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

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 2

Maternal HFD negatively affects neuron development in the midbrain SN dopaminergic circuitry.

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Maternal HFD negatively affects neuron development in the midbrain SN do...
(A) Reference for midbrain substructure anatomical location. Labeling of DA neurons in the SN and VTA using TH as a marker followed by binarization of the signal for analysis in (B) CC and (C) CH offspring. (D) Reference for nigrostriatal tract anatomical location. Additional IHC labeling in the nigrostriatal tract of (E) CC and (F) CH offspring. Quantification of the intensity of staining in the (G) SN pars reticulata (white oval in B) and corresponding (H) nigrostriatal tract (white box in E; n = 6–9 per diet group). Scale bars: 500 μm. *P < 0.05, and **P < 0.01, 2-sided Student’s t test. RMC, red magnocellular nucleus; PBP, parabrachial pigmented nucleus; PIF, parainterfascicular nucleus; ml, medial lemniscus; 3n, oculomotor nerve; cp, cerebral peduncle; SNCD, substantia nigra, compact part; SNR, substantia nigra, reticular part; SNL, substantia nigra, lateral part; f, fornix; ns, nigrostriatal tract; mfb, medial forebrain bundle; EP, entopeduncular nucleus; opt, optic tract; sox, supraoptic decussation.