Anatomic, functional and molecular studies of neural systems involved in behavioral activation, fear memory and inhibition of defense responses

• Grant number: 22/14359-0
• Support Opportunities: Research Projects - Thematic Grants
• Start date: March 01, 2024
• End date: February 28, 2029
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Newton Sabino Canteras
• Grantee: Newton Sabino Canteras
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Danilo Bilches Medinas ; Fernando Augusto de Oliveira Ribeiro ; Simone Cristina Motta
• Associated scholarship(s): 24/12092-1 - Statistical modeling, bioinformatics, and computational data processing procedures and methods applied to the functional analysis of neural circuitry, BP.TT

Abstract

This proposal consists of three research projects. In the first project, we will evaluate a site located in the pontine periventricular region called nucleus incertus (NI) which is a critical element in the process of behavioral activation. We will initially investigate several behavioral situations in which we will seek the contrast between high and low behavioral activation. In these different behavioral situations, we will evaluate the NI activation pattern and the changes in the NI proteomic profile. We will also determine how NI activation and inhibition can influence frames with low and high behavioral activation, respectively. Likewise, from the results of the proteomic profiles, we will manipulate the molecular pathways as a functional validation of the mechanisms of activation and inhibition that operate in the NI. Finally, we will investigate how manipulation of the main projection sources for the NI can modulate behavioral activation and inhibition in the examined behavioral models. We believe that this project will bring critical information to the understanding of behavioral activation control, and underlying psychiatric disorders such as anxiety and depression. In the second project, we will investigate how distinct threatening stimuli (i.e., aversive physical stimuli and predatory exposure) are integrated into the Subiculum (SUB) > hypothalamic pathways for the organization of contextual defense responses. Therefore, we will evaluate both the pattern of cell activation and the proteomic profile of SUB cells that project to the hypothalamus in the context associated with the predator and that associated with the aversive physical stimulus. We will also evaluate in this project how the aversive memory reconsolidation process modifies the cellular activity and the proteomic profile of SUB cells that project to the hypothalamus. Thus, we will analyze both from a functional and molecular point of view the participation of SUB in the encoding of fear memory for different aversive stimuli, as well as its involvement in the reconsolidation of fear memory. The third project aims to investigate fear inhibitory systems, a very limited explored issue and of fundamental importance to understand how fear can be inhibited in order to favor other more adaptive behaviors for the moment. Therefore, we will evaluate the impact of different GABAergic afferents to the dorsal part of the central gray matter (dorsal PAG) in the control of defense and predatory hunting responses. In this sense, we will examine the pattern of activation of GABAergic sites that project to the dorsal PAG during exposure to the predatory context, as well as during predatory hunting, and through optogenetic inhibition, we will examine how the selective inhibition of GABAergic projections specific to the dorsal PAG influence the predatory context and predatory hunting. Finally, we will analyze how GABAergic fibers interact with GABAergic and glutamatergic neurons of the dorsal PAG through electrophysiology experiments. (AU)