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

Massimo Trusel, Alvaro Nuno-Perez, Salvatore Lecca, Harumi Harada, Arnaud L. Lalive, Mauro Congiu, Kiwamu Takemoto, Takuya Takahashi, Francesco Ferraguti, Manuel Mameli

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


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. Learning to predict a threat is crucial for survival. Trusel et al. identify the plasticity of neural circuit elements within the lateral habenula as a mechanism instrumental in guiding anticipation and avoidance of external aversive events.

Original languageEnglish (US)
Pages (from-to)120-127.e4
Issue number1
StatePublished - Apr 3 2019
Externally publishedYes


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

ASJC Scopus subject areas

  • Neuroscience(all)


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