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The gut–brain axis mediates sugar preference

April 2020
Nature 580(7804):1-6

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The taste of sugar is one of the most basic sensory percepts for humans and other animals. Animals can develop a strong preference for sugar even if they lack sweet taste receptors, indicating a mechanism independent of taste1–3. Here we examined the neural basis for sugar preference and demonstrate that a population of neurons in the vagal ganglia and brainstem are activated via the gut–brain axis to create preference for sugar. These neurons are stimulated in response to sugar but not artificial sweeteners, and are activated by direct delivery of sugar to the gut. Using functional imaging we monitored activity of the gut–brain axis, and identified the vagal neurons activated by intestinal delivery of glucose. Next, we engineered mice in which synaptic activity in this gut-to-brain circuit was genetically silenced, and prevented the development of behavioural preference for sugar. Moreover, we show that co-opting this circuit by chemogenetic activation can create preferences to otherwise less-preferred stimuli. Together, these findings reveal a gut-to-brain post-ingestive sugar-sensing pathway critical for the development of sugar preference. In addition, they explain the neural basis for differences in the behavioural effects of sweeteners versus sugar, and uncover an essential circuit underlying the highly appetitive effects of sugar.

Glucose and MDG preference a, When mice are given a choice between 600 mM glucose or 600 mM MDG, using a brief-access (1 h) test, naive animals display a small preference for glucose over MDG (n = 5, two-tailed paired t-test, P = 0.0406), probably because MDG is slightly less sweet and thus not as attractive. Values are mean ± s.e.m. b, c, Although the non-caloric sugar analogue MDG is very effective in causing a preference switch (see Fig. 1), it does not cause increases in plasma glucose or release of insulin. Mice were gavaged with glucose or MDG, and plasma glucose and insulin levels were sampled before (Pre), and at 15 min after the gavage (Post). b, Plasma glucose after glucose gavage (red bars). n = 7, two-tailed paired t-test, P = 4 × 10⁻⁵. Plasma glucose after MDG gavage (blue bars). n = 6, two-tailed paired t-test, P = 0.36. c, Plasma insulin levels after glucose gavage (red bars). n = 7, two-tailed paired t-test, P = 7 × 10⁻⁶. Plasma insulin levels after MDG gavage (blue). n = 6, two-tailed paired t-test, P = 0.94. Values are mean ± s.e.m.

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Vagal neurons responding to intestinal glucose are also activated by SGLT1 agonists a, Traces of vagal neurons responding to a 10-s pulse of 500 mM intestinal glucose, also challenged with a 10-s pulse of 500 mM 3-OMG. Shown are sample neurons from 2 animals. b, Traces of vagal neurons responding to a 10-s pulse of 500 mM intestinal glucose, also challenged with a 10-s pulse of 500 mM galactose. Shown are sample neurons from two animals for expanded time scales (from Fig. 4d). c, Traces of vagal neurons responding to a 10-s pulse of 500 mM intestinal glucose, also challenged with a 10-s pulse of 500 mM fructose and 500 mM mannose. Shown are sample neurons from three mice. d, Traces of vagal neurons responding to two consecutive 10-s pulses of 500 mM intestinal glucose, before and after treating the intestinal segment with 8 mM phlorizin for 5 min. Note the loss of responses. e, Because responses, in general, show some decay during the time of the experiment (in part due to desensitizing and bleaching of the fluorescent signals), we also analysed the average decay of corresponding glucose responses in the absence of any blocker. The graphs compare the loss of responses during normal decay, and in response to the blocker. For normal decay (left), n = 11 neurons, Pre = 230.8 arbitrary units (a.u.), Post = 172.8 a.u.; for blocker (right), n = 31 neurons, Pre = 229.7 a.u., Post = 67.0 a.u. All values are mean ± s.e.m. Scale indicates average integral of the responses to the two trials before and after inhibition.

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Fos responses are robust and reliable a, The brain diagram illustrates the position of the NST and the plane of the sectioning. Shown are cNST sections stained with Fos antibodies after exposing the animals to 90 min of 600 mM sucrose, 600 mM glucose or 30 mM AceK. Each panel is a confocal maximal projection image from Bregma −7.5 mm consisting of 3 sections 15 μm apart. Each panel (sucrose, glucose or AceK) represents a different animal, n = 3 independent experiments. Note the robustness of the signals across animals. See Methods for details. b, Mice were stimulated with 600 mM 3-OMG (n = 6 mice) or 600 mM galactose (n = 3 mice) (see also Fig. 4, Extended Data Fig. 10). Note strong Fos signals in cNST neurons, n = 2 independent experiments (total of 9 mice). Scale bars, 100 μm.

