Lecture 15 - Circadian Rhythms

Biorhythms

natural, repeating cycles in biological processes that help organisms adapt to predictable changes in the environment

• a true biological rhythm is self sustaining, endogenous to the organism

Circadian rhythms with non-daily periodicity

• ultradian

• infradian

• circannual

  • migration (e.g., birds traveling seasonally)

  • hibernation (e.g., bears, ground squirrels in winter)

  • seasonal breeding (e.g., deer mating in fall)

  • molting/coat changes (winter vs summer fur)

Ultradian

less than 1 day (e.g., feeding, breathing, REM/NREM cycles)

Infradian

over many days (e.g., reproductive cycle)

Circannual

yearly (e.g., mating)

Circadian Rhythm

• about 24 hour period

• self sustaining

• entrained by zeitgeber (usually light)

• free running without zeitgebers

Zeitgeber

environmental or exogenous cue that sets the internal ‘clock’

Endogenous rhythm

circadian rhythms are generated internally, even without external cues, but they are synchronized (entrained) by the environment

Zeitgebers (time-givers)

light is the most powerful cue, but feeding times, temperature, and social activity can also reset the clock

Multiple systems

circadian control extends beyond sleep—wake cycles to hormone release (e.g., cortisol, melatonin), body temperature, digestion, and even gene expression in most cells

Suprachiasmatic necleus (SCN

• lesions disrupt rhythm

• isolated SCN still has a rhythm

• transplantation of SCN restores rhythm in an animal with an SCN lesion

• neurons themselves are oscillators

  • rhythmic activity occurs in cell culture

  • in fetus, circadian pattern emerges before synapse

SCN

• influences all other rhythms through different pathways

• SCN uses neural routes to influence other hypothalamic nuclei that regulate many different systems/behaviors

• controls sleep—wake cycle

• controls homeostasis

SCN and pineal gland

• the pineal gland secretes melatonin in response from the suprachiasmatic nucleus, the brain’s master circadian clock

• during darkness, the SCN stimulates the pineal gland to increase melatonin release, which promotes sleepiness

• during daylight, light detected by the retina inhibits this pathway, leading to low melatonin levels and promoting wakefulness

What controls oscillations in the SCN?

• insight from fruit flies

• short lives

• don’t need a lot of space in lab

• small genome

The Drosophila clock

• per: the first clock gene to be cloned

• circadian oscillation of mRNA and protein levels

• mutations can cause a shorter or longer rhythm

• tim: the second gene that controls rhythmicity

Genetic basis of 24hr rhythm

• Daytime activation

• Protein accumulation

• Nighttime inhibition

• Negative feedback loop

• Cycle reset

• Light entrainment

• Outcome

Daytime activation

CLOCK (CLK) and CYCLE (CYC) form a complex that activates transcription of per and tim genes

Protein accumulation

PER and TIM proteins gradually build up in the cytoplasm during the day

Nighttime inhibition

PER-TIM complexes form, enter the nucleus, and inhibit CLK-CYC, shutting down their own transcription

Negative feedback loop

Reduced per and tim mRNA leads to eventual degradation of PER and TIM proteins

Cycle reset

As PER and TIM degrade, CLK-CYC activity resumes, starting a new cycle

Light entrainment

CRYPTOCHROME (CRY) detects blue light in the morning, triggers TIM degradation, and resets the clock

Outcome

This feedback loop produces a ~24-hour circadian rhythm that regulates behavior and physiology

Suprachiasmatic nucleus (SCN) in mammals

• in mammals the transcription factors are CLOCK and BMAL1

• specialized retinal ganglion cells (with melanopsin, a photopigment sensitive to blue light) send signals directly to the SCN

• from there, the SCN coordinates hormonal and autonomic outputs to regulate body rhythms

Melanopsin and Drosophila CRY are…

analogous (both respond to blue light for circadian entrainment) but not homologous in function