Myocardial infarction (MI) in rats is accompanied by apoptosis in the limbic system and a behavioural syndrome similar to models of depression. We have already shown that probiotics can reduce post-MI apoptosis and designed the present study to determine if probiotics can also prevent post-MI depressive behaviour. We also tested the hypothesis that probiotics achieve their central effects through changes in the intestinal barrier. MI was induced in anaesthetised rats via 40-min transient occlusion of the left anterior coronary artery. Sham rats underwent the same surgical procedure without actual coronary occlusion. For 7 d before MI and between the seventh post-MI day and euthanasia, half the MI and sham rats were given one billion live bacterial cells of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 per d dissolved in water, while the remaining animals received only the vehicle (maltodextrin). Depressive behaviour was evaluated 2 weeks post-MI in social interaction, forced swimming and passive avoidance step-down tests. Intestinal permeability was evaluated by oral administration with fluorescein isothiocyanate -dextran, 4 h before euthanasia. MI rats displayed less social interaction and impaired performance in the forced swimming and passive avoidance step-down tests compared to the sham controls (P,0·05). Probiotics reversed the behavioural effects of MI (P, 0·05), but did not alter the behaviour of sham rats. Intestinal permeability was increased in MI rats and reversed by probiotics. In conclusion, L. helveticus R0052 and B. longum R0175 combination interferes with the development of post-MI depressive behaviour and restores intestinal barrier integrity in MI rats. Key words: Probiotics: Myocardial infarction: Depression: Intestinal barrierAfter myocardial infarction (MI), 65 % of patients present depressive symptoms (1) , and about 20 % of them incur major depression (1,2) . Evidence of a poor prognosis is particularly strong in patients with such symptoms (3 -6) : the risk of cardiac death within 6 months after acute MI is approximately four times greater in patients with depression compared to nondepressed control subjects (5) . The mechanism is still hypothetical, but it has been postulated that the inflammatory state observed after MI is responsible for post-MI depression (7) .Elevation of pro-inflammatory cytokine levels (8,9) has been documented after myocardial ischaemia, and their attenuation is correlated with depressive behaviour reduction (10) . Our previous study indicated that MI rats present symptoms that are similar to human depression. MI rats drink significantly less sucrose and remain more immobile in the forced swimming test, indicating a state of anhedonia and behavioural despair, respectively. These behavioural signs are blocked by the tricyclic anti-depressant, desipramine, the selective serotonin reuptake inhibitor, sertraline (11,12) , and the cytokine synthesis inhibitor pentoxifylline (13) . The present experimental model of post-MI depression manifest...

Proinflammatory cytokines play a central role in depression-like behaviour and apoptosis in the limbic system after myocardial infarction (MI). A PUFA n-3 diet or the combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 probiotics, when given before the ischaemic period, reduce circulating proinflammatory cytokines as well as apoptosis in the limbic system. The present study was designed to determine if the same nutritional interventions maintain their beneficial effects when started after the onset of the reperfusion period and attenuate depression-like behaviour observed after MI. MI was induced by the occlusion of the left anterior descending coronary artery for 40 min in rats. After the onset of reperfusion, animals were fed with a high-or low-PUFA n-3 diet, combined or not with one billion live bacteria of L. helveticus and B. longum. At 3 d post-MI, caspase-3 enzymatic activities and terminal 2 0 -deoxyuridine, 5 0 -triphosphate (dUTP) nick-end labelling (TUNEL)-positive cells were decreased in the CA1, dentate gyrus (DG) and amygdala with the high-PUFA n-3 diet, as compared to the three other diets. Probiotics attenuated caspase-3 activity and TUNEL-positive cells in the DG and the medial amygdala. At 2 weeks post-MI, depression-like behaviour was observed in the low-PUFA n-3 diet without probiotics-group, and this behaviour was attenuated with the high-PUFA n-3 diet or/and probiotics. These results indicate that a high-PUFA n-3 diet or the administration of probiotics, starting after the onset of reperfusion, are beneficial to attenuate apoptosis in the limbic system and post-MI depression in the rat.Key words: n-3 Fatty acids: Apoptosis: Limbic system: Diet: Behaviour: Hippocampus: Amygdala Depressive mood is common after myocardial infarction (MI) (1) and 20 % of MI patients develop an episode of major depression (2) . The association of depression with MI is critical, as the mortality rate is increased three to four times in depressed MI patients compared to non-depressed MI patients (3) . As the level of non-responders is still high with antidepressant treatments (4,5) and that the treatment may interfere with myocardial infarct size (6) , new antidepressant strategies need to be identified for such cases.The physiopathology of depression is complex and different mechanisms are involved (7) . Our previous work and that of others indicate that proinflammatory cytokines may play a key role in depression-like behaviour (8 -10) . Indeed, injection of proinflammatory cytokines is followed by depression-like behaviour (11) . Post-MI increased levels of proinflammatory cytokines are accompanied by apoptosis in the hippocampus and the amygdala, another physiopathological element of depression (8,9,12) .Dietary interventions can be used to prevent the post-MI elevation of proinflammatory cytokines. For example, we have shown that high-PUFA n-3 diets reduce the circulating level of TNFa after MI (13) . High-PUFA n-3 diets also reduce levels of monocyte chemotactic protein-1 (...

Key Messages• Myocardial infarction induces apoptosis in the amygdala.• Probiotics reverse the increase in caspase activities in the amygdala after MI, and their beneficial outcome is abolished by vagotomy.• This finding underscores vagus nerve involvement in the beneficial effect of probiotics in an animal model of post-MI depression.• Probiotics were administered daily, 14 days before myocardial ischemia and until euthanasia. Vagotomy was induced in designed groups before 40 min of myocardial ischemia. After 3 days of reperfusion activity of the caspase-3 or -8 in the amygdala was determined. AbstractBackground Myocardial infarction (MI) is associated with apoptosis in the amygdala and, ultimately, with clinical signs of depression. Different treatments have proven to be beneficial in preventing depression, including combination of the probiotics Lactobacillus helveticus and Bifidobacterium longum for prophylaxis. We have speculated previously that the benefit of these probiotics is due to their anti-inflammatory properties, and evidence suggests that an intact vagus nerve is important for this effect to occur. This study was designed to ascertain vagus nerve involvement in the beneficial influence of probiotics on caspase activities in our post-MI animal model of depression.Methods Probiotics and/or vehicle were administered daily to male adult rats, 14 days before MI and until euthanasia. Vagotomy was performed in subgroups of rats 40 min before MI. They were sacrificed after 3 days of reperfusion, and MI size was assessed along with caspase-3 and -8 activities in the amygdala. Key Results Probiotics had no effect on infarct size but vagotomy increased it. Caspase-3 and caspase-8 activities in the amygdala were higher in MI than in sham-operated rats, and this outcome was reversed by probiotics. The beneficial influence of probiotics was abolished by vagotomy. Conclusions & Inferences Our data indicate that the effect of probiotics on caspase activities in the amygdala after MI depends on an intact vagus nerve.