Orexin mechanisms in the prelimbic cortex modulate the expression of contextual conditioned fear

Rationale: Despite the existing anatomical and physiological evidence pointing to the involvement of orexinergic projections from the lateral hypothalamus (LH) in regulating fear-related responses, little is known regarding the contribution of the orexin system in the prelimbic cortex (PL) on contextual fear.

Objectives: We investigated the role of orexin-A (Orx_A) and orexin type 1 receptors (Orx₁R) in the PL during the expression of contextual conditioned fear in mice.

Methods: Neural tract tracing of the LH-PL pathway and Orx₁R immunoreactivity in the PL of C57BL/6 male mice were performed. In a pharmacological approach, the animals were treated with either the Orx₁R selective antagonist SB 334,867 (3, 30, and 300 nM/0.1 µL) or Orx_A (28, 70, and 140 pmol/0.1 µL) in the PL before the test session of contextual fear conditioning.

Results: Neural tract tracing deposits in the LH showed some perikarya, mainly axons and terminal buttons in the PL, suggesting LH-PL reciprocate pathways. Furthermore, we showed a profuse network comprised of Orx₁R-labeled thin varicose fibers widely distributed in the same field of LH-PL pathways projection. The selective blockade of Orx₁R with SB 334,867 at 30 and 300 nM in the PL caused a decrease in freezing response, whereas the treatment with Orx_A at 140 pmol promoted an increase in freezing response.

Conclusion: In summary, these data confirmed an anatomical link between LH and PL, established the presence of Orx₁R in the PL, and a modulatory role of the orexin system in such structure, possibly mainly via Orx₁R, during contextual fear conditioning.