Toward developing a navigation model of the aging brain in the marmoset

Yale University, New Haven CT

Investigators

Abstract

Project Summary The entorhinal cortex (ERC) and perirhinal cortex are the initial sites of cortical tau pathology and degeneration in the common, sporadic form of Alzheimer's disease (AD). In the ERC, tau pathology is first seen in cell islands in layer II, the major source of inputs to the hippocampus necessary for the formation of new memories. Consistent with this pattern of degeneration, the earliest symptoms of AD are recent memory deficits, which correlate with tau pathology in ERC and related synapse loss in the hippocampus. Learning what makes the ERC so vulnerable to initial tau pathology and its basic neurobiological function is thus critical for understanding the etiology and potential treatment of AD. Seminal studies in the medial ERC in rodents and bats have shown that its neural activity creates a representation of the environment through a set of functionally distinct cell types that encode various spatial and non-spatial navigational variables. Recent discoveries of social place cells and of ERC to hippocampal pathways that carry social signals suggest that the ERC might provide the flexible neural code to map both physical and social environments. However, there have been no physiological studies of the marmoset ERC to determine if their functional organization is similar to rodents and macaques. Learning about the physiology and function of the marmoset ERC is now a critical question, as marmosets are rapidly being developed as an important primate model of AD. Studies in rodents and macaques have shown evidence of calcium dysregulation, a major contributor to tau hyperphosphorylation, in the aging ERC. However, the relationship of calcium signaling to grid cell physiology has not been examined. One likely mechanism may be an enrichment of N-methyl-D-aspartate receptor (NMDAR) with GluN2B subunits, that close slowly and flux high levels of calcium. Although there have been some elegant studies of neuromodulatory influences on grid cell physiology in rodents, remarkably little is known about the molecular mechanisms mediating neurotransmission in the adult ERC. Given the importance of the ERC to the early etiology of AD and the emergence of the marmoset model to study AD, it will be essential to learn about the healthy physiological signatures of ERC function in marmosets for comparisons to upcoming genetic models. Understanding the basic neurobiology will also be critical in order to use this animal model to dissect the molecular events that render these circuits particularly vulnerable to tau pathology. Aim 1 of the proposed research will perform the first functional characterization of neurons in the marmoset ERC by examining whether dynamic space mapping is found in marmoset ERC and whether these maps are flexibly modulated by social context. Aim 2 will analyze the role of NMDAR mechanisms in primate ERC physiology, an area where little is known.