Lung inflammation induced by silica particles triggers hippocampal inflammation, synapse damage and memory impairment in mice.

BACKGROUND: Considerable evidence indicates that a signaling crosstalk between the brain and periphery plays important roles in neurological disorders, and that both acute and chronic peripheral inflammation can produce brain changes leading to cognitive impairments. Recent clinical and epidemiological studies have revealed an increased risk of cognitive impairment and dementia in individuals with impaired pulmonary function. However, the mechanistic underpinnings of this association remain unknown. Exposure to SiO2 (silica) particles triggers lung inflammation, including infiltration by peripheral immune cells and upregulation of pro-inflammatory cytokines. We here utilized a mouse model of lung silicosis to investigate the crosstalk between lung inflammation and memory. METHODS: Silicosis was induced by intratracheal administration of a single dose of 2.5 mg SiO2/kg in mice. Molecular and behavioral measurements were conducted 24 h and 15 days after silica administration. Lung and hippocampal inflammation were investigated by histological analysis and by determination of pro-inflammatory cytokines. Hippocampal synapse damage, amyloid-ß (Aß) peptide content and phosphorylation of Akt, a proxy of hippocampal insulin signaling, were investigated by Western blotting and ELISA. Memory was assessed using the open field and novel object recognition tests. RESULTS: Administration of silica induced alveolar collapse, lung infiltration by polymorphonuclear (PMN) cells, and increased lung pro-inflammatory cytokines. Lung inflammation was followed by upregulation of hippocampal pro-inflammatory cytokines, synapse damage, accumulation of the Aß peptide, and memory impairment in mice. CONCLUSION: The current study identified a crosstalk between lung and brain inflammatory responses leading to hippocampal synapse damage and memory impairment after exposure to a single low dose of silica in mice.

Repeated forced-swimming test in intact female rats: behaviour, oestrous cycle and enriched environment.

Psychopharmacology used animal models to study the effects of drugs on brain and behaviour. The repeated forced-swimming test (rFST), which is used to assess the gradual effects of antidepressants on rat behaviour, was standardized only in males. Because of the known sex differences in rats, experimental conditions standardized for males may not apply to female rats. Therefore, the present work aimed to standardize experimental and housing conditions for the rFST in female rats. Young or adult Wistar female rats were housed in standard or enriched environments for different experimental periods. As assessed in tested and nontested females, all rats had reached sexual maturity by the time behavioural testing occurred. The rFST consisted of a 15-min session of forced swimming (pretest), followed by 5-min sessions at 1 (test), 7 (retest 1) and 14 days (retest 2) later. The oestrous cycle was registered immediately before every behavioural session. All sessions were videotaped for further analysis. The immobility time of female rats remained similar over the different sessions of rFST independent of the age, the phase of the oestrous cycle or the housing conditions. These data indicate that rFST in female Wistar rats may be reproducible in different experimental conditions.

Failure to detect the action of antidepressants in the forced swim test in Swiss mice.

OBJECTIVE: The aims of this study were to replicate previously published experiments and to modify the protocol to detect the effects of chronic antidepressant treatment in mice. METHODS: Male Swiss mice (n=6-8/group) housed in reversed light/dark cycle were randomly assigned into receive vehicle (10% sucrose), sub-effective doses (1 and 3 mg/kg) or effective doses (10 and 30 mg/kg) of bupropion, desipramine, and fluoxetine and a candidate antidepressant, sodium butyrate (1-30 mg/kg) per gavage (p.o.) 1 h before the forced swim test (FST). Treatments continued daily for 7 and 14 days during retests 1 and 2, respectively. In an additional experiment, mice received fluoxetine (20 mg/kg) or vehicle (10% sucrose or 0.9% saline) p.o. or i.p. before the FST. Mice housed in reversed or standard light/dark cycles received fluoxetine (20 mg/kg) prior FST. Video recordings of behavioural testing were used for blind assessment of the outcomes. RESULTS: According to the expected, doses of antidepressants considered sub-effective failed to affect the immobility time of mice in the FST. Surprisingly, acute and chronic treatment with the high doses of bupropion, desipramine, and fluoxetine or sodium butyrate also failed to reduce the immobility time of mice in the FST. Fluoxetine 20 mg/kg was also ineffective in the FST when injected i.p. or in mice housed in normal light/dark cycle. CONCLUSION: Data suggest the lack of efficacy of orally administered bupropion, desipramine, fluoxetine in the FST in Swiss mice. High variability, due to high and low immobility mice, may explain the limited effects of the treatments.