Review article
A critical review of chronic stress effects on spatial learning and memory

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Abstract

The purpose of this review is to evaluate the effects of chronic stress on hippocampal-dependent function, based primarily upon studies using young, adult male rodents and spatial navigation tasks. Despite this restriction, variability amongst the findings was evident and how or even whether chronic stress influenced spatial ability depended upon the type of task, the dependent variable measured and how the task was implemented, the type and duration of the stressors, housing conditions of the animals that include accessibility to food and cage mates, and duration from the end of the stress to the start of behavioral assessment. Nonetheless, patterns emerged as follows: For spatial memory, chronic stress impairs spatial reference memory and has transient effects on spatial working memory. For spatial learning, however, chronic stress effects appear to be task-specific: chronic stress impairs spatial learning on appetitively motivated tasks, such as the radial arm maze or holeboard, tasks that evoke relatively mild to low arousal components from fear. But under testing conditions that evoke moderate to strong arousal components from fear, such as during radial arm water maze testing, chronic stress appears to have minimal impairing effects or may even facilitate spatial learning. Chronic stress clearly impacts nearly every brain region and thus, how chronic stress alters hippocampal spatial ability likely depends upon the engagement of other brain structures during behavioral training and testing.

Introduction

Research showing that adrenal hormones produced by stress could impact hippocampal structure (Aus Der Mühlen and Ockenfels, 1969, Landfield et al., 1978, Landfield et al., 1981), helped drive investigations to probe the relationship between stress and the hippocampus. The hippocampus is positioned to detect and respond to stress because of its rich concentration of receptors for glucocorticoids (McEwen et al., 1968, McEwen et al., 1969). Long-term exposure to stress or glucocorticoids produces numerous documented changes in hippocampal structure that include altered neurochemistry, excitability, neurogenesis, neuronal morphology and even cell death (for reviews on many of these processes, see Bremner, 2006, Conrad, 2006, Conrad, 2008, Diamond et al., 2004, Herman and Seroogy, 2006, Joëls et al., 2004, Kim and Yoon, 1998, Lucassen et al., 2006, McEwen and Magarinos, 2001, Sapolsky, 2003, Sousa and Almeida, 2002, Tamashiro et al., 2005, Wolf, 2008). Investigators began to explore the relationship between chronic stress and spatial ability, after decades of research showing that the hippocampus is essential in spatial learning and memory, (Jarrard, 1983, Morris et al., 1982, O'Keefe and Nadel, 1978, Olton et al., 1979, Sutherland et al., 2001).

A consideration of the studies discussed in this review is that chronic stress is assumed to have altered hippocampal structure. Some studies support this concept with direct measures, but many studies rely upon established findings to infer that similar processes have occurred. As an example, stress or glucocorticoids can potentially kill hippocampal neurons (for review, see Sapolsky et al., 1986, Sapolsky, 1992), but not always (for review, see Conrad, 2008). In another example, chronic restraint produces hippocampal dendritic retraction, or the pruning of dendritic arbors (Vyas and Mitra, 2002, Watanabe et al., 1992a, Watanabe et al., 1992b, Watanabe et al., 1992c, Wood et al., 2004), which can be accelerated under intense stress (Lambert et al., 1998, McKittrick et al., 2000). Importantly, hippocampal dendritic retraction takes time to develop (Luine et al., 1996, McLaughlin et al., 2007), and self-corrects following recovery from chronic stress (Conrad et al., 1999, Sousa et al., 2000, Vyas et al., 2004). Consequently, behavioral investigations could potentially miss the window of when stress-induced dendritic retraction is present. Even when conditions are optimal and behavioral assessment coincides with hippocampal dendritic retraction, stress-induced functional outcomes most often reflect moderate changes from structural reorganization, rather than severe outcomes caused by cell loss.

