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bioRxiv · 10.1101/2021.06.30.450398

Early neuroadaptations to an obesogenic diet identify the schizophrenia-related ErbB4 receptor in obesity-induced hippocampal abnormalities

Vega-Torres, J. D.·Ontiveros-Angel, P.·Terrones, E.·Stuffle, E. C.·Solak, S.·Tyner, E.·Oropeza, M.·Dela Pena, I.·Obenaus, A.·Ford, B. D.·Figueroa, J. D.
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Abstract

Childhood obesity leads to hippocampal atrophy and altered cognition. However, the molecular mechanisms underlying these impairments are poorly understood. The neurotrophic factor neuregulin-1 (NRG1) and its cognate ErbB4 receptor play critical roles in hippocampal maturation and function. This study aimed to determine whether altered NRG1-ErbB4 activities may partly explain hippocampal abnormalities in rats exposed to an obesogenic Western-like diet (WD). Lewis rats were randomly divided into four groups (12 rats/group): 1) control diet+vehicle (CDV); 2) CD+NRG1 (CDN) (daily intraperitoneal injections: 5 g/kg/day; between postnatal day, PND 21-PND 41); 3) WD+VEH (WDV); 4) WD+NRG1 (WDN). Neurobehavioral assessments were performed at PND 43-49. Brains were harvested for MRI and molecular analyses at PND 49. We found that NRG1 administration reduced hippocampal volume (7%) and attenuated hippocampal-dependent cued fear conditioning in CD rats (56%). NRG1 administration reduced PSD-95 protein expression (30%) and selectively reduced hippocampal cytokine levels (IL-33, GM-CSF, CCL-2, IFN-{gamma}) while significantly impacting microglia morphology (increased span ratio and reduced circularity). WD rats exhibited reduced right hippocampal volume (7%), altered microglia morphology (reduced density and increased lacunarity), and increased levels of cytokines implicated in neuroinflammation (IL-1, TNF-, IL-6). Notably, NRG1 synergized with the WD to increase hippocampal ErbB4 phosphorylation and the tumor necrosis alpha converting enzyme (TACE/ADAM17) protein levels. Together, these data suggest a novel interaction between obesogenic diet exposure and TACE/ADAM17-NRG1-ErbB4 signaling during hippocampal maturation. Our results indicate that supraoptimal ErbB4 activities may contribute to the abnormal hippocampal structure and cognitive vulnerabilities observed in obese individuals. HighlightsO_LIObesogenic diet consumption during adolescence induces anxiety-like behaviors before the onset of obesity-related changes in metabolism. C_LIO_LIObesogenic diet-driven abnormal behaviors co-occurred with alterations in hippocampal pro-inflammatory cytokine profiles. C_LIO_LIObesogenic diet consumption attenuates exogenous NRG1 effects on hippocampal-related behaviors and structure. C_LIO_LIExogenous NRG1 administration during adolescence resulted in reduced hippocampal volumes and domain-specific cognitive impairments. C_LIO_LIExogenous NRG1 administration has potent immunomodulatory actions and alters hippocampal microglia morphology. C_LI

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Vega-Torres, J. D., Ontiveros-Angel, P., Terrones, E., Stuffle, E. C., Solak, S., Tyner, E., Oropeza, M., Dela Pena, I., Obenaus, A., Ford, B. D., Figueroa, J. D.. 2021-07-01. Early neuroadaptations to an obesogenic diet identify the schizophrenia-related ErbB4 receptor in obesity-induced hippocampal abnormalities. https://doi.org/10.1101/2021.06.30.450398

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