Mouse maternal protein restriction during preimplantation alone permanently alters brain neuron proportion and adult short-term memory

Abstract

Maternal protein malnutrition throughout pregnancy and lactation compromises brain development in late gestation and after birth, affecting structural, biochemical, and pathway dynamics with lasting consequences for motor and cognitive function. However, the importance of nutrition during the preimplantation period for brain development is unknown. We have previously shown that maternal low-protein diet (LPD) confined to the preimplantation period (Emb-LPD) in mice, with normal nutrition thereafter, is sufficient to induce cardiometabolic and locomotory behavioral abnormalities in adult offspring. Here, using a range of in vivo and in vitro techniques, we report that Emb-LPD and sustained LPD reduce neural stem cell (NSC) and progenitor cell numbers at E12.5, E14.5, and E17.5 through suppressed proliferation rates in both ganglionic eminences and cortex of the fetal brain. Moreover, Emb-LPD causes remaining NSCs to up-regulate the neuronal differentiation rate beyond control levels, whereas in LPD, apoptosis increases to possibly temper neuron formation. Furthermore, Emb-LPD adult offspring maintain the increase in neuron proportion in the cortex, display increased cortex thickness, and exhibit short-term memory deficit analyzed by the novel-object recognition assay. Last, we identify altered expression of fragile X family genes as a potential molecular mechanism for adverse programming of brain development. Collectively, these data demonstrate that poor maternal nutrition from conception is sufficient to cause abnormal brain development and adult memory loss.

Age dependent effects of protein restriction on dopamine release

“…In humans, protein deficiency and a low protein diet are associated with muscle wasting, stunted growth and increased vulnerability to infections, but may also, to some extent, contribute to obesity by generally increasing appetite [2][3][4]. Furthermore, protein deficiency and severe protein malnutrition are especially detrimental during development and early life when demand is highest [5][6][7]. Numerous species, including humans and rodents, regulate their food intake and food-related behaviors to avoid protein deficiency [8][9][10][11][12][13].…”

Ontogeny and programming of the fetal temporal cortical endocannabinoid system by moderate maternal nutrient reduction in baboons ( Papio spp.)

“…; Gould et al. ; Sinclair ). The window of fetal brain susceptibility to nutritional insult remains an open question in relation to interaction between periconceptual nutrition and offspring neurological development (Sinclair ).…”

Maternal programming by hypoxia alters the molecular composition of the oviduct of her offspring, the first pathway her grandchildren will transit: a potential novel pathway for intergenerational programming?

“…The critical importance of the periconceptional period for normal development has been elegantly shown in a mouse model of low protein diet by Fleming and colleagues (Gould et al . ). The model they have used involves the provision of either a normal protein diet – 18% casein throughout pregnancy – or a low protein, 9% casein diet restricted to 3.5 days from breeding, followed by a normal protein diet.…”

“…F1 offspring of mice on the short term, periconceptional low protein diet show adverse cardiovascular, locomotor and brain development and memory in adulthood (Gould et al . ). In addition to the importance of the observations in increasing the breadth and depth of understanding of adverse effects of fetal hypoxia, this study continues the work by this research group that links programming to premature ageing (Niu et al .…”