The reversibility of stress-induced structural changes in the hippocampus is especially encouraging for psychiatric conditions, such as depression, as there are similarities. Depressed individuals show reduced hippocampal volume (Campbell et al., 2004, McKinnon et al., 2009, Sheline et al., 1996) and impaired hippocampal-dependent declarative memory (Vasic et al., 2008). Moreover, these structural and functional outcomes are not permanent, as depressed individuals on antidepressant therapy show similar hippocampal volumes as non-depressed controls (Neumeister et al., 2005, Sheline et al., 2003), and of those in remission, hippocampal volumes increase (Frodl et al., 2008). The plasticity of the hippocampus in depressed individuals is consistent with the rodent literature investigating hippocampal dendritic structure and spatial ability following chronic stress (see Czéh and Lucassen, 2007). These studies support the interpretation that chronic stress and depression can influence the hippocampus in a highly dynamic labile manner.

The purpose of this review is to evaluate the effects of chronic stress on hippocampal-dependent function in rodents, with an emphasis on spatial navigation tasks. While hippocampal function can be ascertained using other tasks, such as contextual fear conditioning (Kim and Fanselow, 1992, Phillips and LeDoux, 1992), there are exceptions (Hall et al., 1996, Maren and Fanselow, 1997). Consequently, this review will focus upon spatial tasks that incorporate navigational parameters. To further optimize comparisons across studies, this review will focus on young male rats, although on occasion, studies using mice and tree shrews will be discussed to extend insights into a particular paradigm. Reviews about the effects of chronic stress on hippocampal function in females, aged or developing rodents can be found elsewhere (Bowman, 2005, Luine, 2002, Luine et al., 2007, McEwen and Milner, 2007, McLaughlin et al., 2009, Romeo et al., 2004).

Section snippets

Chronic stress effects using appetitively motivated tasks with food or water reward

The premise underlying food-rewarded tasks is that rats are motivated to obtain food, emphasizing the importance in ascertaining whether motivation is similar across experimental manipulations. This is especially relevant in chronically stressed rodents, which are often used as models to investigate major depressive disorder (for reviews, see Blackburn-Munro and Blackburn-Munro, 2001, Fuchs et al., 2004, Gold and Chrousos, 2002, Lee et al., 2002, Willner, 1997). According to the American

Chronic stress effects using appetitively motivated tasks without food reward

Many studies have investigated spatial recognition memory using two-trial tasks that capitalize upon rodents' innate tendency to explore novelty, to determine whether the rats “recognize” an event from a previous trial (Ennaceur and Delacour, 1988). The advantage of using two-trial tasks is that spatial recognition memory can be assessed quickly, an important consideration, given the discussion that many chronic stress paradigms produce changes in the hippocampus that are dynamic and reversible

Chronic stress effects using aversively motivated tasks: Morris water maze (MWM) and strategy use

The MWM allows for the assessment of spatial learning and memory without incorporating food reward that can potentially confound an experimental manipulation. However, the MWM capitalizes upon aversive motivation, indicating that neurobiological substrates underlying emotional arousal are more likely involved than observed in the appetitively motivated tasks. For example chronic stress produced by 6 h/d/21 d restraint impairs hippocampal-dependent spatial memory on the appetitively motivated

Chronic stress effects using aversively motivated tasks: radial arm water maze (RAWM)

Within the last decade, the radial arm water maze (RAWM) was developed to assess spatial abilities. The RAWM is a spatial task that integrates components of the land version of the RAM with the motivational component of a water escape task (MWM) to eliminate the need for extra controls to determine strategy or motivation (Fig. 1E and Diamond et al., 1999). Moreover, one can measure learning, as well as reference and working memory within a relatively short period (over two days). Hippocampal

Synopsis of the behavioral findings

A consistent theme throughout this review is the importance of the duration of chronic stress and the time frame from the end of chronic stress to the start of behavioral assessment. Chronic stress paradigms that incorporate the wire mesh restraint procedure for 6 h/d/21 d in Sprague Dawley rats often do so because the parameters for altering hippocampal dendritic retraction are well described: restraint for 6 h/d/21 d causes CA3 dendritic retraction (Kleen et al., 2006, Magariños and McEwen, 1995a

Acknowledgments

Funding was provided by the Arizona Biomedical Research Commission. The author thanks Katie M. Coombs, Ann N. Hoffman and Thu N. Huynh for their critical review of the manuscript.

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