title: Memory and hippocampal architecture following short-term midazolam in western diet-treated rats.
abstract: The impact of short-term benzodiazepine exposure on cognition in middle-aged or older patients is a highly debated topic among anesthesiologists, critical care physicians and public media. "Western diet" (WD) consumption is linked to impaired cognition as well. The combination of benzodiazepines with substantial exposure to WD might set the stage for increased hippocampal vulnerability for benzodiazepines leading to exaggerated cognitive impairment in the postoperative period. In this study, Fischer 344 rats were fed either WD or standard rodent diet from 5 to 10.5 months of age. Rats were exposed to midazolam or placebo two days prior to an MRI scan using Diffusional Kurtosis Imaging (DKI) to assess brain microstructural integrity, followed by behavioral testing using a water radial arm maze. Hippocampal tissue was collected to assess alterations in protein biochemistry in brain regions associated with learning and memory. Our results showed that rats exposed to the combination of midazolam and WD had significantly delayed time of learning and exhibited spatial memory impairment. Further, we observed an overall increase of kurtosis metrics in the hippocampus and increased expression of the mitochondrial protein VDAC2 in midazolam-treated rats. Our data suggest that both the short-acting benzodiazepine midazolam and WD contribute to negatively affect the brain in middle-aged rats. This study is the first application of DKI on the effects of midazolam and WD exposure, and the findings demonstrate that diffusion metrics are sensitive indicators of changes in the complexity of neurite architecture.
authors.affiliation: Department of Anesthesiology, University of Utah School of Medicine, Salt Lake City, UT 84132, United States. Electronic address: dorothea.rosenberger@hsc.utah.edu.
authors.forename: Dorothea S
authors.initials: DS
authors.lastname: Rosenberger
authors.affiliation: Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC 29425, United States; Center for Biomedical Imaging, Medical University of South Carolina, Charleston, SC 29425, United States; Department of Neuroscience and the Center on Aging, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Falangola
authors.affiliation: Department of Neuroscience and the Center on Aging, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ledreux
authors.affiliation: Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC 29425, United States; Center for Biomedical Imaging, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Xingju
authors.initials: X
authors.lastname: Nie
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, 98195, United States.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Suhre
authors.affiliation: Department of Neuroscience and the Center on Aging, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Boger
authors.affiliation: Department of Neuroscience and the Center on Aging, Medical University of South Carolina, Charleston, SC 29425, United States; Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, United States.
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Granholm
mesh_terms: D000367:Age Factors; D000777:Anesthetics / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D066273:Diet, Western / Q000009:adverse effects*; D038524:Diffusion Magnetic Resonance Imaging; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050152:Intra-Abdominal Fat / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D008874:Midazolam / Q000009:adverse effects*; D009929:Organ Size / Q000187:drug effects; D011916:Rats, Inbred F344; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism; D050996:Voltage-Dependent Anion Channel 2 / Q000378:metabolism
chemical_list: D000777:Anesthetics; C494764:Vdac1 protein, rat; C494767:Vdac2 protein, rat; D050996:Voltage-Dependent Anion Channel 2; D050995:Voltage-Dependent Anion Channel 1; D008874:Midazolam
keywords: Diffusional kurtosis imaging; Midazolam; Spatial memory; Western diet