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Endothelial ErbB4 deficit induces alterations in exploratory behavior and brain energy metabolism in mice.

ABSTRACT: AIMS:The receptor tyrosine kinase ErbB4 is present throughout the primate brain and has a distinct functional profile. In this study, we investigate the potential role of endothelial ErbB4 receptor signaling in the brain. RESULTS:Here, we show that the endothelial cell-specific deletion of ErbB4 induces decreased exploratory behavior in adult mice. However, the water maze task for spatial memory and the memory reconsolidation test reveal no changes; additionally, we observe no impairment in CaMKII phosphorylation in Cdh5Cre;ErbB4f/f mice, which indicates that the endothelial ErbB4 deficit leads to decreased exploratory activity rather than direct memory deficits. Furthermore, decreased brain metabolism, which was measured using micro-positron emission tomography, is observed in the Cdh5Cre;ErbB4f/f mice. Consistently, the immunoblot data demonstrate the downregulation of brain Glut1, phospho-ULK1 (Ser555), and TIGAR in the endothelial ErbB4 conditional knockout mice. Collectively, our findings suggest that endothelial ErbB4 plays a critical role in regulating brain function, at least in part, through maintaining normal brain energy homeostasis. CONCLUSIONS:Targeting ErbB4 or the modulation of endothelial ErbB4 signaling may represent a rational pharmacological approach to treat neurological disorders.

SUBMITTER: Wu G

PROVIDER: S-EPMC6492688 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Endothelial ErbB4 deficit induces alterations in exploratory behavior and brain energy metabolism in mice.

Wu Gang G Liu Xiu-Xiu XX Lu Nan-Nan NN Liu Qi-Bing QB Tian Yun Y Ye Wei-Feng WF Jiang Guo-Jun GJ Tao Rong-Rong RR Han Feng F Lu Ying-Mei YM

CNS neuroscience & therapeutics 20170418 6

<h4>Aims</h4>The receptor tyrosine kinase ErbB4 is present throughout the primate brain and has a distinct functional profile. In this study, we investigate the potential role of endothelial ErbB4 receptor signaling in the brain.<h4>Results</h4>Here, we show that the endothelial cell-specific deletion of ErbB4 induces decreased exploratory behavior in adult mice. However, the water maze task for spatial memory and the memory reconsolidation test reveal no changes; additionally, we observe no imp ...[more]

PMID: 28421673

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Project description:BACKGROUND:Consecutive peripheral immune challenges can modulate the responses of brain resident microglia to stimuli. High-fat diet (HFD) intake has been reported to stimulate the activation of astrocytes and microglia in the arcuate nucleus (ARC) of the hypothalamus in obese rodents and humans. However, it is unknown whether intermittent exposure to additional peripheral immune challenge can modify HFD-induced hypothalamic glial activation in obese individuals. METHODS:In this study, we administered 1?mg/kg LPS (or saline) by intraperitoneal (i.p.) injection to 8-week-old male mice after 1, 2, or 8?weeks of a regular diet (show) or HFD. The level of interleukin-1? (IL-1?) and tumor necrosis factor-? (TNF-?) expression in the plasma and hypothalamic tissue was analyzed 24?h after each LPS injection. The behaviors of the animals in the four groups (the chow-saline, chow-LPS, HFD-saline, and HFD-LPS groups) were examined 5?months after exposure to chow or a HFD. Morphological examination of microglia in related brain regions was also conducted. RESULTS:The plasma levels and hypothalamic mRNA levels of IL-1? and TNF-? were significantly upregulated 24?h after the first injection of LPS but not after the second or third injection of LPS. Chow-LPS mice displayed increased exploratory behavior 5?months after feeding. However, this LPS-induced abnormal exploratory behavior was inhibited in HFD-fed mice. Chronic HFD feeding for 5?months induced apparent increases in the number and cell body size of microglia, mainly in the ARC, and also increased the size of microglia in the nucleus accumbens (NAc) and insula. Moreover, microglial activation in the ARC, anterior cingulate cortex (ACC), insula, and basolateral amygdala (BLA) was observed in chow-LPS mice. However, microglial activation in the analyzed brain regions was suppressed in HFD-LPS mice. CONCLUSIONS:Altogether, the results indicate that intermittent peripheral challenge with LPS might prime microglia in the ARC and NAc to modify their response to chronic HFD feeding. Alternatively, chronic HFD feeding might mediate microglia in LPS-affected brain regions and subsequently suppress LPS-induced atypical exploratory behavior. Our findings suggest that the interaction of intermittent acute peripheral immune challenges with chronic HFD intake can drive microglia to amend the microenvironment and further modify animal behaviors in the later life.

Dataset Information

Endothelial ErbB4 deficit induces alterations in exploratory behavior and brain energy metabolism in mice.

Publications

Endothelial ErbB4 deficit induces alterations in exploratory behavior and brain energy metabolism in mice.

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