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Neurotensin neurons in the extended amygdala control dietary choice and energy homeostasis

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Abstract

Obesity is a global pandemic that is causally linked to many life-threatening diseases. Apart from some rare genetic conditions, the biological drivers of overeating and reduced activity are unclear. Here, we show that neurotensin-expressing neurons in the mouse interstitial nucleus of the posterior limb of the anterior commissure (IPAC), a nucleus of the central extended amygdala, encode dietary preference for unhealthy energy-dense foods. Optogenetic activation of IPACNts neurons promotes obesogenic behaviors, such as hedonic eating, and modulates food preference. Conversely, acute inhibition of IPACNts neurons reduces feeding and decreases hedonic eating. Chronic inactivation of IPACNts neurons recapitulates these effects, reduces preference for sweet, non-caloric tastants and, furthermore, enhances locomotion and energy expenditure; as a result, mice display long-term weight loss and improved metabolic health and are protected from obesity. Thus, the activity of a single neuronal population bidirectionally regulates energy homeostasis. Our findings could lead to new therapeutic strategies to prevent and treat obesity.

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Fig. 1: IPACNts neurons are activated by palatable food in vivo.
Fig. 2: IPACNts neurons encode the hedonic value of a tastant.
Fig. 3: IPACNts neurons encode the hedonic value of an odor.
Fig. 4: Activation of IPACNts neurons regulates dietary choices.
Fig. 5: Inhibition and inactivation of IPACNts neurons both disrupt feeding.
Fig. 6: Inactivation of IPACNts neurons protects from obesity and ameliorates metabolic syndrome.
Fig. 7: IPACNts neurons send output and receive input to and from brain regions involved in energy homeostasis.

Data availability

All data are contained in the main text, Extended Data or Supplementary Information. Source data are provided with this paper.

Code availability

Custom code is available on GitHub at https://github.com/Alefurlan/IPACpaper.

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Acknowledgements

We thank T. Russo for technical assistance and members of the Li laboratory for helpful discussions. This work was supported by grants from EMBO (ALTF 458–2017, A.F.), the Swedish Research Council (2017-00333, A.F.), the Charles H. Revson Senior Fellowship in Biomedical Science (19–23, A.F.), the National Institutes of Health (R01MH101214, R01MH108924, R01DA050374 and R01NS104944, B.L.), the Cold Spring Harbor Laboratory and Northwell Health Affiliation (B.L.), the Feil Family Neuroscience Endowment (B.L.) and the German Academic Scholarship Foundation (E.C.G.).

Author information

Authors and Affiliations

Authors

Contributions

A.F. and B.L. conceived and designed the study. A.F. conducted the experiments and analyzed data. A.C. assisted with the photometry experiments with food odors and the data analysis. S. Boyle set up behavioral rigs and generated MATLAB code for controlling behavioral devices and analyzing photometry data. R.S. assisted with the smFISH experiments. R.R. and J.H. assisted with operating the metabolic cages. E.C.G. assisted with the GTT and ITT experiments. R.S. and E.C.G. collected tissue samples and performed quantitative PCR experiments. J.G. assisted with the EPM and OF experiments. S. Beyaz provided critical reagents. T.J. supervised the experiments by E.C.G. and assisted with interpreting metabolic data. S.D.S. supervised the experiments by A.C. and assisted with analyzing and interpreting the data. A.F. and B.L. wrote the paper with input from all authors.

Corresponding authors

Correspondence to Alessandro Furlan or Bo Li.

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Competing interests

The authors declare no competing interests.

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Nature Neuroscience thanks Roger Adan, Alexander Nectow, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 IPACNts neurons encode the hedonic value of a stimulus.

(a) Schematics showing the locations of optic fiber placement in the mice used in Figs. 2 and 3. (b) Feeding behavior of mice when presented with HFD (green) or chow (orange), for 20 minutes, in food restricted (FR, left) or sated condition (right). N = 8. Group effect: F(1,7)=95.19, p < 0.0001, **p < 0.01; ****p < 0.0001; Two-way RM ANOVA, Sidak’s test. (c, d) Schematics of the experimental setup (c) and task structure (d) used in Fig. 2. Bottom panel: representative raster plot showing licking behavior following liquid delivery. (e) Drinking behavior of wild-type mice when presented with Intralipid 0.5% (Fat 0.5%, green) or water (orange), in a 2-bottle preference test, for 72-h, in sated condition. N = 6 mice. ***P = 0.0003, paired t-test. (f-h) Food-restricted (FR) mice (f) and water-restricted (WR) mice (g, h) were presented with equal volumes of liquids in the same session. Left: Area under the curve (AUC) of GCAMP6f signals. Right: licking behavior (behavior) of mice. AUC and licking behavior were measured in a 3-s window following the first lick. Paired t-tests, n = 5 mice/group in all panels. (f) Sucrose (green) or sucralose (orange); AUC: p = 0.1071 (n.s.); Behavior: *p = 0.0462. (g) Monosodium glutamate (MSG, green) or water (orange); AUC: p = 0.3008 (n.s.); Behavior: p = 0.7061 (n.s.). (h) Citric acid (green) or water (orange); AUC: p = 0.1997 (n.s.); Behavior: p = 0.8677 (n.s.).

