Studying Hibernation Biology to Gain Insights into Fatigue - Beyond the Symptom: The Biology of Fatigue
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Beyond the Symptom:
The Biology of Fatigue
September 27 – 28, 2021
Studying
Hibernation
Biology to
Gain Insights
into Fatigue
Kelly L. Drew, PhD
Center for Transformative
Research in Metabolism,
University of Alaska Fairbanks
Disclaimer and Disclosures Disclaimer This certifies that the views expressed in this presentation are those of the author and do not reflect the official policy of the NIH. Disclosure I have a financial interest in Be Cool Pharmaceutics.
Hibernation is energy conservation.
“Fatigue” is an adaptation to resource
limitation.
Seasonal Cycle of the Arctic Ground Squirrel
Thermoregulatory changes anticipate hibernation onset by
45 days – Free Ranging AGS
Seasonal decrease in
metabolism leads to a
decrease in Tb and a
decrease in food intake Sheriff et al., 2012, J Comp Physiol B
A torpid (hibernating) Arctic
45
ground squirrel.
40
body temperature (°C)
35
30
25
20
15
10
5
0
-5
AGS (Urocitellus 8/1/99 12/1/99 4/1/00
parryii)
Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
em ergence reproduction natal grow th & hibernation
em ergence fattening
9/21/2021 This Photo by Unknown
6
Author is licensed under
CC BY-NC
Laboratory housed animals – 22°C; 12:12 L:D
Winter sleepiness accompanies lower metabolic rate and body temperature (in animals that
are not hibernating) Decreased sensitivity to caffeine
Increased sensitivity to adenosine receptor agonists
Golden mantel
ground squirrel
(Callospermophi
lus lateralis)
Walker et al., 1980, Hibernation and Circannual Rhythms of Sleep,
Physiological Zoology, Vol. 53(1), pp. 8-11
9/21/2021
Human circannual
rhythms also revolve
around resource
availability
• A seasonal rhythm modulates
thermogenesis and underlies
expression of hibernation and
seasonal sleepiness.
• Seasonal rhythm is associated with
enhanced A1 adenosine receptor
signaling.
9/21/2021 8
https://www2.ucar.edu/atmosnews/just-published/4279/interior-alaska-subsistence-hunting-warming-world
9/21/2021 9
The Adenosine Model of Hibernation
The Model
The Summer-Winter
transition increases
sensitivity to A1
adenosine receptor Sleep
signaling so that in
winter sleep extends
into torpor.
Summer-Winter Switch
Modified from Jinka et al., 2011Adenosine is a retaliatory metabolite and inhibitory
neuromodulator at the heart of energy homeostasis
p-AMPK
(active)
AMPKK
AMPK
(inactive) AMP/ATP
NT5E
ATP ADP AMP Ado S-adenosylhomocysteine
cAMP AdK
PKA PKA
(active) (inactive)
A1 A3
Go
A2A A2B
Gi Gi Gs Gs
AC
gCa2+;gK+ Inhibits Excites
This Photo by
Unknown cAMP ATP CNS A1AR turn down the
Author is
licensed under CNS A1AR increase homeostatic thermostat
sleep drive
CC BYSeasonal increase in sensitivity of A1AR in arctic ground squirrels
housed at 20°C and 12:12 L:D
9/21/2021 12CNS regulation of “fatigue” in the winter season
requires A1 adenosine receptors
4:20 L:D; 2°C
Summer Winter
O2 Consumption (mLg-1h-1)
Core body temperature (°C)
Summer (off Winter
season)
A1AR agonist CHA or Veh (blinded) icv
Off-season (summer): May- June
0 6 12 18 24 0 6 12 18 24
Early hibernation season: Sep-Oct
Time (h)
Mid hibernation season (winter):
December
Study Design A1AR stimulation is necessary and sufficient to induce
hibernation in arctic ground squirrels
Spontaneous hibernation reversed by A1AR antagonist (CPT),
but not A2AAR antagonist (MSX-3)
A3AR agonist (2-CL-IB MECA) did not induce hibernation
9/21/2021 Jinka et al., 2011 13Seasonal modulation of Median Preoptic
thermoregulatory circuits explain Nucleus
seasonal response to CHA
Raphe Pallidus
Frare et al.,Energy homeostasis may be communicated from the periphery to the
brain through retaliatory, signaling metabolites like adenosine
Rice et al., in
prep
n=7-10Tanycytes may permit transport of adenosine from
blood to brain through seasonal expression of
adenosine kinase
Frare and Drew, 2021 J. Neuroanatomy, 113, 101920Mechanisms regulating hibernation may underlie mechanisms relevant to fatigue • In hibernation sleep transitions into torpor (extreme fatigue?) • Regulated by increased gain in purinergic signaling • Whole body metabolism communicates with brain • Tanycytes are positioned to regulate body-brain communication.
Thank you! • Tulasi Jinka • Sarah Rice • Zac Carlson • Carla Frare • Angelo D’Alessandro • Julie Haines Funding • P20GM130443
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