Spatial memory impairment and changes in hippocampal morphology are triggered by high-fat diets in adolescent mice. Is there a role of leptin?

Neurobiol Learn Mem. 2013 Nov;106:18-25. doi: 10.1016/j.nlm.2013.06.012. Epub 2013 Jun 29.


Recent evidence has established that consumption of high-fat diets (HFD) is associated with deficits in hippocampus-dependent memory. Adolescence is an important period for shaping learning and memory acquisition that could be particularly sensitive to the detrimental effects of HFD. In the current study we have administered this kind of diets to both adolescent (5-week old) and young adult (8-week old) male C57BL mice during 8 weeks and we have evaluated its effect on (i) spatial memory performance in the novel location recognition (NLR) paradigm, and (ii) spine density and neural cell adhesion molecule (NCAM) expression in hippocampal CA1 pyramidal neurons. In order to characterize the eventual involvement of central leptin receptors we have also investigated the functionality of leptin receptors within the hippocampus. Here we report that animals that started to consume HFD during the adolescence were less efficient than their control counterparts in performing spatial memory tasks. In contrast to that, mice that were submitted to HFD during the young adult period displayed intact performance in the NLR test. In mice receiving HFD from the adolescence, the behavioral impairment was accompanied by an increase of dendritic spine density in CA1 pyramidal neurons that correlated with the up-regulation of neural cell adhesion molecule (NCAM) in this area. Deficits in spatial memory occurred concomitantly with a desensitization of the proteinkinase B (Akt) pathway coupled to hippocampal leptin receptors. In contrast, the STAT3 pathway remained unaffected by HFD. All effects of HFD were long-lasting because they remained intact even after 5 weeks of food restriction. Our results provide further evidence of the susceptibility of the hippocampus to HFD in adolescent individuals and suggest that leptin signaling integrity in this brain area is pivotal for memory performance.

Keywords: Dendritic spine density; High-fat diet; Leptin resistance; Spatial memory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Blood Glucose
  • CD56 Antigen / metabolism
  • Dendritic Spines / drug effects
  • Dendritic Spines / metabolism
  • Diet, High-Fat*
  • Dietary Fats / metabolism
  • Dietary Fats / pharmacology*
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Leptin / blood
  • Male
  • Maze Learning / drug effects*
  • Mice
  • Pyramidal Cells / drug effects*
  • Pyramidal Cells / metabolism
  • Receptors, Leptin / metabolism*


  • Blood Glucose
  • CD56 Antigen
  • Dietary Fats
  • Leptin
  • Ncam1 protein, mouse
  • Receptors, Leptin