Activation, but not inactivation, of the medial or lateral orbitofrontal cortex impaired context-specific fear encoding.

In laboratories, classical fear conditioning and extinction procedures are commonly used to study the behavioral and neural mechanisms underlying fear regulation. Contextual fear conditioning involves the association of an aversive event with the environment where it occurs, which engages the hippocampus and its interactions with the amygdala. The orbitofrontal cortex (OFC), divided into the lateral OFC (lOFC) and medial OFC (mOFC) subregions, plays a crucial role in integrating contextual information from the hippocampus and modulating behavioral responses based on the anticipated outcomes of the context. Because of the extensive anatomical connections of the OFC with the fear circuit, including the hippocampus, the amygdala, and the medial prefrontal cortex, and the reasoning that proper retrieval of fear-related memory is context-dependent, we raised the question to investigate the ability of the animals to discriminate between contexts when they were trained under differential OFC activation levels during the encoding of contextual fear memory. In this study, we conducted a contextual fear conditioning procedure in rats using footshock as an unconditioned stimulus (US), followed by the test of their fear levels in contexts same (dangerous) or different (safe) from the conditioning context. We used a pharmacological approach to modulate the activation levels of the lOFC or the mOFC during conditioning to examine their roles on context-specific fear encoding. Our findings showed that the animals could accurately distinguish between the two contexts in control and OFC hypoactivation groups, but failed to do so if they were trained under OFC hyperactivation. Therefore, OFC hyperactivity disturbed the encoding of contextual information during fear acquisition.