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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. Changing behavior. Learning. Background. Learning. Changing behavior.
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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
Changing behavior Learning Background
Learning Changing behavior Neuromodulation Balance of excitation and inhibition Background
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"
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
Results The role of auditory cortex in auditory fear learning Activity in auditory cortexis required for fear learning in this paradigm.
FM-sweep L2/3 Foot shock Results
Results Activation L1 Inhibition
Results The afferent pathwaysmediating activation of L1 interneurons during foot shocks Glutamatergic projections from higher cortical areas 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 absenceof foot shocks
Results Glutamatergic peak Nicotinic peck L1 interneuronactivation was biphasic
Results All L1 interneurons showed responses to nicotine puffs that were blocked by the same antagonists and could fire L1 interneurons
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.
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
Results L2/3 fast-spiking PV+ interneurons are inhibited by L1 interneurons during foot shocks
Results Freely moving animal test Putative pyramidal neurons Putative interneurons The shock removes feed-forward inhibition in pyramidal neurons during auditory input
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
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
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
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
Results Does this circuit contribute to the fear learning?
Conclusion4 Nicotinic disinhibition of the auditory cortexselectively duringfoot shock is required for associative fear learning
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.