UNCONTROLLABLE STRESS IMPAIRS THE ACQUISITION OF CONDITIONED INHIBITION: IMPLICATIONS FOR THE INVOLVEMENT OF THE LATERAL HABENULA

Conditioned inhibition, a fundamental behavioral mechanism alongside conditioned excitation, emerges when a conditioned stimulus (CS) becomes associated with the absence of an unconditioned stimulus (US). Previously, we have demonstrated that the lateral habenula (LHb) critically mediates conditioned inhibition, as explicitly unpaired training induces a retardation of excitatory conditioning. Uncontrollable stress induces widespread dysregulation in neural systems and learning deficits, with studies linking stress to LHb hyperactivation in both animal models and humans with depression. LHb with stress exposure exhibits impaired processing of reward signals and negative prediction errors, potentially contributing to learning impairments. While LHb integrity is essential for acquiring conditioned inhibition, the impact of stress-induced LHb dysfunction on this process remains unexplored. To address this gap, we investigated the effects of uncontrollable stress on conditioned inhibition. Animals underwent 60 minutes of restraint and 60 tail shocks, and were then explicitly unpaired with a light cue and food 24 hours later. The inhibitory property of light generated by explicitly unpaired training of the light with the food was assessed through a retardation test, where excitatory learning of the light with food was delayed. While unstressed animals showed a significant delay, stressed animals exhibited no such retardation. This finding suggests that uncontrollable stress disrupts the acquisition of conditioned inhibition. Supported by the Korea Research Foundation Grant funded by the Korean Government (RS-2024-00440371 to Jung-Soo Han).