Perinatal protein malnutrition results in genome-wide disruptions of 5-hydroxymethylcytosine at regions that can be restored to control levels by an enriched environment

ABSTRACT

Maternal malnutrition remains one of the major adversities affecting brain development and long-term mental health outcomes, increasing the risk to develop anxiety and depressive disorders. We have previously shown that malnutrition-induced anxiety-like behaviours can be rescued by a social and sensory stimulation (enriched environment) in male mice. Here, we expand these findings to adult female mice and profiled genome-wide ventral hippocampal 5hmC levels related to malnutrition-induced anxiety-like behaviours and their rescue by an enriched environment. This approach revealed 508 differentially hydroxymethylated genes associated with protein malnutrition and that several genes (N = 34) exhibited a restored 5hmC abundance to control levels following exposure to an enriched environment, including genes involved in neuronal functions like dendrite outgrowth, axon guidance, and maintenance of neuronal circuits (e.g. Fltr3, Itsn1, Lman1, Lsamp, Nav, and Ror1) and epigenetic mechanisms (e.g. Hdac9 and Dicer1). Sequence motif predictions indicated that 5hmC may be modulating the binding of transcription factors for several of these transcripts, suggesting a regulatory role for 5hmC in response to perinatal malnutrition and exposure to an enriched environment. Together, these findings establish a role for 5hmC in early-life malnutrition and reveal genes linked to malnutrition-induced anxious behaviours that are mitigated by an enriched environment.

KEYWORDS:

• 5-hydroxymethylcytosine
• perinatal Malnutrition
• enriched Environment
• anxiety
• ventral Hippocampus
• epigenetics
• neuronal Development

Acknowledgments

This work was supported by the Agencia Nacional de Promoción Científica y

Tecnológica, Argentina (Grants PICT-2013-0653 EC and PICT 2016-0218 MC), Universidad de Buenos Aires (Grant UBACYT20020130100011) (EC), CONICET (PIP 2015-2017 N°11220150100175CO) (MC), University of Wisconsin-Madison department of Neurological Surgery (RSA), NARSAD Young Investigator Grant from the Brain & Behavioral Research Foundation #22669 (LP), and a Ruth L. Kirschstein National Research Service Award (MH113351-02) (AM). The authors would like to thank the University of Buenos Aires for granting a fellowship for short-stay abroad (CA), which facilitated the collaboration.

Disclosure statement

No potential conflict of interest was reported by the authors.

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Funding

This work was supported by the Agencia Nacional de Promoción Científica y Tecnológica [PICT-2013-0653]; Agencia Nacional de Promoción Científica y Tecnológica [PICT 2016-0218]; Brain and Behavior Research Foundation [22669]; National Institute of Mental Health [MH113351-02]; Consejo Nacional de Investigaciones Cientifi y Tecnicas (argentina) [PIP 2015-2017 N°11220150100175CO]; School of Medicine and Public Health, University of Wisconsin-Madison; Universidad de Buenos Aires [UBACYT20020130100011].