Preventing adolescent stress-induced cognitive and microbiome changes by diet

Abstract

Psychological stress during adolescence may cause enduring cognitive deficits and anxiety in both humans and animals, accompanied by rearrangement of numerous brain structures and functions. A healthy diet is essential for proper brain development and maintenance of optimal cognitive functions during adulthood. Furthermore, nutritional components profoundly affect the intestinal community of microbes that may affect gut-brain communication. We adopted a relatively mild stress protocol, social instability stress, which when repeatedly administered to juvenile rats modifies cognitive behaviors and plasticity markers in the brain. We then tested the preventive effect of a prolonged diet enriched with the ω-3 polyunsaturated fatty acids eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid and vitamin A. Our findings highlight the beneficial effects of this enriched diet on cognitive memory impairment induced by social instability stress, as stressed rats fed the enriched diet exhibited performance undistinguishable from that of nonstressed rats on both emotional and reference memory tests. Furthermore, in stressed rats, the decline in brain-derived neurotrophic factor expression in the hippocampus and shifts in the microbiota composition were normalized by the enriched diet. The detrimental behavioral and neurochemical effects of adolescent stress, as well as the protective effect of the enriched diet, were maintained throughout adulthood, long after the exposure to the stressful environment was terminated. Taken together, our results strongly suggest a beneficial role of nutritional components in ameliorating stress-related behaviors and associated neurochemical and microbiota changes, opening possible new venues in the field of nutritional neuropsychopharmacology.

Keywords: SCFA; contextual fear conditioning; gut microbiota; memory; novel object recognition.

Fig. 1.

(A) Time line for the adolescent social instability stress experiment. Adolescent rats were randomly assigned to three experimental groups: NSCD, SCD, and SED. (B and C) Effects of stress and enriched diet on body weight at PND 45 on completion of the stress procedure (B) and at PND 70 (C). n = 18–24 rats/group. ***P < 0.001, *P < 0.05 vs. NSCD rats; ^##P < 0.01, ^#P < 0.05 vs. NSCD by one-way ANOVA and the Bonferroni test.

Fig. 2.

The enriched diet prevented stress-induced cognitive impairment in the novel object recognition test. (A and C) Stress did not affect the performance of either adolescent or adult rats when the test was performed at 1 h after training. (B and D) Adolescent and adult stressed rats showed memory impairment when tested at 4 h after training, which was prevented by dietary supplementation with ω-3 PUFA/vitamin A. n = 6–8 rats/group. ***P < 0.001; **P < 0.01; *P < 0.05 vs. familiar object within each experimental group by two-way ANOVA and the Bonferroni test.

Fig. 3.

The enriched diet prevented immediate (A) and long-term (B) stress-induced cognitive impairment in the contextual fear conditioning test. Rat freezing time did not differ at training regardless of treatment condition. When tested at 24 h after training, the SCD rats showed a lower freezing time than the NSCD rats, and the SED rats showed no stress-induced cognitive impairment. n = 9–10 rats/group. ***P < 0.001, **P < 0.01 vs. respective training; ^###P < 0.001, ^#P < 0.05 vs. SCD by one-way ANOVA and the Bonferroni test.

Fig. 4.

The enriched diet restored BDNF expression in the brain of stressed rats. (A and B) Stress decreased BDNF levels in the hippocampus in both adolescent (A) and adult (B) rats. The enriched diet restored BDNF expression to control levels. (C and D) In the prefrontal cortex of stressed rats, the BDNF decrease did not reach statistical significance in either adolescence (C) or adulthood (D); nonetheless, the enriched diet augmented BDNF expression compared with stressed and control rats. (Insets) Representative immunoblots for each experimental group. n = 8–10 rats/group. **P < 0.01; *P < 0.05 vs. NSCD; ^###P < 0.001, ^##P < 0.01, ^#P < 0.05 vs. SCD by one-way ANOVA and Bonferroni’s test.

Fig. 5.

Social instability stress shapes the gut microbiome in adolescence. (A and B) PCA plots displaying beta diversity of the gut microbiome in adolescent (A) and adult (B) rats. (C–E) PCA plots comparing beta diversity of the gut microbiome for each treatment between adulthood and adolescence. (F) Changes in gut microbiome composition (genera) in adolescence (T1) and adulthood (T2). Changes in genera in each age group are depicted as follows: (i) SCD vs. NSCD, (ii) SED vs. SCD, (iii) SED vs. NSCD. *P < 0.1, **P < 0.01, post hoc Benjamini–Hochberg test.