels in fed versus fasted states.

RESULTS:
- Orexin A and Orexin B increased food consumption after injection.
- Fasting led to higher orexin levels, while feeding reduced orexin levels.
- These findings support the role of orexin in energy balance and feeding regulation.

142
Q

Outline the Yamanaka et al., (2003) study into transgenic orexin mice.

A

METHODS:
- Generated transgenic mice with orexin neurons labelled using GFP (Green Fluorescent Protein).
- Prepared brain slices from these animals and recorded electrical activity from orexin cells.
- Investigated how orexin neuron activity responded to:
- Glucose levels (low vs high).
- Nutritive balance signals, such as ghrelin (hunger hormone) and leptin (satiety hormone).

RESULTS:
- Glucose levels:
- Low or no glucose: Orexin neurons fired.
- High glucose: No firing observed.
Nutritive signals:
- Ghrelin (hunger hormone): Increased orexin neuron firing.
- Leptin (satiety signal): Suppressed orexin neuron firing.

These results demonstrated that orexin neurons are regulated by energy balance signals, including glucose, ghrelin, and leptin.

143
Q

Outline the Chemelli et al. (1999) study into Orexin knockout mice (PART 1: Methods and Initial Observations).

A

METHODS:
- Researchers investigated the role of orexin by:
- Injecting orexin to observe its effects.
- Creating Orexin Knockout (KO) mice that could not produce orexin.
Purpose: To study orexin’s role in food consumption and general behaviour.

RESULTS (Initial Observations):
- Unexpected finding: Orexin KO mice showed behaviours similar to narcolepsy, a sleep disorder.
- This led researchers to explore the link between orexin and narcolepsy further.

144
Q

Outline the Chemelli et al. (1999) study into Orexin knockout mice (PART 2: Sleep Patterns and REM Analysis).

A

METHODS:
- Used EEG to measure brain activity and created hypnograms to track sleep stages (wakefulness, slow-wave sleep (SWS), and REM sleep).
- Compared wild-type (WT) mice with Orexin KO mice.

RESULTS:
WT mice: Showed normal sleep patterns with sustained periods of wakefulness, SWS, and well-organised REM sleep.
Orexin KO mice:
- Frequently transitioned directly from wakefulness to REM sleep (an abnormal and unnatural pattern).
- Spent more total time asleep compared to WT mice.
- Hypnograms revealed disorganised sleep patterns and REM instability.
Detailed REM Analysis:
- EMG and EEG recordings showed that during REM episodes, Orexin KO mice experienced instant muscle atonia (paralysis typical of REM sleep).

145
Q

Outline the Chemelli et al. (1999) study into Orexin knockout mice (PART 3: Behavioural Analysis and Conclusions).

A

METHODS:
- Researchers videotaped the mice to observe their behaviour during wakefulness and sleep.

RESULTS (Behavioural Observations):
- Orexin KO mice exhibited episodes where they were awake and moving, followed by sudden arrested states (immobility), resembling cataplexy in humans.
- These behavioural episodes mirrored symptoms of narcolepsy, including sudden REM onset and muscle atonia.

CONCLUSIONS:
- This study provided strong evidence linking orexin deficiency to narcolepsy, suggesting that orexin is critical for regulating wakefulness and sleep stability.

146
Q

How does the absence of orexin signalling affect behavioural state transitions in mice?

A

In orexin knockout (KO) mice, there are more transitions between behavioural states compared to wild-type (WT) mice.

This instability indicates that orexin is crucial for maintaining stable behavioural states.

147
Q

How do transitions between wakefulness, NREM, and REM differ between wild-type (WT) and orexin KO mice?

A

WT mice:
- Fewer transitions between states.
- Stable progression: Wake → NREM → REM and back.

KO mice:
- Increased transitions between all states.
- Frequent transitions between Wake ↔ NREM and Wake ↔ REM.
- Indicate disrupted regulation of sleep-wake states.

148
Q

What is the role of orexin in preventing cataplexy in mice?

A

WT mice:
- Rare transitions into cataplexy (a sudden loss of muscle tone).

KO mice:
- Frequent transitions from Wake → Cataplexy.
- Suggests that orexin prevents inappropriate muscle atonia during wakefulness.

149
Q

How do light and dark cycles affect state transitions in orexin KO mice?

