Mapping Orexin-Regulated Circuits in the Mouse Brain – UROP Symposium

Mapping Orexin-Regulated Circuits in the Mouse Brain

Anacarolina Silveri

Research Mentor(s): Paula Goforth
Program: Biomed
Authors: Anacarolina Silveri, Claudia Saveski, Paul Sabatini, Paula Goforth

Abstract

Background: The orexin/hypocretin system comprises two neuropeptides, orexin-A and orexin-B, and their G protein-coupled receptors (GPCR), orexin receptors 1 and 2 (OX1R and OX2R), which differ in their affinities for the orexin peptides. Orexins are produced exclusively in lateral hypothalamic neurons, which project throughout many brain regions to regulate diverse physiological functions. Our overall interest is the neural circuitry and mechanisms by which orexin regulates multiple functions.
We are specifically interested in examining the retrosplenial cortex (RSC) region and its regulation by the orexin system because of the relationship between Alzheimer’s disease and RSC dysfunction. The RSC is a crucial substrate for navigation and spatial memory, an altered function beginning in the early stages of Alzheimer’s disease. Because this dysfunction in the RSC occurs early in the course of the disease, this region serves as a potential target for therapeutic intervention. In these studies, we examine whether RSC cells contain both OX1R and OX2R receptors and whether those cells project to the same or different regions.
Methods: Using unique mouse models expressing cre-recombinase in OXR-containing neurons, we stereotaxically injected viruses that contain cre-dependent tracers to examine the afferents and efferents of OXR-containing neurons in the RSC. We hypothesized that OXR-containing cells in the RSC project to and receive input from areas important for spatial memory.
Findings and Implications: Our results conclude that OX1R and OX2R are expressed in the RSC, although OX1R cells are restricted to layer 6 of the RSC. We also found that OX1R receive input and project to the thalamus and hippocampus, areas known to contribute to spatial memory function. These findings may provide a basis for further study into the cellular basis of AD-related RSC dysfunction, spatial memory deficits, and potential orexin-based therapies for AD.

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