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. 2014 Sep 10;34(37):12470-80.
doi: 10.1523/JNEUROSCI.0542-14.2014.

Acute neuroinflammation impairs context discrimination memory and disrupts pattern separation processes in hippocampus

Jennifer Czerniawski  1 , John F Guzowski  2
Affiliations

Acute neuroinflammation impairs context discrimination memory and disrupts pattern separation processes in hippocampus

Jennifer Czerniawski et al. J Neurosci. .

Abstract

Although it is known that immune system activation can impair cognition, no study to date has linked cognitive deficits during acute neuroinflammation to dysregulation of task-relevant neuronal ensemble activity. Here, we assessed both neural circuit activity and context discrimination memory retrieval, in a within-subjects design, of male rats given systemic administration of saline or lipopolysaccharide (LPS). Rats were exposed over several days to two similar contexts: one of which was paired with weak foot shock and the other was not. After reaching criteria for discriminative freezing, rats were given systemic LPS or saline injection and tested for retrieval of context discrimination 6 h later. Importantly, LPS administration produced an acute neuroinflammatory response in dorsal hippocampus at this time (as assessed by elevation of proinflammatory cytokine mRNA levels) and abolished retrieval of the previously acquired discrimination. The impact of neuroinflammation on hippocampal CA3 and CA1 neural circuit activity was assessed using the Arc/Homer1a cellular analysis of temporal activity by fluorescence in situ hybridization imaging method. Whereas the saline-treated subjects discriminated and had low overlap of hippocampal ensembles activated in the two contexts, LPS-treated subjects did not discriminate and had greater ensemble overlap (i.e., reduced orthogonalization). Additionally, retrieval of standard contextual fear conditioning, which does not require context discrimination, was not affected by pretesting LPS administration. Together, the behavioral and circuit analyses data provide compelling evidence that LPS administration impairs context discrimination memory by disrupting cellular pattern separation processes within the hippocampus, thus linking acute neuroinflammation to disruption of specific neural circuit functions and cognitive impairment.

Keywords: computation; discrimination; hippocampus; imaging; memory; neuroinflammation.