Source data

Extended Data Fig. 2 Response of IPACNts neurons to odors from several diets.

(a, b) Heatmaps of the response of IPACNts neurons in individual mice to odors derived from different food sources, under sated or food-restricted condition, as indicated. Dashed lines indicate the onset of odor presentation. (c) Average GCaMP6f signals from IPACNts neurons in food-restricted mice aligned to the presentation of different odors (dashed line). (d) Area under the curve (AUC) of the responses in individual mice in (c) in a 3-s window following odor presentation. N = 4 mice. F(3,9)=10.36, p = 0.0028; *p < 0.05, **p < 0.01, n.s., p > 0.05; one-way RM ANOVA, Holm-Sidak’s test. (e) Average GCaMP6f signals from IPACNts neurons in sated mice aligned to odor presentation (dashed line). (f) Area under the curve (AUC) of the responses in individual mice in (e) in a 3-s window following odor presentation. N = 5 mice. F(3,12)=5.169, p = 0.0160; *p < 0.05, p > 0.05 (n.s); one-way RM ANOVA, Holm-Sidak’s test.

Source data

Extended Data Fig. 3 Characterization of behavioral effects following activation of IPACNts neurons.

(a) Optic fiber placement for mice in Fig. 4. (b) Effect of photostimulation of IPACNts neurons in mice fed dark chocolate (DCh), chow, sucrose, HFD, white chocolate (WCh). ChR2 (n = 9) or GFP (n = 6) for DCh, ChR2 (n = 9) or GFP (n = 8) for chow, sucrose, HFD, WCh. Two-way RM ANOVA, Sidak’s test. DCh, group effect: F(1,13)=7.374, p = 0.0177; chow, group effect: F(1,15)=8.999, p = 0.0090; sucrose, group effect: F(1,15)=7.829, p = 0.0135; HFD, group effect: F(1,15)=21.22, p = 0.0003; WCh, group effect: F(1,15)=22.56, p = 0.0003. (c) Effect of photostimulation of IPACNts neurons in mice presented with an inedible pencil eraser. ChR2 (n = 9) or GFP (n = 6). two-way RM ANOVA, Sidak’s test. Gnawing, interaction effect: F(2,26)=4.939, p = 0.0152; intake: F(2,26)=1.066, p = 3591 (n.s.). ****p < 0.0001; p > 0.05(n.s.). (d, e) Photostimulation of IPACNts neurons increased the number (d) and the duration (e) of feeding bouts in ChR2 (n = 9) but not GFP mice (n = 7). (d) GFP: *p = 0.0465, ChR2: **p = 0.0028; (e) GFP: p = 0.0982(n.s.), ChR2: ***p = 0.0007, paired t-test. (f) Effect of photostimulation of IPACNts neurons in ChR2 mice fed quinine-flavored or plain chow pellets (n = 5). Interaction effect: F(2,8)=9.476, p = 0.0078, **p < 0.01, two-way RM ANOVA, Sidak’s comparisons test. (g) Effect of photostimulation of IPACNts neurons on liquid consumption (control for Fig. 4e). GFP mice (n = 5), interaction effect: F (4, 16)=1.119, p = 0.3820 (n.s.). Two-way RM ANOVA. (h) Self-stimulation paradigm (left) and quantification of the poking responses of ChR2 (n = 9) and GFP mice (n = 8). Group effect: F(1,15)=37.63, p < 0.0001; ****p < 0.0001; p > 0.05 (n.s.), two-way RM ANOVA, Sidak’s test. (i) Distance traveled in the RTPP/A task. ChR2 (n = 11) and GFP (n = 8) mice. Group effect: F(1,17)=34.11, p < 0.0001; ****p < 0.0001; p > 0.05 (n.s.), two-way RM ANOVA, Sidak’s test. (j) Distance traveled in the open field test. ChR2 (n = 8) and GFP (n = 6) mice. Group effect: F(1,12)=17.30, p = 0.0013; ****p < 0.0001; p > 0.05 (n.s.) two-way RM ANOVA, Sidak’s test.

Source data

Extended Data Fig. 4 Inactivation of IPACNts neurons impairs hedonic perception.

