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Maternal high-fat diet during lactation reprograms the dopaminergic circuitry in mice
R.N. Lippert, … , P. Kloppenburg, J.C. Brüning
R.N. Lippert, … , P. Kloppenburg, J.C. Brüning
Published June 8, 2020
Citation Information: J Clin Invest. 2020;130(7):3761-3776. https://doi.org/10.1172/JCI134412.
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Research Article Development Neuroscience

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

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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 5

CH male offspring, and not females, exhibit hyperlocomotive behavior.

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CH male offspring, and not females, exhibit hyperlocomotive behavior.
(A...
(A–D) Representative tracking of animals in the OFT in a (A) CC male (n = 32), (B) CH male (n = 24), (C) CC female (n = 31), and (D) CH female (n = 31). Quantification of ambulatory episodes (E), jump counts (F), rearing events (I), and stereotypic behaviors (J) in CC (circles) versus CH (squares) males at 6 months of age. Quantification of ambulatory episodes (G), jump counts (H), rearing events (K), and stereotypic behaviors (L) in CC (circles) versus CH (squares) females at 6 months of age. (M–T) Chemogenetic activation of young animals at 8 to 10 weeks of age tracked over time after CNO injection at t = 0′ followed by AUC analysis of the second hour (n = 9–15 per diet/genotype/sex, combination of at least 2 different experimental rounds). Vertical counts in males over time (M) and in the second hour (N). Vertical counts in females over time (O) and in the second hour (P). Ambulatory episodes in males over time (Q) and in the second hour (R). Ambulatory episodes in females over time (S) and in the second hour (T). Locomotive behavior in 6-month-old CC versus CH males (U) and females (W) with repeated daily exposure to the OFT. EZM total distance traveled in male (V) and female (X) animals (n = 7–15 per diet/sex/genotype; results indicate a combination of at least 2 separate experiments). *P < 0.05, **P < 0.01, and ***P < 0.001, Student’s t test (E–L) as well as a mixed effects analysis (M, O, Q, and S) or 2-way ANOVA (N, P, R, T, V, X, U, and W with repeated measures).

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