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Séminaire - Johannes LetzkusDisinhibition, a circuit mechanism for associative learning

Abstract :

Learning causes a change in how information is processed by neuronal circuits. Whereas synaptic plasticity, an important cellular mechanism, has been studied in great detail, we know much less about how learning is implemented at the level of neuronal circuits and, in particular, how interactions between distinct types of neurons within local networks contribute to the process of learning.

 Activity in neuronal circuits is tightly regulated by inhibition supplied by distinct types of inhibitory interneurons. We employed a combination of cell-type specific recordings and optogenetic activity manipulations to determine how inhibition in auditory cortex and the amygdala contributes to auditory fear learning. Our results indicate that foot-shocks, which drive learning in this paradigm, lead to inhibition of parvalbumin-positive interneurons contacting the perisomatic domain of principal cells in both brain areas. In auditory cortex, this response is mediated by acetylcholine release leading to time-locked firing of layer 1 interneurons, which in turn inhibit parvalbumin-positive interneurons. Together with optogenetic manipulations of learning and recordings from putative principal neurons, these results suggest that foot-shocks gate plasticity induction through disinhibition in both auditory cortex and the amygdala. In contrast, during the auditory conditioned stimulus, amygdala parvalbumin-positive interneurons are excited and indirectly disinhibit the dendrites of principal neurons via inhibition of somatostatin-positive interneurons, thereby enhancing auditory responses and promoting cue–shock associations.

 Together with other recent work, our results suggest that disinhibition is a key circuit mechanisms for induction of experience-dependent plasticity during associative learning. In addition, our experiments demonstrate that plasticity induction is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different types of local interneurons. 

Selected publications

Wolff, S.B.E., Gruendemann, J., Tovote, P., Krabbe, S., Jacobson, G.A., Müller, C., Herry, C., Ehrlich, I., Friedrich, R.W., Letzkus, J.J.*, Lüthi, A.* Amygdala interneuron subtypes control fear learning through disinhibition. Nature; 509; 453-458.

Senn, V., Wolff, S.B.E., Herry, C., Grenier, F., Ehrlich, I., Müller, C., Letzkus, J.J., Lüthi, A. (2014) Plasticity of action potential kinetics in two distinct amygdala-prefrontal pathways mediating fear extinction. Neuron; 81; 428-437.

Letzkus, J.J.*, Wolff, S.B.E.*, Meyer, E.M.M., Tovote, P., Courtin, J., Herry, C., Lüthi, A. (2011) A disinhibitory microcircuit for associative fear learning in auditory cortex. Nature; 480; 331-335.

Ciocchi, S., Herry, C., Grenier, F., Wolff, S.B.E., Letzkus, J.J., Vlachos, I., Ehrlich, I., Sprengel, R., Deisseroth, K., Stadler, M.B., Müller, C., Lüthi, A. (2010) Encoding of conditioned fear in central amygdala inhibitory circuits. Nature; 468; 277-282.

Kole M.H.*, Letzkus J.J.*, Stuart G.J. (2007) Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy. Neuron 55; 633-647.

Kampa, B.M., Letzkus, J.J., Stuart, G.J. (2006) Cortical feed-forward networks for binding different streams of sensory information. Nature Neuroscience 9 (12); 1472-73.

Cyril Herry (cyril.herry @ inserm.fr)