A molecular gradient along the longitudinal axis of the human hippocampus informs large-scale behavioral systems

Jacob W Vogel,Boris Bernhardt,Andrew Doyle,Renaud La Joie,Alexandr Diaz-Papkovich,Gil D Rabinovici,Claude Lepage,Rhalena A Thomas,Etienne Vachon-Presseau,Michel J Grothe,Reinder Vos De Wael,Alan C Evans,Yasser Iturria-Medina

doi:10.1038/s41467-020-14518-3

Abstract

The functional organization of the hippocampus is distributed as a gradient along its longitudinal axis that explains its differential interaction with diverse brain systems. We show that the location of human tissue samples extracted along the longitudinal axis of the adult human hippocampus can be predicted within 2mm using the expression pattern of less than 100 genes. Futhermore, this model generalizes to an external set of tissue samples from prenatal human hippocampi. We examine variation in this specific gene expression pattern across the whole brain, finding a distinct anterioventral-posteriodorsal gradient. We find frontal and anterior temporal regions involved in social and motivational behaviors, and more functionally connected to the anterior hippocampus, to be clearly differentiated from posterior parieto-occipital regions involved in visuospatial cognition and more functionally connected to the posterior hippocampus. These findings place the human hippocampus at the interface of two major brain systems defined by a single molecular gradient.

Highlights

The functional organization of the hippocampus is distributed as a gradient along its longitudinal axis that explains its differential interaction with diverse brain systems
We show that a graduated pattern of gene expression along the hippocampal longitudinal axis predicts the location of a brain tissue sample along this axis, and that distinct interactions between the anterior and posterior hippocampus with specific brain systems can be predicted by the genomic similarity shared between those brain systems and the different poles of the hippocampus
We found that samples with greater genomic similarity to the anterior hippocampus showed greater hypometabolism in frontotemporal dementia (FTD) compared to Alzheimer’s disease (AD), whereas samples more similar to the posterior hippocampus showed greater hypometabolism in AD compared to FTD (r2 = 0.118; Fig. 5a)

Summary

Introduction

The functional organization of the hippocampus is distributed as a gradient along its longitudinal axis that explains its differential interaction with diverse brain systems. While some consensus over implicated genes has been met, all of these studies have been performed exclusively in rodents, and it is unclear whether similar genes and proteins are involved in regulating and characterizing the anterior–posterior axis of the human hippocampus This distinction is important, as the human hippocampus bears a different anatomy from that of rodents, participates in ostensibly more complicated cognitive systems, and shows selective vulnerability to diseases unique to humans. As yet, such explorations have been severely limited due to the complications of measuring regionally detailed gene expression in the human brain. We show that a graduated pattern of gene expression along the hippocampal longitudinal axis predicts the location of a brain tissue sample along this axis, and that distinct interactions between the anterior and posterior hippocampus with specific brain systems can be predicted by the genomic similarity shared between those brain systems and the different poles of the hippocampus

Methods

Results

Conclusion