Lecture 5 - Circadian Rhythms and Disease (1)

How does a functional circadian clock affect animal behaviour and survival?

• Study with chipmunks (released into wild and tracked for 80 days):

  • Intact SCN (healthy clock): 80% survival after 80 days in the wild.

  • Damaged SCN (impaired clock): Only 20% survived; 80% died.

• Behaviour differences seen:

  • Healthy chipmunks: Active during the day (foraging), hide at night (avoid nocturnal predators, e.g wealses).

  • SCN-lesioned chipmunks: Disrupted 24 hour rhythms, active day and night → more likely to be predated.

• Conclusion: A properly functioning circadian clock is critical for survival by aligning activity/rest cycles with environmental risks.

What Causes Disruption to Circadian Rhythms

• Shift work: Working outside 7 am–7 pm.

• Social jet lag: Internal rhythms clash with societal schedules and normal environment.

• Jet lag: Travel across time zones misaligns internal clock with local time.

What Are The Consequences of Altered Circadian Rhythms

• Health problems.

• Increased risk of accidents and errors:

  • Industrial disasters (Chernobyl, Three Mile Island, NASA Challenger disaster).

  • Road accidents (impaired reflexes due to sleep loss).

  • Environmental accidents (Exxon oil spill).

• Many major accidents are linked to fatigue from circadian disruption.

How do circadian rhythms affect cancer patient outcomes?

• Patients with strong, robust circadian rhythms:

  • Better quality of life (QoL)

  • Increased survival

• Patients with poor or disrupted rhythms:

  • Lower QoL

  • Reduced survival

• Maintaining strong circadian rhythms may improve both well-being and prognosis in cancer.

What is Chronotype?

• The individual preference for bed and wake times

• Largely genetically determined (born, not made)

• 2 Main Types:

  • Larks (morning types) – wake up early, sleep early

  • Owls (evening types) – wake up late, sleep late

• Implications:

  • Owls adapt more easily to shift work; larks’ health is more impacted by shift work

  • Linked to mood/depression, eating disorders, smoking, and drinking

What is Social Jetlag

• Misalignment between the internal biological clock and social/environmental schedule

  • Chronic and more harmful than regular jet lag (one-off occurence)

• Linked to obesity, mood issues, aggression, and poor academic performance

• Chronic SJL = health risks due to repeated circadian disruption

What is the Interaction Between Chornotype and Social Jet Lag?

• Owls experience more SJL due to society’s early schedules

• Chronic SJL disproportionately affects health in morning types (larks)

• Highlights the importance of aligning social schedules with individual chronotypes

What are the consequences of long-term night shift work on health and circadian rhythm

• Night shift workers struggle to adapt due to daylight exposure after shifts, which disrupts the SCN and sleep

• Long-term effects include:

  • 40% increase in cardiovascular disease (CVD)

  • Higher incidence of mental health issues (anxiety, depression)

  • Sleep disruption

  • 80% risk of gastrointestinal disorders (e.g., dyspeptic ulcers)

  • Increased cancer risk: Danish study of nurses (20 years night shift) → greater breast cancer risk; WHO recognises circadian disruption as a cancer risk factor

Why is Sleep Important

• It is a basic homeostatic need and important for learning, memory growth and repair

  • Memory settles in the brain during sleep, and is the time of growth in children

• Sleep deprivation (awake for >27 hours) associated with

  • Cognitive impairment

  • Performance impairment → slowed reaction time

  • Immune impairement → prone to cold and flu

• Awake for extended periods said to equivalent being legally drunk

  • Power naps effective in brinign individuals back to an awake state

How Is Sleep Measured and Catergorised?

• Use of electroencephalography (EEG) to measure cortical activity during sleep

  • Electrical waves correspond to different phases of sleep

• Sleep stages are visualised with a hypnogram:

  • Awake → NREM 1 → NREM 2 → NREM 3/4 → REM → cycles repeat

  • ~70–90 min per cycle, with ~5 per night

• Slow-wave NREM sleep (stages 3/4) shortens as night progresses, while REM (dream) periods lengthen.

What happens during Non-Rapid Eye Movement (NREM) sleep?

• NREM Stage 2: memory consolidation occurs.

• NREM Stages 3 + 4: Slow Wave Sleep (deep sleep).

  • Difficult to wake someone.

  • Important for cell repair, immune system strengthening, and growth.

• Updated 2007 classification by the American Academy of Sleep Medicine merges stages 3 and 4 into a single deep sleep stage.

What happends during Rapid Eye Movement Sleep?

• Rapid Eye Movement; eyes blink/dart side to side.

• Dreaming occurs; EEG resembles an awake person.

• Total muscle paralysis (except eyes and diaphragm) prevents acting out dreams.

• Becomes longer as the night progresses; it normally ends the sleep cycle before waking.

What is the Structure of Sleep?

• Awake → NREM 1 → NREM 2 → NREM 3/4 → REM

• Stage 1 (NREM1): Shortest phase, occurs at sleep onset.

  • ~5% of total sleep time.

  • Usually not revisited during the night.

• Stage 2 (NREM2): Memory formation and consolidation occur here.

