Modeling Circadian Rhythms By Dr Nathaniel J Kingsbury Friday October 24 2014 1000 am Southwick Hall Room 401 In this seminar I will Explore the biology of circadian rhythms and provide motivation for modeling them ID: 238985
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Slide1
Use of Differential Equations in Modeling Circadian Rhythms
By Dr. Nathaniel J. Kingsbury
Friday, October 24, 2014, 10:00 a.m.
Southwick Hall, Room 401Slide2
In this seminar, I will…
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 researchSlide3
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 equationsSlide4
Maladies of Poor Circadian Rhythms
Elderly suffer in particular:
Sleep loss and early wake times
1
Poor mood, poor memory, cognitive decline
2
Linked to accidents, other health problems, and mortality
3
1Buysse D. et. al. (2005) Circadian patterns of sleep, sleepiness, and performance in older and younger adults. Sleep 28:1365–13762 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 13:341–3434http://over40fitnessguide.com/wp-images/tired-elderly.jpg, Accessed April 23, 2014
4Slide5
The Suprachiasmatic Nucleus (SCN)
The brain can be divided by region, and each region has a distinct function
The SCN is one of the best examples of this
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
SCNSlide6
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 5amLights were off for 24h; rhythm is preservedLights were off for 24h; rhythm preservedSCN was surgically removed; rhythm is lostSCN was surgically removed, rhythm is lost
SCN from Population
1 was transplanted into Population 2
Continued
to e
xercise at random times
Got
r
hythm
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, 664–668Slide7
More Experimental Techniques:Bioluminescence
Freeman,
et. al. “
GABA Networks Destabilize Genetic Oscillations
in the Circadian Pacemaker.”
Neuron
78, 799–806, 2013.Slide8
More experimental techniques:Microelectrode arrays
200µm
Freeman,
et. al. “
GABA Networks Destabilize Genetic
Oscillations in
the Circadian Pacemaker.”
Neuron
78, 799–806, 2013.Slide9
Why Model
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 experimentModels can develop hypotheses testable in a labSlide10
Limit Cycle Oscillators
Strogatz
, Steven H. "Exploring complex networks."
Nature
410.6825 (2001): 268-276.Slide11
Types of Networks
Strogatz
, Steven H. "Exploring complex networks."
Nature
410.6825 (2001): 268-276.Slide12
Model Network vs. Experimental NetworkSlide13
Making the Network
Network (Graph) Adjacency matrixSlide14
Circadian Rhythm Model
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
+
-Slide15
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
time (minutes)
A—
B —
C —Slide16
Neurotransmitters connect the network
GABA
(
γ
-
aminobutyric
acid): inhibitory; reduces firing rate
VIP (vasoactive intestinal peptide): excitatory; stimulates transcription of Period geneSlide17
Types of model manipulation: light entrainment
Entrainment of the network to light-dark cycles.
Phase shifts (simulates jet lag)
Length of daylight period
We are very interested in learning what is important for resynchronization to this kind of phase shift
Days
time of day (h)0 12 24Slide18
Basic Output ExampleSlide19
To speed up or slow down?
12:00 am 9:00am
Advancers
Switchers (w/GABA)
DelayersSlide20
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!