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

Author(s)

Oliveira, Gabriela V. M. ; Hernandes, Paloma M. ; Santos, Fabio H. dos ; Soares, Victor P. M. N. ; Falconi-Sobrinho, Luiz Luciano ; Coimbra, Norberto C. ; Wotjak, Carsten T. ; Almada, Rafael Carvalho

• Document type: Journal article
• Source: Psychopharmacology; v. N/A, p. 12-pg., 2024-10-10.

Abstract

RationaleDespite 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.ObjectivesWe 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.MethodsNeural 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 mu L) or OrxA (28, 70, and 140 pmol/0.1 mu L) in the PL before the test session of contextual fear conditioning.ResultsNeural 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.ConclusionIn 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. (AU)

• FAPESP's process: 21/06557-3 - The role of Orexin-A in the medial prefrontal cortex in the expression of contextual conditioned fear
• Grantee: Gabriela Vitar Mendes Oliveira
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 20/02724-0 - The role of the orexinergic system in the medial prefrontal cortex in the expression of contextual conditioned fear
• Grantee: Fabio Henrique dos Santos
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 19/05255-3 - Study of the role of glutamatergic pathways from the anterior cingulate cortex on nitrergic mechanisms of the ventromedial hypothalamus and periaqueductal grey matter involved in the genesis of defensive responses evoked in mice threatened by snakes
• Grantee: Luiz Luciano Falconi Sobrinho
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/15050-7 - Study of the role played by endocannabinoid and endovaniloid signalling in the pallidum on the activity of the neostriatum-pallido-nigral disinhibitory and nigro-tectal inhibitory pathways during the organization of innate fear of animals confronted to snakes
• Grantee: Norberto Cysne Coimbra
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/14073-6 - Testing emotional vulnerability to threat in adults using a virtual reality paradigm of fear associated with autonomic variables
• Grantee: Norberto Cysne Coimbra
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/15757-6 - Fear and anxiety: role of the orexinergic system in the medial prefrontal cortex
• Grantee: Victor Paschoal Marquezin Nicolli Soares
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 18/03898-1 - Fear and anxiety: role of the orexinergic system in the medial prefrontal cortex
• Grantee: Rafael Carvalho Almada
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 19/01713-7 - Fear and anxiety: role of orexinergic system in the prefrontal cortex
• Grantee: Rafael Carvalho Almada
• Support Opportunities: Scholarships in Brazil - Young Researchers
• FAPESP's process: 13/10984-8 - Influence of the anterior cingulate cortex and involvement of hypothalamic NMDA and AMPA/kainite glutamatergic receptorsin the organization of the defensive behaviorand innate fear-induced antinociception elaborated by posterior hypothalamus
• Grantee: Luiz Luciano Falconi Sobrinho
• Support Opportunities: Scholarships in Brazil - Master