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Medial prefrontal D1 dopamine neurons control food intake

Abstract

Although the prefrontal cortex influences motivated behavior, its role in food intake remains unclear. Here, we demonstrate a role for D1-type dopamine receptor–expressing neurons in the medial prefrontal cortex (mPFC) in the regulation of feeding. Food intake increases activity in D1 neurons of the mPFC in mice, and optogenetic photostimulation of D1 neurons increases feeding. Conversely, inhibition of D1 neurons decreases intake. Stimulation-based mapping of prefrontal D1 neuron projections implicates the medial basolateral amygdala (mBLA) as a downstream target of these afferents. mBLA neurons activated by prefrontal D1 stimulation are CaMKII positive and closely juxtaposed to prefrontal D1 axon terminals. Finally, photostimulating these axons in the mBLA is sufficient to increase feeding, recapitulating the effects of mPFC D1 stimulation. These data describe a new circuit for top-down control of food intake.

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Figure 1: Characterization of prefrontal neurons activated during feeding.
Figure 2: Physiological responses to prefrontal D1 photoactivation.
Figure 3: Prefrontal D1 photostimulation leads to increased food intake.
Figure 4: Photoinhibition of prefrontal D1 neurons reduces food intake.
Figure 5: Prefrontal D1 neurons project to and activate the mBLA.
Figure 6: Photostimulation of prefrontal D1 terminals in the mBLA increases intake.

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Acknowledgements

We thank X. Sun and C. Calarco for experimental assistance. This work was supported by R01DK098994 (R.J.D.), F32DK091172 (B.B.L.), and the State of Connecticut Department of Mental Health and Addiction Services (R.J.D.).

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Authors and Affiliations

Authors

Contributions

B.B.L., N.S.N. and R.J.D. conceived the study; B.B.L., N.S.N., R.-J.L., C.A.G. and G.K.A. conducted the experiments and analyzed the data; C.E.B., D.M.G., M.S., D.J.G. and K.D. provided viral constructs and genotyping support; B.B.L., N.S.N. and R.J.D. wrote the manuscript.

Corresponding author

Correspondence to Ralph J DiLeone.

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Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Validation of Drd1a-cre+ neurons using immunohistochemistry.

(a) Left, Nucleus accumbens stained for dopamine D1R (green); Right, overlay with Cre (red). Cre+ nuclei are only present within the D1 immunofluorescent area (scale bar = 100 μm). (b) Left, medial prefrontal cortex stained for D1R; Right, overlay with Cre. Outlines demark border of high versus low D1 fluorescence. White arrowheads denote example nuclei positive for Cre. (scale bar = 50 μm) (c) The percentage of Cre+ nuclei of the entire field for both high and low D1 immunoreactivity (n = 3 animals; High = 17.7 ± 0.7; Low = 2.7 ± 1.8, mean ± s.e.m.).

Supplementary Figure 2 Broad field of Cre and Fos immunoreactive nuclei in the mPFC of Drd1a-cre+ animals.

(a) Cre (green), Fos (red), and overlay in control, non-deprived animals. (b) Cre, Fos, and overlay in food deprived animals re-fed for 90 min (scale bar = 100 μm).

Supplementary Figure 3 Characterization of ChR2 and electrophysiological properties of D1-negative neurons.

(a) ChR2/eYFP expression in the mPFC of a Drd1a-cre+ animal after viral injection. (b) No expression was seen in Drd1a-cre- animals (scale bar = 100μm). (c) Micrograph of filled, D1-negative neuron in a Drd1a-cre+ animal (scale bar = 60μm). (d) Physiological properties of a D1-negative neuron in response to depolarizing and hyperpolarizing currents. There is both voltage sag (red arrow) and rebound depolarization (blue).

Supplementary Figure 4 Responses by hour for overnight feeding paradigm.

(a) Responses by hour during the “Light” epoch for Drd1a-cre+ and Drd1a-cre- animals. (b) Responses by hour during the “No-Light” epoch. (c) Summed responses during the on/off light periods during the “Light” epoch for Drd1a-cre+ animals (n = 6 animals, t5 = 2.0, P = 0.094, 2-tailed, paired t-test; On = 101.5 ± 9.5 s.e.m.; Off = 88.8 ± 12.4, mean ± s.e.m.). (d) Ratio of the responses during the on/off light periods during the “Light” epoch for Drd1a-cre+ animals. There is a 20% increase when the laser is on.

