Cognitive and Emotional Alterations Are Related to Hippocampal Inflammation in a Mouse Model of Metabolic Syndrome

et al. (2011) Cognitive and Emotional Alterations Are Related to Hippocampal Inflammation in a Mouse Model of Metabolic Syndrome. PLoS ONE 6(9): e24325. doi:10.1371/journal.pone.0024325 Cognitive and Emotional Alterations Are Related to Hippocampal Inflammation in a Mouse Model of Metabolic Syndrome Anne-Laure Dinel 0 Caroline Andre 0 Agne` s Aubert 0 Guillaume Ferreira 0 Sophie Laye 0 Nathalie 0 Michelle L. Block, Virginia Commonwealth University, United States of America 0 1 Nutrition et Neurobiologie Inte gre e, INRA UMR 1286 , Bordeaux , France , 2 University of Bordeaux , Bordeaux , France Converging clinical data suggest that peripheral inflammation is likely involved in the pathogenesis of the neuropsychiatric symptoms associated with metabolic syndrome (MetS). However, the question arises as to whether the increased prevalence of behavioral alterations in MetS is also associated with central inflammation, i.e. cytokine activation, in brain areas particularly involved in controlling behavior. To answer this question, we measured in a mouse model of MetS, namely the diabetic and obese db/db mice, and in their healthy db/+ littermates emotional behaviors and memory performances, as well as plasma levels and brain expression (hippocampus; hypothalamus) of inflammatory cytokines. Our results shows that db/db mice displayed increased anxiety-like behaviors in the open-field and the elevated plus-maze (i.e. reduced percent of time spent in anxiogenic areas of each device), but not depressive-like behaviors as assessed by immobility time in the forced swim and tail suspension tests. Moreover, db/db mice displayed impaired spatial recognition memory (hippocampusdependent task), but unaltered object recognition memory (hippocampus-independent task). In agreement with the wellestablished role of the hippocampus in anxiety-like behavior and spatial memory, behavioral alterations of db/db mice were associated with increased inflammatory cytokines (interleukin-1b, tumor necrosis factor-a and interleukin-6) and reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus but not the hypothalamus. These results strongly point to interactions between cytokines and central processes involving the hippocampus as important contributing factor to the behavioral alterations of db/db mice. These findings may prove valuable for introducing novel approaches to treat neuropsychiatric complications associated with MetS. - Funding: This work was supported by Institut National de la Recherche Agronomique and Region Aquitaine (grant number 2008-1301-038; SL). ALD was supported by a doctoral fellowship from the Institut Danone. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. For several decades, the prevalence of the metabolic syndrome (MetS) and related comorbidities continuously increases worldwide at alarming rate. This syndrome is defined as a constellation of interrelated metabolic dysregulations, including abdominal obesity, hypertension, hyperglycemia, insulin-resistance, leptinresistance and hypercortisolemia [13]. Mounting evidence highlights that patients with MetS often experience a higher prevalence of mood symptoms and cognitive dysfunctions than the general age-matched population [46]. The overwhelming influence of metabolic and neuropsychiatric disorders considerably impairs the quality of life of MetS patients and results in incremental costs to health care systems around the world [7]. Actually, neuropsychiatric symptoms emerge as significant risk factors for aggravation of MetS and related health outcomes, particularly cardiovascular diseases and type 2 diabetes (T2D) [812]. Even so, relatively little is known about the pathophysiological mechanisms contributing to the development of neuropsychiatric symptoms in the context of MetS. Recent evidence suggests that some major biological systems, including the inflammatory system, may participate in both MetS and neuropsychiatric disorders [1315]. Inflammation is a key component of MetS, as elevated circulating levels of inflammatory mediators facilitate the development of this condition [16,17]. Severe obesity is associated with an inflammatory profile characterized by increased plasma production of cytokines and resulting in an imbalance of the cytokine network [18]. Similarly, T2D is associated with a shift of the balance between proinflammatory and anti-inflammatory cytokines toward inflammation [19]. Consequently, MetS is presently viewed not only as a metabolic disorder, but also as an inflammatory disease affecting both innate and acquired immune systems [17,20]. Abundant evidence supports immune-to-brain communication, with peripheral cytokines acting on the brain to induce local production of cytokines and to influence pathways involved in the regulation of mood and cognition, including neurotransmitter metabolism, neuroendocrine function and neural plasticity [21,22]. Interestingly, we and others have identified peripheral and central inflammatory factors as important mediators of the neuropsychiatric symptoms observed in many medical illnesses sharing chronic systemic inflammation as a common denominator [2226]. We have found in mice that the selective activation of enzymatic pathways involved in brain monoamine metabolism by interferon-c (IFN-c) and tumor necrosis factor-a (TNF-a) mediates development of depressive-like behaviors in response to chronic infection [2426]. The same mechanisms likely contribute to the high incidence of depressive disorders reported in medically ill patients chronically treated with IFN-a [27] or in elderly subjects exhibiting systemic low-grade inflammation as manifested by increased serum levels of C-reactive protein (CRP) and interleukin-6 (IL-6) [28]. Besides, converging animal [2931] and clinical findings [3234] support a main role for IL-6 in mood disorders and cognitive decline. Mounting evidence suggests that systemic inflammation, particularly higher peripheral IL-6, is associated with brain inflammation [35,36] that might adversely affect mood, learning and memory through processes related to neurodegeneration and structural remodeling [3739]. These processes mainly affect the hippocampus [4042], a key brain area for memory formation and mood [43,44]. A sizeable number of molecules are well-known to influence hippocampal synaptic plasticity contributing to mood and memory processes, but the brain-derived neurotrophic factor (BDNF) is a major candidate in the context of MetS. BDNF has been found critical in a number of memory tasks [45] and represents an essential constituent of central neural circuits involved in regulating energy homeostasis [46]. Intact hippocampal BDNF signaling determines antidepressant efficacy and influences anxiety-like behaviors [47]. Moreover, hippocampal BDNF mR (...truncated)