Lipocalin-2 is involved in emotional behaviors and cognitive function

Abstract

Lipocalin-2 (LCN2), an iron-related protein well described to participate in the innate immune response, has been shown to modulate spine morphology and to regulate neuronal excitability. In accordance, LCN2-null mice are reported to have stress-induced anxiety. Here we show that, under standard housing conditions, LCN2-null mice display anxious and depressive-like behaviors, as well as cognitive impairment in spatial learning tasks. These behavioral alterations were associated with a hyperactivation of the hypothalamic–pituitary–adrenal axis and with an altered brain cytoarchitecture in the hippocampus. More specifically, we found that the granular and pyramidal neurons of the ventral hippocampus, a region described to be associated with emotion, were hypertrophic, while neurons from the dorsal hippocampus, a region implicated in memory and cognition, were atrophic. In addition, LCN2-null mice presented synaptic impairment in hippocampal long-term potentiation. Whether the LCN2 effects are mediated through modulation of the level of corticosteroids or through a novel mechanism, the present observations bring further into light this immune-related protein as a player in the fine-tuning of behavior and of synaptic activity.

Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice

“…In our studies, this central elevation in Lcn2 expression occurs in a more physiologically relevant model in the presence of peripheral inflammation and metabolic endotoxemia. The impact of increased Lcn2 in the hippocampus has been suggested to involve regulation of microglia activation and changes in neuronal morphology and plasticity associated with depression and anxiety (Mucha et al, 2011; Ferreira et al, 2013). Collectively, our results support a model in which elevated central and peripheral Lcn2/NGAL mediate the impact of chronic inflammatory peripheral disease on the central nervous system in association with behavioral dysfunction (Gouweleeuw et al, 2015).…”

“…Chronic inflammation is a key factor in depressive and obesity states (Miller and Raison, 2015; Ramirez and Sheridan, 2016). Changes in central Lipocalin-2 ( Lcn2 ) are associated with depression and anxiety (Mucha et al, 2011; Ferreira et al, 2013). The increased secretion of tumor necrosis factor (TNF) and other cytokines in the presence of HFHF diet or during psychological stress exposure can trigger additional changes and immune responses in metabolically active tissues such as gut, liver, and the adipose tissue that ultimately can affect the brain functions (Spruss et al, 2009; Jan et al, 2011; Milanski et al, 2012; Li et al, 2013a; Skrzypiec et al, 2013; Bailey, 2016).…”

The role of neutrophil gelatinase associated lipocalin (NGAL) as biological constituent linking depression and cardiovascular disease

“…The change in behavior was associated with an activation of the hypothalamic-pituitary-adrenal (HPA) axis (Ferreira et al, 2013). In contrast, locomotion activity of NGAL -/-mice did not change in an open field test; only when stimulated with LPS the absence of NGAL was uncovered (Jang et al, 2013).…”

Astrocyte Transcriptome from the Mecp2308-Truncated Mouse Model of Rett Syndrome

“…In addition, LCN2-null mice presented synaptic impairment in hippocampal long-term potentiation (Ferreira et al 2013). Our results suggest that LCN2 may be abnormally secreted by Mecp2-mutant astrocytes and may alter spine morphology and neuronal excitability on mutant as well as wild-type neurons.…”

“…Interestingly, LCN2 has been shown to modulate spine morphology and to regulate neuronal excitability. As previously described by Ferreira and colleagues (Ferreira et al 2013), LCN2-null mice displayed increased anxiety and depressive-like behaviors compared to wild-type controls as assessed by the decreased time they spent in the open arms of the elevated plus maze test and the decreased time spent in the light compartment of the light/dark box test when compared to wild-type mice (Ferreira et al 2013). …”