Circadian Rhythms: Lecture 4 Proseminar in Biological Psychology

Circadian Rhythms Circa: "about” Dies: “day" Circadian rhythms are physiological and behavioral characteristics that follow a daily, or circadian, pattern 24 hour period

Biological Rhythms Ultradian: cycles lasts shorter than a day - milliseconds it takes for a neuron to fire - 90 minutes sleep cycle (REM and NON REM sleep) - hunger - YOUR ATTENTION SPAN IN CLASS! Infradian: cycles lasts longer than a day - monthly menstrual cycle - hibernation in animals - bird migration Circadian: cycles lasting 24 hr - sleep-wake cycle - body temperature - testosterone levels: highest around 6:00 am, low at 6:00 pm

What dictates or governs our 24 hr cycle?

Environmental Cues: the light/dark cycle Zeitgerbers: German for “Time Giver” Meals Temperature Social activity The tide (marine animals) Entrainment

Zeitgebers ….no circadian rhythms?

We Do Not Need Environmental Cues for Circadian Rhythms Persistence of rhythm in constant conditions (LL/DD) & (Temp): tend to drift.. Under natural conditions, the clocks are precise. Rhythm can be entrained So  CR=daily rhythm is endogenously generated, but still susceptible to modulation by 24-hour environmental cycles endogenous "clock How do we know that these rhythms aren't entirely environmentally induced?

Jean Jacques d’Ortous de Mairan (1729) First Time Evidence for a Endogenous Clock French Astronomer Jean Jacques d’Ortous de Mairan (1729) Heliotrope leaves closed at night Observed the persistence of leaf movement in plants placed in constant dark For 2 centuries nobody cared!!!

Psychiatrist August Forel (1910) Noticed bees returning to the breakfast table at the same time of day to get jam

Psychiatrist August Forel (1910) the bees returned at the same time of the day even when the food was not present Hey Fred, where’s the jam?

von Frisch & Beling (1920) First experiment done in the lab setting Used Bees – set out sugar in water for several days 2. Bees came as expected When not offered bees continued to show up Performed the experiment in a salt mine = same result

Early Human Evidence of an Endogenous Clock 1931 – Wiley Post (Aviator) Flew eastward around the world in 8 1/2 days (208 hrs) - flying ability adversely affected - sleep was disrupted - general feeling of uneasiness - nausea First person to report JET LAG internal clock not adjusted to environmental clock

Blind animals still show circadian rhythms Other Evidence Blind animals still show circadian rhythms - Blind people show circadian cycles - Some strains of Mice have virtually no retina but still have circadian rhythms

Put Animals & Humans in “Constant Conditions” Constant Conditions: LIGHT/LIGHT DARK/DARK “Free Running” = without cues How close is the endogenous clock to 24 hr cycle?

TAU Depends on the Species Mus musculus (mouse) = 23.5 The ‘natural’ period of a biological rhythm free-running in constant conditions: TAU Depends on the Species Mus musculus (mouse) = 23.5 Homo Sapiens (Humans) = 25?24.18 Mesocricetus auratus (Hamster) = 24.1

the phase indicator while free Measurement of Tau Running Wheel Activity 14L/10D Mouse (23.5) Hamster (24.1) Onset of running wheel activity is used the phase indicator while free Running = CT12 Actogram

Measurement of Tau in humans Actiwatch

Suprachiasmatic Nucleus SCN Densely packed collection of small cells The Clock – Oscillator Suprachiasmatic Nucleus SCN Densely packed collection of small cells (only 20,000) anterior hypothalamus Midline in a shallow impression of the optic chiasm

Suprachiasmatic Nucleus (SCN)                                                        

SCN neurons project to other hypothalamic regions Body Temp (Dorsal) Sub paraventricular Zone Sleep & waking (Ventral) Sub paraventricular Zone Feeding, sleep, temperature, hormones SCN neurons project to other hypothalamic regions

SCN Retino-hypothalamic Tract Retina-Geniculate-Striate Pathway – Ventral View SCN Retino-hypothalamic Tract Anterior Portion of the Hypothalamus  (SCN) Superior to optic chiasm, receives input from optic nerves (RHT); this input synchronizes the “clock” in the SCN to the exterior day-night cycle

Innervation of the Pineal Gland in Humans –needs SCN Dependent on the Light/Dark Cycle

Evidence for SCN - Biological Clock 1900’s Simpson & Galbriath Rectal Temp every 2 hours for 2 months!!!!!

Evidence for SCN - Biological Clock Lesions here interfere with circadian rhythms 1967 – C. P. Richter (rats) Hypothalamic Lesions = disrupted eating , drinking, activity 1972 Moore & Eichler Stephan & Zucker SCN Lesions disrupted running wheel activity, drinking, hormones

Important! Changed the pattern of sleep not the amount Evidence for SCN - Biological Clock Lesions here interfere with circadian rhythms (rodents, primates) Still show rhythms but desynchronized to environment L/D cycles (sleep at inappropriate times) Abolishes rhythms completely feeding, locomotor activity, sleep, temperature, hormones Important! Changed the pattern of sleep not the amount

Increased metabolic activity (Schwartz & Gainer, 1977) SCN                                                         night day Increased metabolic activity (Schwartz & Gainer, 1977) So..SCN keeps track of day or night But not whether you are diurnal or nocturnal Injected 2-DG in rats…same results in squirrel monkeys

Other Major Evidence for SCN - Biological Clock SCN cells invivo and invitro confer rhythminicity - in tissue culture - transplantation Electrophysiological studies - electrical activity continues even after surgical removal from hypothalamus - other brain sites also show this but need a connection the SCN Lesions of visual cortex have no effect on rhythms Severing RHT = free running rhythm

All show circadian rhythms Displaying individual rhythms Tissue Culture Electrophysiological studies - electrical activity continues even after surgical removal from hypothalamus SCN neurons (4) All show circadian rhythms Displaying individual rhythms …coolio

Remove clock from the animal and clock still exhibits a sustained circadian rhythm

Ralph, M. R. and Menaker, M. (1989) Transplantation Studies – Cooler Stuff Ralph et al (1990) Removed SCN from Mutant Hamsters (short tau 22 hrs) Transplanted SCN into hamsters that had lesioned SCN Restored….Sleep/Wake Cycle ….not regular cycle BUT….the short rhythms!! VISA VERSA…same results!!!!  transplant to Mutants

Transplantation Studies – Coolest Stuff Silver et al (1996) Lesioned SCN of Hamster = abolished rhythms Got donor SCN placed in tiny semipermeable capsule transplanted into III ventricle Chemicals, nutrients in NO SYNAPTIC TRANSMISSION Reestablished rhythms! ??? Chemical

What makes the clock tick? Hands of the SCN “Main Oscillator” (SCN cells) But what about at the molecular level? GENES (contain the instructions that tells a cell what its job will be) Cells contain a newly discovered protein (clock protein) that regulates gene function and which shows 24-hr variations in cellular levels that appears to account for 24-hr variations in neuronal activity