More Americans are consuming diets higher in saturated fats and refined sugars than ever before, and based on increasing obesity rates, this is a growing trend among older adults as well. While high saturated fat diet (HFD) consumption has been shown to sensitize the inflammatory response to a subsequent immune challenge in young adult rats, the inflammatory effect of HFD in the already-vulnerable aging brain has not yet been assessed. Here, we explored whether short-term (3 days) consumption of HFD would serve as a neuroinflammatory trigger in aging animals, leading to cognitive deficits. HFD impaired long-term contextual (hippocampal-dependent) and auditory-cued fear (amygdalar-dependent) memory in aged, but not young adult rats. Short-term memory performance for both tasks was intact, suggesting that HFD impairs memory consolidation processes. Microglial markers of activation Iba1 and cd11b were only increased in the aged rats, while MHCII was further amplified by HFD. Furthermore, these HFD-induced long-term memory impairments were accompanied by IL-1β protein increases in both hippocampus and amygdala in aged rats. Central administration of IL-1RA in aged rats following conditioning mitigated both contextual and auditory-cued fear memory impairments caused by HFD, strongly suggesting that IL-1β plays a critical role in these effects. Voluntary wheel running, known to have anti-inflammatory effects in the hippocampus, rescued hippocampal-dependent but not amygdalar-dependent memory impairments caused by HFD. Together, these data suggest that short-term consumption of HFD can lead to memory deficits and significant brain inflammation in the aged animal, and strongly suggest that appropriate diet is crucial for cognitive health.

Amplified neuroinflammatory responses following an immune challenge occur with normal aging and can elicit or exacerbate neuropathology. The mechanisms mediating this sensitized or "primed" immune response in the aged brain are not fully understood. The alarmin high mobility group box 1 (HMGB1) can be released under chronic pathological conditions and initiate inflammatory cascades. This led us to investigate whether HMGB1 regulates age-related priming of the neuroinflammatory response. Here, we show that HMGB1 protein and mRNA were elevated in the hippocampus of unmanipulated aged rats (24-month-old F344XBN rats). Furthermore, aged rats had increased HMGB1 in the CSF, suggesting increased HMGB1 release. We demonstrate that blocking HMGB1 signaling with an intracisterna magna (ICM) injection of the competitive antagonist to HMGB1, Box-A, downregulates basal expression of several inflammatory pathway genes in the hippocampus of aged rats. This indicates that blocking the actions of HMGB1 might reduce age-associated inflammatory priming. To test this hypothesis, we evaluated whether HMGB1 antagonism blocks the protracted neuroinflammatory and sickness response to peripheral Escherichia coli (E. coli) infection in aged rats. ICM pretreatment of aged rats with Box-A 24 h before E. coli infection prevented the extended hippocampal cytokine response and associated cognitive and affective behavioral changes. ICM pretreatment with Box-A also inhibited aging-induced potentiation of the microglial proinflammatory response to lipopolysaccharide ex vivo. Together, these results suggest that HMGB1 mediates neuroinflammatory priming in the aged brain. Blocking the actions of HMGB1 appears to "desensitize" aged microglia to an immune challenge, thereby preventing exaggerated behavioral and neuroinflammatory responses following infection.

Exposure to stressors can enhance neuroinflammatory responses, and both stress and neuroinflammation are predisposing factors in the development of psychiatric disorders. Females suffer disproportionately more from several psychiatric disorders, yet stress-induced changes in neuroinflammation have primarily been studied in males. Here we tested whether exposure to inescapable tail shock sensitizes or 'primes' neuroinflammatory responses in male and female rats. At 24 h post-stress, male and female rats exposed to a peripheral immune challenge enhanced neuroinflammatory responses and exacerbated anxiety- and depressive-like behaviors. These changes are likely glucocorticoid dependent, as administering exogenous CORT, caused a similar primed inflammatory response in the hippocampus of male and female rats. Further, stress disinhibited anti-inflammatory signaling mechanisms (such as CD200R) in the hippocampus of male and female rats. In males, microglia are considered the likely cellular source mediating neuroinflammatory priming; stress increased cytokine expression in ex vivo male microglia. Conversely, microglia isolated from stressed or CORT treated females did not exhibit elevated cytokine responses. Microglia isolated from both stressed male and female rats reduced phagocytic activity; however, suggesting that microglia from both sexes experience stress-induced functional impairments. Finally, an immune challenge following either stress or CORT in females, but not males, increased peripheral inflammation (serum IL-1β). These novel data suggest that although males and females both enhance stress-induced neuroinflammatory and behavioral responses to an immune challenge, this priming may occur through distinct, sex-specific mechanisms.

The role of insulin in the brain is still not completely understood. In the periphery, insulin can decrease inflammation induced by lipopolysaccharide (LPS); however, whether insulin can reduce inflammation within the brain is unknown. Experiments administrating intranasal insulin to young and aged adults have shown that insulin improves memory. In our animal model of chronic neuroinflammation, we administered insulin and/or LPS directly into the brain via the fourth ventricle for 4 weeks in young rats; we then analyzed their spatial memory and neuroinflammatory response. Additionally, we administered insulin or artificial cerebral spinal fluid (aCSF), in the same manner, to aged rats and then analyzed their spatial memory and neuroinflammatory response. Response to chronic neuroinflammation in young rats was analyzed in the presence or absence of insulin supplementation. Here, we show for the first time that insulin infused (i.c.v.) to young rats significantly attenuated the effects of LPS by decreasing the expression of neuroinflammatory markers in the hippocampus and by improving performance in the Morris water pool task. In young rats, insulin infusion alone significantly improved their performance as compared to all other groups. Unexpectedly, in aged rats, the responsiveness to insulin was completely absent, that is, spatial memory was still impaired suggesting that an age-dependent insulin resistance may contribute to the cognitive impairment observed in neurodegenerative diseases. Our data suggest a novel therapeutic effect of insulin on neuroinflammation in the young but not the aged brain.

Quitting smoking leads to improved outcomes for patients with cancer, yet too few patients receive cessation services during their oncology healthcare visits. The National Cancer Institute (NCI) dedicated Cancer Moonshot funding for NCI-Designated Cancer Centers to develop a population-based approach to reach all patients who smoke with tobacco treatment services. As a result, the Cancer Center Cessation Initiative (C3I) offers an unparalleled opportunity to identify effective implementation strategies and barriers to delivering tobacco treatment services across multiple clinical oncology settings. Over one year after receiving funding, the first cohort of C3I funded Centers demonstrated progress in hiring tobacco treatment specialists, adding new tobacco treatment programs, and integrating EHR-based tobacco treatment referrals. However, tobacco treatment program reach remains low in some settings, even using a broad definition of patient engagement. Centers identified implementation challenges related to staff training needs, devising new clinical workflows, and engagement of IT leadership. Understanding implementation challenges may help other clinical oncology settings effectively implement tobacco treatment programs, leading to improved cancer outcomes by helping patients quit smoking.