1 a disinhibitory microcircuit for associative fear learning in the auditory cortex johannes j....
TRANSCRIPT
![Page 1: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/1.jpg)
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
![Page 2: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/2.jpg)
2
Learning Changing behavior
Background
![Page 3: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/3.jpg)
3
Learning Changing behavior
Balance of excitation and inhibition
Neuromodulation
Background
![Page 4: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/4.jpg)
4
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
![Page 5: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/5.jpg)
5
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
![Page 6: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/6.jpg)
6
Results
The role of auditory cortex in auditory fear learning
Activity in auditory cortex is required for fear learning in this paradigm.
![Page 7: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/7.jpg)
7
Results
L2/3
FM-sweep
Foot shock
![Page 8: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/8.jpg)
8
Results
L1
Activation
Inhibition
![Page 9: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/9.jpg)
9
Results
Glutamatergic projections from higher cortical areas
Cholinergic afferents from the basal forebrain
The afferent pathways mediating activation of L1 interneurons during foot shocks
![Page 10: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/10.jpg)
10
Results
Cholinergic afferents from the basal forebrain
Electrical microstimulation of the basalforebrain caused strong excitation of L1 interneurons in the absence of foot shocks
![Page 11: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/11.jpg)
11
Results
Glutamatergic peak
Nicotinic peck
L1 interneuron activation was biphasic
![Page 12: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/12.jpg)
12
Results
All L1 interneurons showed responses to nicotinepuffs that were blocked by the same antagonistsand could fire L1 interneurons
![Page 13: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/13.jpg)
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.
![Page 14: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/14.jpg)
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
![Page 15: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/15.jpg)
15
Results
L2/3 fast-spiking PV+ interneurons are inhibited by L1 interneurons during foot shocks
![Page 16: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/16.jpg)
16
Results
The shock removes feed-forwardinhibition in pyramidal neurons during auditory input
Freely moving animal test
Putative interneurons
Putativepyramidal neurons
![Page 17: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/17.jpg)
17
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
![Page 18: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/18.jpg)
18
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
![Page 19: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/19.jpg)
19
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
![Page 20: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/20.jpg)
20
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
![Page 21: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/21.jpg)
21
ResultsDoes this circuit contribute to the fear learning?
![Page 22: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/22.jpg)
22
Conclusion4
Nicotinic disinhibition of the auditory cortex selectively during foot shock is required for associative fear learning
![Page 23: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/23.jpg)
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.
![Page 24: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/24.jpg)
24
![Page 25: 1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip](https://reader036.vdocuments.site/reader036/viewer/2022062320/56649c785503460f9492dd7a/html5/thumbnails/25.jpg)
25
Thank you