Study of the role of endocannabinoid and endovanilloid signaling in the paleostriatum in mental disorders on depressive-like behavior and instinctive fear of a psychobiological risk assessment test

• Grant number: 23/01003-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): June 01, 2023
• Effective date (End): December 31, 2025
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Principal Investigator: Norberto Cysne Coimbra
• Grantee: Weverton Castro Coelho-Silva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

There is a growing interest in the neural bases of behaviours associated with anxiogenic and depressive-like effects. Innovative studies focused on biochemical and pharmacological mechanisms of cannabinoids seem to be suitable for providing new therapeutic targets for mental disorders treatment. Brain-derived neurotrophic factor (BNDF) and rampamycin-target protein complex 1 (mTOR1) signaling pathway essential for long-term structural changes underlying synaptic plasticity in hippocampus-dependent learning and memory that is impaired in Eif4e mice -bp1/2 double knockout (DKO) subjected to chronic stress and contextual aversive memory, which has become a promising avenue for the study of new drugs for the treatment of psychiatric disorders. Studies suggest that the midbrain tectum (MT) is a key midbrain area for the elaboration of defensive responses during threatening situations. In addition, the deep layers of the superior colliculus (cpCS) and the dorsal periaqueductal grey matter (dPAG) are under tonic inhibitory control by GABAergic nigrotectal pathways. The globus pallidus (GP) has a high density of cannabinoid receptor type 1 (CB1) and TRPV1 endovanilloid channel and sends disinhibitory projections to the ventral midbrain. This work aims to investigate the role of GP CB1- and TRPV1-mediated endocannabinoid- and endovanilloid-signalling in male and female mice with deprtssion and anxiety comorbid condition in a dangerous situation, such as when confronted by Bothrops jararaca pit vipers in a risk assessment test. Initially, through the Restraint Stress Test (RST), Chronic Social Defeat Stress (CSDS), Splash Test (ST) and Forced Swim Test (FST) the depressive-type behavior will be evaluated. Independent groups of animals will be pretreated with either AM251, URB597, URB602 or 6-hydroxy-capsaicin in the GP, and then submitted to the AR model with either toy or an alive snake, with the registration of defense behavior. Finally, the morphology of the nigro-tectal pathway will be studied, in order to investigate the subtype of GABAergic neurons that project to cpCS and SCPd and the effect of stimulation of axon terminals of this double GABAergic link, through optogenetics.Keywords: endocannabinoids, endovanilloids, eEF2K, globus pallidus, defense behavior.