LECTURE 14: Hormones, Biological Clocks,

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Psy 137 Behavioral Endocrinology Lecture 6
Biological Rhythms
Website http//mentor.lscf.ucsb.edu/course/summer
/psyc137/
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Why Should Behavioral Endocrinologists be
Interested in Biological Clocks?

• Timing of many motivated behaviors modulated by
  hormones is critical.
• Parental care
• Sexual behaviors
• Territoriality
• Locomotor activities
• Food and water intake
• Torpor
• Hibernation

• Timing of many hormone-receptor interactions is
  critical.
• Estrogen/Progresterone/Estrus cycles
• Insulin/Food intake
• Prolactin/oxytocin/Nursing behaviors
• Glucocorticoid/stress responses

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Chronobiology

• Scientific study of biological clocks and their
  associated rhythms
• Also called Biochronometry
• Began in the early 1960s
• Had to counteract the dogma of constant
  homeostasis in biology and medicine

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Chrono-terminology

• Borrowed terms and concepts extensively from
  engineering disciplines to describe biological
  clocks and associated rhythms.
• Rhythm A recurrent event that is characterized
  by its period, frequency, amplitude, and phase.
• Period The length of time required to complete
  one cycle of the rhythm in question For
  instance, the amount of time required to go from
  peak to peak or trough to trough.
• Frequency Computed as the number of completed
• cycles per unit of time For example, 2
  cycles per day.
• Amplitude The amount of change above and below
• the average value i.e. the distance of the
  peak or nadir
• from the average.
• Phase Represents a point on the rhythm relative
  to
• some objective time point during the cycle

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Components of Biological Rhythms

• Rhythm a recurrent event
• Period a cycle
• Frequency cycles per unit of time
• Amplitude change above/below the average value
• Phase a point on the rhythm relative to some
  objective time point during the cycle

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Exogenous vs Endogenous Control of Biological
Clocks

• Some behavioral rhythms have been recognized
  since ancient times, but they have generally been
  attributed to exogenous (outside the organism)
  factors that elicit behavioral responses (e.g.
  dawn-dusk, seasons) which are called zeitgebers
  (german for time giver).
• Recent evidence indicates that endogenous (inside
  the organism) timing mechanisms mediate many of
  the observed rhythms in physiology and behavior.

• How is it determined whether a rhythm is the
  result of exogenous factors or an endogenous
  clock?
• Isolation experiments (a.k.a. constant
  conditions)

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Jean Jacques dOrtous de Mairan found that the
tensionrelaxation pattern of a heliotropic
plant persisted when isolated from exogenous
factors.
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Examples of Mammalian Rhythms
These rhythms are highly synchronized under
normal conditions. Under constant conditions
(i.e. no external cues) they persist but become
desynchronized indicated they are generated
independently.
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Recent Evidence that Biological Clocks are
Endogenous

• Animals maintained in constant conditions aboard
  a spacecraft orbiting far above the earth, and
  presumably away from subtle geophysical cues,
  display biological rhythms with periods/amplitude
  similar to those observed on earth.
• Animals maintained in adjacent, but individual,
  cages in the absence of environmental cues
  display biological rhythms with slightly
  different periods, suggesting that they are not
  being driven by the same subtle geophysical cue
• The period (and phase) of the biological rhythms
  of one individual can be transferred to another
  individual by means of tissue transplants

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COMPARISON OF BIOLOGICAL RHYTHMS

• Many biological rhythms persist in constant
  conditions and approximate geophysical cues
• Circadian, Revolution of planet 24 h bio
  22-26 h
• Circatidal, Tides 12.4 h bio 11-14 h
• Circalunar, Phases of the moon 29.5 days bio
  26-32 d
• Circannual, Seasons of the year 365.25 d bio
  300-400 d

• Some rhythms persist in constant conditions, but
  do not correspond to any known geophysical cue
• Ultradian shorter than circadian rhythms
• Infradian longer than circadian rhythms

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Types of Biological Clocks and Rhythms
LH Secretion in Female Ground Squirrels
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Experiments Measuring Circadian Rhythms
Free-running rhythm (endogenous timing)
-activity rhythms are generated endogenously but
respond to light as a zeitgeber ENTRAINMENT.
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Usefulness of biological clocks

• Synchronizing the internal physiological and
  biochemical processes of animals
• To promote efficient functioning
• E.g. sleep-wake patterns sleep is not just
  period of low activity, but rather, an active
  biological state in which many processes are
  increased, including brain activity which is
  about the same as when a person is awake and
  relaxed.
• Synchronizing the activites of animals with their
  environments (including social)
• To prepare for predictable events (e.g., winter,
  night, etc.)
• e.g. anticipation/predicting high food
  availability can allow animal to minimize
  dangerous activity (i.e. going to food site) and
  maximize advantageous activity (i.e. getting the
  food).
• e.g. sexual exhaustion in male rats after
  prolonged mating rat takes 4 days to recover
  sexual motivation which matches female
  reproductive (estrous) cycle.

