Influences of Environmental Geometry and Aging on Cognitive Mapping Mechanisms

PROJECT SUMMARY | Spatial navigation is fundamental to survival, and entorhinal cortex (EC) function may
be fundamental to forming and remembering cognitive maps. The Nobel Prize-winning discovery that EC
neurons map environments with grid-like signals has given rise to a class of theories that grid-like metrics from
EC facilitate spatial orientation, planning, and navigation to goals. Deficits in these same navigational abilities
are a hallmark of both healthy aging and Alzheimer’s-related dementia (ADRD), and EC dysfunction is one of
the earliest effects of Alzheimer’s disease and is associated with pre-clinical cognitive decline as well. However,
at this time, despite convergent evidence that EC is central to memory and cognitive mapping, how human EC
contributes to spatial memory mechanisms remains largely theoretical, and how grid-like signal declines (that
have been observed in aging and as a pre-clinical biomarker for Alzheimer’s disease in APOE-ε4 carriers) can
contribute to declines in spatial ability in aging and ADRD remains remarkably poorly understood.
This proposal will leverage several powerful virtual-navigation and fMRI paradigms to address three gaps
in the literature: Aim 1 is to understand how the structure of environments is represented in the human brain.
Extensive psychological evidence demonstrates that environmental barriers fragment and distort people’s
memory and sense of space. Aim 1 will address why - testing strong predictions that EC encodes spatial metrics
that humans use to orient and locate themselves in space, and that barriers shape people’s sense of space in
part by anchoring and shaping the spatial metrics from EC. Aim 2 is to address how spatial signals in EC interact
with the hippocampus, and contribute to hippocampal-dependent memory. It is believed that the hippocampus
builds relational maps of different aspects of our life. The proposed studies will test this, and theories that grid-
like EC signals inform 1) how different parts of our environment are segregated in hippocampal memory, but
also 2) how the hippocampus encodes similarities between navigational experiences. Aim 3 is to test a neural-
mechanistic model of how the hippocampal-EC system contributes to well-known age-related deficits in spatial
cognition. Aim 3 will use a battery of cutting-edge neuroimaging methods and psychological measures. The
researchers will test the hypothesis that navigation deficits can be understood through a functional network-level
perspective of how routes become integrated into map-like memory, how people perceive and update spatial
knowledge, and how individual, age-related differences in such knowledge influence navigational strategies.
Collectively, this body of work will 1) test fundamental predictions about how space and environmental
structure are encoded in the human brain, and 2) establish a deep mechanism-level understanding of the marked
changes in spatial cognition that occur in aging, mild cognitive impairment, and Alzheimer’s disease. The insights
from these tests are necessary if researchers hope to explain, predict, or ultimately develop interventions that
could treat the changes in navigation ability that can come with age.

Grant Number: 5R01AG073250-04
NIH Institute/Center: NIH
Principal Investigator: Thackery Brown