Circadian Rhythms and Psychiatric Disorders Flashcards
How does the circadian clock demonstrate its endogenous nature?
(1) When light is switched off, animals still exhibit sleep–wake rhythms that shift in timing—this shows an internal, self-sustaining rhythm.
(2) In constant darkness, the clock free-runs, indicating that without external cues, the intrinsic period may shorten (if the bending is to the left) or lengthen (if to the right).
(3) Evolutionarily, in humans, our internal timer is set close to 24 hours even in the absence of light cues.
(4) The master clock is located in the SCN (suprachiasmatic nucleus) just above the optic chiasm; lesioning the SCN abolishes circadian rhythms.
What is the significance of peripheral clocks in the body?
(1) Besides the SCN, organs like the liver, kidney, heart, and even isolated fibroblasts have their own autonomous clocks.
(2) Each tissue’s clock regulates organ-specific gene expression—only about 10% of the proteome is rhythmic and varies between tissues.
(3) This independence allows for tailored, local regulation of physiological processes despite a unified central rhythm.
What are the key molecular processes that drive circadian rhythms?
(1) Transcription-Translation Feedback Loop:
- Clock genes are expressed, their proteins are synthesized, then they return to the nucleus to inhibit their own transcription, creating oscillatory cycles.
(2) Delay Mechanisms:
- Phosphorylation (by kinases such as casein kinases) flags clock proteins for degradation via the proteasome.
- These phosphorylation “delays” are crucial for setting the rhythm’s period.
(3) Genetic Mutations:
- Mutations (e.g., tau mutation in hamsters, PER2 or CKIδ mutations in humans) alter degradation rates, affecting chronotype (early risers vs. night owls) without changing sleep architecture.
How does the dual oscillator model explain mood cycling in bipolar disorder?
(1) Two Rhythms:
- In addition to the 24‑hour circadian clock, a second oscillator—driven by dopamine—can produce a ~48‑hour cycle.
(2) Clinical Observations:
- Some bipolar patients exhibit alternating manic and depressive episodes with corresponding changes in sleep patterns (e.g., very short sleep on manic days, regular sleep on depressive days).
(3) Endogenous Nature:
- Even in time-isolation (constant conditions), patients can maintain a 48‑hour rhythm, indicating that this oscillator is intrinsic.
What role does dopamine play in circadian disruptions linked to psychiatric disorders?
(1) Dopamine Oscillator:
Normally silent, a dopamine-driven rhythm can be activated by factors like methamphetamine or in bipolar disorder, creating an additional rhythmic cycle.
(2) Mechanism:
Methamphetamine reverses the dopamine transporter, releasing high dopamine levels and triggering this second rhythm.
(3) Nucleus Accumbens (NucAcc):
As the primary target of dopamine neurons, it is crucial for this process; eliminating dopamine fibers in the NucAcc abolishes the second rhythmic component.
(4) Misalignment Hypothesis:
A mismatch between the 24‑hour circadian clock and the dopamine oscillator may underlie mood cycling in disorders like bipolar disorder.
(5) Treatment Insight:
Certain antipsychotics may help by dampening the second oscillator, promoting alignment between the two systems and stabilizing mood.
What is the difference between central and peripheral circadian clocks, and where are they located?
(1) Central Clock:
- Located in the SCN (suprachiasmatic nucleus) of the brain.
- Receives light information via the RHT (retinohypothalamic tract) to synchronize the body’s rhythms.
(2) Peripheral Clocks:
- Found in various organs such as the kidney, liver, and even in fibroblasts (e.g., NIH 3T3 cells).
- Operate autonomously but are normally synchronized by the SCN.
What are the conserved features of clock genes from bacteria to mammals?
(1) They exhibit oscillating levels of mRNAs, proteins, or cellular activity.
(2) They function through autoregulatory feedback loops, where clock proteins regulate their own transcription.
What is the core mechanism of the mammalian circadian clock?
(1) It is based on intracellular transcription-translation feedback loops.
(2) Clock proteins (e.g., CLOCK and BMAL1) activate the transcription of genes (like PER), whose protein products then feedback to inhibit their own transcription, creating a rhythmic cycle.
What do studies involving Bmal1 knock-out mice and tau mutant hamsters reveal about circadian rhythms?
(1) Bmal1 Knock-out Mice: Show disrupted locomotor activity rhythms, demonstrating the gene’s essential role in maintaining circadian cycles.
