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

Abstract

ObjectiveThe 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.MethodsAdult 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.ResultsBoth 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.ConclusionsMetabolic 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.

Nucleus accumbens cytoarchitecture predicts weight gain in children

“…Recent work in juvenile rats has extended these findings by demonstrating reactive gliosis within the NAcc induced by a high-calorie diet (67,68), which has been more specifically linked to the consumption of saturated fats in adult mice (69). Consumption of a diet high in saturated fats not only increased proinflammatory signals in the NAcc but was also associated with compulsive sucrose seeking in mice (69), suggesting that a diet high in saturated fat may trigger neuroinflammation prior to, or independent of, weight gain and may induce high caloric food-seeking behaviors. Thus, diet-induced gliosis implicates a local inflammatory reaction both resulting from and contributing to excess consumption of unhealthy foods, which may explain the observed association between NAcc cellularity and weight gain.…”

“…For example, there has been substantial evidence demonstrating increased inflammatory markers within the hypothalamus related to diet-induced obesity in rodents (60-64), including changes within hypothalamic glial cells (65,66) that ultimately interfere with the regulation of food intake (64). Recent work in juvenile rats has extended these findings by demonstrating reactive gliosis within the NAcc induced by a high-calorie diet (67,68), which has been more specifically linked to the consumption of saturated fats in adult mice (69). Consumption of a diet high in saturated fats not only increased proinflammatory signals in the NAcc but was also associated with compulsive sucrose seeking in mice (69), suggesting that a diet high in saturated fat may trigger neuroinflammation prior to, or independent of, weight gain and may induce high caloric food-seeking behaviors.…”

Meaningful Associations in the Adolescent Brain Cognitive Development Study

“…To illustrate this, we used Cohen's and point-biserial &' to estimate the effect size of a dichotomous "exposure" index: very obese (here defined as a body mass index (BMI) ≥ 30) and a continuous brain "outcome": restriction spectrum imaging component (N0), a measure sometimes related to cellularity, in the Nucleus Accumbens (NAcc). Recent work has highlighted a potential role of neuroinflammation in the NAcc in animal models of dietinduced obesity 77 . We included baseline data from subjects without missing BMI and NAcc N0 data, also excluding 5 subjects with NAcc N0 values < 0 (leaving = 10659 subjects, of which 184 subjects had BMI ≥ 30, or 1.7%).…”

An Integrative Approach to Neuroinflammation in Psychiatric disorders and Neuropathic Pain

“…Chronic inflammatory conditions such as multiple sclerosis, RA, inflammatory bowel disease, obesity, and even spinal cord injury are often comorbid with depression. 33 – 36 In fact, patients with RA suffer depression rates of 9.5% to 41.5% which is significantly higher compared with the general population (6.7%). 37 These diseases result in increased levels of circulating pro-inflammatory cytokines and CRP which are thought to contribute to the development of depression.…”