Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model

doi:10.1016/j.expneurol.2007.01.003

Experimental Neurology

Volume 204, Issue 2, April 2007, Pages 733-740

https://doi.org/10.1016/j.expneurol.2007.01.003 Get rights and content

Abstract

Sepsis is a disease with a high and growing prevalence worldwide. Most studies on sepsis up to date have been focused on reduction of short-term mortality. This study investigates cognitive and neuroanatomical long-term consequences of sepsis in a rat model.

Sepsis was induced in male Wistar rats weighing 250–300 g by an i.p. injection of bacterial lipopolysaccharide (LPS, 10 mg/kg). Three months after complete recovery from sepsis, animals showed memory deficits in the radial maze and changes in open field exploratory patterns but unaffected inhibitory avoidance learning. Behavioral findings were matched by sepsis-induced loss of neurons in the hippocampus and the prefrontal cortex on serial sections after NeuN-staining and reduced cholinergic innervation in the parietal cortex measured by immunoradiography of vesicular acetylcholine transporter (VAChT).

Together these results suggest that sepsis can induce persistent behavioral and neuroanatomical changes and warrant studies of the neurological long-term consequences of sepsis in humans.

Introduction

Sepsis is a frequent condition accounting for 2.26 cases per 100 hospital discharges which translates into an annual burden of approximately 750,000 cases in the US population (Angus et al., 2001). An essential feature of sepsis is the rapid production of cytokines, chemokines, prostaglandins and nitric oxide (NO) (Rietschel et al., 1996). The potential neurotoxic effects of these proinflammatory mediators have been well documented (Chao et al., 1995, Hu et al., 1997, Zhao et al., 2001, Reimann-Philipp et al., 2001, Liu et al., 2002). Accordingly, cell death within the central nervous system during sepsis has been described in rodent models and humans (Messaris et al., 2004, Sharshar et al., 2004, Semmler et al., 2005). The inflammatory and immune responses evoked in sepsis may create not only an acute brain dysfunction, septic encephalopathy, which occurs in the majority of septic patients (Pine et al., 1983, Young et al., 1990, Sprung et al., 1990), but possibly also long-term deficits. Nevertheless, only a few investigations have addressed the long-term consequences of sepsis and have lead to partly conflicting results (Perl et al., 1995, Heyland et al., 2000, Granja et al., 2004). Recently, in rats recovered from sepsis induced by cecal ligation and puncture, impaired avoidance learning and habituation patterns, but no changes in basal activity were observed 10 and 30 days after surgery (Barichello et al., 2005a, Barichello et al., 2005b). In the present study, we investigated whether sepsis induced by i. p. injection of lipopolysaccharide (LPS) in rats leads to persistent impairment of cognitive capacities and neuroanatomical changes.

Section snippets

Animals and animal procedures

Male Wistar rats (Charles River, Sulzfeld, Germany) weighing 250–300 g were housed in groups of four under standard conditions at a temperature of 22 °C (± 1 °C) and a 12 h light–dark cycle (light from 06:00 to 18:00) with free access to standard food (Altromin, Soest, Germany) and tap water.

To initiate experimental sepsis, rats (n = 18) received 10 mg/kg of LPS (0127:B8, E. coli; Sigma) dissolved in 1 ml sodium chloride (0.9%) intraperitoneally. Control animals (n = 18) received the vehicle alone.

Results

Experimental induction of sepsis led to typical symptoms (e.g. piloerection, tachypnoe, social withdrawal) within 48 h. Within this period, LPS-treated animals lost 67 ± 23 g body weight. In contrast control animals gained 21 ± 8 g weight. LPS-treated animals recovered from experimentally induced sepsis, showed normal home-cage behavior 1 week after LPS injection and regained normal body weight. Three animals died within 24 h after LPS injection due to multiorgan failure.

Open-field activity

Discussion

Here, we show that LPS-induced sepsis in rats leads to long-term consequences including behavioral deficits, neuronal loss in hippocampal subregions and the prefrontal cortex, and reduced cholinergic innervation of postrolandic cortical areas.

General activity and habituation were unaffected in LPS-treated animals in the open field and radial maze test. However, in the open field experiment, animals spent more time immediately near the walls or in the corners of the open field after recovery

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Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model

Abstract

Introduction

Section snippets

Animals and animal procedures

Results

Discussion

Neuroscience

Neuroscience

Brain Res.

Neurosci. Biobehav. Rev.

Neurochem. Int.

Behav. Brain Res.

Behav. Brain Res.

Behav. Brain Res.

Neuroscience

Brain Res. Bull.

Neuroscience

J. Neurosci. Methods

Trends Neurosci.

Exp. Neurol.

Neuroscience

J. Chem. Neuroanat.

J. Physiol. Paris

Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care

Crit. Care Med.

Vesicular acetylcholine transporter (VAChT) protein: a novel and unique marker for cholinergic neurons in the central and peripheral nervous systems

J. Comp. Neurol.

Cognitive impairment in sepsis survivors from cecal ligation and perforation

Crit. Care Med.

Long-term cognitive impairment in sepsis survivors

Crit. Care Med.

Oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation

Crit. Care Med.

Animal models of sepsis: setting the stage

Nat. Rev., Drug Discov.