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Rhythm Entrainment
Exposure to light can change onset of biological
rhythm as a function subjective time of day.
Subjective Day Subjective Night
Photononresponsive Photoresponsive
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Rhythm Entrainment
Giving bright light pulses at different phases of
the rhythm produces variable shifts (0 4) in
endogenous rhythm. -this results in entrainment
across days.
Phase Response Curve
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General Characteristics of Biological Clocks and
Rhythms

• Biological clocks are found at every level of
  organization within an organism.
• Single-celled organisms possess circadian rhythms
  so the machinery necessary to generate a rhythm
  must exist at the level of individual cells.
• So, in multi-cellular organisms, does every cell
  possess its own biological clock?
• Perhaps, but in multi-cellular organisms, it
  appears as if these individual biological clocks
  have been organized into some sort of
  hierarchical fashion with feedback imposed from
  above.
• E.g., cells taken from hamster adrenals and
  maintained in culture will free-run at different
  rates. In the intact hamster, they free-run at
  the same rate.

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General Characteristics of Biological Clocks and
Rhythms

• Inherited
• When mutant animals with free-running circadian
  rhythms gt 25 hrs are mated with each other, their
  offspring tend to have longer free-running
  periods than the offspring of mutants with
  free-running rhythms lt 23 hrs (and vice versa)

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General Characteristics of Biological Clocks and
Rhythms

• Temperature independence
• activities or events that change body temperature
  don't significantly alter circadian clocks
• otherwise there would be speed-ups and slow-downs
  and eventually all resemblance to a 24 hr period
  would be lost

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General Characteristics of Biological Clocks and
Rhythms

• Relatively resistant to the influence of
  chemicals
• If not, the food consumed would constantly be
  altering biological clocks.
• A few pharmacological manipulations have been
  shown, however, to affect clocks
• Protein synthesis inhibitors
• Alcohol (EtOH)
• Lithium
• Heavy water (deuterium)

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General Characteristics of Biological Clocks and
Rhythms

• Independence from behavioral feedback
• Suppose a hamster housed in DD is expresses a
  24.25 h cycle of wheel running onset.
• The hamster's wheel is locked for 10 days and hen
  it is unlocked.
• What time will the hamster begin to run?
• 2 predictions
• 1) 15 min after last time-- suggesting that the
  clock suspended time-keeping while the rhythm of
  wheel running activity was not being expressed
• 2) 150 min after last time suggesting that the
  clock continued to run even in the absence of
  behavioral feedback. Prediction 2 is the correct
  answer.

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General Characteristics of Biological Clocks and
Rhythms

• Entrainment is limited to specific ranges
• A circadian rhythm can be entrained to a 23 h day
  by providing 11.5 h of light and 11.5 h of dark
  (same for 12.5 h light/12.5 h dark).
• However, 10 h light and 10 h dark does not result
  in entrainment to a 20 hr day
• Instead, results in free-running with sporadic
  entrainment attained at irregular intervals.
• In hamsters, wheel running can be entrained to
  the following range 18-26 hrs.

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Master clocks

• Circadian clocks have been isolated after
  demonstrating that lesions eliminate circadian
  rhythms
• Eyes of amphibians
• Pineal glands of fish, reptiles, and birds
• Suprachiasmatic nuclei (SCN) of the anterior
  hypothalamus in mammals
• Slices from the SCN maintain circadian rhythms of
  electrical activity
• SCN transplants cause recipient's rhythm to match
  that of donor
• Environmental light entrains oscillations of SCN

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Time Keeping in the SCN

• Individual cells in SCN are capable of generating
  circadian rhythms via mRNA-protein interactions.
• Cells are coupled by GAP JUNCTIONS.

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Effect of SCN Lesions
NOTE this is constant conditions animal can
still entrain to a light-dark cycle
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SCN Transplant
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Input to clock
light--gteyes (photoreceptors)--gtretinohypothalamic
tract--gtSCN
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Biological clock circuit
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Biological Rhythms Affect Hormones
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Output from clock There are many but one has
been extensively studied in mammals
SCN--gtPVN--gtMFB--gtSCG--gtPineal pathway (where
neural information is transduced into a hormonal
message)
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Dual Regulation of Sleep

• Body needs sleep long-term deprivation
  death homeostatic component
• Tiredness is not a direct function of lack of
  sleep
• pulling the all-nighter results in progressive
  decreased alertness with a temporary rebound in
  the morning this rebound diminishes with
  prolonged deprivation.
• Thus, there appears to be circadian and
  homeostatic components to sleep-wake cycles.

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Biological Rhythms Affect Physiology
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Biological Rhythms in Motivation

• Meal-time hunger not proportional to food
  deprivation.
• Food entrainment independent of light
  entrainment and SCN.

