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 8

Electrophysiological consequences in response to maternal HFD in D1 MSNs and changes to neuron development in D2 MSNs pinpoint overall imbalance in dorsal striatum circuitry.

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Electrophysiological consequences in response to maternal HFD in D1 MSNs...
(A) Representative electrophysiological trace and current clamp of D1 MSN. (B) Left: representative image of a D1 MSN in white. Scale bar: 50 μm. Right: accompanying images showing dsred labeling of TdTomato signal (top), DAT staining (middle) and the overlay of the 2 (bottom). Scale bar: 20 μm. (C) Recording from CC and CH D1 MSNs at baseline showing decreased membrane potential and increased spontaneous firing in CH D1 MSNs. (D) Membrane potential in CC (n = 20) versus CH (n = 22) D1 MSNs. (E) Percentage of spontaneously firing D1 MSNs. (F) Comparison of 2 different current injections in CC and CH males. (G) Quantification of mean AP frequency with increasing current injection in CC versus CH males. (H) Comparison of 2 different current injections in CC and CH females. (I) Quantification of mean AP frequency with increasing current injection in CC versus CH females. (J) Whole brain imaging in CC versus CH animals using the DRD1TOM. (K) Quantification of staining in J in CC (n = 4) versus CH (n = 3) animals. SN, substantia nigra; Str, striatum; GPex, external globus pallidus; GPin, internal globus pallidus. (L) Whole brain imaging in CC versus CH animals using Adora2aTOM. (M) Quantification of staining in L in CC (n = 3) versus CH animals (n = 3). GP, globus pallidus; VP, ventral pallidum. Analysis of current injection was performed using a sigmoidal Boltzmann fit for both data sets to determine curve fit. *P < 0.05, and ****P < 0.001, Fisher exact test (D), F test (E), or 2-way ANOVA with Bonferroni’s post hoc analysis (K and M).