Ketamine attenuates habenula activity in response to aversive outcomes during Pavlovian learning

Abstract

Ketamine is an NMDA receptor antagonist with rapid-antidepressant properties when administered at a sub-anesthetic dose. Preclinical models indicate that a direct injection of ketamine into lateral habenula (Hb), a small midbrain structure with an evolutionarily preserved role in aversive learning across mammals, can rapidly relieve depression-like behavior. However, there is limited evidence to explain how ketamine acts on the function of the human habenula. In a translational computational neuroscience study, 70 healthy adult volunteers were randomised in a 1:1 ratio to receive ketamine or placebo (NaCl 0.9%). We used an aversive Pavlovian conditioning paradigm combined with 7-Tesla functional neuroimaging to show that ketamine attenuates habenula response during aversive stimuli expectations and outcomes 24 hours post-infusion. We further present preliminary evidence suggesting that when aversive learning occurs after ketamine infusion, reduced habenula activity during the learning process may lead to downstream effects that diminish the aversive impact of negative affective memories. These findings provide translational support for preclinical models of ketamines mechanisms in humans.