Supplementary Figure 5 Characterization of behavioral responses during photoactivation.

(a) Quantification of cage crosses throughout the 30 minutes of the ‘light’ period for Drd1a-cre+ animals. Note that there are no large increases or decreases in activity as a function of light, but a general decrease in activity over time. (b) Total activity counts show no differences over the illumination period (n = 4, t3 = 0.3, P = 0.77, 2-tailed, paired t-test; On = 32.3± 5.8; Off = 34.0± 7.6, mean ± s.e.m.). (c) Amount of a palatable, high-fat diet consumed during the overnight feeding paradigm (n = 4,5 animals; t7 = 2.4, P = 0.045, 2-tailed t-test; Cre- = 4.3± 0.1; Cre+ = 4.6± 0.1, mean ± s.e.m.). (d) Proportion of licks during the Light and No Light epochs for animals in the high-fat overnight feeding paradigm. Dashed line represents chance (0.5, n = 4 animals, t3 = 1.0, P = 0.38, 2-tailed, paired t-test; No-Light = 0.43± 0.15; Light = 0.57± 0.15, mean ± s.e.m.). (e) Proportion of nose-pokes into a non-reinforced port for high fat animals (n = 4 animals, t3 = 3.2, P = 0.05, 2-tailed, paired t-test; No-Light = 0.64± 0.8; Light = 0.36± 0.8, mean ± s.e.m.).

Supplementary Figure 6 Inhibition of prefrontal D1 neurons decreases illuminated, but not total intake.

(a) Normalized pellet consumption in food restricted Drd1a-cre+ and Drd1a-cre- animals during four, 15-min off/on cycles of yellow (590 nm) light. (b) Total amount of pellets consumed in the food restricted test (n = 4,4, t6 = 0.4, P = 0.76, 2-tailed t-test; Cre+ = 34.0± 2.0; Cre- = 35.3± 3.4, mean ± s.e.m.).

Supplementary Figure 7 D1 PFC axons project to several nuclei.

Dense projections to both the dorso-medial striatum (a) and medial nucleus accumbens (NAc, b) were observed in all animals. Less dense projections innervated the lateral hypothalamus (c) (scale bar = 500μm). (d) Overlays of ChR2/eYFP (green) and Fos (red) in Drd1a-cre+ and Drd1a-cre- animals (scale bar = 100μm). (e) Quantification of Fos-positive nuclei in the NAc of Drd1a-cre+ and Drd1a-cre− animals (n = 6,3 animals, F(1,6) = 1.0, P = 0.35, genotype factor, 2-way ANOVA).

Supplementary Figure 8 Fos nuclei in mBLA after PFC photostimulation of Drd1a-cre+ animals are localized to CaMKII neurons.

(a) Confocal micrographs of CaMKII (green), Fos (red), and overlay. Arrowheads denote neurons containing both Fos and CaMKII (scale bar = 100μm). (b) Fluorescent micrographs of PV (green), Fos, and overlay. Arrowhead denotes overlap of PV with Fos.

Supplementary Figure 9 Lack of lateralized Fos in the mPFC of mBLA-stimulated Drd1a-cre+ animals.

The lack of difference in activity between ipsilateral and contralateral sides suggests that there is little antidromic activation of the PFC (n = 3 animals, t4 = 0.7, P = 0.53, 2-tailed, t-test; Ipsi = 99.6± 10.7; Contra = 89.6± 10.3, mean ± s.e.m.).

Supplementary Figure 10 Locomotor activity after blue and yellow co-illumination in mBLA.

The lack of difference in corner explorations over the five, 30 s sessions suggests there is little effect of yellow light on freezing behavior (n = 3 animals, F(4,16) = 0.5, P = 0.759, 2-Way ANOVA, interaction of session x light).

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Land, B., Narayanan, N., Liu, RJ. et al. Medial prefrontal D1 dopamine neurons control food intake. Nat Neurosci 17, 248–253 (2014). https://doi.org/10.1038/nn.3625

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