Susceptibility of Female Mice to the Dietary Omega-3/Omega-6 Fatty-Acid Ratio: Effects on Adult Hippocampal Neurogenesis and Glia

Int J Mol Sci. 2022 Mar 21;23(6):3399. doi: 10.3390/ijms23063399.


Maternal intake of omega-3 (n-3 PUFAs) and omega-6 (n-6 PUFAs) polyunsaturated fatty acids impacts hippocampal neurogenesis during development, an effect that may extend to adulthood by altering adult hippocampal neurogenesis (AHN). The n-3 PUFAs and n-6 PUFAs are precursors of inflammatory regulators that potentially affect AHN and glia. Additionally, n-3 PUFA dietary supplementation may present a sexually dimorphic action in the brain. Therefore, we postulated that dietary n-6/n-3 PUFA balance shapes the adult DG in a sex-dependent manner influencing AHN and glia. We test our hypothesis by feeding adult female and male mice with n-3 PUFA balanced or deficient diets. To analyze the immunomodulatory potential of the diets, we injected mice with the bacterial endotoxin lipopolysaccharide (LPS). LPS reduced neuroblast number, and its effect was exacerbated by the n-3 PUFA-deficient diet. The n-3 PUFA-deficient diet reduced the DG volume, AHN, microglia number, and surveilled volume. The diet effect on most mature neuroblasts was exclusively significant in female mice. Colocalization and multivariate analysis revealed an association between microglia and AHN, as well as the sexual dimorphic effect of diet. Our study reveals that female mice are more susceptible than males to the effect of dietary n-6/n-3 PUFA ratio on AHN and microglia.

Keywords: LPS; adult neurogenesis; bacterial endotoxin lipopolysaccharide; dentate gyrus; diet; microglia; omega 3; polyunsaturated fatty acids; sexual dimorphism; systemic inflammation.

MeSH terms

  • Animals
  • Diet
  • Fatty Acids, Omega-3* / pharmacology
  • Fatty Acids, Omega-6* / pharmacology
  • Fatty Acids, Unsaturated / pharmacology
  • Female
  • Hippocampus
  • Lipopolysaccharides / toxicity
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microglia
  • Neurogenesis


  • Fatty Acids, Omega-3
  • Fatty Acids, Omega-6
  • Fatty Acids, Unsaturated
  • Lipopolysaccharides