A tale of two circuits: CCK NTS neuron stimulation controls appetite and induces opposing motivational states by projections to distinct brain regions

Roman, Carolyn W.; Sloat, Stephanie R.; Palmiter, Richard D.

doi:10.1016/j.neuroscience.2017.06.049

Cited by 58 publications

(60 citation statements)

References 33 publications

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“…Given the reduction in food intake we observed, it was important to evaluate whether induction of malaise and/or aversion could be contributing to the effect seen, particularly as the DVC is implicated in mediating these responses in addition to satiety (Maniscalco & Rinaman, ). This particularly important in light of the increased in c‐FOS immunoreactivity observed in the lPBN of DVC::GFAP hM3Dq mice after CNO treatment, which may indicate the activation of a NTS‐lPBN pathway previously reported to reduce food intake through aversion/negative salience (Roman et al, ). To do this, we used a CPA assay utilizing a protocol previously used by our group to indicate aversive responses/negative salience in response to chemogenetic activation of prefrontal cortex‐projecting locus coeruleus neurons (LC PFC ) in rats (Hirschberg, Li, Randall, Kremer, & Pickering, ).…”

Section: Discussionmentioning

confidence: 70%

“…of DVC astrocytes increased c‐FOS expression in the NTS and AP (Figure a–e), and the lPBN, a downstream target of NTS neurons (Figure f–i) in DVC::GFAP hM3Dq mice compared with DVC::GFAP mCherry control mice. However, in the PVH, another projection target of satiety signaling NTS neurons (D'Agostino et al, ; Roman, Sloat, & Palmiter, ), there was no difference in the number of c‐FOS expressing cells between groups (Figure j–m). This is consistent with DVC astrocyte activation signaling to neuronal circuitry implicated in regulation of energy homeostasis (Atasoy, Betley, Su, & Sternson, ; Carter, Soden, Zweifel, & Palmiter, ).…”

Section: Resultsmentioning

confidence: 87%

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Regulation of food intake by astrocytes in the brainstem dorsal vagal complex

Macdonald

Holmes

Beall

et al. 2019

Glia

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A role for glial cells in brain circuits controlling feeding has begun to be identified with hypothalamic astrocyte signaling implicated in regulating energy homeostasis. The nucleus of the solitary tract (NTS), within the brainstem dorsal vagal complex (DVC), integrates vagal afferent information from the viscera and plays a role in regulating food intake. We hypothesized that astrocytes in this nucleus respond to, and influence, food intake. Mice fed high‐fat chow for 12 hr during the dark phase showed NTS astrocyte activation, reflected in an increase in the number (65%) and morphological complexity of glial‐fibrillary acidic protein (GFAP)‐immunoreactive cells adjacent to the area postrema (AP), compared to control chow fed mice. To measure the impact of astrocyte activation on food intake, we delivered designer receptors exclusively activated by designer drugs (DREADDs) to DVC astrocytes (encompassing NTS, AP, and dorsal motor nucleus of the vagus) using an adeno‐associated viral (AAV) vector (AAV‐GFAP‐hM3Dq_mCherry). Chemogenetic activation with clozapine‐N‐oxide (0.3 mg/kg) produced in greater morphological complexity in astrocytes and reduced dark‐phase feeding by 84% at 4 hr postinjection compared with vehicle treatment. hM3Dq‐activation of DVC astrocytes also reduced refeeding after an overnight fast (71% lower, 4 hr postinjection) when compared to AAV‐GFAP‐mCherry expressing control mice. DREADD‐mediated astrocyte activation did not impact locomotion. hM3Dq activation of DVC astrocytes induced c‐FOS in neighboring neuronal feeding circuits (including in the parabrachial nucleus). This indicates that NTS astrocytes respond to acute nutritional excess, are involved in the integration of peripheral satiety signals, and can reduce food intake when activated.

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Section: Discussionmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 87%

Regulation of food intake by astrocytes in the brainstem dorsal vagal complex

Macdonald

Holmes

Beall

et al. 2019

Glia

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“…CCK NTS neurons are activated following a meal and induce satiety in mice. Additionally, a projection from these neurons to the PBN is aversive (Roman et al, 2017). Satiety may arise from feeling pleasantly (sated) or unpleasantly full, such as after eating too much food.…”

Section: Discussionmentioning

confidence: 99%

Encoding of an engram for food location by satiety-promoting Drd2 hippocampal neurons

