Ketamine attenuates habenula activity in response to aversive outcomes during Pavlovian learning
OpenAlex – February 10, 2026
Source: OpenAlex
Summary
Ketamine significantly reduces habenula activity in response to aversive stimuli, potentially transforming how we understand depression treatment. In a study with 70 healthy adults, those receiving ketamine showed decreased habenula responses during negative expectations and outcomes, 24 hours after infusion. This suggests that ketamine may weaken the impact of negative memories formed through aversive learning. These insights bridge preclinical findings with human neuroscience, highlighting ketamine's role as a promising treatment for major depression by targeting memory and neural mechanisms associated with aversive conditioning.
Abstract
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 ketamine’s mechanisms in humans.