Named Series: Diet, Inflammation and the Brain High-fat diet consumption disrupts memory and primes elevations in hippocampal IL-1b, an effect that can be prevented with dietary reversal or IL-1 receptor antagonism Julia L. Sobesky ⇑ , Ruth M. Barrientos, Henning S. De May, Brittany M. Thompson, Michael D. Weber, Linda R. Watkins, Steven F. Maier Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA article info Article history: Received 11 April 2014 Received in revised form 5 June 2014 Accepted 25 June 2014 Available online xxxx Keywords: High-fat diet Hippocampus Interleukin-1b Fear conditioning hIL-1RA Dietary reversal Memory abstract High-fat diet (HFD)-induced obesity is reaching worldwide proportions. In addition to causing obesity, HFDs also induce a variety of health disorders, which includes cognitive decline. Hippocampal function may be particularly vulnerable to the negative consequences of HFD, and it is suspected that ‘primed’ neuroinflammatory processes may mediate this response. To examine the link between diet, hippocam- pal function and neuroinflammation, male Wistar rats were fed a medium or HFD. Hippocampal memory function was measured using contextual pre-exposure fear conditioning (CPE-FC). Rats fed a HFD dem- onstrated impaired memory, an effect that was augmented with longer duration of HFD consumption. HFD-induced memory impairments were linked to potentiated levels of interleukin-1 beta (IL-1b) protein in the hippocampus 2 h after the foot-shock that occurs during CPE-FC. Central IL-1 receptor antagonism, with intracisterna magna (ICM) administration of hIL-1RA prior to the foot-shock prevented the diet- induced memory disruption, suggesting a critical role for IL-1b in this phenomenon. Additionally, obese animals whose diet regimen was reversed from HFD back to standard chow recovered memory function and did not demonstrate a foot-shock-induced hippocampal IL-1b increase. Interestingly, dietary reversal neutralized the negative impact of HFD on memory and IL-1b, yet animals maintained physiological evi- dence of obesity (increased body mass and serum leptin), indicating that dietary components, not body mass, may mediate the negative effects on memory. Ó 2014 Elsevier Inc. All rights reserved. 1. Introduction There is a well-established link between human obesity and cognitive decline (Sellbom and Gunstad, 2012). Specifically, hippo- campally-dependent functions may be particularly vulnerable (Kanoski and Davidson, 2011; Francis and Stevenson, 2013), as many studies have linked high-caloric diets with decreased con- textual and spatial memory (Winocur and Greenwood, 2005; Valladolid-Acebes et al., 2011; Kosari et al., 2012; Ross et al., 2012; Yamada-Goto et al., 2012). This is most likely the result of dietary-induced alterations in hippocampal synaptic plasticity (Molteni et al., 2002; Wu et al., 2004; Stranahan et al., 2008; Hwang et al., 2010). However, the mechanisms underlying how high-caloric diets cause hippocampal dysfunction are largely unknown. It is possible that diet and obesity may induce cognitive disrup- tion by impacting neural inflammatory processes. Obesity is often characterized by increased and altered peripheral inflammatory processes (Mito et al., 2000; Das, 2010; Donath and Shoelson, 2011) and peripheral inflammation can induce neuroinflammation (Maier and Watkins, 1998), leading to the notion that central inflammatory processes may also be altered with obesity. The pro-inflammatory cytokine interleukin-1 beta (IL-1b) is required for proper hippocampal memory function (Schneider et al., 1998; Yirmiya et al., 2002; Avital et al., 2003). However, elevated or exag- gerated central levels of IL-1b are detrimental to cognitive process- ing (Gibertini et al., 1995; Barrientos et al., 2002; Yirmiya and Goshen, 2011) as the duration of hippocampal-based cognitive impairment mirrors the duration of elevated hippocampal IL-1b (Barrientos et al., 2009a) and inflammation-induced cognitive decline is prevented when IL-1b action is blocked with IL-1 recep- tor antagonist (IL-1RA) (Pugh et al., 1998; Palin et al., 2004; Frank http://dx.doi.org/10.1016/j.bbi.2014.06.017 0889-1591/Ó 2014 Elsevier Inc. All rights reserved. ⇑ Corresponding author. Address: Department of Psychology and Neuroscience, Campus Box 345, University of Colorado, Boulder, CO 80309, USA. Tel.: +1 616 403 5401. E-mail address: julia.sobesky@colorado.edu (J.L. Sobesky). Brain, Behavior, and Immunity xxx (2014) xxx–xxx Contents lists available at ScienceDirect Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi Please cite this article in press as: Sobesky, J.L., et al. High-fat diet consumption disrupts memory and primes elevations in hippocampal IL-1b, an effect that can be prevented with dietary reversal or IL-1 receptor antagonism. Brain Behav. Immun. (2014), http://dx.doi.org/10.1016/j.bbi.2014.06.017