  • Majority of sleep is spent in this stage.

What Areas of the Brain Are Involved in Regulating Sleep and Wakefulness

• Different areas of the brain regulate different aspects of sleep wake

  • VLPO (ventrolateral pre-optic area, in the forebrain): promotes slow-wave sleep; located near the SCN, at the base of the brain.

  • Brainstem/arousal areas (ascending reticular activating system): trigger wakefulness.

• The interaction of these regions regulates transitions between sleep and wake.

What is the flip-flop model of sleep-wake regulation?

• Interaction between VLPO and arousal centres → mutal inhibition.

• Daytime: arousal centers active, VLPO inhibited → wakefulness.

• Night: VLPO active, arousal centers inhibited → sleep.

  • This “switch” allows rapid and stable transitions between sleep and wak

How Do Circadian Rhythms Regulate Sleep Wake Cycles?

• Strong overlap between sleep mechanisms and circadian rhythms.

• Sleep is regulated by two interacting processes:

  1. Homeostatic sleep drive (Process S): builds during wakefulness, peaks at night, and decreases during sleep.

  2. Circadian drive for arousal (Process C): signals from the circadian system (e.g., melatonin increase at night, decreased core body temperature and blood pressure) promote sleep at night and wakefulness in the morning.

  • before wake, melatonin decreaees, core body temperture and bloop pressure increase to promte wakefulness

• The interaction of Process S and Process C determines sleep timing and quality.

What is the Opponent Process Model of sleep and how does it explain poor sleep in night shift workers?

• The model suggests sleep is regulated by the balance of Process S (homeostatic sleep drive) and Process C (circadian arousal).

• Example:

  • Night shift worker at 7 am: Process S high (very sleepy) but Process C high (promotes wakefulness).

  • The clash between the two processes leads to poor quality, fragmented sleep.

What does the circadian drive for arousal regulate, and what happens if the SCN is damaged

• It organises activity and sleep across 24 hours.

  • Actograms show animals move consistently at specific times and sleep at night.

• SCN lesion (damage): removes circadian input, leaving only homeostatic sleep drive.

  • Results in random bouts of activity and sleep throughout day and night.

  • No consistent 24-hour rhythm; short sleep bouts as sleep pressure builds, loss of rhythmicity.

How Does Sleep Reflect Underlying Circadian Activity?

• Sleep is indicative of underlying clock activity with timing follows the circadian clock;

  • Normally sleep/wake occurs roughly at the same times daily, with slight weekend shifts that are normal → 24 hour pattern present

  • SCN lesions → arrhythmic sleep/wake patterns → wake and sleep randomly

  • Damage to RHT → SCN runs independently, unable to detect environment → revert to spontaneous ~24.5-hour rhythm (sleep slightly later each day).

What are examples of circadian-related sleep disorders?

• Delayed Sleep Phase Syndrome: go to bed & wake up later than normal.

• Advanced Sleep Phase Syndrome: go to bed & wake up earlier than normal

How do insomnia and hypersomnia affect sleep patterns?

• Insomnia: normal bedtime, fragmented sleep, waking in the night, daytime tiredness, may require naps.

• Hypersomnia: excessive sleep (4+ hrs more than normal), naps during the day.

What are the main circadian-specific sleep disorders?

• Caused by alterations in sleep

  • Advanced Sleep Phase Syndrome: go to bed and wake up very early

  • Delayed Sleep Phase Syndrome: go to bed and wake up later than normal

  • Non-24-Hour Sleep: occurs when photoreceptors or the retinohypothalamic tract (RHT) are damaged

• These disorders show misalignment between internal rhythms and the external environment

How are sleep disorders linked to neurodegenerative and psychiatric diseases?

• Neurodegenerative diseases:

  • Alzheimer’s: fragmented sleep, hypersomnia

  • Parkinson’s and Huntington’s: sleep disruptions

• Psychiatric disorders:

  • Schizophrenia: irregular sleep cycles, fragmented sleep, hypersomnia/hyposomnia

• 20% of the general population is affected

  • higher prevalence in the elderly, obese, and shift-workers

How is sleep related to mental health disorders?

• Insomnia: affects ~20% of the general population

• Depression: 20% lifetime risk with sleep maintenance insomnia or early morning awakening

• 44% of Antidepressant full responders still experience sleep disturbances

• Anxiety disorders: associated with chronic sleep disturbance and sleep loss

What is Seasonal Affective Disorder (SAD)?

• Individuals who become depressed during the Autumn and Winter periods

  • Aka Winter Blues

• This occurs due to shortening of days, with the circadian system exposed to less light triggering depressive sympotms

What Can Be Done To Counteract Seasonal Affective Disorder (SAD)?

• Regular sleeping habits, waking and sleeping at the same time

• Going outside → natural light has greater blue light outside than in fluorescent light → promotes wakefulness

• Being near a window can promote wakefulness – let natural light in

• Exercise

• Travel to sunny areas

How Is Sleep Affected in Major Depressive Disorder?

