Biological Rhythms pt 1

Chronobiology and Rhythms

Study of biological clocks and rhythms

A recurrent event (cycle) that has a specific length, frequency, and phase

Cyclical Graphs

Amplitude: Maximum height of wave

Period Lenth: From the start of one wave to the start of another

Rhythmic Variation in Endocrine Function

In hamsters

Daily pulsatile release of LH is programmed (hourly and daily)

Seasonal variation (more active during breeding season)

Annual body mass in ground squirrels

Three squirrels body mass was constantly monitored conditions were similar to nature

There was a change in body mass that modeled natural environments

This is a circannual rhythm (not the same as seasonal)

Circannual Rhythm

Endogenous but seasonal rhythms can be due to tracking the environment (exogenous)

Biological Rhythms and Health

Coincide with cognitive deficits and cortical atrophy, diabetes, ulcers, cancer, hypertension and cardiovascular disease, physiological, death

Biological Clocks

Each clock has its own timing that can be free-running or entrained.

Free running clocks are not synchronized to environmental cues

Entrained clocks are based on endogenous rhythm synchronized to periodic environmental cues (Zeitgeber: environmental time cue)

Circalunar Behavior and Antlion Larvae

Hunt by building sand pits to trap passing ants/insects

There is a circalunar rhythm of trap volume (this rhythm will free run in constant dark lab conditions) larger volume when moon is full and smaller when moon is new

Why do we need biological clocks

Coordinate activities with other individuals (parental duties, hunting, foraging, mating)

Increase activity at times when it is possible to be more productive

Avoid/reduce predation

Prepare the body for environmental changes

Circadian Activity Rhythms in Rabbit Pups

Mothers nurse once a day for less than 5 mins, before this pups will become more active

Circatidal Activity

In fiddler crabs

12.4 hours for tidal cycle

Endogenous cycle in fiddler crabs increases activity during low tides, persists even without intertidal zone however become free running and not entrained

Circadian Rhythms and Humans

Are on a cycle of about 24 hours

Decrease in Growth hormone during the day

Decrease in melatonin during the day that increases at night, goes back down then increases again in the morning

Cortisol peaks in the early hours in the morning

K+ excretion is highest during the day and drops at night

Temperature is highest during the day and drops at night

Work Schedules and Endocrine Physiology

Adrenaline levels are relatively high during working hours and low during sleep

New night-shift workers exhibit a reverse pattern (adrenaline is high during sleep and low during work)

Eventually adrenaline are somewhat dysregulated, peaks at different times which will impact health

Person does not have time to adjust and normalize

Daily Changes in Cortisol

Covary with daily changes in activity

All the following are reduced when cortisol is very low

Working memory

Reaction time

Subjective Measures of Alertness

Shift Work and Health

Affect physical and mental health

Learning memory deficits, slowed reaction time, reduced vigilance, exacerbation of pre-existing disorders, reduced sleep efficiency, type 2 diabetes, cardiovascular problems, obesity, ulcers

Rotating Shifts and Women

Risks with all shifts

Night shifts cause shortened menstrual cycles, reduced fertility, hormonal problems, miscarriage etc

Jet Lag

Effects on the brain and recovery over time

Causes transient decreases in volume of hippocampus, a brain region important in learning memory, reduced right temporal lobe volume

In flight attendants with shorter recovery times they had decreases in volume in hippocampus, Temporal lobe volume, and cortisol concentration, cognitive defects, behavior etc\

Slower reaction times and fewer correct responses from short recovery crew

Rhythms and Pharmacokinetics

ADME, Adsorption, distribution, metabolism, and elimination of drugs vary across the day

EX: Theophylline a bronchodilator for asthma is best given at night as it stays in the blood a lot more

Chronopharmacokinetics

Why are there daily changes in sensitivity to chemotherapy

Drug toxicity

Drugs are most effective at time of least toxicity

Higher doses can be tolerated at the time of least toxicity

Daily (diurnal) changes in catabolic enzymes of cancer drugs and in mitotic index of carcinoma cells

Benefits of Chroinotherapy

Children with acute lymphoblastic leukemia have 5-year survival rates of 80% with chronotherapy but 40% with traditional chemotherapy

Metastatic Colorectal Carcinoma have 53-66% response rates with chronotherapy, 32% response in flat administration

Mechanisms of Circadian Rhythms

First clock gene Per

Discovered in fruit flys with short and long circadian periods and flies that were arrhythmic

LOcalization of Circadian Clocks

At the level of the cell

Single cell organisms exhibit circadian rhythms

Biological Clocks

Depend on various cell processes

Cell membrane permeability

Protein synthesis

Ion balance and transport

Protein Kinase

Genes to protein translation

These allow for the cell to regulate circadian clock but do not cause the regulation

Clock gene

Master regulator of circadian rhythms

Upstream from Per and is a transcription factor that produces clock

Constitutively expressed

Controlled by feedforward and negative feedback loops\

Expressed in the Suprachiasmatic nucleus (SCN) but is also throughout the body

SCN

Circadian rhythm regulator in the brain

Molecular Mechanism of Circadian Clocks

Clock is constitutively expressed

Clock + BMAL1 form heterodimers (changes in BMAL1 cause changes in clock)

Heterodimer binds to DNA and induces transcription of Per, Cry, REV-ERB, RORs

Per and Cry will be phosphorylated by protein kinases and repress transcription of more genes and effect REV-ERB and ROR (upstream of BMAL1)

REV-ERB and ROR will regulate the transcription of Bmal1 (inhibition) and also regulate other things

Process is on a 20 hour cycle in the SCN

These process also induce transcription of other proteins