Young adult and aged female rats are vulnerable to amygdala-dependent, but not hippocampus-dependent, memory impairment following short-term high-fat diet.

Global populations are increasingly consuming diets high in saturated fats and refined carbohydrates, and such diets have been well-associated with heightened inflammation and neurological dysfunction. Notably, older individuals are particularly vulnerable to the impact of unhealthy diet on cognition, even after a single meal, and pre-clinical rodent studies have demonstrated that short-term consumption of high-fat diet (HFD) induces marked increases in neuroinflammation and cognitive impairment. Unfortunately though, to date, most studies on the topic of nutrition and cognition, especially in aging, have been performed only in male rodents. This is especially concerning given that older females are more vulnerable to develop certain memory deficits and/or severe memory-related pathologies than males. Thus, the aim of the present study was to determine the extent to which short-term HFD consumption impacts memory function and neuroinflammation in female rats. Young adult (3 months) and aged (20-22 months) female rats were fed HFD for 3 days. Using contextual fear conditioning, we found that HFD had no effect on long-term contextual memory (hippocampus-dependent) at either age, but impaired long-term auditory-cued memory (amygdala-dependent) regardless of age. Gene expression of Il-1β was markedly dysregulated in the amygdala, but not hippocampus, of both young and aged rats after 3 days of HFD. Interestingly, modulation of IL-1 signaling via central administration of the IL-1 receptor antagonist (which we have previously demonstrated to be protective in males) had no impact on memory function following the HFD in females. Investigation of the memory-associated gene Pacap and its receptor Pac1r revealed differential effects of HFD on their expression in the hippocampus and amygdala. Specifically, HFD induced increased expression of Pacap and Pac1r in the hippocampus, whereas decreased Pacap was observed in the amygdala. Collectively, these data suggest that both young adult and aged female rats are vulnerable to amygdala-dependent (but not hippocampus-dependent) memory impairments following short-term HFD consumption, and identify potential mechanisms related to IL-1β and PACAP signaling in these differential effects. Notably, these findings are strikingly different than those previously reported in male rats using the same diet regimen and behavioral paradigms, and highlight the importance of examining potential sex differences in the context of neuroimmune-associated cognitive dysfunction.