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

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.

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.

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.

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.

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.