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

Autor: Cayla M. Duffy, Tammy A. Butterick, J. J. Hofmeister, Joshua P. Nixon
Rok vydání: 2018
Předmět:
Genetically modified mouse
Male
medicine.medical_specialty
Cognitive Neuroscience
Saturated fat
Experimental and Cognitive Psychology
Mice
Transgenic
Diet
High-Fat
Neuroprotection
Hippocampus
050105 experimental psychology
Article
03 medical and health sciences
Behavioral Neuroscience
0302 clinical medicine
Memory
Orexin Receptors
Internal medicine
mental disorders
medicine
Animals
0501 psychology and cognitive sciences
Cognitive Dysfunction
Obesity
Cognitive decline
Ataxin-3
Neuroinflammation
Orexins
business.industry
05 social sciences
Neurodegeneration
digestive
oral
and skin physiology
medicine.disease
Orexin
Mice
Inbred C57BL
Endocrinology
nervous system
Ataxin
Encephalitis
business
Neuroscience
psychological phenomena and processes
hormones
hormone substitutes
and hormone antagonists
030217 neurology & neurosurgery
Zdroj: Neurobiology of learning and memory. 157
ISSN: 1095-9564
Popis: 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 0.05, reduced avoidances p 0.0001). Mice were then placed on HFD (45% total fat, 31.4% saturated fat) or remained on normal chow (NC; 4% total fat and 1% saturated fat), and TWAA was retested at 2 and 4 weeks. Learning impairment was evident at both 2 and 4 weeks in O/A3 mice fed HFD for following diet exposure vs. WT mice on normal chow or HFD (increased escapes, reduced avoidances p 0.05). Additionally, O/A3 mice had increased gene expression of the microglial activation marker Iba-1 (measured via qRT-PCR, p 0.001). Further characterization of the microglial immune response genes in hippocampal tissue revealed a significant increase in CX3 chemokine receptor 1 (CX3CR1), tumor necrosis factor-alpha (TNF-α) and the mitochondria-associated enzyme immune responsive gene-1 (Irg1). Collectively, our results indicate that orexin loss impairs memory, and that HFD accelerates hippocampus-dependent learning deficits and the onset of neuroinflammation.
Databáze: OpenAIRE
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