A

During the dark phase (active period):
- KO mice show significantly more transitions between Wake ↔ NREM and Wake ↔ REM.

During the light phase (inactive period):
- KO mice exhibit similar instability, with increased transitions compared to WT mice but the effect is slightly less pronounced.

150
Q

Outline the Willie et al., (2003) study into Orexin 2 receptor knockout (Ox2R-/-) mice.

A

METHODS:
- Generated Ox2R-/- mice lacking functional orexin 2 receptors (OX2R), preventing orexin from binding to its primary receptor.
- Conducted behavioural and physiological analyses to investigate the role of OX2R in sleep-wake regulation.
- Compared these knockout mice to wild-type (WT) mice.
- Examined wake and non-REM sleep transitions, as well as receptor localisation in brain regions associated with sleep and arousal.

RESULTS:
- Wake/Non-REM Transitions: Ox2R-/- mice showed abnormal transitions between wakefulness and non-REM sleep, with frequent instability.
- Behavioural Phenotype: Mice displayed attacks of non-REM sleep during wakefulness, disrupting their ability to maintain stable wake states.
- Receptor-Specific Insights: Highlighted OX2R’s critical role in stabilising wakefulness and regulating sleep transitions.

151
Q

Outline the Mahoney et al. (2019) study into rodent models with alterations in orexin signalling.

A

METHODS:
- Developed rodent models with different disruptions to orexin signalling, including:
- Orexin-tTA; TetO-DTA: Rapid death of orexin neurons.
- Orexin-ataxin 3: Gradual orexin neuron loss from birth.
- Ox-/- mice: No orexin A or B.
- Ox1r-/-; Ox2r-/- mice: No OX1R or OX2R receptors.
- Single receptor knockouts: Mice lacking only OX1R or OX2R.

RESULTS:
Complete orexin KO (Ox-/- or Ox1r-/-; Ox2r-/- mice):
- Shortened wake periods.
- Frequent cataplexy.
- Quick transitions to REM sleep.
Single receptor KO:
- OX1R KO: Minimal effects, no cataplexy.
- OX2R KO: Slightly reduced wakefulness, rare cataplexy.
Neuron death models (Orexin-tTA and Orexin-ataxin 3):
- Showed narcolepsy-like symptoms as orexin signalling decreased.

CONCLUSION:
- OX2R is essential for stabilising wakefulness and preventing cataplexy, while OX1R plays a minor role.
- Progressive orexin loss helps study how narcolepsy develops.

152
Q

What did Lin et al., (1999) discover in relation to narcolepsy?

A

Orexin was found to be the at the core of narcolepsy in dogs.

153
Q

Outline narcolepsy in Doberman Pinschers.

A

It’s inherited as an autosomal-recessive fully penetrant phenotype.

Defective canine narcolepsy gene encodes Hctr2/Ox2R receptor.

Truncated receptor protein which does not localise to membrane and does not bind to ligands.

(Defective receptor; orexin is still produced).

154
Q

What is the cause of narcoleptic labradors?

A

Their Hcrtc2/Ox2R gene has distinct mutation skipping exon 6 leading to truncated receptor protein.

155
Q

What is the cause of narcoleptic Dachshunds?

A

Point mutation in Hcrtr2/Ox2R gene results in receptor protein that reaches membrane but cannot bind the hypocretin.

156
Q

Outline the methods and main findings of Peyron et al. (2000) and Hungs & Mignot (2001) studies on orexin deficiency in narcolepsy (PART 1).

A

METHODS:
- Examined post-mortem brain tissue from narcoleptic patients and controls.
- Focused on the lateral hypothalamus, measuring orexin mRNA expression.
- Used age-matched controls to compare expression.
- Tested whether the deficit was specific to orexin by also measuring melanin-concentrating hormone (MCH) levels, expressed by nearby neurons.

RESULTS:
- Narcoleptic patients had a complete absence of orexin mRNA in the lateral hypothalamus, while controls had abundant expression.
- MCH levels were unchanged, confirming the deficit was specific to orexin.

157
Q

What did the Peyron et al. (2000) study reveal about orexin levels in CSF and its link to narcolepsy (PART 2)?

A

CSF Findings:
- Narcoleptic patients had severely reduced orexin levels in cerebrospinal fluid (CSF) compared to controls.

