The Neurobiology of Sleep, Wakefulness, and Circadian Rhythms

Mentimeter Review of Sleep Concepts

• REM Sleep Characteristics: While REM (Rapid Eye Movement) sleep is often deep, it is technically referred to as "paradoxical sleep." This is because the Electroencephalogram (EEG) pattern during REM sleep is strikingly similar to the EEG pattern of a person who is awake.

• Sleep and Aging: As humans age, they experience significantly less slow-wave sleep. Instead of deep phases, there is more frequent movement between Phase 1, Phase 2, REM, and waking up, followed by a return to Phases 1 and 2.

• Sleep Rhythms in Adolescents: The "midterm" (the time halfway between falling asleep and waking up) is significantly higher in adolescent males. This indicates that adolescent males tend to go to bed later and wake up later, though it does not necessarily imply they sleep for a longer or shorter total duration.

The Pineal Gland and Melatonin

• Historical Context: Rene Descartes, famous for the phrase "I think, therefore I am," considered the pineal gland the "seat of the soul."

  • Anatomical Position: The gland is located approximately in the center of the brain—between the front and back and between dorsal and ventral positions—which led to beliefs that it was the center of being or a "third eye."

• Hormonal Function: The pineal gland is a gland in the hormonal system, similar to the pituitary, thyroid, or adrenal glands. It produces the hormone melatonin.

• Melatonin across Species: Melatonin levels rise at night in all animals.

  • Diurnal Animals: In animals awake during the day (like humans), melatonin induces sleep.

  • Nocturnal Animals: In animals awake at night (like rats and mice), melatonin induces wakefulness.

• Role in Human Sleep: Melatonin is primarily important for staying asleep (prolonging sleep) rather than falling asleep quickly.

• Medical and Pharmacological Implications:

  • Depression: New antidepressant drugs selectively activate the pineal gland to produce melatonin. This can improve sleep and mood in specific heterogeneous groups of patients.

  • Caffeine Inhibition: Caffeine selectively inhibits the production of melatonin. Chronic caffeine consumption can lead to the down-regulation of melatonin receptors, reducing the hormone's influence over time.

Neurobiology of Sleep and Arousal

• Brain Structures:

  • Suprachiasmatic Nucleus (SCN): This is the primary "clock" of the brain. It utilizes a biological rhythm where the proteins per and tim are activated by clock, and subsequently inhibit clock in a nearly $24$-hour cycle.

  • Reticular Formation: Located in the brain stem.

  • Pontomesencephalon: A specific part of the reticular formation. It does not produce its own rhythm but is governed by the SCN. It distributes the SCN "clock signal" to the rest of the brain through upward pathways to the cortex and downward pathways to the spinal cord to generate activity.

  • Thalamus: Acts as a sensory relay station. During sleep, GABA activity decreases stimulation in the thalamus, preventing sensory information (visual, auditory, tactile, gustatory, and olfactory) from reaching the cortex.

  • Hypothalamus: A cluster of structures involved in internal regulation (temperature, thirst, hunger) and strongly involved in sleep and wakefulness.

  • Locus Coeruleus: The primary site for the production and release of noradrenaline in the brain.

• Neurotransmitters Promoting Wakefulness and Alertness:

  • Acetylcholine: Increases activity.

  • Glutamate: A primary excitatory neurotransmitter.

  • Noradrenaline (Norepinephrine): Increases alertness. "Norepinephrine" is the term used in America, while "Noradrenaline" is used in the rest of the world.

  • Histamine: Increases wakefulness. Antihistamine drugs (especially old-fashioned ones) cause sedation because they block receptors involved in alertness.

  • Orexin: Involved in keeping people awake and alertness regulation.

• Neurotransmitters and Drugs Promoting Sleep:

  • GABA: A strong inhibitory, abundant neurotransmitter that promotes sleep and reduces connectivity across brain areas.

  • Benzodiazepines (e.g., Diazepam): Anxiolytic drugs that enhance GABA neurotransmission. They are strongly sedative and can make driving dangerous.

  • Propofol: An anesthetic drug that stimulates GABA receptors to induce rapid sleep (within $2$ to $3$ seconds).

  • Ketamine: A glutamate antagonist. By blocking glutamate (which promotes wakefulness), high doses of ketamine induce anesthesia. Developed in the 1950s, it can cause hallucinations and delusions at anesthetic doses. Low doses are currently registered in the United States for treatment-resistant depression.

Adaptive and Local Sleep

• Local Sleep Phenomenon: Because many GABA neurons are small "interneurons" that do not project to other areas, sleep can be local. Parts of the brain can sleep while others remain awake.

• Evolutionary Examples:

  • Dolphins: Can sleep with one hemisphere of the brain at a time.

  • Greater Frigate Bird: These birds can fly for $7$ to $8$ months without settling. During flight, they sleep for only about $45$ minutes per day in $10$-second bursts, often using only half the brain. When on land to lay eggs, they sleep for $12$ hours a day to compensate.

Theories on why we sleep

• Universality: All animals sleep, from Planaria (which have existed for approximately $700 \times 10^6$ years) to humans, suggesting a critical biological necessity.

• Restoration Theories:

  • Glymphatic System: The brain's waste clearance system. Sleep helps discard waste products like broken-down neurotransmitters. Poor sleep is correlated with Alzheimer's disease, which involves the accumulation of misfolded proteins like beta amyloid in plaques and tangles.

  • Hormonal Regulation: Growth hormone peaks during sleep (essential for development). Cortisol levels typically drop during the night and rise in the morning; sleep loss disrupts this smooth rhythm.

  • Immune System: Sleep allows for the consolidation and restoration of the immune system to its normal state. Interrupted sleep is linked to low-level inflammation.

• Cognitive and Memory Theories:

  • Synaptic Homeostasis Hypothesis: During sleep, "synaptic pruning" occurs. New connections made during the day are refined; random "noise" connections are removed to optimize the signal.

  • Sleep Spindles: Occurring in Stage 2 sleep, these are directly correlated with memory consolidation. Fewer spindles correlate with poorer memory recall the next day.

Sleep Disturbances and Phenomena

• Sleepwalking: A state where part of the brain is asleep but the motor cortex is awake. Individuals can perform complex tasks like moving furniture, cooking, or even starting a car.

• Lucid Dreaming: Awareness that one is dreaming while still in the dream state. Associated with increased activity in the frontal cortex (the area related to awareness). Approximately $1/4$ to $1/5$ of people experience this regularly.

• Research on Communication during Sleep: A 2021 study by Conkoli et al. demonstrated that subjects in dreaming stages could respond to external questions using eye blinks (e.g., $-1$ blink for yes, $-2$ for no).

  • Subjects could solve simple numerical problems like $8 - 6 = 2$ or $2 + 3 = 5$ and confirmed hearing the questions upon waking.

• Narcolepsy: Characterized by excessive daytime sleepiness and sudden bouts of sleep, often triggered by intense emotion or stimulation.

  • Biological Cause: Associated with a reduction in orexin or a lack of the orexin receptor, often due to genetic factors.