Stress undermines reward-guided cognitive performance through synaptic depression in the lateral habenula

Alvaro Nuno-Perez, Massimo Trusel, Arnaud L. Lalive, Mauro Congiu, Denise Gastaldo, Anna Tchenio, Salvatore Lecca, Mariano Soiza-Reilly, Claudia Bagni, Manuel Mameli

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Weighing alternatives during reward pursuit is a vital cognitive computation that, when disrupted by stress, yields aspects of neuropsychiatric disorders. To examine the neural mechanisms underlying these phenomena, we employed a behavioral task in which mice were confronted by a reward and its omission (i.e., error). The experience of error outcomes engaged neuronal dynamics within the lateral habenula (LHb), a subcortical structure that supports appetitive behaviors and is susceptible to stress. A high incidence of errors predicted low strength of habenular excitatory synapses. Accordingly, stressful experiences increased error choices while decreasing glutamatergic neurotransmission onto LHb neurons. This synaptic adaptation required a reduction in postsynaptic AMPA receptors (AMPARs), irrespective of the anatomical source of glutamate. Bidirectional control of habenular AMPAR transmission recapitulated and averted stress-driven cognitive deficits. Thus, a subcortical synaptic mechanism vulnerable to stress underlies behavioral efficiency during cognitive performance.

Original languageEnglish (US)
Pages (from-to)947-956.e5
Issue number6
StatePublished - Mar 17 2021
Externally publishedYes


  • AMPA receptors
  • lateral habenula
  • reward-guided behaviors
  • stress

ASJC Scopus subject areas

  • Neuroscience(all)


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