Transcript journal club CO2 Cell Paper

The Amygdala Is a Chemosensor that Detects Carbon Dioxide and Acidosis to Elicit
Fear Behavior , Ziemann et al. Cell 2009
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The brain's defensive system needs to be highly adaptive
to generate rapid autonomic and behavioral responses to
threatening stimuli, such as a predator in the forest, a
bully at the office, or an aversive stimulus in the
laboratory…..
The Amygdala, a collection of nuclei buried
in the temporal lobe of the brain, is
essential for both innate and learned fear in
rodents and humans.
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Neuroanatomy proved the amaygdala as a convergence point of multimodel
sensory information – linked and derived closely from Pavlovian fear
conditioning.
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Coincident activity among sensory afferents in the BLA -> potentiation of
glutamatergic synapses in the conditioned stimulus pathway -> learned fear
response.
 mediated by direct connections between the BLA and the central
nucleus of the amygdala (CEA), which in turn projects to hypothalamic,
midbrain, and medullary centers that regulate heart rate, freezing
behavior, and respiration
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BLA = the lateral, basolateral, and basomedial nuclei)
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CO2 evoked prominent fear-like freezing
behavior compared to air. ASIC1a−/− mice
were significantly impaired relative to
wild-type controls
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ASIC1a antagonists PcTx1 and A-317567
reduced 10% CO2-evoked freezing in
wild-type mice but had no effect on CO2evoked freezing in the ASIC1a−/− mice.
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CO2 increases anxiety-like behavior in
the open field test
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ASIC1a+/+ mice avoided the CO2
chamber, whereas ASIC1a−/− did not.
Consequently, the ASIC1a+/+ spent
significantly less time on the CO2 side
than the ASIC1a−/− mice
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CO2 enhanced freezing in ASIC1a+/+ mice
during context fear conditioning
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Previous CO2 exposure potentiated
context-evoked fear memory in
ASIC1a+/+ mice but not in ASIC1a−/−
mice
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They measured pH in the basolateral amygdala of anesthetized mice and found that
breathing CO2 reduced pH of both genotypes similarly . They recorded similar
reductions in the lateral ventricle. Baseline pH in the mice breathing air was less than
the expected range likely due to respiratory suppression during anesthesia.
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YES
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YES
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Systemic HCO3− administration in
order to raise Amygdala ph
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In ASIC1a+/+ mice:
 Attenuates CO2 freezing
 Inhibition of contectually
conditioned fear response
 Attenuates freezing response to
predator odor
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Microinjections
breathing
CO2 reduces
of acidic
pH
ACSF into
throughout
the
amygdala
the+ brain
a ph sensor
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Although ASIC1a expression is
abundant
(A)
Injecting
in the
acidic
amygdala,
ACSF into
it the
is also
widely distributed
amygdala
of an anaesthetized
in the CNS.
mouse lowered amygdala pH by
several tenths of a pH unit.
(B) Acid injection lowered pH to 6.8
or below.
(C) Acidic injections
Wouldthat
pH reductions
hit the
amygdala versus
limited
those
tothat
the missed.
(D) local acidicamygdala
and vehicle
produce
injections
hits vs. miss – fear
freezing
behavior?
response
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Injection of adeno-associated virus
encoding ASIC1a into the amygdala
of ASIC1a-/- mice
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expressing ASIC1a in the
basolateral amygdala restored CO2evoked freezing
injections that missed the
amygdala or expression of GFP had
minimal effects on CO2-evoked
freezing.
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Ziemann et al. 2009 suggests
 that changes in extracellular pH in the amygdala trigger cationic
currents mediated by ASIC1a channels.
 that inhalation of carbon dioxide (CO2) decreases the pH in the
amygdala and yields freezing behavior in mice.
 Genetic deletion or pharmacological disruption of ASIC1a channels
reduces fear associated with CO2 inhalation
 and viral-mediated expression of ASIC1a in the BLA of ASIC1adeficient mice restores CO2-induced fear.
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