Nucleus accumbens inflammation mediates anxiodepressive behavior and compulsive sucrose seeking elicited by saturated dietary fat

• Published in: Molecular metabolism (Germany) Vol. 10; pp. 1 - 13
• Main Authors: Décarie-Spain, Léa, Sharma, Sandeep, Hryhorczuk, Cécile, Issa-Garcia, Victor, Barker, Philip A., Arbour, Nathalie, Alquier, Thierry, Fulton, Stephanie
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.04.2018; Elsevier
• Subjects: Animals; Anxiety; Anxiety Disorders - etiology; Anxiety Disorders - metabolism; Anxiety Disorders - physiopathology; Depression; Depressive Disorder - etiology; Depressive Disorder - metabolism; Depressive Disorder - physiopathology; Diet, High-Fat - adverse effects; Diet-induced obesity; Dietary fatty acids; Dietary Sucrose - adverse effects; Food Addiction - etiology; Food Addiction - metabolism; Food Addiction - physiopathology; Food reward; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Inflammation - metabolism; Male; Mice; Mice, Inbred C57BL; Neuroinflammation; Nuclear factor kappa-b; Nucleus Accumbens - metabolism; Nucleus Accumbens - pathology; Original; CRP; PR; Ad; EPM; HFD; Food reward; ITT; MHC; IKKβ; LFD; NFkB; TNF; LPS; βgal; GFP; NAc; IFN-γ; Diet-induced obesity; IKKdn; Anxiety; Iba-1; Dietary fatty acids; FST; Neuroinflammation; Depression; i.p; DIO; IL-1β; GFAP; Nuclear factor kappa-b; CORT; HPA; OGTT
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2018.01.018

The incidence of depression is significantly compounded by obesity. Obesity arising from excessive intake of high-fat food provokes anxiodepressive behavior and elicits molecular adaptations in the nucleus accumbens (NAc), a region well-implicated in the hedonic deficits associated with depression and in the control of food-motivated behavior. To determine the etiology of diet-induced depression, we studied the impact of different dietary lipids on anxiodepressive behavior and metabolic and immune outcomes and the contribution of NAc immune activity. Adult C57Bl/6 mice were subjected to isocaloric high-fat/high-sucrose diets (HFD), enriched in either saturated or monounsaturated fat, or a control low-fat diet (LFD). Metabolic responses, anxiodepressive behavior, and plasma and NAc inflammatory markers were assessed after 12 weeks. In separate experiments, an adenoviral construct inhibiting IKKβ, an upstream component of the nuclear factor kappa-b (NFkB) pathway, was a priori injected into the NAc. Both HFDs resulted in obesity and hyperleptinemia; however, the saturated HFD uniquely triggered anxiety-like behavior, behavioral despair, hyperinsulinemia, glucose intolerance, peripheral inflammation, and multiple pro-inflammatory signs in the NAc, including reactive gliosis, increased expression of cytokines, antigen-presenting markers and NFкB transcriptional activity. Selective NAc IKKβ inhibition reversed the upregulated expression of inflammatory markers, prevented anxiodepressive behavior and blunted compulsive sucrose-seeking in mice fed the saturated HFD. Metabolic inflammation and NFкB-mediated neuroinflammatory responses in the NAc contribute to the expression of anxiodepressive behavior and heightened food cravings caused by a diet high in saturated fat and sugar. [Display omitted] •Saturated HFD uniquely triggers metabolic impairments & depressive behavior.•Nucleus accumbens (NAc) inflammation & gliosis are distinct features of the saturated HFD.•Depressive behavior & NAc immune activation are mediated by IKKβ/NFκB signaling.•Inhibiting NAc IKKβ/NFκB suppresses compulsive sucrose seeking in mice fed the saturated HFD.