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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