Altered navigational strategy use and visuospatial deficits in hAPP transgenic mice

Abstract

Navigation deficits are prominent in Alzheimer's disease (AD) patients and transgenic mice expressing familial AD-mutant hAPP and Aβ peptides. To determine the impact of strategy use on these deficits, we assessed hAPP and nontransgenic mice in a cross maze that can be solved by allocentric (world-based) or egocentric (self-based) strategies. Most nontransgenic mice used allocentric strategies, whereas half of hAPP mice were egocentric. At 3 months, all mice learned the cross maze rapidly; at 6 months, only allocentric hAPP mice were impaired. At 3 and 6 months, hAPP mice had reduced hippocampal Fos expression, which correlated with cross maze learning in older mice. Striatal pCREB expression was unaltered in hAPP mice, suggesting striatal sparing. We conclude that egocentric strategy use may be an earlier indicator of hAPP/Aβ-induced hippocampal impairment than spatial learning deficits. Persistent use of allocentric strategies when egocentric strategies are available is maladaptive when there is hippocampal damage. Interventions promoting flexibility in selecting learning strategies might help circumvent otherwise debilitating navigational deficits caused by AD-related hippocampal dysfunction.

Introduction

Spatial problems can be approached by different strategies that determine which environmental cues are used to navigate. Allocentric strategies encode locations relative to a world-based map and rely on distal geometric cues. Egocentric strategies encode locations relative to the current position of the navigator and rely on idiothetic and local environmental cues (Gallistel and Cramer, 1996, Hermer and Spelke, 1994). Rats typically engage allocentric strategies when learning locations and switch to egocentric strategies after overtraining (Chang and Gold, 2003b), whereas C57BL/6 mice typically use allocentric strategies persistently in spite of overtraining (Middei et al., 2004b, Passino et al., 2002).

Many neural structures subserve navigation (Kesner, 2000, Kesner and Rogers, 2004, Maguire et al., 1998, Morris et al., 1982, Morris et al., 1990, O’Keefe and Nadel, 1978, Silva et al., 1998, Sweatt, 2004). Allocentric strategies are impaired by hippocampal lesions and promoted by hippocampal stimulation, whereas egocentric strategies are impaired by large striatal lesions and promoted by striatal stimulation (Chang and Gold, 2003a, Chang and Gold, 2003b, McIntyre et al., 2003, McIntyre et al., 2002, Packard, 1999, Packard and McGaugh, 1996). More restricted striatal lesions have revealed that the dorsomedial striatum may contribute to allocentric learning, and the dorsolateral striatum to egocentric strategies (Devan et al., 1999, Yin and Knowlton, 2004).

Alzheimer's disease (AD), the most common cause of dementia, results in progressive cognitive decline (Albert, 1996, Evans et al., 1989, Hebert et al., 2003). AD-related spatial disability is common (McKhann et al., 1984), affecting roughly 39% of patients (Henderson et al., 1989), and profoundly impairs daily activities (Fitten et al., 1995, Perry and Hodges, 2000). While it is well established that AD affects the hippocampus more than the striatum (Braak and Braak, 1991, Morrison and Hof, 2002, Petrella et al., 2003), the mechanisms underlying AD-related spatial disabilities are poorly understood, and why navigation deficits vary in severity in patients with otherwise similar disease profiles is unknown.

Amyloid-β (Aβ) peptides, which play key roles in AD pathogenesis (Selkoe and Schenk, 2003, Tanzi and Bertram, 2005, Walsh and Selkoe, 2004), elicit diverse behavioral alterations when produced in neurons of human amyloid precursor protein (hAPP) transgenic mice (Kobayashi and Chen, 2005). Here, we used hAPP mice to test the hypotheses that hAPP/Aβ affects hippocampus-dependent learning strategies more than striatum-dependent strategies and that innate proclivity to use one or the other strategy determines the severity of AD-related learning deficits. To ascertain whether alterations in spatial learning and strategy use are related to hippocampal or striatal impairments, we assessed baseline levels of synaptic activity-dependent proteins in these regions, which are thought to reflect tonic neuronal activity (Lyford et al., 1995, Temple et al., 2003) and can serve as sensitive biomarkers of Aβ-induced neuronal dysfunction (Chin et al., 2005, Chin et al., 2004, Palop et al., 2005, Palop et al., 2003). We first determined whether strategy alterations in the hAPP mice as a group related to regional patterns of neural dysfunction. Next, we assessed whether measures of hippocampal and striatal function predicted strategy preference and spatial learning on an individual basis among hAPP mice.