1. 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

2. Background
Learning
Changing behavior

3. Learning Changing behavior Neuromodulation Background
Balance of excitation and inhibition
Neuromodulation

4. 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"

5. The role of auditory cortex in fear memory acquisition is contentious
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.

6. The role of auditory cortex in auditory fear learning
Results
The role of auditory cortex in auditory fear learning
Activity in auditory cortex is required for fear learning in this paradigm.

7. Results
L2/3
FM-sweep
Foot shock

8. Results
Activation L1
Inhibition

9. Results
The afferent pathways mediating activation
of L1 interneurons during foot shocks
Glutamatergic projections
from higher cortical areas
Cholinergic afferents
from the basal forebrain

10. Cholinergic afferents from the basal forebrain
Results
Cholinergic afferents
from the basal forebrain
Electrical microstimulation of the basalforebrain caused strong excitation of L1 interneurons in the absence of foot shocks

11. Results
Glutamatergic peak
Nicotinic peck
L1 interneuron activation was biphasic

12. Results All L1 interneurons showed responses to nicotine
puffs that were blocked by the same antagonists
and could fire L1 interneurons

13. 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.

14. 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

15. Results
L2/3 fast-spiking PV+ interneurons are inhibited by L1 interneurons during foot shocks

16. Freely moving animal test
Results
Freely moving animal test
Putative
pyramidal
neurons
Putative interneurons
The shock removes feed-forward
inhibition in pyramidal neurons
during auditory input

17. L1 interneurons inhibit L2/3 PV+ interneurons
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

18. Disinhibition is /is not the main effect of foot
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

19. How does sensory input interact
Results
How 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 greater
activity than tones alone
coincidence of tone and shock excited
putative pyramidal neurons much more
than tone alone

20. L2/3 pyramidal neurons are disinhibited by
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

21. Results
Does this circuit contribute to the fear learning?

22. Conclusion4
Nicotinic disinhibition of the auditory cortex selectively during foot shock is required for associative fear learning

23. 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.

25. Thank you