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Neuron. 2019 Apr 3;102(1):120-127.e4. doi: 10.1016/j.neuron.2019.01.025. Epub 2019 Feb 11.

Punishment-Predictive Cues Guide Avoidance through Potentiation of Hypothalamus-to-Habenula Synapses.

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Department of Fundamental Neuroscience, University of Lausanne, 1005 Lausanne, Switzerland.
Department of Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Department of Physiology, Graduate School of Medicine, Yokohama City University, 236-0004 Yokohama, Japan.
Department of Fundamental Neuroscience, University of Lausanne, 1005 Lausanne, Switzerland; Inserm, UMR-S 839, 75005 Paris, France. Electronic address:


Throughout life, individuals learn to predict a punishment via its association with sensory stimuli. This process ultimately prompts goal-directed actions to prevent the danger, a behavior defined as avoidance. Neurons in the lateral habenula (LHb) respond to aversive events as well as to environmental cues predicting them, supporting LHb contribution to cue-punishment association. However, whether synaptic adaptations at discrete habenular circuits underlie such associative learning to instruct avoidance remains elusive. Here, we find that, in mice, contingent association of an auditory cue (tone) with a punishment (foot shock) progressively causes cue-driven LHb neuronal excitation during avoidance learning. This process is concomitant with the strengthening of LHb AMPA receptor-mediated neurotransmission. Such a phenomenon occludes long-term potentiation and occurs specifically at hypothalamus-to-habenula synapses. Silencing hypothalamic-to-habenulainputs or optically inactivating postsynaptic AMPA receptors within the LHb disrupts avoidance learning. Altogether, synaptic strengthening at a discrete habenular circuit transforms neutral stimuli into salient punishment-predictive cues to guide avoidance.


AMPA receptors; avoidance; lateral habenula; long-term potentiation

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