Cognitive capacities decline with age, an event accompanied by the altered transcription of synaptic plasticity genes. Here, we show that the transcriptional induction of Bdnf by a mnemonic stimulus is impaired in aged hippocampal neurons. Mechanistically, this defect is due to reduced NMDA receptor (NMDAR)-mediated activation of CaMKII. Decreased NMDAR signaling prevents changes associated with activation at specific Bdnf promoters, including displacement of histone deacetylase 4, recruitment of the histone acetyltransferase CBP, increased H3K27 acetylation, and reduced H3K27 trimethylation. The decrease in NMDA-CaMKII signaling arises from constitutive reduction of synaptic cholesterol that occurs with normal aging. Increasing the levels of neuronal cholesterol in aged neurons in vitro, ex vivo, and in vivo restored NMDA-induced Bdnf expression and chromatin remodeling. Furthermore, pharmacological prevention of age-associated cholesterol reduction rescued signaling and cognitive deficits of aged mice. Thus, reducing hippocampal cholesterol loss may represent a therapeutic approach to reverse cognitive decline during aging.

Impaired glucose metabolism and mitochondrial decay greatly increase with age, when cognitive decline becomes rampant. No pharmacological or dietary intervention has proven effective, but proper diet and lifestyle do postpone the onset of neurodegeneration and some nutrients are being investigated. We studied insulin signaling, mitochondrial activity and biogenesis, and synaptic signaling in the hippocampus and cortex following dietary supplementation with bioactive phospholipid concentrates of krill oil (KOC), buttermilk fat globule membranes (BMFC), and a combination of both in aged rats. After 3 months of supplementation, although all groups of animals showed clear signs of peripheral insulin resistance, the combination of KOC and BMFC was able to improve peripheral insulin sensitivity. We also explored brain energy balance. Interestingly, the hippocampus of supplemented rats—mainly when supplemented with BMFC or the combination of KOC and BMFC—showed an increase in intracellular adenosine triphosphate (ATP) levels, whereas no difference was observed in the cerebral cortex. Moreover, we found a significant increase of brain-derived neurotrophic factor (BDNF) in the hippocampus of BMFC+KO animals. In summary, dietary supplementation with KOC and/or BMFC improves peripheral and central insulin resistance, suggesting that their administration could delay the onset of these phenomena. Moreover, n-3 fatty acids (FAs) ingested as phospholipids increase BDNF levels favoring an improvement in energy state within neurons and facilitating both mitochondrial and protein synthesis, which are necessary for synaptic plasticity. Thus, dietary supplementation with n-3 FAs could protect local protein synthesis and energy balance within dendrites, favoring neuronal health and delaying cognitive decline associated to age-related disrepair.

The increasing incidence of age-induced cognitive decline justifies the search for complementary ways of prevention or delay. We studied the effects of concentrates of phospholipids, sphingolipids, and/or 3-n fatty acids on the expression of genes or miRNAs related to synaptic activity and/or neurodegeneration, in the hippocampus of aged Wistar rats following a 3-month supplementation. The combination of two phospholipidic concentrates of krill oil (KOC) and buttermilk (BMFC) origin modulated the hippocampal expression of 119 miRNAs (11 were common to both BMFC and BMFC + KOC groups). miR-191a-5p and miR-29a-3p changed significantly only in the BMFC group, whereas miR-195-3p and miR-148a-5p did so only in the combined-supplemented group. Thirty-eight, 58, and 72 differentially expressed genes (DEG) were found in the groups supplemented with KOC, BMFC and BMFC + KOC, respectively. Interaction analysis unveiled networks of selected miRNAs with their potential target genes. DEG found in the KOC and BMFC groups were mainly involved in neuroactive processes, whereas they were associated with lysosomes and mRNA surveillance pathways in the BMFC + KOC group. We also report a significant reduction in hippocampal ceramide levels with BMFC + KOC. Our results encourage additional in-depth investigations regarding the potential beneficial effects of these compounds.

There are important individual differences in adaptation and reactivity to stressful challenges. Being subjected to strict social confinement is a distressful psychological experience leading to reduced emotional well-being, but it is not known how it can affect the cognitive and empathic tendencies of different individuals. Cortisol, a key glucocorticoid in humans, is a strong modulator of brain function, behavior, and cognition, and the diurnal cortisol rhythm has been postulated to interact with environmental stressors to predict stress adaptation. The present study investigates in 45 young adults (21.09 years old, SD = 6.42) whether pre-pandemic diurnal cortisol indices, overall diurnal cortisol secretion (AUCg) and cortisol awakening response (CAR) can predict individuals’ differential susceptibility to the impact of strict social confinement during the Coronavirus Disease 2019 (COVID-19) pandemic on working memory, empathy, and perceived stress. We observed that, following long-term home confinement, there was an increase in subjects’ perceived stress and cognitive empathy scores, as well as an improvement in visuospatial working memory. Moreover, during confinement, resilient coping moderated the relationship between perceived stress scores and pre-pandemic AUCg and CAR. In addition, in mediation models, we observed a direct effect of AUCg and an indirect effect of both CAR and AUCg, on change in perceived self-efficacy. These effects were parallelly mediated by the increase in working memory span and cognitive empathy. In summary, our findings reveal the role of the diurnal pattern of cortisol in predicting the emotional impact of the COVID-19 pandemic, highlighting a potential biomarker for the identification of at-risk groups following public health crises.