Abstract
The maternal perinatal environment modulates brain formation, and altered maternal nutrition has been linked to the development of metabolic and psychiatric disorders in the offspring. Here, we showed that maternal high-fat diet (HFD) feeding during lactation in mice elicits long-lasting changes in gene expression in the offspring's dopaminergic circuitry. This translated into silencing of dopaminergic midbrain neurons, reduced connectivity to their downstream targets, and reduced stimulus-evoked dopamine (DA) release in the striatum. Despite the attenuated activity of DA midbrain neurons, offspring from mothers exposed to HFD feeding exhibited a sexually dimorphic expression of DA-related phenotypes, i.e., hyperlocomotion in males and increased intake of palatable food and sucrose in females. These phenotypes arose from concomitantly increased spontaneous activity of D1 medium spiny neurons (MSNs) and profoundly decreased D2 MSN projections. Overall, we have unraveled a fundamental restructuring of dopaminergic circuitries upon time-restricted altered maternal nutrition to induce persistent behavioral changes in the offspring.
Highlights
Rates of obesity and overweight far surpass underweight, with the prevalence of obesity in females exceeding that of males in all adult age categories [1]
Maternal high-fat diet (HFD) permanently reprograms the mRNA profile of midbrain DA neurons
In order to study the effect of maternal diet on brain development, we used a previously developed maternal dietary manipulation paradigm to expose WT animals to an HFD during the lactation period [9]
Summary
Rates of obesity and overweight far surpass underweight, with the prevalence of obesity in females exceeding that of males in all adult age categories [1]. We show that maternal HFD exposure during lactation is sufficient to elicit distinct changes in gene expression in key dopaminergic circuits of the offspring, genes affecting neuronal development, ion channel expression, and locomotor behavior This translates into disturbed firing and silencing in a large proportion of DA midbrain neurons, reduced functional connectivity to their downstream target sites, and reduced stimulus-evoked DA release in the striatum. Despite reduced DA neuron activity, their reduced connectivity, and decreased DA release in their target sites, offspring from mothers exposed to HFD feeding during lactation exhibited elevation in DA-related behaviors, namely hyperlocomotion in males and increased intake of palatable food and sucrose in females These phenotypes result from concomitant direct changes in downstream medium spiny neurons (MSNs). We have uncovered a fundamental and permanent restructuring of basal ganglia circuitry in response to HFD insult during early postnatal development
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