Presentation on theme: "Johannes J. Letzkus, Steffen B. E. Wolff, Elisabeth M. M"— Presentation transcript:
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
3 Learning Changing behavior Neuromodulation Background Balance of excitation and inhibitionNeuromodulation
4 BackgroundFast-spiking PV+ basket cellsDifferent types of interneuron in the layersof 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 BackgroundBilateral 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 contentiousA 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 ResultsThe role of auditory cortex in auditory fear learningActivity in auditory cortex is required for fear learning in this paradigm.
9 ResultsThe afferent pathways mediating activationof L1 interneurons during foot shocksGlutamatergic projectionsfrom higher cortical areasCholinergic afferentsfrom the basal forebrain
10 Cholinergic afferents from the basal forebrain ResultsCholinergic afferentsfrom the basal forebrainElectrical microstimulation of the basalforebrain caused strong excitation of L1 interneurons in the absence of foot shocks
11 ResultsGlutamatergic peakNicotinic peckL1 interneuron activation was biphasic
12 Results All L1 interneurons showed responses to nicotine puffs that were blocked by the same antagonistsand could fire L1 interneurons
13 Conclusion 1Activity of cholinergic basal forebrain neurons is both necessary and sufficient to fire L1 interneurons during foot shocks, and that acetylcholine activates nAChRs on L1 interneuronsAcetylcholine is released rapidly (<50 ms) after an aversive stimulus.Activation of L1 interneurons in turn is likely to have a central role infear-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 ResultsL2/3 fast-spiking PV+ interneurons are inhibited by L1 interneurons during foot shocks
16 Freely moving animal test ResultsFreely moving animal testPutativepyramidalneuronsPutative interneuronsThe shock removes feed-forwardinhibition in pyramidal neuronsduring auditory input
17 L1 interneurons inhibit L2/3 PV+ interneurons Conclusion 2L1 interneurons inhibit L2/3 PV+ interneuronsExcitation of L1 interneurons by aversive stimuliserves to remove both spontaneous and feed-forwardinhibition provided by PV+ interneurons to surroundingpyramidal neurons
18 Disinhibition is /is not the main effect of foot ResultsDisinhibition is /is not the main effect of footshocks in L2/3 pyramidal cells?Inhibition of PV+ interneurons is a dominant influenceshaping foot-shock responses in pyramidal neurons
19 How does sensory input interact ResultsHow does sensory input interactwith foot-shock-mediated disinhibition?Calcium imageFreely moving recordingFoot shocks cause a strong enhancementof the calcium signal integralTone/shock compounds elicit much greateractivity than tones alonecoincidence of tone and shock excitedputative pyramidal neurons much morethan tone alone
20 L2/3 pyramidal neurons are disinhibited by Conclusion 3L2/3 pyramidal neurons are disinhibited byaversive stimuli via inhibition of PV+ interneurons.Cholinergic afferentsfrom the basal forebrainAversive stimulation, FSPV+CS
21 ResultsDoes this circuit contribute to the fear learning?
22 Conclusion4Nicotinic disinhibition of the auditory cortex selectively during foot shock is required for associative fear learning
23 DiscussionDisinhibition 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.