Aspartame and the hippocampus: Revealing a bi-directional, dose/time-dependent behavioural and morphological shift in mice

Neurobiol Learn Mem. 2017 Mar;139:76-88. doi: 10.1016/j.nlm.2016.12.021. Epub 2016 Dec 31.


Changes, in behaviour, oxidative markers of stress and hippocampal morphology were evaluated following aspartame administration. Mice, (20-22g each) were given vehicle (10ml/kg) or aspartame (20, 40, 80 and 160mg/kg) daily for 28days. They were tested in the Y-maze, radial-arm maze and elevated plus-maze (EPM) after the first and last dose of vehicle or aspartame; and then sacrificed. Hippocampal slices were analysed for aspartic acid, nitric oxide (NO) and superoxide dismutase (SOD); and processed for general histology and neuritic plaques. Glial fibrillary-acid protein (GFAP) expression and neuron-specific enolase (NSE) activities were determined. Radial-arm maze scores increased significantly after acute administration at 80 and 160mg/kg. Repeated administration at 20 and 40mg/kg (Y-maze) and at 40mg/kg (radial-arm maze) was also associated with increased scores, however, performance decreased at higher doses. EPM tests revealed anxiogenic responses following both acute and repeated administration. Significant increase in SOD and NO activities were observed at 40, 80 and 160mg/kg. Neuron counts reduced at higher doses of aspartame. At 40, 80 and 160mg/kg, fewer GFAP-reactive astrocytes were observed in the cornus ammonis, but increased GFAP-reactivity was observed in the dentate gyrus subgranular zone. NSE-positive neurons were readily identifiable within the dentate gyrus at the lower doses of aspartame; but at 160mg/kg, there was marked neuron loss and reduction in NSE-positive neurons. Oral aspartame significantly altered behaviour, anti-oxidant status and morphology of the hippocampus in mice; also, it may probably trigger hippocampal adult neurogenesis.

Keywords: Adult neurogenesis; Anatomy; Memory; Neurobehaviour; Non-nutritive sweetener; Oxidative stress.

MeSH terms

  • Animals
  • Anxiety / metabolism
  • Aspartame / administration & dosage*
  • Aspartic Acid / metabolism
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Behavior, Animal / drug effects*
  • Cell Count
  • Dose-Response Relationship, Drug
  • Glial Fibrillary Acidic Protein / metabolism
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Male
  • Maze Learning / drug effects*
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism
  • Nitric Oxide / metabolism
  • Oxidative Stress / drug effects*
  • Phosphopyruvate Hydratase / metabolism
  • Superoxide Dismutase / metabolism
  • Sweetening Agents / administration & dosage*


  • Glial Fibrillary Acidic Protein
  • Sweetening Agents
  • Aspartic Acid
  • Nitric Oxide
  • Superoxide Dismutase
  • Phosphopyruvate Hydratase
  • Aspartame