Western diet consumption impairs memory function via dysregulated hippocampus acetylcholine signaling

Abstract

Western diet (WD) consumption during development yields long-lasting memory impairments, yet the underlying neurobiological mechanisms remain elusive. Here we developed an early life WD rodent model to evaluate whether dysregulated hippocampus (HPC) acetylcholine (ACh) signaling, a pathology associated with memory impairment in human dementia, is causally-related to WD-induced cognitive impairment. Rats received a cafeteria-style WD (access to various high-fat/high-sugar foods; CAF) or healthy chow (CTL) during the juvenile and adolescent periods (postnatal days 26-56). Behavioral, metabolic, and microbiome assessments were performed both before and after a 30-day healthy diet intervention beginning at early adulthood. Results revealed CAF-induced HPC-dependent contextual episodic memory impairments that persisted despite healthy diet intervention, whereas CAF was not associated with long-term changes in body weight, body composition, glucose tolerance, anxiety-like behavior, or gut microbiome. HPC immunoblot analyses after the healthy diet intervention identified reduced levels of vesicular ACh transporter in CAF vs. CTL rats, indicative of chronically reduced HPC ACh tone. To determine whether these changes were functionally related to memory impairments, we evaluated temporal HPC ACh binding via ACh-sensing fluorescent reporter in vivo fiber photometry during memory testing, as well as whether the memory impairments could be rescued pharmacologically. Results revealed dynamic HPC ACh binding during object-contextual novelty recognition was highly predictive of memory performance and was disrupted in CAF vs. CTL rats. Further, HPC alpha-7 nicotinic receptor agonist infusion during consolidation rescued memory deficits in CAF rats. Overall, these findings identify dysregulated HPC ACh signaling as a mechanism underlying early life WD-associated memory impairments.

Early- but not late-adolescent Western diet consumption programs for long-lasting memory impairments in male but not female rats

“…We implemented a "junk food" cafeteria-style diet to model a Western diet (WD) in the present experiments, a model that we previously developed for early life diet exposure in rats (Hayes et al, 2023; as well as adulthood exposure (Hayes et al, 2022).…”

“…For this round of behavior, NOIC was performed from PN 125-129, NOR was conducted from PN 134-135, Zero Maze was completed on PN 136, and Open Field was conducted on PN 138. NOR, Zero Maze, and Open Field were only conducted in females due to our previous findings that 30-d WD diet consumption during the entire adolescent stage in male rats does not affect object-novelty recognition, anxiety-like behavior, or locomotor activity via these assessments (Hayes et al, 2023). A timeline of procedures, which were the same for both sexes, is shown in Fig.…”

“…Further, to determine whether these distinct adolescent developmental periods differentially program for long-lasting memory impairments, and whether these associations are sexually dimorphic, behavioral assessments were conducted after both short (2-4 weeks) and long (10-12 weeks) periods of healthy diet intervention in both male and female rats. We have previously shown that consumption of this WD model during the entire adolescent period (PN 26-56) leads to HPC-dependent memory impairments that persist despite a 5-week healthy diet intervention in both male and female rats (Hayes et al, 2023; Tsan, Sun, et al, 2022). Here we expand these findings by examining the role of specific developmental windows within the adolescent period (early vs. late) in mediating such effects.…”

“…We implemented a “junk food” cafeteria-style diet to model a Western diet (WD) in the present experiments, a model that we previously developed for early life diet exposure in rats (Hayes et al, 2023; Tsan, Sun, et al, 2022) as well as adulthood exposure (Hayes et al, 2022). This WD diet was composed of free-choice ad libitum access to high-fat high-sugar chow (HFHS diet; Research Diets D12415, Research Diets, New Brunswick, NJ, USA; 20% kcal from protein, 35% kcal from carbohydrate, 45% kcal from fat), potato chips (Ruffles Original, Frito Lay, Casa Grande, AZ, USA), chocolate-covered peanut butter cups (Reese’s Minis Unwrapped, The Hershey Company, Hershey, PA, USA), and 11% weight/volume (w/v) high-fructose corn syrup-55 (HFCS) beverage (Best Flavors, Orange, CA, USA), placed in separate food/drink receptacles in the home cage for each animal.…”

“…In order to match initial body weights by group per sex, on PN 26 rats were pseudo-randomly assigned to groups of: early-adolescent consumption of the WD diet (WD-EA, n=12/sex), which was exposure from PN 26-41; late-adolescent consumption of the WD diet (WD-LA, n=12/sex), which was exposure from PN 41-56; or consumption of the healthy standard chow throughout both periods (CTL, n=12-13/sex). These PN periods are based on generalized stages of development in rodents (Sengupta, 2013; Tirelli et al, 2003) and separate the larger adolescent PN 26-56 period we have previously studied with this WD diet model (Hayes et al, 2023; Tsan, Sun, et al, 2022) into distinct early-adolescent and late-adolescent stages. When the WD-EA and WD-LA were not receiving WD, they were given healthy standard chow (LabDiet 5001, the same diet as the CTL group).…”