Circadian Rhythm and Sleep Stages

Circadian Rhythm Regulation

• SCN (suprachiasmatic nucleus) receives light signals, triggering BMAL1 and CLOCK gene transcription.
• BMAL1 and CLOCK proteins dimerize, triggering CRY gene transcription.
• CRY and PER proteins dimerize.
• CRY/PER complex translocates to the nucleus to inhibit BMAL1/CLOCK gene transcription, creating a negative feedback loop.
• Specialized retinal ganglion cells (RGCs) contain melanopsin, a light-sensitive pigment; light depolarizes RGCs, signaling SCN via the retinohypothalamic tract.
• SCN activates the paraventricular nucleus, triggering the superior cervical ganglion, then the pineal gland, for melatonin synthesis.

Brain Waste Removal

• Glymphatic system removes brain waste via cerebrospinal fluid, driven by glial cells and located near brain ventricles.

Stages of Sleep

• Awake:
  • Resting: Alpha waves (8-13 Hz), high frequency, low amplitude.
  • Mental activity: Beta waves (14-60 Hz).
• Stage 1: First hour of drowsiness, theta waves (4-8 Hz), lower frequency, higher amplitude.
• Stage 2: Sleep spindles (1-2 second bursts of 10-12 Hz activity) and K complexes; interaction between thalamic and cortical neurons.
• Stage 3: Slow-wave sleep (SWS), delta waves (0.4-4 Hz); moderate deep sleep.
• Stage 4: Deepest sleep, also characterized by delta waves.
• REM (Rapid Eye Movement) Sleep: EEG signals similar to wakefulness; increased activity in amygdala, parahippocampal gyrus, and anterior cingulate cortex; decreased activity in dorsolateral prefrontal cortex, which suggests emotional valence in dreams.

REM Sleep Mechanisms

• Pontine reticular formation (PRF): Causes muscle paralysis during REM sleep.
  • Releases glutamatergic signals to GABAergic interneurons, which synapse with motor neurons, preventing movement.
  • Inhibits sensations by sending inhibitory inputs to the dorsal column nuclei.
  • Blocks locus coeruleus from releasing norepinephrine, further preventing motor activation.
  • Sends signals to the superior colliculus to drive rapid eye movements.
  • Sends signals through the lateral geniculate nucleus to the occipital cortex to trigger EEG patterns.

Neurochemicals and Sleep Regulation

• Cholinergic neurons (Nucleus Basalis): Increased activity in REM and wakefulness; reduced during non-REM sleep.
• Locus coeruleus neurons: Promote wakefulness, reduce activity ahead of REM stage.
• Tuberomammillary nucleus (hypothalamus): Promotes wakefulness; inactive during REM and non-REM sleep.
• Raphe nuclei: Promote wakefulness, release serotonin, reduce activity during both REM and Non-REM sleep.
• Orexin: Promotes wakefulness, activates monoaminergic nuclei; inhibits REM sleep onset. Orexin loss suggests sleep-onset problems..
• Ventral Lateral Preoptic Nucleus (VLPO): Suppresses wakefulness, promotes sleep onset, sends GABAergic projections to Ascending Activating System (AAS). Reduced VLPO function correlates with sleep disruption and/or insomnia.

Sleep Disorders

• Sleep deprivation: Increased medial temporal lobe activity (irritability); decreased dorsal striatum and dorsal prefrontal cortex activity. Ampakines can counteract these effects.
• Narcolepsy: Wakefulness-to-REM attacks. Orexin 2 receptor mutations or loss of orexin.
• Somnambulism: Sleepwalking; occurs during Stage 3; impaired cognitive performance and judgement.
• REM Sleep Disorder: Patients reinact vivid or violent dreams.
• Insomnia: Upregulation of AAS; acute stress leads to high-frequency sleep; VLPO suppression of wakefulness, VLPO loss probable contributor. Benzodiazepines enhance GABAergic effect to address VLPO loss. CBT can treat psychological factors.

Explore the intricate mechanisms of circadian rhythm regulation, including the role of the SCN, CRY and PER proteins, and the impacts of light on melatonin synthesis. Additionally, delve into the stages of sleep, including awake states and brain waste removal via the glymphatic system. Test your understanding of these essential biological processes.