While all groups are affected by the COVID-19 pandemic, the elderly, underrepresented minorities, and those with underlying medical conditions are at the greatest risk. The high rate of consumption of diets high in saturated fats, sugars, and refined carbohydrates (collectively called Western diet, WD) worldwide, contribute to the prevalence of obesity and type II

It is argued that the hippocampus contributes to contextual fear conditioning by supporting the acquisition of a conjunctive memory representation of context, which associates with shock. This function was examined by studying the context pre-exposure facilitation effect (CPFE). A rat that is shocked immediately after being placed into a context subsequently displays almost no fear of that context. However, if it is pre-exposed to the context the day before immediate shock, it displays significant freezing to that context. By using 5-aminomethyl-3-hydroxysoxazole to temporarily inactivate the dorsal hippocampus (DH) at three different phases of the procedure, which produces the CPFE, we show that the hippocampus is necessary for the following: (1) acquisition of the context memory, (2) retrieval of this memory at the time of immediate shock, and (3) retrieval of the context-shock memory at the time of testing. In contrast, inactivating the DH before a standard contextual shock experience had no effect on contextual fear conditioning. These results support the view that two processes can support contextual fear conditioning: (1) conditioning to the conjunctive representation, which depends on the hippocampus, and (2) conditioning to the features that make up the context, which does not.

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It has been proposed that contextual fear conditioning depends on 2 processes: (a) construction of a conjunctive representation of the features that make up the context and (b) association of the representation with shock. Support for this view comes from studies indicating that prior exposure to the conditioning context facilitates contextual fear conditioning supported by immediate shock. Thus, conditioning produced by immediate shock is to the memory representation of the preexposed context, which is activated by retrieval cues associated with this context. The authors' experiments support this interpretation and indicate that this process depends on an intact hippocampal formation. These results support the hypothesis that the hippocampal formation supports contextual fear conditioning by storing a conjunctive representation of context.The importance of fear conditioning to the neurobiology of memory emerged when it was reported that fear to the context or place in which shock occurred (contextual fear) and fear to a discrete auditory cue paired with the shock were differentially dependent upon the hippocampal formation (Kim & Fanselow, 1992;Phillips & LeDoux, 1992;Selden, Everitt, Jarrard, & Robbins, 1991). Damage to the hippocampal formation impaired contextual but not auditory-cue fear conditioning. The selectivity of the result suggested that the study of contextual fear conditioning would provide a valuable method for studying the mechanisms by which the hippocampus contributes to memory and is now commonly used for this purpose.Several theorists have argued that contextual fear conditioning depends on two independent learning processes: The rat (a) constructs and stores a conjunctive representation of the independent features of the context and (b) associates that representation with shock (see Fanselow & Rudy, 1998;Rudy, 1996;Rudy & Morledge, 1994;Young, Bohenek, & Fanselow, 1994). In this framework, it is the acquisition of the conjunctive representation that requires the hippocampus. The associative process does not.There is considerable support for the view that rats can acquire a representation of context, independent of associating it with shock. This support comes from a range of experiments that have demonstrated what we call the context preexposure facilitation effect-the fact that preexposure to the conditioning context the day before a context-shock experience can enhance the low levels of fear contextual conditioning that otherwise would occur

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The circadian system regulates many physiological functions including inflammatory responses. For example, mortality caused by lipopolysaccharide (LPS) injection varies depending on the time of immunostimulation in mammals. The effects of more subtle challenges on the immune system and cellular mechanisms underlying circadian differences in neuroinflammatory responses are not well understood. Here we show that adult male Sprague-Dawley rats injected with a sub-septic dose of LPS during the light phase displayed elevated sickness behaviors and hippocampal cytokine production compared to rats injected during the dark phase. Microglia are the primary central nervous system (CNS) immune cell type and may mediate diurnal differences in sickness response, thus we explored whether microglia demonstrate temporal variations in inflammatory factors. Hippocampal microglia isolated from adult rats rhythmically expressed inflammatory factors and circadian clock genes. Microglia displayed robust rhythms of TNFα, IL1β and IL6 mRNA, with peak cytokine gene expression occurring during the middle of the light phase. Microglia isolated during the light phase were also more reactive to immune stimulation; such that, ex vivo LPS treatment induced an exaggerated cytokine response in light phase-isolated microglia. Treating microglia with corticosterone ex vivo induced expression of the circadian clock gene Per1. However, microglia isolated from adrenalectomized rats maintained temporal differences in clock and inflammatory gene expression. This suggests circadian clock gene expression in microglia is entrained by, but oscillates in the absence of, glucocorticoids. Taken together, these findings demonstrate that microglia possess a circadian clock that influences inflammatory responses. These results indicate time-of-day is an important factor to consider when planning inflammatory interventions such as surgeries or immunotherapies.

We previously reported that aging BNXF344 rats are more vulnerable to disruptions of memory consolidation processes following an injection of E. coli than are young rats. Furthermore, this disruption was specific to hippocampal-dependent memory. In the present study we examined the time course of the level of the proinflammatory cytokine IL-1β in young and old rats following a peripheral injection of E. coli. Compared to young rats, aging rats treated with E. coli showed an exaggerated and prolonged up-regulation of IL-1β protein in the hippocampus, but not in hypothalamus, parietal cortex, prefrontal cortex, serum or spleen. Aging rats showed greater hippocampal IL-1β protein levels than their young counterparts 4h after E. coli, and these levels remained significantly elevated for 8 but not 14 days after E. coli. In a second experiment, aging rats exhibited anterograde memory consolidation impairments 4 and 8 days after an E. coli injection, but not after 14 days. A third experiment revealed that following an E. coli injection, bacterial clearance from the spleen and peritoneum was not impaired in aged rats, suggesting that elevations in hippocampal IL-1β were not mediated by impaired clearance in the periphery in aging rats. These data suggest that the exaggerated and prolonged elevation of IL-1β, specifically in the hippocampus, may be responsible for hippocampal-dependent memory impairments observed in aging rats following a bacterial infection.

To investigate the role of the pro-inflammatory cytokine interleukin-1beta (IL-1β) in post-operative cognitive dysfunction (POCD) in aged rats, we employed laparotomy to mimic human abdominal surgery in adult (3 mo) and aged (24 mo) F344/BN rats. We demonstrated that memory consolidation of the hippocampal-dependent contextual fear conditioning task is significantly impaired in aged, but not young rats 4 days following surgery. Hippocampal-independent auditory-cued fear memory was not disrupted by laparotomy in either age group. The hippocampal-dependent memory impairment was paralleled by elevations of IL-1β in the hippocampus of aged animals 1 and 4 days following surgery. These findings support our substantial line of previous research showing that aged animals are more vulnerable to cognitive decline following a peripheral immune challenge. In addition, we demonstrated that a single intracisternal administration of interleukin-1 receptor antagonist (IL-1RA; 112ug) at the time of surgery was sufficient to block both the behavioral deficit and the neuroinflammatory response. Injecting the same dose of IL-1RA peripherally failed to have a protective effect. These data provide strong support for the specific role of central, not peripheral IL-1β in POCD. Furthermore, the long-lasting presence of IL-1RA in the brain (4 days) compared to in the blood (<24 hr) underscores the value of intracisternal administration of IL-1RA for therapeutic purposes.