L
D
Start Food Entrainment 3 h during L
Activity preceding food presentation
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Hormones Affect Biological Rhythms

• Hamsters start running 5-10 min after dark.
• This statement is true of males but only
  partially true for females.
• Every 4th night (coincident with estrus), females
  show a spontaneous phase advance in their
  activity onset (called scalloping).
• Possibly functions as a means to increase chance
  of meeting a mate.
• Scalloping is abolished by ovariectomy.
• Estradiol treatment of free-running,
  ovariectomized hamsters reduces the period of
  activity onset

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Hormones Affect Biological Rhythms

• Other sex steroids also modulate CRs
• Progesterone lengthens the period of circadian
  rhythms possibly by counteracting the effects of
  estradiol
• Androgens also affect circadian rhythms.
• Castration lengthens and androgen replacement
  restores the period of free-running locomotor
  rhythms in male mice

• Hypophysectomy shortens tau
• Thyroidectomy shortens tau

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Are there different clocks for rhythms of
different lengths or are longer rhythms simply
the result of the multiplication of shorter
rhythms?
Relation between rhythms of different periods.

• e.g., is the 4-day (96 h) estrous cycle of a
  hamster the result of a 4-day clock cycling once
  or a 1-day clock cycling 4 times?
• Evaluated in studies of free-running rhythms in
  female hamsters.
• Phase shifts of entrainment were accompanied by
  proportionate shifts in estrous cycle (light-
  dark cycle changed to 25 h, then estrous cycle
  changed to 100 h-- if reduced to 20 h, then
  estrous cycle switched to 80 h)

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Circannual hibernation rhythms in 5 ground
squirrels.
YEAR
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Photoperiod

• Day length or the amount of light per day.

In Winter I get up at night, And dress by yellow
candle-light, In Summer, quite the other way, I
have to go to bed by day. --Robert Louis
Stevenson, 1885 A Childs Garden of Verses

• Photoperiod changes across seasons
• How does this impact biological rhythms?
• Do biological clocks predict this change?

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Photoperiodism

• Photoperiodism has evolved in virtually all taxa
  of plants and animals that experience seasonal
  changes in their habitats.
• Among vertebrate animals, photoperiodism is
  linked to a number of seasonal adaptations,
  including reproductive, metabolic, immunological,
  and morphological adaptations to cope with
  seasonal changes in ambient conditions.

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Photoperiodism

• Although the precise mechanisms underlying
  photoperiodism differ among taxa, individuals
  that respond to day length can precisely, and
  reliably, ascertain the time of year with just
  two bits of data
• (1) the length of the daily photoperiod
• (2) whether day lengths are increasing or
  decreasing.

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Non-Tropical Animals May Evoke a Suite of
Seasonal Adaptations to Increase the Odds of
Survival and Reproductive Success

• The initial demonstration of photoperiod
  regulating mammalian reproduction was reported
  for European field voles, Microtus agrestis by
  Baker and Ranson in 1932
• Currently, the role of photoperiod in mediating
  seasonal adaptations has been documented for
  hundreds of vertebrate species.

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• Syrian, or golden, hamsters (Mesocricetus
  auratus) represent the most common mammalian
  model used in laboratory investigations of
  photoperiodism.
• Hamsters, in common with most small mammals, are
  long-day breeders.
• Gestation is relatively brief in these animals
  mating, pregnancy, and lactation occur during the
  long days of late spring and early summer.

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Seasonal breeding in hamsters
Critical Photoperiod
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Reproductive Regression
Decreased Testis Size Decreased Steroid
Production
4
3
Serum Testosterone (ng/ml)
2
1
0
Long Days
Short Days
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Reproductive Regression
Decreased Testis Size Decreased Sperm Production
Short-Day Testis
Long-Day Testis
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What Is the Meaning of Reproductive Regression?

• Cessation of spermatogenesis
• Cessation of steroidogenesis
• Cessation of androgen-dependent traits
• Including behavior

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Variation in Reproductive Response to Short Days
in the Lab

• Prairie Voles (Microtus ochrogaster)

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Variation in Reproductive Response to Short Days
in the Lab

• Deer Mice (Peromyscus maniculatus)

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Seasonal Aggression in Red Deer
RUT
Aggression
T
HIGH
Antler growth
LOW
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Human behavior also varies on an annual basis
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Human disease and mortality also varies on an
annual basis
Death from Cardiovascular Diseases Peak in the
Winter
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Seasonal Affective Disorder (SAD)

• Winter depression
• Depressed affect, lethargy, loss of libido,
  hypersomnia, excessive weight gain, carbohydrate
  cravings, anxiety, and inability to concentrate
  or focus
• Ends in the summer
• Frequently diagnosed as Bipolar II depression
  or Atypical Bipolar Disorder
• Prevalence 1-10 with higher in higher
  latitudes
• Sex difference 3.5x higher in women than men
  (also linked during postmenstrual period)
• May result from improper entrainment as
  shortening of day length leads to early melatonin
  secretion.
• Treatment has included litium, antidepressants,
  or estrogen and more recently light (1500 lux)