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

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 μg/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-γ) 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-1α, TNF-α, 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.HighlightsObesogenic diet consumption during adolescence induces anxiety-like behaviors before the onset of obesity-related changes in metabolism.Obesogenic diet-driven abnormal behaviors co-occurred with alterations in hippocampal pro-inflammatory cytokine profiles.Obesogenic diet consumption attenuates exogenous NRG1 effects on hippocampal-related behaviors and structure.Exogenous NRG1 administration during adolescence resulted in reduced hippocampal volumes and domain-specific cognitive impairments.Exogenous NRG1 administration has potent immunomodulatory actions and alters hippocampal microglia morphology.