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 longterm 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.

Association of Parental Famine Exposure With Offspring Depression and Cognition Function

“…There is evidence that malnutrition during pregnancy is associated with poorer cognitive function in the offspring ( 9 ). Studies in rodents have shown that increasing risk of cognitive disorder is associated with perinatal malnutrition through structural, functional, and molecular changes in brain development ( 10 ). Additionally, malnutrition in an individual during the fetal period and even in the early stages of life is also a risk factor for depression.…”

Enriquecimento ambiental concomitante ao estresse crônico imprevisível induz comportamento tipo-ansioso e diminui a expressão do fator neurotrófico derivado do cérebro (BDNF) no córtex pré-frontal de camundogos.

“…Em contrapartida, a exposição ao EA melhora parâmetros moleculares e comportamentais em modelos de estresse, como má nutrição perinatal (ALBERCA et al, 2020;BERARDINO et al, 2019), estresse por imobilização ou contenção (ASHOKAN;HEGDE;MITRA, 2016;BHAGYA et al, 2017;MARIANNO;ABRAHAO;CAMARINI, 2017;MORADI-KOR et al, 2019;NOVAES et al, 2017;SHILPA et al, 2017) e separação ou privação materna (FRANCIS et al, 2002;MENEZES et al, 2020).…”