Acute fasting inhibits central caspase-1 activity reducing anxiety-like behavior and increasing novel object and object location recognition

Abstract

Background Inflammation within the central nervous system (CNS) is frequently comorbid with anxiety. Importantly, the pro-inflammatory cytokine most commonly associated with anxiety is IL-1β. The bioavailability and activity of IL-1β is regulated by caspase-1-dependent proteolysis vis-a-vis the inflammasome. Thus, interventions regulating the activation or activity of caspase-1 should reduce anxiety especially in states that foster IL-1β maturation. Methods Male C57BL/6j, C57BL/6j mice treated with the capase-1 inhibitor biotin-YVAD-cmk, caspase-1 knockout (KO) mice and IL-1R1 KO mice were fasted for 24 hours or allowed ad libitum access to food. Immediately after fasting, caspase-1 activity was measured in brain region homogenates while activated caspase-1 was localized in the brain by immunohistochemistry. Mouse anxiety-like behavior and cognition were tested using the elevated zero maze and novel object/object location tasks, respectively. Results A 24 h fast in mice reduced the activity of caspase-1 in whole brain and in the prefrontal cortex, amygdala, hippocampus, and hypothalamus by 35%, 25%, 40%, 40%, and 40% respectively. A 24 h fast also reduced anxiety-like behavior by 40% and increased novel object and object location recognition by 21% and 31%, respectively. IL-1β protein, however, was not reduced in the brain by fasting. ICV administration of YVAD decreased caspase-1 activity in the prefrontal cortex and amygdala by 55%, respectively leading to a 64% reduction in anxiety like behavior. Importantly, when caspase-1 KO or IL1-R1 KO mice are fasted, no fasting-dependent reduction in anxiety-like behavior was observed. Conclusions Results indicate that fasting decrease anxiety-like behavior and improves memory by a mechanism tied to reducing caspase-1 activity throughout the brain.

HFD refeeding in mice after fasting impairs learning by activating caspase-1 in the brain

“…Here we show that overnutrition following IF in the form of a HFD-refeed can impair mouse memory/learning in as little as 2 h. The present model was used to model spontaneous ab-lib consumption of food following IF, which is germane to many current CRbased weight loss/control approaches n [38]. In our previous work, we found that mice fasted for 24 h have improved cognition and decreased caspase-1 activity in the brain [15]. From a teleological standpoint, this hunger-associated enhancement in learning/memory is not surprising in that nutritional stress should be motivating and assist in foraging and/or food-finding behaviors.…”

“…As we have previously shown, acute fasting improves mouse memory while reducing caspase-1 activity in the brain [15]. Due to the well-recognized role of IL-1β in learning and memory [16], activation of caspase-1 in the CNS appears critical to the impact of stress on cognition [17,18].…”

“…3) for 2 h. For behavioral experiments, mice underwent the training phase for NOR or NLR prior to refeeding at 23.5 h of fasting. Food disappearance was measured as previously described [15]. In brief, food was placed in a dish inside the fasting arena and the reduction of weight of the dish + food before and after 2 h of refeeding was equated to food consumption.…”

“…NLR testing was utilized to test spatial memory and performed as previously described [15,18]. In brief, mice were placed in a spatiallycued learning/memory arena (26 cm × 48 cm × 21 cm) containing two identical objects placed at the same end of the arena.…”

“…For each amygdala analyzed, four regions of interest (ROIs) were delineated so as to cover the entire amygdala. Area of staining for each amygdala was determined using ImageJ (National Institute of Health) and an automated algorithm we developed and previously published [15]. In brief, area of staining was normalized to cell count and the results for each ROI were summed together.…”