Iron and n-3 fatty acid depletion, alone and in combination, during early development provoke neurochemical changes, anhedonia, anxiety and social dysfunction in rats

ABSTRACT

Objectives: Both iron and omega-3 (n-3) fatty acids (FA) play important roles in the development and functioning of the brain. We investigated the effects of n-3 FA and iron deficiencies, alone and in combination, during early development on behaviour and brain monoamines in rats. Methods: Using a 2-factorial design, female Wistar rats were randomly allocated to one of four diet groups: Control, n-3 FA deficient (n-3 FAD), iron deficient (ID), or n-3 FAD + ID. Females received these diets throughout mating, pregnancy and lactation. Offspring (n = 24/group; male:female = 1:1) continued on the same diet until post-natal day 42–45, and underwent a sucrose preference test (SPT), novel object recognition test, elevated plus maze (EPM) and social interaction test (SIT). Results: ID offspring consumed less sucrose in the SPT and spent more time in closed arms and less time in open arms of the EPM than non-ID offspring. In female offspring only, ID and n-3 FAD reduced time approaching and together in the SIT, with an additive effect of ID and n-3 FAD for even less time approaching and spent together in the n-3 FAD + ID group compared to controls. ID offspring had higher striatal dopamine and norepinephrine and lower frontal cortex dopamine concentrations. N-3 FAD and ID affected frontal cortex serotonin concentrations in a sex-specific manner. Conclusions: Our results suggest that ID and n-3 FAD during early development provoke anhedonia, anxiety and social dysfunction in rats, with potential additive and attenuating effects when combined. These effects may in part be attributed to disturbances in brain neurochemistry and may be sex-specific.

KEYWORDS:

• Social behaviour
• anxious behaviour
• cognition
• early development
• iron deficiency
• monoamines
• n-3 fatty acid deficiency
• psychiatric comorbidity

Acknowledgements

We would like to thank the personnel of the North-West University Vivarium (Mr Cor Bester, Mr Kobus Venter and Mrs Antoinette Fick) for their assistance with executing the animal study. Furthermore, we would like to thank Dr Estelle Venter, Ms Mamokete Pule, Ms PJ Alley and Mrs Laetitia Jordaan for their help during the execution of the animal study. We thank Mrs Cecile Cooke and Dr Adriaan Jacobs for their assistance with the laboratory analyses. The authors would also like to acknowledge Prof DeWet Wolmarans and Dr Marisa Möller-Wolmarans for their valuable advice and training in the setting up and refinement of the Noldus Software and related behavioural protocols. C.M.S., J.B. and B.H.H. conceptualised and designed the study; E.T.K., J.B. and L.Z. supervised and executed the animal experimental procedures; E.T.K. and L.Z. supervised and performed the laboratory analyses; E.T.K., L.Z. and J.B. analysed the data; B.H.H advised on the behavioural tests used; all authors assisted in the interpretation of results; E.T.K., L.Z. and J.B. wrote the paper. All authors reviewed and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The authors declare that all data associated with the current study are available from the corresponding author upon reasonable request.

Additional information

Funding

Financial support for this study was provided by the National Research Foundation (NRF), South Africa [CPRR13090934565].

Notes on contributors

Erna T. Kemp

Erna T. Kemp is a Doctor of Philosophy (Ph.D.) candidate at the Centre of Excellence for Nutrition of the North-West University in Potchefstroom, South Africa. Her Ph.D. focuses on the neurodevelopmental effects of maternal iron and omega-3 fatty acid deficiency and depletion, alone and in combination, in the offspring.

Lizelle Zandberg

Lizelle Zandberg is a Senior Lecturer at the Centre of Excellence for Nutrition of the North-West University in Potchefstroom, South Africa. Her research is in the field of molecular nutrition where she studies the underlying molecular mechanisms of fatty acids and micronutrients as role players in neuro- and immune competence, using rodent models, and human intervention and observational studies.

Brian H. Harvey

Brian H. Harvey is a Professor at the Centre of Excellence for Pharmaceutical Sciences of the North-West University in Potchefstroom, South Africa, and programme leader in preclinical research at the South African Medical Research Council’s Unit on Risk and Resilience in Mental Disorders at the Department of Psychiatry and the Neuroscience Institute of the University of Cape Town in Cape Town, South Africa, and an Honorary Professor at the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia. Brian employs translational rodent and zebra fish models to study the neurobiological basis of risk and resilience in human psychiatric disorders and uses these models as research platforms for novel drug development.

Cornelius M. Smuts

Cornelius M. Smuts is a Professor in Nutrition and the Director of the Centre of Excellence for Nutrition of the North-West University in Potchefstroom, South Africa. His research focuses on the effects of omega-3 fatty acids on maternal outcomes, the interactions between omega-3 fatty acids and micronutrients on cognition, behaviour and immune function, as well as different nutritional intervention strategies to improve infant growth and development.

Jeannine Baumgartner

Jeannine Baumgartner is a Lecturer in Nutritional Sciences at King’s College London and holds an honorary appointment as Extraordinary Associate Professor in Nutrition at the Centre of Excellence for Nutrition of the North-West University in Potchefstroom, South Africa. Currently, her research focuses on studying the role of micronutrients and omega-3 fatty acids in the development and functioning of the brain, bones, immune system, and gut microbiome in animal models, and human intervention and observational studies.