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

• Published in: Neuron (Cambridge, Mass.) Vol. 109; no. 6; pp. 947 - 956.e5
• Main Authors: Nuno-Perez, Alvaro, Trusel, Massimo, Lalive, Arnaud L., Congiu, Mauro, Gastaldo, Denise, Tchenio, Anna, Lecca, Salvatore, Soiza-Reilly, Mariano, Bagni, Claudia, Mameli, Manuel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.03.2021; Elsevier Limited; Cell Press
• Subjects: AMPA receptors; Animals; Cognition & reasoning; Cognition - physiology; Cognitive ability; Decision making; Glutamatergic transmission; Habenula; Habenula - physiology; lateral habenula; Luteinizing hormone; Male; Mental depression; Mental disorders; Mice; Mice, Inbred C57BL; Neuronal Plasticity - physiology; Neurotransmission; Receptors, AMPA - metabolism; Reinforcement; Reward; reward-guided behaviors; Stress; Stress, Psychological - physiopathology; Synaptic depression; Synaptic strength; Synaptic Transmission - physiology; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; stress; reward-guided behaviors; AMPA receptors; lateral habenula
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2021.01.008

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. [Display omitted] •A specific phase during an appetitive cognitive task engages LHb neuronal dynamics•The strength of excitatory synapses in LHb neurons predicts cognitive performance•Stress triggers cognitive impairments and disrupts LHb neuronal activity•Deficits in reward-guided behaviors require a decrease in LHb AMPAR transmission Effective evaluation of costs and benefits is fundamental for survival and vulnerable to stress. Nuno-Perez et al. show that the strength of AMPAR transmission within the mouse lateral habenula governs the incidence of non-rewarded choices in a reward-guided task. Stress weakens habenular excitatory synapses and consequently augments non-rewarded decisions.