Orexinergic type 2 receptor in the dorsal hippocampus: an advance in the study of contextual fear conditioning

• Grant number: 25/00686-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2025
• End date: March 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Rafael Carvalho Almada
• Grantee: Rafael Fonteles Soriano
• Host Institution: Faculdade de Ciências e Letras (FCL-ASSIS). Universidade Estadual Paulista (UNESP). Campus de Assis. Assis , SP, Brazil
• Associated research grant: 18/03898-1 - Fear and anxiety: role of the orexinergic system in the medial prefrontal cortex, AP.JP

Abstract

The ability to identify and react to stressful or threatening situations is essential to the survival of living beings. The dorsal hippocampus (DH) is widely highlighted as a critical region in the formation of episodic memories and modulation of emotional behavior, playing a central role in learned fear. Multiple neurotransmitters participate in the neurobiology of fear and anxiety, and the orexinergic system has attracted increasing scientific interest. Orexinergic neurons originating in the lateral hypothalamus (LH) project to limbic structures, including the DH, which expresses both orexin receptor type 1 (Orx1R) and type 2 (Orx2R). Recently, our group demonstrated that selective blockade of Orx1R in DH impairs both the acquisition and expression of contextual conditioned fear (Proc. FAPESP n° 2023/00888-3). However, the involvement of Orx2R in the regulation of these processes in DH remains poorly understood. This study aims to investigate the role of Orx2R in DH in the organization and expression of behavioral responses associated with learned fear. To this end, the effects of selective blockade of Orx2R on the expression of contextual conditioned fear will be evaluated. Mice will receive intra-DH injections of the selective Orx2R antagonist, TCSOX 229, at doses of 3, 30, and 300 nM before the test session. We hypothesize that orexinergic mechanisms in the DH, particularly those mediated by Orx2R, are crucial for the expression of defensive responses related to learned fear.