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The development of sugar preference a, Glucose stimulates cNST neurons in mice lacking the sweet taste receptor (T1R2/3−/−), or in mice lacking the TRPM5 ion channel (TRPM5−/−). See Fig. 1e for quantification. T1R2/3−/−, n = 5 mice, ANOVA followed by Tukey’s HSD post hoc test, P < 0.0001; TRPM5−/−, n = 7 mice, ANOVA followed by Tukey’s HSD post hoc test, P < 0.0001. Values are mean ± s.e.m. Scale bars, 100 μm. b, Direct intragastric infusion of glucose, but not AceK, robustly activates the cNST. n = 2 independent experiments. Scale bars, 100 μm. c, d, Genetic silencing of vagal sensory neurons. c, Sugar-preference graphs for wild-type mice (n = 5 mice), demonstrating the robust development of preference for sugar versus artificial sweetener (see also Fig. 1). By contrast, silencing of the sensory neurons in the nodose ganglia, by bilateral injection of AAV-DIO-TetTox into the nodose ganglia of Vglut2-cre mice (see Methods), abolishes the development of sugar preference; n = 3 mice, two-sided Mann–Whitney U-test, P = 0.035. Values are mean ± s.e.m. d, However, silencing vagal sensory neurons does not impair the innate attraction to sweet solutions; shown are behavioural responses to AceK versus water, and glucose versus water (n = 3 animals, preference index for AceK = 0.82, preference index for glucose = 0.85). Values are mean ± s.e.m.

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Retrograde labelling from cNST a, A fluorescent retrograde tracer (red RetroBeads, Lumafluor) was stereotactically injected into the cNST to label its inputs. The nodose ganglia and dorsal root ganglia were checked for transfer of the fluorescent label after 6–7 days. The nodose ganglion (vagal neurons), but not the dorsal root ganglion (spinal neurons), was robustly labelled⁶⁰. n = 2 independent experiments. b, RetroBeads were also injected into the cuneate nucleus, a brainstem area near but distinct from the cNST. Vagal neurons were not labelled. By contrast, note robust labelling of spinal neurons (n = 2 independent experiments). Nuclei were counterstained with DAPI (blue). Scale bars, 200 μm (Brainstem), 50 μm (nodose, DRG). c, Validation of TRAPing procedure to confirm that the sugar-activated cNST neurons marked by the expression of Fos are the same as the ones labelled by Cre recombinase in the genetic TRAPing experiments. We genetically labelled the sugar-induced TRAPed neurons with a Cre-dependent fluorescent reporter⁶¹, and then performed a second cycle of sugar stimulation followed by Fos antibody labelling. d, Top, neurons labelled by the Cre-dependent reporter after sugar TRAPing (‘sugar-TRAP’, pseudocoloured red) are the same as those labelled by Fos after a second cycle of sugar stimulation (‘sugar-Fos’, green; see Methods and text for details), >80% of Sugar-Fos neurons are also sugar-TRAP positive (n = 7 animals). Middle, note that the few neurons labelled after water-TRAP in response to water do not overlap with those labelled with Fos antibodies after sugar stimulation. Bottom, the sugar-TRAP neurons are also activated by the non-caloric sugar analogue MDG; >80% of MDG-Fos are sugar-TRAP positive. Scale bar, 20 μm.

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Nature | Vol 580 | 23 April 2020 | 511

Article

The gut–brain axis mediates sugar

preference

Hwei-Ee Tan1,2,4, Alexander C. Sisti1,3,4, Hao Jin1,3, Martin Vignovich1,3, Miguel Villavicencio1,3,

Katherine S. Tsang1,3, Yossef Goffer3 & Charles S. Zuker1,3 ✉

The taste of sugar is one of the most basic sensory percepts for humans and other

animals. Animals can develop a strong preference for sugar even if they lack sweet taste

receptors, indicating a mechanism independent of taste1–3. Here we examined the

neural basis for sugar preference and demonstrate that a population of neurons in the

vagal ganglia and brainstem are activated via the gut–brain axis to create preference for

sugar. These neurons are stimulated in response to sugar but not articial sweeteners,

and are activated by direct delivery of sugar to the gut. Using functional imaging we

monitored activity of the gut–brain axis, and identied the vagal neurons activated by

intestinal delivery of glucose. Next, we engineered mice in which synaptic activity in

this gut-to-brain circuit was genetically silenced, and prevented the development of

behavioural preference for sugar. Moreover, we show that co-opting this circuit by

chemogenetic activation can create preferences to otherwise less-preferred stimuli.

