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1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip.

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Presentation on theme: "1 A disinhibitory microcircuit for associative fear learning in the auditory cortex Johannes J. Letzkus, Steffen B. E.Wolff, Elisabeth M. M. Meyer, Philip."— Presentation transcript:

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 Tovote, Julien Courtin, Cyril Herry & Andreas Lu¨thi

2 2 Learning Changing behavior Background

3 3 LearningChanging behavior Balance of excitation and inhibition Neuromodulation Background

4 4 Fast-spiking PV+ basket cells Background " Pyramidal neuron disinhibition is involved in auditory fear conditioning " Different types of interneuron in the layers of somatosensory cortex of juvenile rats

5 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

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

7 7 Results L2/3 FM-sweep Foot shock

8 8 Results L1 Activation Inhibition

9 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

10 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

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

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

13 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 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 15 Results L2/3 fast-spiking PV+ interneurons are inhibited by L1 interneurons during foot shocks

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

17 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

18 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

19 19 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 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

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

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

23 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.

24 24

25 25 Thank you


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