(a) HFD intake over a 2-h period in sated NtsCre mice expressing mCherry (gray, control) or KORD (red) injected with DMSO or SalB. mCherry mice, n = 7; KORD mice, n = 5. paired t-test. Cherry DMSO-SaLB: p = 0.7748, (n.s.); KORD DMSO-SaLB: p = 0.1066 (n.s.). Paired t-test.(b) Percentage change of HFD intake in food-restricted mice expressing mCherry (gray, control) or KORD (red) when injected with SaLB, normalized to their intake when injected with DMSO, within 30 minutes from food presentation. mCherry mice, n = 7; KORD mice, n = 5. *p = 0.0326. Unpaired t-test. (c) Daily water intake of the GFP mice (n = 10) and TeLC mice (n = 8) fed chow. p = 0.8023 (n.s.), unpaired t-test. (d) Daily water intake of the GFP mice (n = 10) and TeLC mice (n = 8) fed HFD. *p = 0.0305, unpaired t-test. (e) Schematic of the 2-bottle preference test (left) for sucralose (center) and sucrose (right). Sucralose: GFP mice (n = 5), TeLC mice (n = 5): **p = 0.0055, unpaired t-test. Sucrose: GFP mice (n = 6); TeLC mice (n = 5); p = 0.6488 (n.s.), unpaired t-test. Legend: L, left bottle, R, right bottle. (f) Comparison of energy intake from chow and HFD diets (derived from Fig. 5i and j). GFP (n = 10): ****p < 0.0001; TeLC mice (n = 8): p = 0.3562 (n.s.); paired t-test. (g) Change in energy intake after the switch from chow to HFD. ***P = 0.0002, unpaired t-test.

Source data

Extended Data Fig. 5 Inactivation of IPACNts neurons has positive metabolic effects.

(a) Changes in body weight (BW) following injection (d0). GFP mice (n = 11): F(3, 30)=6.588, p = 0.0015; **p < 0.01; ***p < 0.001; TeLC mice (n = 10): F(3, 27)=28.11, p < 0.0001; ****p < 0.0001, p > 0.05 (n.s.); one-way RM ANOVA, Sidak’s test. (b) Volume of carbon dioxide produced (VCO2) by GFP (n = 10) and TeLC mice (n = 8). Group effect: F(1, 16)=5.745, p = 0.0291, two-way RM ANOVA. (c) Average carbon dioxide production (VCO2) of the mice in (b). GFP (n = 10); TeLC (n = 8). Group effect: F(1, 16)=5.603, p = 0.0309; *p < 0.05, p > 0.05 (n.s.); two-way RM ANOVA, Sidak’s test. (d) Respiratory exchange ratio (RER) of GFP (n = 10) and TeLC mice (n = 8). Interaction effect: F(70,1120) = 5.042, p < 0.0001, two-way RM ANOVA. (e) Average RER of GFP (n = 10) and TeLC mice (n = 8) fed chow. Interaction effect: F(1, 16)=7.546, *p = 0.0143; two-way RM ANOVA, Sidak’s test. (f) Average energy expenditure of GFP (n = 10) and TeLC mice (n = 8) fed HFD. Group effect: F(1, 16)=6.526, p = 0.0212; *p < 0.05, n.s., p > 0.05; two-way RM ANOVA, Sidak’s test. (g) Average oxygen consumption (VO2) of GFP (n = 10) and TeLC mice (n = 8) fed HFD. Group effect: F(1, 16)=6.066, *p = 0.0255, p > 0.05 (n.s.); two-way RM ANOVA, Sidak’s test. (h) Average carbon dioxide production (VCO2) of GFP (n = 10) and TeLC mice (n = 8) fed HFD. Group effect: F(1, 16)=5.276, *p = 0.0355, p > 0.05 (n.s.); two-way RM ANOVA, Sidak’s test. (i) Average locomotor activity of GFP (n = 10) and TeLC mice (n = 8) fed HFD. Group effect: F(1,16)=25.21, p < 0.0001; ****p < 0.0001, p > 0.05 (n.s.), two-way RM ANOVA, Sidak’s test.

Source data

Extended Data Fig. 6 Network of IPACNts neurons.

(a) Representative images of brain areas innervated by IPACNts (green) and mBSTNts (red) neurons. Scale bar: 100 μm. STLV: ventral lateral division of the BNST; STMA: anterior medial division; VP: ventral pallidum; CPu: caudate putamen; IPAC: interstitial nucleus of the posterior limb of the anterior commissure (aca); LC: locus coeruleus; PBN: parabrachial nu.; CeA: central amygdala; BLA: basolateral amygdala; PAG: periacqueductal gray; DR: dorsal raphe. (b) Representative image of smFISH for Nts on retrograde labelled CT-B+ neurons in the IPAC. The square in the image show the high-magnification area showed in Fig. 7h (right). Scale bar: 100 μm. (c) Schematics showing the locations of optic fiber placement in the mice used in Fig. 7. (d) Effect of light delivery into the IPAC of the ChR2 (n = 9) or GFP (n = 5) mice on gnawing (left) and consumption (right) of inedible items (that is, pencil eraser). Gnawing (group effect): F(1,12)=11.51, p = 0.0053, two-way RM ANOVA, Sidak’s test. ****p < 0.0001. Intake: (group effect): F(1,12)=0.5327, p = 4783, two-way RM ANOVA. (e) Preference of ChR2 (n = 8) and GFP mice (n = 6) for the left chamber side. Interaction effect: F(2,24)=125.1; p < 0.0001; ****p < 0.0001; p > 0.05 (n.s.). Two-way RM ANOVA, Sidak’s test.

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Furlan, A., Corona, A., Boyle, S. et al. Neurotensin neurons in the extended amygdala control dietary choice and energy homeostasis. Nat Neurosci 25, 1470–1480 (2022). https://doi.org/10.1038/s41593-022-01178-3

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