Early life stress decreases cell proliferation and the number of putative adult neural stem cells in the adult hypothalamus

Abstract

Stress is a potent environmental factor that can confer potent and enduring effects on brain structure and function. Exposure to stress during early life (ELS) has been linked to a wide range of consequences later in life. In particular, ELS exerts lasting effects on neurogenesis in the adult hippocampus, suggesting that ELS is a significant regulator of adult neural stem cell numbers and function. Here, we investigated the effect of ELS on cell proliferation and the numbers of neural stem/precursor cells in another neurogenic region: the hypothalamus of adult mice. We show that ELS has long-term suppressive effects on cell proliferation in the hypothalamic parenchyma and reduces the numbers of putative hypothalamic neural stem/precursor cells at 4 months of age. Specifically, ELS reduced the number of PCNA + cells present in hypothalamic areas surrounding the 3rd ventricle with a specific reduction in the proliferation of Sox2+/Nestin-GFP + putative stem cells present in the median eminence at the base of the 3rd ventricle. Furthermore, ELS reduced the total numbers of β-tanycytes lining the ventral 3rd ventricle, without affecting α-tanycyte numbers in more dorsal areas. These results are the first to indicate that ELS significantly reduces proliferation and β-tanycyte numbers in the adult hypothalamus, and may have (patho)physiological consequences for metabolic regulation or other hypothalamic functions in which β-tanycytes are involved.

LAY SUMMARY

• We show for the first time, long-lasting effects of exposure to early life stress on cellular plasticity in the hypothalamus of adult mice.

• Stress in the first week of life resulted in reduced numbers of (proliferating) stem cells in specific subregions of the hypothalamus at an adult age.

• This loss of stem cells and decreased proliferation highlights how early life stress can affect hypothalamic functions in later life.

Keywords:

• Early life stress
• hypothalamus
• neural stem cell
• neurogenesis
• tanycyte
• metabolism

Acknowledgments

We acknowledge the assistance of Ronald Breedijk and Mark Hink at the Leeuwenhoek Centre for Advanced Microscopy, University of Amsterdam for providing technical assistance with the confocal microscope.

Disclosure statement

The authors declare that they have no conflict of interest.

Additional information

Funding

The experimental work was financed by grants from the Innovational Research Incentives Scheme VIDI 864.09.016 from the Netherlands organization for Scientific Research (NWO), the International Foundation for Alzheimer’s Research (ISAO), Alzheimer Nederland and ERA-NET-NEURON EJTC 2016 grant to CPF. A.K. is supported by JPI CogniPlast, Nederlands Organisatie voor Wetenschappelijk Onderzoek (NWO)-Meervoud, and an NWO Food, Cognition, and Brain Grant. PJL is supported by Alzheimer Nederland, and the Urban Mental Health program of the University of Amsterdam.

Notes on contributors

Pascal Bielefeld

Pascal Bielefeld is a neuroscience PostDoc at the university of Amsterdam, currently at Babraham Institute, Cambridge, United Kingdom.

Maralinde R. Abbink

Maralinde R. Abbink is a neuroscience PhD candidate at the university of Amsterdam, currently at Novartis Netherlands.

Anna R. Davidson

Anna R. Davidson is a neuroscience undergrad student at the university of Amsterdam, currently at Solentim, United Kingdom.

Niels Reijner

Niels Reijner is a neuroscience undergrad student at the university of Amsterdam.

Oihane Abiega

Oihane Abiega is a neuroscience PostDoc at the university of Amsterdam.

Paul J. Lucassen

Paul J. Lucassen is a professor of brain plasticity at the university of Amsterdam.

Aniko Korosi

Aniko Korosi is an associate professor in neuroscience at the university of Amsterdam.

Carlos P. Fitzsimons

Carlos P. Fitzsimons is an assistant professor in neuroscience at the university of Amsterdam.