1 a disinhibitory microcircuit for associative fear learning in the auditory cortex johannes j....
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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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Learning Changing behavior
Background
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Learning Changing behavior
Balance of excitation and inhibition
Neuromodulation
Background
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Fast-spiking PV+ basket cellsBackground
"Pyramidal neuron disinhibition is involved in auditory fear conditioning"
Different types of interneuron in the layers of somatosensory cortex of juvenile rats
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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.
A thalamo-cortico-amygdala pathwaymediates auditory fear conditioning in the intact brain. Eur. J. Neurosci. 24, 894–900 (2006).
Kim, J. J.
The role of auditory cortex in fear memory acquisition is contentious
Background
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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
L2/3
FM-sweep
Foot shock
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Results
L1
Activation
Inhibition
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Results
Glutamatergic projections from higher cortical areas
Cholinergic afferents from the basal forebrain
The afferent pathways mediating activation of L1 interneurons during foot shocks
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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 nicotinepuffs that were blocked by the same antagonistsand 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
The shock removes feed-forwardinhibition in pyramidal neurons during auditory input
Freely moving animal test
Putative interneurons
Putativepyramidal neurons
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Conclusion 2
Excitation of L1 interneurons by aversive stimuli serves to remove both spontaneous and feed-forward inhibition provided by PV+ interneurons to surrounding pyramidal neurons
L1 interneurons inhibit L2/3 PV+ interneurons
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Disinhibition is /is not the main effect of foot shocks in L2/3 pyramidal cells?
Results
Inhibition of PV+ interneurons is a dominant influence shaping foot-shock responses in pyramidal neurons
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ResultsHow does sensory input interact with foot-shock-mediated disinhibition?
Calcium image Freely moving recording
Foot shocks cause a strong enhancement of the calcium signal integral
Tone/shock compounds elicit much greateractivity than tones alone
coincidence of tone and shock excited putative pyramidal neurons much more than tone 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
Aversive stimulation, FS
PV+
CS
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ResultsDoes 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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