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. 2025 Mar;242(3):521-532.
doi: 10.1007/s00213-024-06701-x. Epub 2024 Oct 10.

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

Gabriela V M Oliveira  1 , Paloma M Hernandes  1   2 , Fábio H Dos Santos  1 , Victor P M N Soares  1 , Luiz Luciano Falconi-Sobrinho  2   3   4 , Norberto C Coimbra  2   3   4 , Carsten T Wotjak  5 , Rafael Carvalho Almada  6   7   8
Affiliations

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

Gabriela V M Oliveira et al. Psychopharmacology (Berl). 2025 Mar.

Abstract

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 (OrxA) 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 OrxA (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 OrxA 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.

Keywords: Contextual fear conditioning; Medial prefrontal cortex; Orexin type 1 receptor; Orexin-A; Prelimbic cortex.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The experiments and protocols were approved by the Local Ethics Committee in Animal Experimentation of the Unesp - Assis Campus (CEUA, process 002/2018), which is in agreement with the ethical principles in animal research adopted by the Brazilian College of Animal Experimentation (COBEA) and by National Council for Animal Experimentation Control (CONCEA). Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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