By Dr. Nathaniel J. Kingsbury
Friday, October 24, 2014, 10:00 a.m.
Southwick Hall, Room 401
In this seminar, I will…
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Explore the biology of circadian rhythms and
provide motivation for modeling them
Show the importance of differential equations in
modeling circadian rhythms
Present results and conclusions from active research
Circadian Rhythms: It’s Night and Day
Circadian=24-hour cycle;
 Your biological clock
 Controls your sleep and other patterns
 Found in most life forms
 Is genetic
 Must be flexible
 Systems biologists can describe them using
differential equations
Maladies of Poor Circadian Rhythms
4
Elderly suffer in particular:
 Sleep loss and early wake
times1
 Poor mood, poor memory,
cognitive decline2
 Linked to accidents, other
health problems, and
mortality3
1Buysse
D. et. al. (2005) Circadian patterns of sleep, sleepiness, and performance in older and younger adults. Sleep
28:1365–1376
2 Grandner, M. et. al. (2012) Age and sleep disturbances among American men and women: data from the US Behavioral Risk
Factor Surveillance System. Sleep 35:395–406
3 Ancoli-Israel S, Alessi C (2005) Sleep and aging. Am J Geriatr Psychiatr 13:341–343
4http://over40fitnessguide.com/wp-images/tired-elderly.jpg, Accessed April 23, 2014
The Suprachiasmatic Nucleus (SCN)
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The brain can be divided by region, and each
region has a distinct function
The SCN is one of the best examples of this
SCN
https://angelosscienceportfolio.files.wordpress.com/2013/04/regions_of_the_brain_and_their_functions.jpg, Accessed April 23, 2014
https://a248.e.akamai.net/media.pinterest.com.s3.amazonaws.com/736x/e5/59/1a/e5591a7d78e177db8d6a80d5168123cb.jpg, Accessed April 23, 2014
The Suprachiasmatic Nucleus (SCN): An
experiment
Mice Population 1
Mice Population 2
Lights were on from 5am-5pm
Lights were on from 5pm-5am
Exercised at 5pm
Exercised at 5am
Lights were off for 24h; rhythm is preserved
Lights were off for 24h; rhythm preserved
SCN was surgically removed; rhythm is lost
SCN was surgically removed, rhythm is lost
SCN from Population 1 was transplanted into Population 2
Continued to exercise at random times
Got rhythm from Pop 1, exercised at 5pm
Adapted from: Sujino, M. et al. (2003) Suprachiasmatic nucleus grafts restore circadian behavioral rhythms of
genetically arrhythmic mice. Curr. Biol. 13, 664–668
More Experimental Techniques:
Bioluminescence
Freeman, et. al. “GABA Networks Destabilize Genetic Oscillations
in the Circadian Pacemaker.” Neuron 78, 799–806, 2013.
More experimental techniques:
Microelectrode arrays
200µm
Freeman, et. al. “GABA Networks Destabilize Genetic Oscillations in the Circadian Pacemaker.” Neuron 78, 799–806, 2013.
Why Model
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Systems biologists can use models to describe an
entire complex network in entirety
Experiments are time and energy intensive
Models can be used to validate phenomena found
during experiment
Models can develop hypotheses testable in a lab
Limit Cycle Oscillators
Strogatz, Steven H. "Exploring complex networks." Nature 410.6825 (2001): 268-276.
Types of Networks
Strogatz, Steven H. "Exploring complex networks." Nature 410.6825 (2001): 268-276.
Model Network vs. Experimental
Network
Making the Network
Network (Graph)
Adjacency matrix
Circadian Rhythm Model
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21 components, 21 ODEs
Modeled for each cell within the network
Represent the core molecular clock
DNA
mRNA
Protein
+
-
Hexokinase
https://en.wikipedia.org/wiki/File:Hexokinase_ball_and_stick_model,_with
_substrates_to_scale_copy.png, Accessed May 1, 2014
Biological Oscillations
If A  B; positive feedback; A  B 
 If A
B; negative feedback; A  B 
Repressilator example: A,B, and C are all molecules
present inside a bacterial cell
 A
B, B C, C A
Proteins per cell




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A—
B—
C—
time (minutes)
Neurotransmitters connect the network
VIP (vasoactive intestinal peptide): excitatory; stimulates transcription of Period gene
GABA (γ-aminobutyric acid): inhibitory; reduces firing rate
Types of model manipulation: light
entrainment
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Entrainment of the network to lightdark cycles.
 Phase
shifts (simulates jet lag)
 Length of daylight period
Days
We are very interested in learning
what is important for
resynchronization to this kind of
phase shift
0
12
24 time of day (h)
Basic Output Example
To speed up or slow down?
Advancers
Switchers (w/GABA)
Delayers
12:00 am
9:00am
Conclusions
Systems biology: modeling complex biological systems
Models of circadian rhythms all employ ODEs
My model closely simulates tissue topology, cell
machinery, and signaling
Goal of my research is to find and communicate
hypotheses that may be tested experimentally
My model helps describe how the brain works!