Maternal high-fat diet during lactation reprograms the dopaminergic circuitry in mice
R.N. Lippert, S. Hess, P. Klemm, L.M. Burgeno, T. Jahans-Price, M.E. Walton, P. Kloppenburg, J.C. Brüning
R.N. Lippert, S. Hess, P. Klemm, L.M. Burgeno, T. Jahans-Price, M.E. Walton, P. Kloppenburg, J.C. Brüning
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Research Article Development Neuroscience

Maternal high-fat diet during lactation reprograms the dopaminergic circuitry in mice

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.

Authors

R.N. Lippert, S. Hess, P. Klemm, L.M. Burgeno, T. Jahans-Price, M.E. Walton, P. Kloppenburg, J.C. Brüning

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Figure 1

Maternal HFD alters metabolic profile and causes changes to dopaminergic circuitry.

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Maternal HFD alters metabolic profile and causes changes to dopaminergic...
(A and B) Body weight at P21 in (A) male control diet–exposed (CC, n = 49) and HFD-exposed mice during lactation (CH, n = 31) and (B) female CC (n = 47) and CH (n = 43) offspring with or without HFD exposure during the lactation period. (C and D) Body weight in (C) CC versus CH males and (D) females through adulthood (n = 10–34/diet/sex/genotype/time point). (E) Body fat in CC versus CH males and females. (F) Strategy for midbrain dissection of VTA and SN tissue and subsequent RNA-sequencing pipeline (n = 5–6 mice per diet/sex/brain region). (G) Volcano plots depicting significantly regulated genes in the male SN and female SN. (H) Volcano plots depicting significantly regulated genes in the male VTA and female VTA. Significance after correction for multiple testing plotted as log10 of the Q value versus fold change over CC control group (full description of analysis pipeline in Methods section). (I) Significantly affected genes in males and females and overlapping genes. (J) Heatmap of top 100 overlapping genes shows high similarity between sexes of the same diet groups and dissimilarities between diet groups. (K) GO analysis of top hits in molecular function, cellular component, and biological function. (L) Tree map clustering GO terms based on common themes; square size indicates the absolute log of the P value (larger = more significant). *P < 0.05, and ****P < 0.0001, 2-sided Student’s t test (A, B, and E [female]), Welch’s t test (E [male], due to differences in variances), or mixed-effects analysis with repeated measures (C and D) and also with Bonferroni’s post hoc analysis.