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Figures

Figure 1.
Figure 1.
Cytokine expression in dorsal hippocampus after systemic LPS administration. Mean fold increase (±SEM) in mRNA expression relative to actin and home-cage control subjects (n = 4) for proinflammatory cytokines in dorsal hippocampus 3, 6, or 9 h after intraperitoneal injections of SAL or LPS (n = 3 per group). a, There was a robust increase in IL-1β mRNA expression in dorsal hippocampus after LPS administration 3 and 6 h after injection but not 9 h later. b, TNF-α mRNA levels were significantly elevated in LPS compared with SAL subjects only at the 6 h time point. c, Similar to IL-1β, IL-6 mRNA expression in dorsal hippocampus was significantly higher in LPS-treated rats 3 and 6 h after injection but not 9 h later. *p < 0.05.
Figure 2.
Figure 2.
Context discrimination conditioning is intact before systemic LPS administration. a, Subjects (n = 22) were placed into contexts A and A′ daily in a pseudorandomized order and received a footshock in context A but not context A′. b, After several days, subjects began to exhibit discriminative freezing to context A. c, The mean ± SEM percentage freezing during the last day of training. Subjects assigned to receive LPS (n = 9) or SAL (n = 8) the following day exhibited significantly more freezing in context A than context A′, whereas ND subjects (n = 5) did not. d, A discrimination ratio [(% time freezing in A − A′)/(% time freezing in A + A′)] was calculated for the last day of training. The LPS and SAL groups had significantly higher discrimination ratios than the ND group but did not differ from one another. Therefore, with the exception of the ND group, all subjects reliably expressed robust discriminative conditioning by the end of training, regardless of whether they were assigned to receive systemic administration of SAL or LPS before testing. *p < 0.05.
Figure 3.
Figure 3.
Acute neuroinflammation dramatically impaired context discrimination. a, Experimental design for testing. b, The mean ± SEM percentage freezing during testing. SAL subjects (n = 8) exhibited significantly more freezing in context A than context A′ during testing, whereas LPS (n = 9) and ND (n = 5) subjects did not. c, The discrimination ratio during testing was significantly higher in the SAL group than the LPS and ND groups, which did not differ from each other. d, Freezing scores for individual subjects in contexts A and A′. All subjects in the SAL group exhibited higher freezing in context A than context A′ during testing, whereas individual subjects in both the LPS and ND groups froze either in both contexts A and A′ or in neither context A nor context A′. *p < 0.05.
Figure 4.
Figure 4.
LPS administration did not affect locomotor activity or retrieval of strong simple context fear conditioning. a, Mean ± SEM percentage freezing during testing for subjects exposed to environments A and A′ daily but never presented with a footshock. They were tested on the same day as subjects trained in context discrimination conditioning and injected (intraperitoneally) with SAL (n = 3) or LPS (n = 4) 6 h before testing. Neither group exhibited high levels of freezing to either context during testing, indicating that LPS administration did not decrease levels of locomotor activity or exploration. b, Mean ± SEM percentage freezing during testing for subjects trained in a single context fear conditioning session and administered SAL or LPS 6 h before a 5 min testing session in the training context. Both SAL- and LPS-treated rats exhibited a robust level of freezing during testing, indicating that acute neuroinflammation did not disrupt the retrieval of simple context fear conditioning.
Figure 5.
Figure 5.
IEG expression in dorsal hippocampus. a, Low-magnification image of DAPI-stained dorsal hippocampus indicating the fields imaged for CA1 and CA3. The relative positions analyzed for CA1 (top) and CA3 (bottom, left) are indicated by yellow boxes. b, Representative 20× projection image of CA3 from an SAL-treated rat trained in context discrimination conditioning, showing Arc+ (red arrows), H1a+ (green arrows), Arc/H1a+ (yellow arrows), and negative (white arrows) neurons.
Figure 6.
Figure 6.
Acute neuroinflammation altered neuronal ensemble activity in the hippocampus. The mean ± SEM percentage of Arc+, H1a+, or Arc/H1a+ cells in CA3 (a) and CA1 (b). The mean ± SEM percentage of cells active during exposure to context A′ (H1a+ and Arc/H1a+) and context A (Arc+ and Arc/H1a+) in CA3 (c) and CA1 (d). There was a robust increase in the proportion of cells with Arc+ and H1a+ foci in trained subjects compared with home-cage controls (n = 4) in both hippocampal subfields, with no significant differences among the trained groups. A similarity score was calculated for each subject, with a value of 0 indicating two statistically independent populations and a value of 1 indicating a single neuronal population activated during both context presentations. The similarity scores for LPS (n = 9) and ND (n = 5) subjects were significantly higher than SAL subjects (n = 8) in both CA3 (e) and CA1 (f). These data suggest that acute neuroinflammation degrades the orthogonal representation in CA3 and CA1 to distinct but similar contexts. *p < 0.05. CC, Untrained caged control subjects.
Figure 7.
Figure 7.
Similarity score for CA1 neuronal ensembles after a single exposure to the two training contexts does not differ from LPS-treated subjects. The similarity scores from SAL and LPS subjects from the context discrimination conditioning experiment (right of the dashed line) and from a group that received a single exposure to contexts A′ and A (without footshock presentation) from a separate experiment. SE rats had a higher similarity score compared with trained SAL subjects that exhibited robust context discrimination, indicating that hippocampal neuronal ensembles are actively orthogonalized as a consequence of training. The similarity scores for LPS rats that were impaired in context discrimination and SE rats did not differ, suggesting that neuroinflammation impaired pattern separation processes in the hippocampus.
Figure 8.
Figure 8.
A working model: impact of local cytokine expression on neural pattern separation and context discrimination memory. Under normal conditions (left), neocortical inputs from contexts A and A′ enter the hippocampus in which pattern separation processes drive the orthogonalization of context representations to facilitate discrimination memory. However, in the event of elevated cytokine expression (right), we hypothesize that pattern separation processes that normally occur are blocked, resulting in a degradation of the orthogonal representations and a subsequent impairment in context discrimination memory, leading to behavioral generalization.
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