Conclusion:
- The findings confirmed that orexin deficiency is a hallmark of narcolepsy type 1, specifically affecting orexin-producing neurons in the lateral hypothalamus.

158
Q

What did Thannickal et al., (2000) find about narcoleptic patients?

A

They looked at the orexin expression in brain tissue of control vs narcoleptic patients.

Found that there was an 85-95% loss of orexin producing cells in the narcoleptic patients.

159
Q

What did autopsy studies indicate about narcolepsy?

A

They indicate a decline in orexin/hypocretin cell number in the lateral hypothalamus of people who have had a history of narcolepsy.

160
Q

What did Mahoney et al., (2019) find was common across all models of narcolepsy (humans, mouse models, dogs etc)?

A

There was an absence of orexin signalling that led to poor maintenance of wakefulness (inability to maintain stable behavioural states).

161
Q

Outline how the inclusion of orexin neurons into the flip flop model can explain narcolepsy and its symptoms.

A

The Flip-Flop Model explains how the brain transitions between sleep and wakefulness through two key centres:
1. Wakefulness-promoting centres
2. Sleep-promoting centres (VLPO – Ventrolateral Preoptic Area)

Mechanism:
- Wake State:
- Orexin cells integrate inputs from the limbic system, SCN (suprachiasmatic nucleus), and energy balance signals.
- Orexin then sends strong excitatory signals to wake-promoting centres, which in turn inhibit sleep-promoting centres, maintaining wakefulness.

  • Sleep State:
    • The VLPO (sleep centre) becomes active and inhibits both orexin and wake-promoting centres, maintaining sleep.

Orexin Deficiency and Instability:
- Without orexin signalling, only the mutually inhibitory relationship between sleep and wake centres remains.
- This leads to instability in the system, causing sudden and frequent oscillations between sleep and wake states, as seen in conditions like narcolepsy.

Orexin and Behavioural States:
- Orexin activity corresponds to the behavioural state of the animal:
- More active during wakefulness.
- Less active during sleep.

162
Q

Outline the Mileykovskiy et al., (2005) study into the activity of Orexin cells according to circadian time and it’s relation to behavioural state.

A

METHODS:
- Implant electrodes into the Lateral Hypothalamus (LH) of the brain and record activity of orexin cells whilst they freely move.
- Look to see what activity is occurring in these cells when there are different phenotypic activities occurring.

RESULTS:
- Highest activity in exploratory behaviour; grooming, eating and quiet waking.
- Inactive in SWS/REM.

This shows correlation not causation; this doesn’t show that orexin is driving the activity.

163
Q

Outline how you would perform a study into manipulating the activity of Orexin neurons using optogenetics.

A
  • Introduce light sensitive ion channels into the orexin neurons of animal models using a viral vector.
  • Channelrhodopsin (ChR2) makes cells have an excitatory response to blue light.
  • Halorhodopsin (NpHR) makes cells have an inhibitory response to yellow/orange light.
164
Q

What happens when you activate Orexin cells during REM or SWS?

A

It will move the animal into a state of wakefulness.

165
Q

What happens when you inhibit orexin cells during waking?

A

You induce SWS or REM sleep.

166
Q

Outline the current day pharmacological therapeutic opportunities due to the knowledge of the role of Orexin in narcolepsy.

A

Can’t use orexin directly because the neuropeptide is too long to pass through the BBB.

So there has been generated agonists to orexin receptors.

To do this, you need to know the crystalline structure of the receptor .

This became available post 2020.

A lot of side effects from orexin agonists as the orexin producing cells project to many areas that control many functions.

Using antagonists currently.

167
Q

What are DORAs?

A

Dual Orexin Receptor Antagonists.

168
Q

Outline & Summarise the role of Orexins/Hypocretins in Narcolepsy.

A

Orexins/Hypocretin neuropeptides involved in many homeostatic processes.

Absence of orexin/hypocretin neurons or their signalling is associated with an inability to maintain wakefulness.

There is a loss of orexin/hypocretin neurons in the brains of people who have had a history of narcolepsy.

Thus, this small cluster of neurons is very influential in regulatory brain and behavioural states.

Very recent work closely associates alterations in orexin cell physiology with aging-related sleep impairment (Li et al., 2022)

Clocks, Sleep & Rhythms Of Life (6 decks)

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