Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome

Abstract

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 (hippocampus-dependent task), but unaltered object recognition memory (hippocampus-independent task). In agreement with the well-established role of the hippocampus in anxiety-like behavior and spatial memory, behavioral alterations of db/db mice were associated with increased inflammatory cytokines (interleukin-1β, tumor necrosis factor-α 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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Anxiety-like behaviors of db/db and db/+ mice.

(A) Percent of time spent in the center area of the open-field and temporal evolution of the number of entries into this area. (B) Number of entries and (C) percent of time spent into the open arms of the elevated plus-maze. Data represent means ± SEM (n = 6/group). * p<.05, ** p<.01 for db/db vs. db/+ mice.

Figure 2. Depressive-like behaviors of db/db and db/+ mice.

Immobility time in the (A) tail suspension test and (B) forced swim test. Data represent means ± SEM (n = 7/group).

Figure 3. Working memory performances of db/db and db/+ mice.

(A) Spatial recognition in the Y-maze expressed as the time spent exploring the novel and the familiar arms. (B) Time spent exploring the novel and the familiar object in the novel object recognition task. In both tasks, measures were assessed over a 5-min test and after 30-min retention. Data represent means ± SEM (n = 7–10/group). * p<.05, ** p<.01 for db/db vs. db/+ mice.

Figure 4. mRNA expression levels of cytokines in the hippocampus and hypothalamus of db/db and db/+ mice.

Relative fold changes in the levels of (A) hippocampal and (B) hypothalamic IL-1β, TNF-α, IL-6, IFN-γ and MCP-1 mRNA expression, as calculated in relation to the averaged value for control saline group. IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; MCP-1, monocyte chemotactic protein-1. Data represent means ± SEM (n = 6/group). * p<.05 for db/db vs. db/+ mice.

Figure 5. mRNA expression levels of GP130, SOCS3 and BDNF in the hippocampus and hypothalamus.

Relative fold changes in the levels of (A–B) hippocampal and (C–D) hypothalamic GP130, SOCS3 and BDNF mRNA expression, as calculated in relation to the averaged value for control saline group. GP130, glycoprotein 130; SOCS3, suppressor of cytokine signaling-3; BDNF, brain-derived neurotrophic factor. Data represent means ± SEM (n = 6/group). * p<.05 for db/db vs. db/+ mice.