Full-length ArticleDietary DHA prevents cognitive impairment and inflammatory gene expression in aged male rats fed a diet enriched with refined carbohydrates
Introduction
The consumption of diets containing high levels of refined carbohydrates impairs learning and memory and leads to significant weight gain in rodents, non-human primates, and humans (Gentreau et al., 2020, Gross et al., 2004, Kanoski and Davidson, 2010, Shively et al., 2019, Spadaro et al., 2015). The mechanisms through which these impairments occur are unclear, although recent evidence suggests neuroimmune signaling as a likely target (Gomes et al., 2020). Moreover, the impacts of refined carbohydrate intake on the aged brain and behavior are unknown. This gap in knowledge is critical, considering the aged brain has a heightened state of baseline inflammation, making it more susceptible to secondary challenges (Barrientos et al., 2015). Indeed, previous work from our lab demonstrated that aged, but not young, rats fed a short-term high fat diet (HFD) have impaired hippocampal- and amygdalar-dependent memory and increased proinflammatory cytokine expression in the hippocampus and amygdala (Spencer et al., 2017). These behavioral deficits were prevented with central infusion of an interleukin-1 β receptor antagonist, suggesting a causal link between neuroinflammation and diet-induced cognitive impairment. However, the role of refined carbohydrate consumption has not been tested in this paradigm.
Aging is associated with a decrease in the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), in the brain (Butler et al., 2020, McNamara et al., 2008, Weiser et al., 2016). DHA has a myriad of functions in the brain, including neuronal signaling, altering membrane structure and function, and lipid mediator production (Layé, 2010). Importantly, DHA also plays a major role in the resolution of inflammation in the brain. Briefly, upon an inflammatory challenge, DHA is cleaved from the phospholipid membrane and metabolized into specialized pro-resolving mediators (SPMs) (Layé, 2010, Layé et al., 2018). These SPMs can be released from cells, mainly neurons and astrocytes, and bind to receptors located on microglia, the resident immune cells of the brain, and resolve their proinflammatory phenotype (De Smedt-Peyrusse et al., 2008, Layé et al., 2018, Rey et al., 2016). In this regard, DHA supplementation can prevent or attenuate a variety of inflammatory insults to the brain, including traumatic brain injury, stroke, and age-related cognitive decline (Butt et al., 2017, Labrousse et al., 2012, Layé, 2010). However, whether DHA protects against carbohydrate-induced insults on cognition and neuroinflammation has not been tested. Similar to SPMs from DHA, SPMs from eicosapentaenoic acid (EPA) may also play a role in the periphery, but are less abundant in the brain (Chen et al., 2013, Layé, 2010, Layé et al., 2018).
Given the above and that the aged brain has elevated baseline inflammation, declining DHA levels could potentiate the proinflammatory response to unhealthy diet consumption. Thus, in this study we tested the hypothesis that consumption of a processed-foods diet (PD), which is high in refined carbohydrates, would impair cognitive function and increase inflammatory gene expression in aged, but not young, rats. Moreover, we hypothesized that DHA supplementation would ameliorate many of these PD-induced effects. Furthermore, we investigated the impacts of both age and diet on weight gain and hypothalamic gene expression.
Section snippets
Subjects
Three- and 24-month old male F344 × BN F1 rats (N = 54, n = 7–10 per group; and two per cage) were utilized. Rats were obtained from the National Institute on Aging Rodent Colony maintained by Envigo (Indianapolis, IN), where they are exclusively available. Due to aged female rats of this strain not being available at the time these experiments were conducted, only male rats were used in this study. Future work will include the use of females. Upon arrival at our facility young rats weighed
DHA prevented PD-induced deficits in contextual and cued-fear memory
We investigated the impact of a PD and DHA on both contextual and cued-fear memory. There were no differences in freezing behavior across groups during the conditioning phase (data not shown). For contextual memory, there was a significant interaction between age and diet, where aged animals fed a PD had significantly less freezing behavior than aged animals fed chow or PD + DHA (F(2,41) = 4.45, p < 0.05; Fig. 1A). For cued-fear memory, animals froze for ~8% of the time during the pre-tone
Discussion
In this study we investigated the impact of PD consumption on cognitive function, neuroinflammatory gene expression, and weight gain in young and aged male rats. Furthermore, we investigated the role of dietary DHA supplementation on mitigating any alterations associated with PD consumption. Taken together, our data suggest PD consumption impaired both hippocampal- and amygdalar-dependent memories in aged, but not young rats, and DHA supplementation prevented these behavioral impairments.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work is supported in part by grants from the National Institute on Aging AG028271 and AG067061 (to R.M.B), from the National Institute of Dental and Craniofacial Research (DE014320) to M.J.B., and the Ohio Agriculture Research and Development Center, OSU (to M.A.B.)
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