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.

Rats injected with by d-phenylalanine, a carbonic anhydrase (CA) activator, enhanced spatial learning, whereas rats given acetazolamide, a CA inhibitor, exhibited impairments of fear memory consolidation. However, the related mechanisms are unclear. We investigated if CAs are involved in a non-spatial recognition memory task assessed using the object recognition test (ORT). Systemic administration of acetazolamide to male CD1 mice caused amnesia in the ORT and reduced CA activity in brain homogenates, while treatment with d-phenylalanine enhanced memory and increased CA activity. We provided also the first evidence that d-phenylalanine administration rapidly activated extracellular signal-regulated kinase (ERK) pathways, a critical step for memory formation, in the cortex and the hippocampus, two brain areas involved in memory processing. Effects elicited by d-phenylalanine were completely blunted by co-administration of acetazolamide, but not of 1-N-(4-sulfamoylphenyl-ethyl)-2,4,6-trimethylpyridinium perchlorate a CA inhibitor that, differently from acetazolamide, does not cross the blood brain barrier. Our results strongly suggest that brain but not peripheral CAs activation potentiates memory as a result of ERK pathway enhanced activation.

The lipid sensor oleoylethanolamide (OEA), an endogenous high-affinity agonist of peroxisome proliferator-activated receptor-α (PPAR-α) secreted in the proximal intestine, is endowed with several distinctive homeostatic properties, such as control of appetite, anti-inflammatory activity, stimulation of lipolysis and fatty acid oxidation. When administered exogenously, OEA has beneficial effects in several cognitive paradigms; therefore, in all respects, OEA can be considered a hormone of the gut-brain axis. Here we report an unexplored modulatory effect of OEA on the intestinal microbiota and on immune response. Our study shows for the first time that sub-chronic OEA administration to mice fed a normal chow pellet diet, changes the faecal microbiota profile, shifting the Firmicutes:Bacteroidetes ratio in favour of Bacteroidetes (in particular Bacteroides genus) and decreasing Firmicutes (Lactobacillus), and reduces intestinal cytokines expression by immune cells isolated from Peyer’s patches. Our results suggest that sub-chronic OEA treatment modulates gut microbiota composition towards a “lean-like phenotype”, and polarises gut-specific immune responses mimicking the effect of a diet low in fat and high in polysaccharides content.

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Several behavioural tests have been developed to study and measure emotionally charged or emotionally neutral memories and how these may be affected by pharmacological, dietary or environmental manipulations. In this review, we describe the experimental paradigms used in preclinical studies to unravel the brain circuits involved in the recognition and memorization of environmentally salient stimuli devoid of strong emotional value. In particular, we focus on the modulatory role of the brain histaminergic system in the elaboration of recognition memory that is based on the judgement of the prior occurrence of an event, and it is believed to be a critical component of human declarative memory. The review also addresses questions that may help improve the treatment of impaired declarative memory described in several affective and neuropsychiatric disorders such as ADHD, Alzheimer's disease and major neurocognitive disorder.