Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms

Abstract

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Episodes of delirium also contribute to rates of long-term cognitive decline, implying that these acute events induce injury. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms remains unexplored. Here we show that systemic inflammation, induced by bacterial LPS, produces both working-memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100 µg/kg) did not affect working memory but impaired long-term memory consoliodation. However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1β replicated, these working memory deficits. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits, without blocking brain IL-1β synthesis. Direct application of IL-1β to ex vivo hippocampal slices induced non-synaptic depolarisation and irrevesible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1β but direct hippocampal action of IL-1β causes neuronal dysfunction and may drive neuronal death. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury contributing to long-term cognitive impairment but that these events are mechanistically dissociable. These data have significant implications for management of cognitive dysfunction during acute illness.

A single systemic inflammatory insult causes acute motor deficits and accelerates disease progression in a mouse model of human tauopathy

“…None of these studies tested impact of systemic inflammation on functional decline in the respective models. Accelerated decline was previously demonstrated in a prion disease model; wherein primed microglia produced exaggerated responses to LPS challenge, increasing microglial IL‐1β, which contributes to sickness behaviour, acute working memory deficits, and accelerated progression of disease [12,17]. Recent studies in humans and mice support the hypothesis that the impact of systemic inflammation is influenced by the extent of underlying pathology [18].…”

“…In the present study, LPS induced robust Il1b mRNA expression in the cortices and spinal cords of C57BL/6 and P301S mice. Although Il1b expression was similar in P301S and C57BL/6 mice, one might still speculate that IL‐1β could drive the observed exaggerated functional deficits: neurons from the degenerating brain were significantly more sensitive to IL‐1β stimulation in other models [17]; hence, it is plausible that IL‐1β levels innocuous in the healthy brain may damage neurons in disease. However, experiments in IL‐1R1 ‐/‐ mice show cytokine redundancy in LPS‐induced neurological deficits; wild‐type and IL‐1R1 ‐/‐ mice with ME7 prion disease injected with LPS developed equivalent sickness, weight loss, and acute working memory deficits [17] suggesting that alternative LPS‐induced inflammatory mediators underpin exaggerated functional deficits in P301S mice.…”

Acute inflammation alters energy metabolism in mice and humans: Role in sickness-induced hypoactivity, impaired cognition and delirium

“…We have previously shown, using the ME7 model, that evolving neurodegeneration progressively increases susceptibility to LPS-induced transient working memory impairments on a T-maze task ( Fig. 3A, (17,22)). We hypothesized that this cognitive vulnerability in ME7 mice may be explained by a greater tendency towards metabolic insufficiency.…”

“…The neuroanatomical and biochemical basis for the marked hypoactivity that occurs in the hours after LPS administration is not fully understood.Among the features ascribed to sickness behavior is cognitive impairment. Peripheral administration of LPS or IL-1b can affect synaptic plasticity (15) and hippocampaldependent learning and memory (15, 16), although the relative preservation of cognitive function is striking given the overt suppression of spontaneous behavior (16,17). Clinically, peripheral bacterial infections, surgeries, or inflammatory traumas can provoke cognitive impairment but this is most problematic when inflammatory insults are either severe or when they occur on a background of advanced age or evolving dementia, to trigger delirium (18,19), an acute onset and fluctuating syndrome characterized by inability to sustain attention, reduced awareness and perception, and profound cognitive impairment (18).…”

“…function of the underlying degenerative state of the brain (25,26). These LPS-induced deficits are prostaglandin-dependent (26), can be mimicked by systemic administration of either IL-1b (26) or TNF-a (27), and can be reduced by systemic administration of IL-1 receptor antagonist (IL-1RA) (16,17). Although LPS-treated ME7 mice show higher levels of microglial IL-1b compared to LPS-treated controls, due to priming of the microglial population (28), it was systemic rather than central IL-1b that contributed to LPS-induced cognitive impairments in this model (17).…”