Adult vitamin D deficiency disrupts hippocampal-dependent learning and structural brain connectivity in BALB/c mice

  • Md. Mamun Al-Amin
  • Robert K. P. Sullivan
  • Nyoman D. Kurniawan
  • Thomas H. J. BurneEmail author
Original Article


Converging evidence from human and animal studies support an association between vitamin D deficiency and cognitive impairment. Previous studies have shown that hippocampal volume is reduced in adults with vitamin D deficiency as well as in a range of disorders, such as schizophrenia. The aim of the current study was to examine the effect of adult vitamin D (AVD) deficiency on hippocampal-dependent spatial learning, and hippocampal volume and connectivity in healthy adult mice. Ten-week-old male BALB/c mice were fed a control (vitamin D 1500 IU/kg) or vitamin D-depleted (vitamin D 0 IU/kg) diet for a minimum of 10 weeks. The mice were then tested for hippocampal-dependent spatial learning using active place avoidance (APA) and on tests of muscle and motor coordination (rotarod and grip strength). The mice were perfused and brains collected to acquire ex vivo structural and diffusion-weighted images using a 16.4 T MRI scanner. We also performed immunohistochemistry to quantify perineuronal nets (PNNs) and parvalbumin (PV) interneurons in various brain regions. AVD-deficient mice had a lower latency to enter the shock zone on APA, compared to control mice, suggesting impaired hippocampal-dependent spatial learning. There were no differences in rotarod or grip strength, indicating that AVD deficiency did not have an impact on muscle or motor coordination. AVD deficiency did not have an impact on hippocampal volume. However, AVD-deficient mice displayed a disrupted network centred on the right hippocampus with abnormal connectomes among 29 nodes. We found a reduction in PNN positive cells, but no change in PV, centred on the hippocampus. Our results provide compelling evidence to show that AVD deficiency in otherwise healthy adult mice may play a key role in hippocampal-dependent learning and memory formation. We suggest that the spatial learning deficits could be due to the disruption of right hippocampal structural connectivity.


Vitamin D Hippocampus Memory Connectome Perineuronal nets (PNNs) 



This research was supported by the National Health and Medical Research Council grant APP1070081 to TB and a University of Queensland International PhD Scholarship to MA. We thank the Queensland Government and Australian Federal Government for funding and operational support of the 16.4T NMR spectrometer through the QLD NMR Network (QNN) and the National Imaging Facility (NIF).

Compliance with ethical standards

Informed consent

Not applicable.

Ethical approval

All experiments conformed to The University of Queensland’s Animal Welfare Unit guidelines for animal use in research and was approved by the University of Queensland Animal Ethics Committee (QBI/376/15).

Conflict of interest

The authors have no conflict of interests to declare.

Ethical statement

All work was carried out in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes under the guidelines of the National Health and Medical Research Council of Australia.

Supplementary material

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Queensland Brain InstituteThe University of QueenslandBrisbaneAustralia
  2. 2.Centre for Advanced ImagingThe University of QueenslandBrisbaneAustralia
  3. 3.Queensland Centre for Mental Health ResearchWacolAustralia

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