Together, these ndings reveal a gut-to-brain post-ingestive sugar-sensing pathway

critical for the development of sugar preference. In addition, they explain the neural

basis for dierences in the behavioural eects of sweeteners versus sugar, and uncover

an essential circuit underlying the highly appetitive eects of sugar.

Sugar is a fundamental source of energy for all animals, and corre-

spondingly, most species have evolved dedicated brain circuits to seek,

recognize and motivate its consumption4. In humans, the recruit-

ment of these circuits for reward and pleasure—rather than nutritional

needs—is thought to be an important contributor to the overconsump-

tion of sugar and the concomitant increase in obesity rates. In the 1800s

the average American consumed less than 4.5kg of sugar per year

;

today, following the broad availability of refined sugar in consumer

products, the average consumption is more than 45kg per year6.

Sweet compounds are detected by specific taste receptor cells

on the tongue and palate epithelium7,8. Activation of sweet taste

receptor cells sends hardwired signals to the brain to elicit recogni-

tion of sweet-tasting compounds

9,10

. We and others have studied the

circuits linking activation of sweet taste receptors on the tongue to

sweet-evoked attraction

8,11,12

. Surprisingly, even in the absence of a

functional sweet-taste pathway, animals can still acquire a preference

for sugar1,2,7. Furthermore, although artificial sweeteners activate the

same sweet taste receptor as sugars, and they may do so with vastly

higher affinities

, they fail to substitute for sugar in generating a behav-

ioural preference13.

Together, these results suggested the existence of a sugar-specific,

rather than sweet-taste-specific pathway, that operates independently

of the sense of taste to create preference for sugar and motivate con-

sumption2,14. Here, we dissect the neural basis for sugar preference.

Sweet versus sugar preference

When non-thirsty, wild-type mice are given a choice between water

and sugar they drink almost exclusively from the sugar solution

. If,

however, they are allowed to choose between an artificial sweetener

(for example, acesulfame K (AceK)) and sugar, using concentrations

at which both are equally attractive, naive mice initially drink from

both bottles at a similar rate (Fig.1a). However, within 24h of expo-

sure to both choices, their preference is markedly altered, such that

by 48h, they drink almost exclusively from the bottle containing sugar

(Fig.1a, b, compare 15h with 48h). This behavioural switch also hap-

pens in knockout (KO) mice lacking sweet taste (Trpm5−/− (hereafter

TRPM5 KO)15,16 or Tas1r2−/−Tas1r3−/− (hereafter T1R2/3 KO)7; Fig.1c).

Similar observations have been made in several studies, primarily using

flavour-conditioning assays

1,2

. Thus, although taste-knockout mice

cannot taste sugar or sweetener, they learn to recognize and choose

the sugar, most probably as a result of strong positive post-ingestive

effects17.

Notably, the preference for sugar does not rely on its caloric

content18. For example, if sugar is substituted for the non-metabolizable

glucose analogue (methyl-α--glucopyranoside (MDG))19 mice still

develop a strong preference for MDG, just as they do for glucose (Fig.1b;

Extended Data Fig.1). Thus, the signalling system recognizes the sugar

molecule itself rather than its caloric content or metabolic products.

https://doi.org/10.1038/s41586-020-2199-7

Received: 12 April 2019

Accepted: 21 February 2020

Published online: 15 April 2020

Check for updates

1Zuckerman Mind Brain Behavior Institute, Howard Hughes Medical Institute and Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. 2Department

of Biological Sciences, Columbia University, New York, NY, USA. 3Department of Neuroscience, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. 4These

authors contributed equally: Hwei-Ee Tan, Alexander C. Sisti. ✉e-mail: cz2195@columbia.edu

Content courtesy of Springer Nature, terms of use apply. Rights reserved

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Aug 2017
J NEUROSCI METH

Background: Motion correction is a challenging pre-processing problem that arises early in the analysis pipeline of calcium imaging data sequences. The motion artifacts in two-photon microscopy recordings can be non-rigid, arising from the finite time of raster scanning and non-uniform deformations of the brain medium. New method: We introduce an algorithm for fast Non-Rigid Motion Correction (NoRMCorre) based on template matching. NoRMCorre operates by splitting the field of view (FOV) into overlapping spatial patches along all directions. The patches are registered at a sub-pixel resolution for rigid translation against a continuously updated template. The estimated alignments are subsequently up-sampled to create a smooth motion field for each frame that can efficiently approximate non-rigid artifacts in a piecewise-rigid manner. Existing methods: Existing approaches either do not scale well in terms of computational performance or are targeted to non-rigid artifacts arising just from the finite speed of raster scanning, and thus cannot correct for non-rigid motion observable in datasets from a large FOV. Results: NoRMCorre can be run in an online mode resulting in comparable to or even faster than real time motion registration of streaming data. We evaluate its performance with simple yet intuitive metrics and compare against other non-rigid registration methods on simulated data and in vivo two-photon calcium imaging datasets. Open source Matlab and Python code is also made available. Conclusions: The proposed method and accompanying code can be useful for solving large scale image registration problems in calcium imaging, especially in the presence of non-rigid deformations.

