High fat diet increases cognitive decline and neuroinflammation in a model of orexin loss

• Published in: Neurobiology of learning and memory 2019-01, Vol.157, p.41-47
• Main Authors: Duffy, C.M., Hofmeister, J.J., Nixon, J.P., Butterick, T.A.
• Format: Article
• Language: English
• Subjects: Animals; Ataxin-3 - genetics; Ataxin-3 - physiology; Cognitive Dysfunction - etiology; Cognitive Dysfunction - physiopathology; Diet, High-Fat; Encephalitis - etiology; Encephalitis - physiopathology; High fat diet; Hippocampus - physiopathology; Male; Memory - physiology; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Neuroinflammation; Obesity; Obesity - complications; Obesity - physiopathology; Orexin Receptors - metabolism; Orexins - genetics; Orexins - physiology; Two-way active avoidance memory task
• ISSN: 1074-7427; 1095-9564
• DOI: 10.1016/j.nlm.2018.11.008

•We tested interaction between diet and cognition in a mouse model of orexin loss.•Mice lacking orexin showed significant impairments in cognition vs. wild-type mice.•Mice were placed on high-fat diet (HFD) and cognition was tested at 2 and 4 weeks.•HFD-fed mice lacking orexin had impaired cognition and high microglial activation.•Our results show orexin loss and HFD synergistically impact cognitive deficits. Midlife obesity is a risk factor for cognitive decline and is associated with the earlier onset of Alzheimer’s disease (AD). Diets high in saturated fat potentiate the onset of obesity, microglial activation, and neuroinflammation. Signaling deficiencies in the hypothalamic peptide orexin and/or orexin fiber loss are linked to neurodegeneration, cognitive impairment, and neuroinflammation. Prior studies show that orexin is neuroprotective, suppresses neuroinflammation, and that treatment with orexin improves cognitive processes in orexin/ataxin-3 (O/A3) mice, a transgenic mouse model of orexin neurodegeneration. Our overall hypothesis is that loss of orexin contributes to high fat diet (HFD)-induced hippocampal neuroinflammation and cognitive decline. To examine this, we tested male O/A3 mice (7–8 mo. of age) in a two-way active avoidance (TWAA) hippocampus-dependent memory task. We tested whether (1) orexin loss impaired cognitive function; (2) HFD worsened cognitive impairment; and (3) HFD increased microglial activation and neuroinflammation. O/A3 mice showed significant impairments in TWAA task learning vs. wild type (WT) mice (increased escapes p