Circadian rhythm and sleep

Mimosa plant experiment

observed that leaves of the mimosa plant open during the day and close at night and leaves continued to open and close on TIME when placed in constant darkness (first investigation into circadian rhythm)

effect of light as an entrainment cue

goal: to determine the effect of light as an entrainment cue on activity

method:  kept subjects in a highly controlled environment for 87 days 

• Entrainment: light-dark cycle maintained 

• Free running: constant light conditions 

results:

• During entrainment, subject had very CONSISTENT activity levels (always starting and ending on the same time of day and is 24 hours) 

• When free-running (constant dark), subject had consistent length of activity, BUT the start and end times changed 

Circadian activity of SCN neurons in culture (SCN is the master clock)

neurons in the SCN fire action potentials according to a circadian clock, even if the SCN is removed from the brain and kept in culture

Lesioned SCN

objective: investigate if the SCN alone is sufficient to generate circadian rhythm

methods: mice receive a lesion (damage) to the SCN, then their activity levels were measured

results: damage to the SCN eliminates daily activity rhythms (if the SCN of an animal is damaged, the animal not only loses its ability to set the clock each day, but also totally loses its ability to maintain a daily rhythm)

Fetal SCN tissue transplantation

objective: investigate if the SCN alone is sufficient to generate circadian rhythm

subjects: mice with genetic mutations in core clock genes that naturally have no circadian rhythms

methods: mouse fetal SCN tissue or cortical tissue was transplanted in the hypothalamus

measurement: mouse activity

results: fetal grafts of SCN tissue restore behavioral circadian rhythm in mice without a functional clock (slide 19)

flight attendant circadian misalignment

OBJECTIVE: examine structural brain differences after different lengths of recovery from circadian misalignment 

SUBJECTS: Flight attendants working transcontinental flights 

METHODS:  MRI and memory tasks after 5 days of recovery or 14 days of recovery 

Measured in brain volume and working memory 

RESULTS: Circadian misalignment leads to poor working memory and changes in the hippocampus that resolve slowly over time 

• The short recovery crew had slower reaction times and worse performance in a memory task 

• The short recovery crew had a smaller left temporal lobe volume 

what is a biological rhythm

recurrent endogenous cycle that persists WITHOUT environmental cues. 

lets organisms anticipate changes in the environment not just react to environment

Circadian Rhythms:

Physical, mental, behavioral changes that follow a 24-hour cycle that persists without environmental cues 

zeitgebers

•  a stimulus from the environment that synchronizes the circadian rhythm to the environment (light is the biggest cue) 

• Phase can shift by a single entertainment stimulus 

Clock genes

•  group of genes that control circadian rhythms

Primary Transcriptional-Translational Feedback Loop: 

Include Bmal1 (B) and Clock proteins bind together to turn ON the Period (Per) and Cryptochrome (Cry) genes. 

Per and Cry proteins bind together and STOP Bmal1 and Clock from turning on the Per and Cry genes 

Secondary Transcriptional - Translational Feedback Loop:

ROR proteins turn on the expression of Clock and Bmal1 genes 

Clock and Bmal 1 turn ON the expression of the REV genes 

REV proteins turn OFF the Clock and Bmal1 genes

Per and Cry proteins turn OFF the REV genes 

Bmal1 and Clock

primary and secondary feedback loop activators

Per and Cry

primary and secondary feedback loop repressors

RORs

secondary feedback loop activators 

REVs

secondary feedback loop repressors

How do circadian rhythms entrain to the environment? 

• Retinohypothalamic Tract 

  • Retina to SCN 

  • Independent of visual pathways 

  • Blind individuals cna still have light-entrained circadian rhythms

• Melanopsin

  • photopigment in retina that are sensitive to blue light

what organ has the second largest influence on circadian rhythms

liver

Circadian Dysregulation 

Sleep deprivation affects hippocampal neuron signaling and impairs memory consolidation 

The special case of teenagers and why we should delay school start times: 

Teens are consistenly operating on social jet lag of several hours 

• Increased attendance/ lower truancy and dropout rate

• Decrease in behavioral problems and disciplinary action 

• Decrease in student involved car accidents 

• Higher GPA 

• Fewer students sleeping in class 

function of sleep spindles

Objective: determine the effect of Alzheimer's disease on sleep spindles and memory consolidation

Subjects: 12 Alzheimer's patients and 12 matched controls 

Methods: participants underwent a verbal declarative memory task, followed by sleep with EEG recording, another verbal memory task

Measured learning task outcomes and sleep spindle activity

Results: Alzheimer’s did worse at verbal memory task of remembering pairs of words compared to controls and had lower power and density in spindles

Sleep and Memory Consolidation

Objective: Investigate if NREM and REM are required for emotional memory consolidation 

Subjects: young adults

Results: As sound was initiated there was a widespread activation spike across 10-30 bands 

Emotional images had a spike in power in low frequency as well as 15-20 bands, which are where sleep spindles are not really in any other bands of sleep

Glymphatic system

Objective: determine how sleep clears waste products from the brain 

Subjects: male and female mice 

Methods: real-time assessment of the diffusion of two different dyes using two-photon imaging in live mice, either asleep or anesthetized

Measured the amount of rapid eye movement

Results: Natural sleep increased interstitial space by 60% 

Dramatic increase in the clearance of the dye in the CSF 

Amyloid proteins were cleared in sleep (remember accumulation of amyloid leads to Alzheimer's)  

More wash in sleep (clearing out all the waste)

stage 1 of sleep N1

falling asleep, light

alpha waves

stage 2 of sleep N2

heart rate slows and body temp drops

theta - sleep spindles and k complexes

stage 3 and 4 of sleep N 3 and 4

deep sleep, muscles and tissues repair

delta

REM sleep

body is paralyzed and dreams begin

k complex

maintains sleep and memory consolidation (amplitude)

sleep spindle

brief burst of neuronal activity (frequency)

adenosine

builds UP during waking hours

sleep-wake homeostasis

longer time awake means more adenosine

melatonin

produces in response to darkness by pineal gland

secreted at night and low levels throughout the day

glymphatic system

• Clears waste from the blood brain barrier 

• Clears wasre from the brain and redistributes resources using cerebrospinal fluid 

• Active during NREM slow wave sleep 

• Glymphatic activity decreased drastically with age 

what stage do alpha waves occur in

when you are awake (the chill vibes DJ)

what stage do theta waves occur in

stage 1 NREM (did I just fall asleep) and stage 2 with sleep spindles (memory consolidation)

what stage do delta waves occur in

stage 3 NREM (Your body is paralyzed, healing, and probably drooling. Hard to wake up. If you do, expect confusion.)

what stage do beta waves occur in

REM sleep (Brain looks awake but your body’s out cold. This is dreamland. You’re paralyzed so you don’t act out your dreams. (Thanks, brain!))