Anxiety and Alzheimer's disease: Behavioral analysis and neural basis in rodent models of Alzheimer's-related neuropathology

Abstract

Alzheimer's disease (AD) pathology is commonly associated with cognitive decline but is also composed of neuropsychiatric symptoms including psychological distress and alterations in mood, including anxiety and depression. Emotional dysfunction in AD is frequently modeled using tests of anxiety-like behavior in transgenic rodents. These tests often include the elevated plus-maze, light/dark test and open field test. In this review, we describe prototypical behavioral paradigms used to examine emotional dysfunction in transgenic models of AD, specifically anxiety-like behavior. Next, we summarize the results of studies examining anxiety-like behavior in transgenic rodents, noting that the behavioral outcomes using these paradigms have produced inconsistent results. We suggest that future research will benefit from using a battery of tests to examine emotional behavior in transgenic AD models. We conclude by discussing putative, overlapping neurobiological mechanisms underlying AD-related neuropathology, stress and anxiety-like behavior reported in AD models.

Keywords: Alzheimer’s disease; Anxiety; Elevated plus-maze; Open field; Stress; Ventral hippocampus; light/dark test.

Figure 1:

Overhead view of common behavioral tasks used to measure anxiety-like behavior in rodents. (A) Elevated plus-maze, (B) zero maze, (C) light/dark test and (D) open field test. Where red shaded marks areas that rodents tend to be when afraid and blue is when they are less afraid.

Figure 2:

Summary of anxiety-like behavior in transgenic rodent models of Alzheimer’s disease using classical behavioral assessments. Increased (↑), decreased (↓), both (↕) or no effect (Ø) compared to wild-type controls. In general, the lifespan of mice and rats are comparable with both ranging between ~2 and 3 years but is dependent on the specific strain used. Thus, 3–6 months of age in rodents roughly corresponds with 20–30 years of age in humans, while 10–14 months of age in rodents would correspond with 38–47 years in humans. Pink: elevated plus maze; green: zero maze; purple: light dark test; blue: open field test; orange: marble burying test

Figure 3:

Summary of the development of neural pathology in transgenic rodent models of Alzheimer’s disease. Note that most rodent models report neuropathology within the first few months of adulthood, between the ages of 1–6 months of age. Blue: start of amyloid beta; purple: plaques; orange: tangles; red: cell loss; green: cognitive impairment.