A disinhibitory microcircuit for
associative fear learning in
the auditory cortex
Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip Tovote,
Julien Courtin, Cyril Herry
& Andreas Lu¨thi
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Background
Learning
Changing
behavior
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Background
Learning
Changing behavior
Neuromodulation
Balance of excitation and inhibition
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Background
Fast-spiking PV+ basket cells
Different types of interneuron in the layers
of somatosensory cortex of juvenile rats
"Pyramidal neuron disinhibition is involved in auditory fear conditioning"
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Background
Bilateral destruction of neocortical and perirhinal
projection targets of the acoustic thalamus does not
disrupt auditory fear conditioning.
Neurosci. Lett. 142, 228–232 (1992)
Romanski, L. M.
The role of auditory cortex in fear
memory acquisition is contentious
A thalamo-cortico-amygdala pathwaymediates
auditory fear conditioning in the intact brain.
Eur. J. Neurosci. 24, 894–900 (2006).
Kim, J. J.
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Results
The role of auditory cortex in auditory fear
learning
Activity in auditory cortex is required for fear learning in this paradigm.
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Results
FM-sweep
L2/3
Foot shock
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Results
Activation
L1
Inhibition
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Results
The afferent pathways mediating activation
of L1 interneurons during foot shocks
Glutamatergic projections
from higher cortical areas
Cholinergic afferents
from the basal
forebrain
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Results
Cholinergic afferents
from the basal forebrain
Electrical microstimulation of the basalforebrain
caused strong excitation of L1 interneurons in
the absence of foot shocks
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Results
Glutamatergic peak
Nicotinic peck
L1 interneuron activation was biphasic
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Results
All L1 interneurons showed responses to nicotine
puffs that were blocked by the same antagonists
and could fire L1 interneurons
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Conclusion 1
Activity of cholinergic basal forebrain neurons is
both necessary and sufficient to fire L1
interneurons during foot shocks, and that
acetylcholine activates nAChRs on L1 interneurons
Acetylcholine is released rapidly (<50 ms) after an aversive stimulus.
Activation of L1 interneurons in turn is likely to have a central role in
fear-conditioning-related plasticity in the cortex.
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How do foot-shock responses in L1 interneurons
affect processing in the local microcircuit?
" L1 interneurons can inhibit interneurons in L2/3 during nicotinic activation"
Fast-spiking,
PV+ interneurons
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Results
L2/3 fast-spiking PV+ interneurons are inhibited by
L1 interneurons during foot shocks
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Results
Freely moving animal test
Putative
Putative
interneurons pyramidal
neurons
The shock removes feed-forward
inhibition in pyramidal neurons
during auditory input
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Conclusion 2
L1 interneurons inhibit L2/3 PV+ interneurons
Excitation of L1 interneurons by aversive stimuli
serves to remove both spontaneous and feed-forward
inhibition provided by PV+ interneurons to surrounding
pyramidal neurons
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Results
Disinhibition is /is not the main effect of foot
shocks in L2/3 pyramidal cells?
Inhibition of PV+ interneurons is a dominant influence
shaping foot-shock responses in pyramidal neurons
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Results
How does sensory input interact
with foot-shock-mediated disinhibition?
Calcium image
Foot shocks cause a strong enhancement
of the calcium signal integral
Freely moving recording
coincidence of tone and shock excited
putative pyramidal neurons much more
than tone alone
Tone/shock compounds elicit much greater
activity than tones alone
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Conclusion 3
L2/3 pyramidal neurons are disinhibited by
aversive stimuli via inhibition of PV+ interneurons.
Cholinergic afferents
from the basal forebrain
PV+
Aversive stimulation,
FS
CS
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Results
Does this circuit contribute to the fear
learning?
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Conclusion4
Nicotinic disinhibition of the auditory
cortex selectively during foot shock is
required for associative fear learning
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Discussion
Disinhibition of pyramidal neurons by foot shocks probably
gated the induction of activity-dependent plasticity in the
auditory cortex and at cortical afferents to the amygdala.
Cholinergic activation of L1 interneurons may also contribute to
memory expression, because basal forebrain neurons acquire a
conditioned response during learning.
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Thank you
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