A combined MRI, histological and immunohistochemical rendering of the rhesus macaque locus coeruleus (LC) enables the differentiation of three distinct LC subcompartments

Abstract

Locus coeruleus (LC) neurons send their noradrenergic axons across multiple brain regions, including neocortex, subcortical regions, and spinal cord. Many aspects of cognition are known to be dependent on the noradrenergic system, and it has been suggested that dysfunction in this system may play central roles in cognitive decline associated with both normative aging and neurodegenerative disease. While basic anatomical and biochemical features of the LC have been examined in many species, detailed characterizations of the structure and function of the LC across the lifespan are not currently available. This includes the rhesus macaque, which is an important model of human brain function because of their striking similarities in brain architecture and behavioral capacities. In the present study, we describe a method to combine structural MRI, Nissl, and immunofluorescent histology from individual monkeys to reconstruct, in 3 dimensions, the entire macaque LC nucleus. Using these combined methods, a standardized volume of the LC was determined, and high-resolution confocal images of tyrosine hydroxylase-positive neurons were mapped into this volume. This detailed representation of the LC allows definitions to be proposed for three distinct subnuclei, including a medial region and a lateral region (based on location with respect to the central gray, inside or outside, respectively), and a compact region (defined by densely packed neurons within the medial compartment). This enabled the volume to be estimated and cell density to be calculated independently in each LC subnucleus for the first time. This combination of methods should allow precise characterization of the LC and has the potential to do the same for other nuclei with distinct molecular features.