(2) Tau Mutation in Hamsters:
a) Mutation in Casein Kinase Iε (CKIε) leads to less stable PER proteins (shortening the inhibition phase of CLOCK/BMAL1).
b) Heterozygous (+/tau): 22-hour period
c) Homozygous (tau/tau): 20-hour period
—> This illustrates how post-translational modifications set the clock’s pace.
How do post-translational modifications of clock proteins influence circadian rhythms and individual chronotypes?
- Phosphorylation (by kinases like CKIε/δ) targets clock proteins (e.g., PER) for degradation, introducing a necessary delay in the feedback loop.
- These modifications determine the period length of the clock.
- Variations in this process contribute to differences in chronotypes, resulting in morning-types (early birds) and evening-types (night owls).
How are the mechanisms of the circadian clock conserved across species?
While the specific genes may differ, the underlying mechanism—oscillating mRNAs/proteins and autoregulatory feedback loops—is highly conserved from bacteria to mammals.
What are the key clinical features and genetic associations of Advanced Sleep Phase Disorder?
(1) Clinical Features:
* Evening sleepiness
* Sleep onset earlier than desired (typically 4-6PM)
* Early morning awakenings (typically 1-4AM)
* Sleep recording generally normal (when performed at the
patient’s desired sleep time)
* Generally in older individuals
* Some examples of familial ASPD
(2) Genetic Associations:
*Familial ASPD (FASPS): Some cases run in families.
*Mutations Identified: Mutations in genes encoding PER2 and Casein Kinase Iδ (CKIδ) have been linked to FASPS, altering circadian regulation.
What is the two-oscillator model in bipolar disorder, and what evidence supports its existence?
- In some bipolar disorder (BD) cases, there appears to be not just a 24-hour circadian clock (driven by the SCN) but also a second endogenous oscillator with a longer period (~48 hours).
- Patients with ultra-rapid cycling (48-hour mood cycles) show corresponding changes in sleep patterns (e.g., very short sleep on manic days and regular sleep on depressed days).
- These cycles persist even in time-isolation, confirming their endogenous origin.
How do rodent studies support the existence of a second circadian oscillator, and what is MASCO?
(1) Experimental Evidence:
- When rodents are given methamphetamine in their drinking water, a second rhythmic locomotor component emerges.
- In dopamine transporter knockout (DATKO) mice or with long-term high-dose methamphetamine (e.g., 100 mg/L), over 30% of the animals exhibit periodicities greater than 40 hours (often ~48 hours).
(2) MASCO:
- This second rhythm is termed the Methamphetamine-Sensitive Circadian Oscillator (MASCO).
- It represents an additional oscillator beyond the classical 24-hour SCN-driven rhythm and extends to sleep patterns.
What role does dopamine play in the second oscillator, and what evidence points to its anatomical localization?
- The second oscillator is closely tied to the dopamine system.
- High dopamine levels, triggered by methamphetamine or observed in DATKO mice, induce this additional rhythmic component.
- Ablation (destruction) of dopamine neurons projecting to the nucleus accumbens (NAc) leads to the loss of the second rhythmic component, implicating these neurons in generating the oscillator.
- The NAc, together with the ventral tegmental area (VTA), is therefore a key site for this dopamine-linked oscillator.
How does the interaction between the circadian clock and the dopamine oscillator result in mood cycling in bipolar disorder?
(1) Two Oscillators:
- The primary oscillator is the 24-hour circadian clock (SCN-driven), and the second is the dopamine-linked oscillator (MASCO) with a period >24 hours (~48 hours in some cases).
(2) Beat Frequency Mechanisms:
- When these two oscillators are not aligned (i.e., they have different periodicities), they create a “beat frequency” effect.
- This misalignment can lead to cyclical variations in sleep, arousal, and mood.
Patients may experience periods when the two oscillators are in sync (feeling well) and periods of misalignment that coincide with mood swings (mania or depression).
What are the implications of the two-oscillator model for understanding and treating bipolar disorder?
- The model suggests that mood cycling in BD may be driven by the interplay between the SCN and the dopamine oscillator.
- Disruption or misalignment of these two rhythmic systems can result in the characteristic mood swings seen in BD.
- Interventions that restore or maintain alignment between the two oscillators (e.g., through medications that modulate dopamine activity) may help stabilize mood.
- Some antipsychotics have been shown to dampen the second oscillator, potentially reducing mood cycling.
