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Metabolism. 2017 Jun;71:70-82. doi: 10.1016/j.metabol.2017.03.005. Epub 2017 Mar 9.

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

Author information

1
Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA.
2
Department of Animal Sciences, University of Illinois, Urbana, IL, USA.
3
School of Molecular and Cellular Biology, University of Illinois, Urbana, IL, USA.
4
Department of Animal Sciences, University of Illinois, Urbana, IL, USA; Department of Pathology, Program in Integrative Immunology and Behavior, University of Illinois, Urbana, IL, USA.
5
Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA; Department of Animal Sciences, University of Illinois, Urbana, IL, USA; Department of Pathology, Program in Integrative Immunology and Behavior, University of Illinois, Urbana, IL, USA. Electronic address: freun@illinois.edu.

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 are 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 24h 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 24h 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 24h 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.

KEYWORDS:

Anxiety; Caspase-1; Fasting; Il-1β; Neuroinflammation

PMID:
28521881
PMCID:
PMC5439304
DOI:
10.1016/j.metabol.2017.03.005
[Indexed for MEDLINE]
Free PMC Article

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