Systemic lipopolysaccharide administration impairs retrieval of context–object discrimination, but not spatial, memory: Evidence for selective disruption of specific hippocampus-dependent memory functions during acute neuroinflammation
Introduction
Cytokines, signaling molecules that mediate the immune response and are beneficial at basal or low levels, can produce sickness behaviors and impair cognition at pathophysiological levels (Dantzer et al., 2008, Yirmiya and Goshen, 2011). There is evidence of cognitive impairment in humans with a variety of disorders that result in elevated cytokine levels, including multiple sclerosis, Alzheimer’s disease, AIDS-related dementia, cancer, and patients undergoing chemotherapy (Kaul et al., 2001, Huijbregts et al., 2004, Meyers et al., 2005, Ahles and Saykin, 2007, Guerreiro et al., 2007).
During an inflammatory response, microglia become activated, resulting in the release of cytokines, including interleukin-1 (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), in the brain (Hanisch, 2002). These pro-inflammatory cytokines have been demonstrated to directly affect neuronal function, including long-term potentiation (LTP), glutamate release, AMPA receptor trafficking, and activation of cell-signaling pathways (O’Connor and Coogan, 1999, Albensi and Mattson, 2000, D’Arcangelo et al., 2000, Tancredi et al., 2000, Vereker et al., 2000, Beattie et al., 2002, Lynch et al., 2004). Because these processes affect synaptic plasticity and neurotransmission, it is apparent that cytokines may impact neuronal processes pertinent to cognition.
There is a high density of cytokine receptors in the hippocampus, particularly the dentate gyrus (DG) (Lechan et al., 1990, Schöbitz et al., 1992), indicating that the hippocampus may be particularly vulnerable during neuroinflammation. Indeed, using animal models, researchers have observed that administration of cytokines or other immunogenic stimuli, including the bacterial endotoxin lipopolysaccharide (LPS), can disrupt hippocampus-dependent learning and memory processes (Oitzl et al., 1993, Gibertini et al., 1995, Pugh et al., 1998, Barrientos et al., 2002). Specifically, several studies have shown that acquisition of the Morris water maze and consolidation of contextual but not cued fear conditioning are disrupted during neuroinflammation (Gibertini et al., 1995, Pugh et al., 1998, Arai et al., 2001, Barrientos et al., 2002, Thomson and Sutherland, 2005). However, there have been mixed results across studies regarding the effect of neuroinflammation on the water maze, as well as observations that cytokines do not impair, and can even facilitate, learning and memory (Cunningham and Sanderson, 2008, Yirmiya and Goshen, 2011), making it difficult to ascertain the precise impact of neuroinflammation on cognition.
Importantly, patients with neuroimmune disorders have reported difficulty with memory retrieval (Thornton et al., 2002, Woods et al., 2007), which can be just as detrimental to daily function as encoding or consolidation deficits. Despite this, however, research to date has focused primarily on memory acquisition and consolidation processes. In a recent study, we examined the effect of acute neuroinflammation induced by systemic LPS injection on retrieval of a simple contextual fear task or a context discrimination fear task (Czerniawski and Guzowski, 2014). Although both tasks are hippocampus-dependent, LPS only impaired retrieval of context discrimination memory. In addition, analysis of neural circuit activity provided evidence that LPS-mediated neuroinflammation impaired pattern separation processes in CA3 and CA1. The behavioral and neural circuit data from this study are consistent with the hypothesis that acute neuroinflammation preferentially disrupts pattern separation functions necessary for context discrimination. In the present study we tested this working hypothesis by examining the effect of systemic LPS administration on retrieval of three additional tasks that vary with respect to hippocampal information processing: the spatial water maze task, context–object discrimination (COD), and novel object recognition (NOR). The water maze is a hippocampus-dependent task that tests navigation and spatial memory, while COD is a hippocampus-dependent task that tests context discrimination (Morris et al., 1982, Aggleton and Brown, 1999, Mumby et al., 2002, Barker and Warburton, 2011). NOR, although similar to COD in that it involves incidental encoding, does not typically require the hippocampus (Barker and Warburton, 2011). Of these three tasks, COD is the only one thought to require hippocampal pattern separation and, accordingly, is the only task predicted to be impaired by LPS treatment.
Section snippets
Subjects
Eighty-nine male Sprague–Dawley rats (Charles River Laboratories, Wilmington, MA) weighing 250–275 g at the time of arrival served as subjects. All animals were individually housed in a temperature-controlled vivarium maintained on a 12 h light/dark cycle. All subjects had access to food and water ad libitum throughout the duration of the experiment and were handled 2 min/day for 5 days before the start of the experiment. On each day prior to training all animals were transported to a holding room
Systemic LPS administration does not impair spatial memory retrieval or reversal learning in the water maze
After 4 days of training to the platform in the “northeast” quadrant and reaching an asymptotic performance, each rat was administered either LPS (n = 22) or SAL (n = 22) on the fifth day. Six hours later, each rat was placed in water maze without the platform for 60 s. The amount time that the rats spent in the target quadrant and zone around the platform were measured as an index of memory for platform location. There was a significant difference in time spent in quadrant platform during testing (t
Discussion
We have demonstrated that systemic LPS administration disrupted memory retrieval in COD, but not NOR or the water maze. Therefore, while LPS-treated rats were able to remember the location of the hidden platform in the water maze and could distinguish a novel object from a familiar one, they were deficient in determining that a previously experienced object was in a different context. Thus, our data indicate that acute neuroinflammation does not impair memory retrieval in all
Acknowledgments
This work was supported by NIH R01 MH08930 (JFG) with additional support from NIH Training in the Neurobiology of Aging Grant AG00096 (JC). The authors thank Terra White for helpful comments on an earlier version of the manuscript.
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