Depletion of dietary phytoestrogens reduces hippocampal plasticity and contextual fear memory stability in adult male mouse

ABSTRACT

Introduction: Phytoestrogens are non-steroidal estrogen analogues and are found primarily in soy products. They have received increasing attention as dietary supplements for estrogen deficiency and as modulators of endogenous estrogen functions, including cognition and emotion. In addition to modifying the levels of circulating sex hormones, phytoestrogens also exert direct effects on estrogen and androgen receptors in the brain and thus effectively modulate the neural circuit functions.

Objective: The aim of this study was to investigate the long-term effects of low phytoestrogen intake (∼6 weeks) on the hippocampal plasticity and hippocampus-dependent memory formation in the adult C57BL/6 male mice.

Methods and Results: In comparison to mice on a diet with normal phytoestrogen content, mice on low phytoestrogen diet showed a significant reduction in the phosphorylation of NR2B subunit, a molecular correlate of plasticity in the Schaffer collateral-CA1 synapse. We observed a profound decrease in long-term potentiation (LTP) in the ventral hippocampus, whereas no effect on plasticity was evident in its dorsal portion. Furthermore, we demonstrated that acute perfusion of slices with an estrogen analogue equol, an isoflovane metabolized from daidzein produced by the bacterial flora in the gut, was able to rescue the observed LTP deficit. Examining potential behavioral correlates of the plasticity attenuation, we found that mice on phytoestrogen-free diet display decreased contextual fear memory at remote but not at recent time points after training.

Conclusions: Our data suggests that nutritional phytoestrogens have profound effects on the plasticity in the ventral hippocampus and ventral hippocampus-dependent memory.

KEYWORDS:

• Phytoestrogens
• equol
• NR2B
• contextual fear memory
• synaptic plasticity
• LTP
• LTD
• ventral hippocampus
• dorsal hippocampus

Acknowledgements

We are grateful to A. Koffi von Hoff, F. Blitz and S. Stork for excellent technical assistance and to A. Deter, A. Bohnstedt and D. Al-Chackmakchie for excellent animal care.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethical approval

All experiments were conducted in accordance with the European and German regulations for animal experiments and were approved by the local authorities (Permission Nr. 203.h-42502-2-887 OvGMD).

Additional information

Funding

The work was supported by grants from the German Research foundation [grant numbers STO488/6 and CRC779/B05 to OS] and CBBS ScienceCampus funded by the Leibniz Association to GC [grant number SAS-2015-LIN-LWC]. DFG.

Notes on contributors

Gürsel Çalışkan

Gürsel Çalışkan is a postdoctoral researcher at the Institute of Biology, Otto-von-Guericke-University Magdeburg, Germany. He received his doctoral degree at the Charité University Medicine Berlin, Germany. His research interests are hippocampal network oscillations and synaptic plasticity in mouse models of fear and anxiety.

Syed Ahsan Raza

Syed Ahsan Raza is a postdoctoral researcher at the Institute of Biology, Otto-von-Guericke-University Magdeburg, Germany and he received his doctoral degree at the same University. His scientific interests circulate around brain circuits involved in different forms of memories in rodents especially fear and fear related disorders.

Yunus E. Demiray

Yunus E. Demiray is a graduate student at the Institute of Biology, Otto-von-Guericke-University Magdeburg, Germany. He studies how extracellular matrix and cytoskeleton dynamics interact and affect neuronal differentiation by using molecular and pharmacological interventions.

Emre Kul

Emre Kul is a graduate student at the Institute of Biology, Otto-von-Guericke-University Magdeburg, Germany. His research encompasses behavioral and biochemical approaches to investigate progression and intervention time-windows of the phenotypes and the pathology associated with mouse models of neurodegenerative diseases.

Kiran V. Sandhu

Kiran V. Sandhu is a postdoctoral researcher at the APC Microbiome Ireland, University College Cork, Ireland. She received her doctoral degree at the Institute of Biology, Otto-von-Guericke-University Magdeburg, Germany. In her research she uses behavioral and molecular approaches to investigate the mechanisms that mediate gut-brain interactions in health and disease.

Oliver Stork

Oliver Stork is Professor for Molecular Neurobiology at the Institute of Biology, Otto-von-Guericke-University Magdeburg, Germany. He received his doctoral degree in Neurobiology at the Swiss Federal Technical University in Zürich. His research is devoted to the molecular and circuit mechanisms of memory formation and their involvement in mental disorders.