Chemogenetics revealed: DREADD occupancy and activation via converted clozapine

Article

Full-text available

Aug 2017

DREADD not the designer compound Designer receptors exclusively activated by designer drugs (DREADDs) constitute a powerful chemogenetic strategy that can modulate nerve cell activity in freely moving animal preparations. Gomez et al. used radioligand receptor occupancy measurements and in vivo positron emission tomography to show that DREADDs expressed in the brain are not activated by the designer compound CNO (clozapine N -oxide). Instead, they are activated by the CNO metabolite clozapine, a drug with multiple endogenous targets. This may have important implications for the interpretation of results obtained with this popular technology. Science , this issue p. 503

A Neural Circuit for Gut-Induced Reward

Article

Sep 2018
CELL

The gut is now recognized as a major regulator of motivational and emotional states. However, the relevant gut-brain neuronal circuitry remains unknown. We show that optical activation of gut-innervating vagal sensory neurons recapitulates the hallmark effects of stimulating brain reward neurons. Specifically, right, but not left, vagal sensory ganglion activation sustained self-stimulation behavior, conditioned both flavor and place preferences, and induced dopamine release from Substantia nigra. Cell-specific transneuronal tracing revealed asymmetric ascending pathways of vagal origin throughout the CNS. In particular, transneuronal labeling identified the glutamatergic neurons of the dorsolateral parabrachial region as the obligatory relay linking the right vagal sensory ganglion to dopamine cells in Substantia nigra. Consistently, optical activation of parabrachio-nigral projections replicated the rewarding effects of right vagus excitation. Our findings establish the vagal gut-to-brain axis as an integral component of the neuronal reward pathway. They also suggest novel vagal stimulation approaches to affective disorders.

A Suite of Transgenic Driver and Reporter Mouse Lines with Enhanced Brain-Cell-Type Targeting and Functionality

Article

Jul 2018

Modern genetic approaches are powerful in providing access to diverse cell types in the brain and facilitating the study of their function. Here, we report a large set of driver and reporter transgenic mouse lines, including 23 new driver lines targeting a variety of cortical and subcortical cell populations and 26 new reporter lines expressing an array of molecular tools. In particular, we describe the TIGRE2.0 transgenic platform and introduce Cre-dependent reporter lines that enable optical physiology, optogenetics, and sparse labeling of genetically defined cell populations. TIGRE2.0 reporters broke the barrier in transgene expression level of single-copy targeted-insertion transgenesis in a wide range of neuronal types, along with additional advantage of a simplified breeding strategy compared to our first-generation TIGRE lines. These novel transgenic lines greatly expand the repertoire of high-precision genetic tools available to effectively identify, monitor, and manipulate distinct cell types in the mouse brain.

Rewiring the Taste System

Article

Aug 2017

In mammals, taste buds typically contain 50-100 tightly packed taste-receptor cells (TRCs), representing all five basic qualities: sweet, sour, bitter, salty and umami. Notably, mature taste cells have life spans of only 5-20 days and, consequently, are constantly replenished by differentiation of taste stem cells. Given the importance of establishing and maintaining appropriate connectivity between TRCs and their partner ganglion neurons (that is, ensuring that a labelled line from sweet TRCs connects to sweet neurons, bitter TRCs to bitter neurons, sour to sour, and so on), we examined how new connections are specified to retain fidelity of signal transmission. Here we show that bitter and sweet TRCs provide instructive signals to bitter and sweet target neurons via different guidance molecules (SEMA3A and SEMA7A). We demonstrate that targeted expression of SEMA3A or SEMA7A in different classes of TRCs produces peripheral taste systems with miswired sweet or bitter cells. Indeed, we engineered mice with bitter neurons that now responded to sweet tastants, sweet neurons that responded to bitter or sweet neurons responding to sour stimuli. Together, these results uncover the basic logic of the wiring of the taste system at the periphery, and illustrate how a labelled-line sensory circuit preserves signalling integrity despite rapid and stochastic turnover of receptor cells.

The gut–brain axis mediates sugar preference

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