{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:39:45Z","timestamp":1779237585696,"version":"3.51.4"},"reference-count":95,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UNC Greensboro Health and Human Sciences Research Grant and Faculty First Award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Consuming a high-fat diet (HFD) has been linked to gene expression alterations and negative behavior changes. The aim of this study was to evaluate the impact of a HFD on behavior and gene expression in the hippocampi of male and female mice from different strains to evaluate sex and genetic differences. C57BL\/6J (B6J) and DBA\/2J (D2J) mice were randomly assigned to either a control diet containing 10% kcal fat or a HFD containing 60% kcal fat for 16 weeks. Behavior was measured using the open field test for anxiety, nestlet shredding for general welfare, and novel object recognition for memory. Alpha synuclein (\u03b1SYN), amyloid precursor protein (APP), and brain-derived neurotrophic factor (BDNF) mRNA expression was assessed. The HFD led to reduced nestlet shredding for male B6J mice exclusively. There was a significant main effect of sex for fecal boli within the B6J strain and higher levels of fecal boli only for HFD male B6Js. No difference in memory was found in either strain. Significant three-way interactions between diet, sex, and strain for mRNA expression of aSYN and APP were found. However, the simple main effect of diet was only significant in the male B6J strain, revealing a 7-fold upregulation of hippocampal \u03b1SYN expression and 10-fold upregulation of APP in the HFD group compared to the control diet group. Although there was a significant strain by sex interaction effect for BDNF expression, there was no effect of diet on either strain. Overall, the HFD treatment impacted male B6J mice the greatest. This study demonstrates that biological sex and genetic factors should be considered when examining the impact of diet on behavior and the brain.<\/jats:p>","DOI":"10.3390\/ijms26189241","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T13:04:44Z","timestamp":1758546284000},"page":"9241","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["High-Fat Diet Alters Behavior and Hippocampal Gene Expression"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8922-8719","authenticated-orcid":false,"given":"Melissa S.","family":"Totten","sequence":"first","affiliation":[{"name":"Chemistry, Biochemistry, and Nutrition Program, Salem College, Winston-Salem, NC 27101, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2188-3379","authenticated-orcid":false,"given":"Ava L.","family":"Peterson","sequence":"additional","affiliation":[{"name":"Chemistry, Biochemistry, and Nutrition Program, Salem College, Winston-Salem, NC 27101, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derek M.","family":"Pierce","sequence":"additional","affiliation":[{"name":"Department of Nutrition, University of North Carolina Greensboro, Greensboro, NC 27412, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1031-1489","authenticated-orcid":false,"given":"Keith M.","family":"Erikson","sequence":"additional","affiliation":[{"name":"Department of Nutrition, University of North Carolina Greensboro, Greensboro, NC 27412, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"114225","DOI":"10.1016\/j.physbeh.2023.114225","article-title":"High-Fat-Sugar Diet Is Associated with Impaired Hippocampus-Dependent Memory in Humans","volume":"268","author":"Atak","year":"2023","journal-title":"Physiol. 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