Pomeranz

Cheng

et al. 2018

Preprint

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Associative learning guides feeding behavior in mammals in part by using cues that link location in 2 space to food availability. However, the elements of the top-down circuitry encoding the memory of the 3 location of food is largely unknown, as are the high-order processes that control satiety. Here we report 4 that hippocampal dopamine 2 receptor (D2R) neurons are specifically activated by food and that 5 modulation of their activity reduce food intake in mice. We also found that activation of these neurons 6 interferes with the valence of food and the acquisition of a spatial memory linking food to a location via 7 projections from the hippocampus to the lateral septum. Finally, we showed that inputs from lateral 8 entorhinal cortex (LEC) to the hippocampus can also drive satiety via activation of D2R cells. These 9 data describe a previously unidentified function for hippocampal D2R cells to regulate feeding behavior 10 and identifies a LEC->Hippocampus->Septal high-order circuit that encodes the memory of food 11 location.

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“…4f-i). However in the paraventricular nucleus of the hypothalamus (PVH), another projection target of satiety signalling NTS neurons 5,21 , there was no difference in the number of c-FOS expressing cells between groups (Fig. 4j-m).…”

Section: Figmentioning

confidence: 99%

Regulation of food intake by astrocytes in the brainstem dorsal vagal complex

Macdonald

Holmes

Beall

et al. 2019

Preprint

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Short title: Brainstem astrocytes regulate feeding 12 Keywords: astrocyte, feeding, chemogenetic, nucleus of the solitary tract, metabolism 13 Declaration of conflict of interest: none 14 15Food intake is controlled by the coordinated action of numerous brain regions but a complete 16 understanding remains elusive 1 . Of these brain regions the brainstem dorsal vagal complex (DVC) is 17 the first site for integration of visceral synaptic and hormonal cues that act to inhibit food intake 2 . 18The DVC consists of three nuclei: the nucleus of the solitary tract (NTS), area postrema (AP) and 19 dorsal motor nucleus of the vagus (DMX). Targeted chemogenetic activation of appetite-responsive 20 NTS neuronal populations causes short term decreases in food intake [3][4][5][6][7] . Astrocytes are a class of 21 glial cell which provide metabolic and structural support to neurons and play an active role in 22 modulating neurotransmission. Within the hypothalamic arcuate nucleus (ARC) astrocytes are 23 regulated by both positive and negative energy balance and express receptors for hormones that 24 influence satiety and hunger [8][9][10][11] . Chemogenetic activation of these ARC astrocytes alters food 25 intake [11][12][13] . Since NTS astrocytes respond to vagal stimulation 14 , we hypothesised that they may be 26 involved in mediating satiety. Here we show that NTS astrocytes show plastic alterations in 27 morphology following excess food consumption and that chemogenetic activation of DVC astrocytes 28 causes a decrease in food intake, by recruiting an appetite-inhibiting circuit, without producing 29 aversion. These findings are the first using genetically-targeted manipulation of DVC astrocytes to 30 demonstrate their role in the brain's regulation of food intake. 31In order to examine whether NTS astrocytes respond to changes in energy status we induced short-32 term positive energy balance by allowing mice to exclusively eat a high-fat chow for 12 hours during 33 the dark-phase. This paradigm induced a feeding binge when compared with standard chow-fed 34 mice ( Fig. 1a). High-fat fed mice had a greater number of glial fibrillary acidic protein (GFAP)-35 immunoreactive astrocytes within the NTS when compared with controls, with the changes being 36 most pronounced in the NTS at the level of the AP ( Fig. 1c-e). GFAP-immunoreactive astrocytes in 37 the NTS adjacent to the AP of high-fat fed mice had greater morphological complexity, as assessed 38 by Sholl analysis 15,16 , and a greater number of processes than those of standard chow fed controls 39 ( Fig. 1f,g). These findings suggest that NTS astrocytes show dynamic reactive changes to the acute 40 nutritional excess caused by consumption of a high-fat diet. 41It is established that Gq-coupled designer receptors exclusively activated by designer drugs 42 (DREADDs) can be used to selectively activate astrocytes by driving increases in intracellular Ca 2+ , the 43 main signalling modality of these cells 11,[17][18][19] . We bilaterally injected the DVC of mice with ...

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A tale of two circuits: CCK NTS neuron stimulation controls appetite and induces opposing motivational states by projections to distinct brain regions

Cited by 58 publications

References 33 publications

Regulation of food intake by astrocytes in the brainstem dorsal vagal complex

Regulation of food intake by astrocytes in the brainstem dorsal vagal complex

Encoding of an engram for food location by satiety-promoting Drd2 hippocampal neurons

Regulation of food intake by astrocytes in the brainstem dorsal vagal complex

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