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A disinhibitory microcircuit for associative fear learning in the auditory cortex

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. Changing behavior. Learning. Background. Learning. Changing behavior.

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A disinhibitory microcircuit for associative fear learning in the auditory cortex

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  1. Adisinhibitory microcircuit for associativefear 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. Changing behavior Learning Background

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

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

  5. Bilateral destruction of neocortical and perirhinalprojection targets of the acoustic thalamus does not disrupt auditory fearconditioning. Neurosci. Lett. 142, 228–232 (1992) A thalamo-cortico-amygdala pathwaymediates auditoryfear conditioning in the intact brain. Eur. J. Neurosci. 24, 894–900 (2006). Romanski, L. M. Kim, J. J. Background The role of auditory cortex in fear memory acquisition is contentious

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

  7. FM-sweep L2/3 Foot shock Results

  8. Results Activation L1 Inhibition

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

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

  11. Results Glutamatergic peak Nicotinic peck L1 interneuronactivation 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 inthe local microcircuit? " L1 interneurons caninhibit interneurons in L2/3 during nicotinicactivation" Fast-spiking, PV+ interneurons

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

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

  17. Conclusion 2 L1 interneurons inhibit L2/3 PV+ interneurons Excitationof L1 interneurons by aversive stimuli serves to remove bothspontaneous and feed-forward inhibition provided by PV+ interneuronsto surrounding pyramidal neurons

  18. Results Disinhibition is /is notthe main effect of foot shocks in L2/3 pyramidal cells? Inhibition of PV+ interneurons is a dominantinfluence shaping foot-shock responses in pyramidal neurons

  19. Results How does sensoryinput interact with foot-shock-mediated disinhibition? Calcium image Freely moving recording Foot shocks cause a strong enhancement of the calcium signalintegral Tone/shock compounds elicit much greater activity than tones alone coincidence of toneand shock excited putative pyramidal neurons much more than tonealone

  20. Cholinergic afferents from the basal forebrain Aversive stimulation, FS Conclusion 3 L2/3 pyramidal neurons are disinhibited by aversive stimuli via inhibitionof PV+ interneurons. PV+ CS

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

  22. Conclusion4 Nicotinic disinhibition of the auditory cortexselectively duringfoot 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 auditorycortex and at cortical afferents to the amygdala. Cholinergic activation of L1 interneurons may also contribute to memoryexpression, because basal forebrain neurons acquire a conditioned response during learning.

  24. Thank you

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