• ~90% of MDD patients report sleep disturbances (difficulty initiating/maintaining sleep, daytime sleepiness)

• Persistent insomnia increases the risk of relapse into depressive episode

  • New mothers at greater risk of postnatal depression due to disrupted parental sleep (infants yet to establish 24 hour rhythms)

• Sleep disruption often precedes manic/depressive episodes in bipolar disorder

• Many antidepressants (tricyclics: amitriptyline, imipramine, clomipramine; non-tricyclics: trazodone, mirtazapine) are sedative, helping improve sleep

• Managing sleep has a therapeutic benefit in depression

How are circadian rhythms and sleep affected in schizophrenia?

• Schizophrenia is characterised by delusions, disorganised thought, and emotional instability

• Pathogenesis is poorly understood; current hypotheses focus on abnormal neurotransmission and neurodevelopment (e.g., altered dopamine signalling)

• Negative symptoms (depression low mood, reduced motivation) respond poorly to treatment and reduce quality of life

• Circadian rhythm instability, sleep disturbances, and fragmented rest-activity patterns are extremely common

• Improving sleep quality often correlates with improvements in negative symptoms and overall quality of life

How Does a SZ Individual's Sleep Pattern Differ from a Normal Individual's?

• Healthy: Regular sleep pattern present

  • Sleep at 11pm; Wake at 7am

• SZ: Delayed rhythm

  • Sleep 5am-6am; Wake 3pm-4pm

How does ageing relate to circadian rhythms and neurodegeneration?

• Increase in ageing population→ neurodegeneration on the rise.

• Adults aged >65 years expected to double from 8% (2010) to 16% (2050).

• Ageing impacts all aspects of physiology and behaviour, including circadian rhythms.

• Circadian system influences ageing and longevity.

How Does Ageing Affect Sleep

• Older adults

  • go to bed earlier

  • longer latency to sleep (longer to fall asleep)

  • Frequent awakenings (fragements and disrupted sleep

  • Tired during the day → Nap

  • Shortening of NREM3/4 and REM

How Does Ageing Affect Circadian Rhythms at the SCN?

• SCN-driven rhythms show dampened amplitude across multiple physiological parameters

• Phase advance: Sleep, cognitive performance, body temperature, cortisol, and plasma glucose rhythms all shift earlier with age.

• Ageing leads to weaker and earlier-occurring circadian rhythms

How Does Eye Function Chnage With Age

• ↓ light exposure → (motility problems and going out less)

• ↓ photoreception, vision problems and cataracts (less information and light transferred to SCN)

• ↓ amplitude circadian oscillator (difference between day and night is less clear)

• change in chronotype → shift towards earlier chronotype

• ↑ sleep disorders

• ↑ concomitant diseases → presence of depression, neurodegenerative disease, dementia and AD – impact circ rhythm

• ↑ likelihood of developing sleep disorders

What are the major circadian changes associated with ageing?

• Overall, ageing alters multiple physiological systems.

• Rhythm changes: Phase advance + reduced amplitude of circadian rhythms.

• Light sensitivity: Decreased light responsiveness → reduced c-Fos induction and impaired light entrainment.

• SCN changes: Lower amplitude of electrophysiological output, hormone secretion, and clock gene expression.

• Clock gene disruption: Altered BMAL1 and CLOCK, both linked to longevity.

• Functional impact: Cognitive decline → impaired memory, mood, and sleep regulation.

How are circadian rhythms linked to neurodegenerative diseases?

• Circadian disruption is associated with Alzheimer’s, Parkinson’s, and Huntington’s disease.

• Sleep/circadian disturbances are often early symptoms and worsen with disease progression.

• Neurodegeneration disrupts rhythms through:

  • Neurotransmitter imbalance

  • Degeneration of key brain nuclei

• Intact circadian systems may have neuroprotective effects, reducing susceptibility to degeneration.

What is Alzheimer’s Disease

• Most Common form of dementia

• Assocaited with sleep problems

• Marked alteration in circadian rhythmicity

• Deterioration of neuronal function in the SCN

• Degeneration of VLPO, SCN and basal forebrain

• Melatonin levels dramatically decreased and the circadian rhythm is lost

How does Alzheimer’s disease affect sleep and circadian rhythms?

• Loss of normal day-night activity pattern: reduced overall activity and weak distinction between day vs night compared to healthy control

• Degeneration of key nuclei: VLPO, SCN, and basal forebrain → impaired circadian regulation.

• Sleep/circadian dysfunction: poorer sleep consolidation and weakened rhythmicity.

• Decreased rhythm amplitude: locomotor activity, body temperature, and melatonin.

• Phase delay of circadian rhythms.

How can sleep and circadian interventions help in Alzheimer’s disease?

• Melatonin supplementation can help restore day–night rhythms.

• Strengthening sleep schedules and patterns improves cognitive function and memory in AD patients.

• Sleep/circadian changes may serve as early indicators of disease and potential therapeutic targets.

How do circadian disturbances contribute to neurodegenerative disease progression and management?

• Circadian disruption can occur secondary to lifestyle or disease progression.

• In many neurodegenerative conditions, circadian disruption is also a core feature of the disease, meaning it should be addressed as part of treatment.