Synaptic depression in the lateral habenula underlies stress-driven cognitive deficits

NUNO-PEREZ A; TRUSEL M; LALIVE A; CONGIU M; TCHENIO A; LECCA S; SOIZA REILLY M; MAMELI M

Congreso; FENS Virtual Forum; 2020

FENS

Rationale: The willingness to obtain a rewardprompts goal-directed behaviours whose execution relies on the onlinedeployment of cognitive processes controlling thought and action. Stressfulevents imperil these cognitive capacities and thus result in suboptimal decision-making,hallmark of neuropsychiatric disorders such as depression and schizophrenia.Most attempts to study the neuronal substrates of stress-driven cognitivedeficits focus on neocortical areas and particularly on the prefrontal cortex.More recently, stress-driven alterations in subcortical circuits have beenassociated with aberrant decision-making. However, the neuronal mechanismsunderlying subcortical contributions to these cognitive processes remainelusive. Aim: Here we examined whether stress impairs reward-guidedcognitive capacities by modulating excitatory synaptic transmission in thelateral habenula (LHb), a subcortical structure that supports appetitivebehaviours and undergoes adaptations upon stress exposure. Methods: Wemodelled decision-making in mice with a reward-guided T-maze paradigm andsubjected animals to a single session of inescapable foot-shocks. Furthermore,we assessed synaptic function in LHb neurons through postsynapticelectrophysiological recordings and manipulated habenular synaptic efficacywith viral approaches. Results: We found that the incidence ofnon-rewarded choices (i.e. errors) negatively correlates with the strength ofexcitatory synapses onto LHb neurons. Stress triggered cognitive deficits andlong-term depression of postsynaptic AMPA receptors within the LHb,irrespective of the anatomical source of glutamate. Bidirectional, LHb-specificmanipulations of small GTPases to mimic and rescue stress-driven synapticdepression recapitulated and averted cognitive deficits, respectively. Conclusion:These data delineate a subcortical synaptic mechanism for cognitive performanceand its deterioration after stress.<!-- /* Font Definitions */ @font-face{font-family:"Cambria Math";panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:roman;mso-font-pitch:variable;mso-font-signature:-536870145 1107305727 0 0 415 0;}@font-face{font-family:Calibri;panose-1:2 15 5 2 2 2 4 3 2 4;mso-font-charset:0;mso-generic-font-family:swiss;mso-font-pitch:variable;mso-font-signature:-536859905 -1073697537 9 0 511 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin:0cm;margin-bottom:.0001pt;mso-pagination:widow-orphan;font-size:12.0pt;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;mso-ansi-language:ES;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}size:612.0pt 792.0pt;margin:70.85pt 70.85pt 70.85pt 70.85pt;mso-header-margin:36.0pt;mso-footer-margin:36.0pt;mso-paper-source:0;}div.WordSection1{page:WordSection1;}