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Periphery signals generated by Piezo-mediated stomach stretch and Neuromedin-mediated glucose load regulate the Drosophila brain nutrient sensor

Oh, Yangkyun; Lai, Jason Sih-Yu; Min, Soohong; Huang, Huai-Wei; Liberles, Stephen D; Ryoo, Hyung Don; Suh, Greg S B
Nutrient sensors allow animals to identify foods rich in specific nutrients. The Drosophila nutrient sensor, diuretic hormone 44 (DH44) neurons, helps the fly to detect nutritive sugar. This sensor becomes operational during starvation; however, the mechanisms by which DH44 neurons or other nutrient sensors are regulated remain unclear. Here, we identified two satiety signals that inhibit DH44 neurons: (1) Piezo-mediated stomach/crop stretch after food ingestion and (2) Neuromedin/Hugin neurosecretory neurons in the ventral nerve cord (VNC) activated by an increase in the internal glucose level. A subset of Piezo+ neurons that express DH44 neuropeptide project to the crop. We found that DH44 neuronal activity and food intake were stimulated following a knockdown of piezo in DH44 neurons or silencing of Hugin neurons in the VNC, even in fed flies. Together, we propose that these two qualitatively distinct peripheral signals work in concert to regulate the DH44 nutrient sensor during the fed state.
PMID: 34015253
ISSN: 1097-4199
CID: 4877522

Response of the microbiome-gut-brain axis in Drosophila to amino acid deficit

Kim, Boram; Kanai, Makoto I; Oh, Yangkyun; Kyung, Minsoo; Kim, Eun-Kyoung; Jang, In-Hwan; Lee, Ji-Hoon; Kim, Sang-Gyu; Suh, Greg S B; Lee, Won-Jae
A balanced intake of macronutrients-protein, carbohydrate and fat-is essential for the well-being of organisms. An adequate calorific intake but with insufficient protein consumption can lead to several ailments, including kwashiorkor1. Taste receptors (T1R1-T1R3)2 can detect amino acids in the environment, and cellular sensors (Gcn2 and Tor)3 monitor the levels of amino acids in the cell. When deprived of dietary protein, animals select a food source that contains a greater proportion of protein or essential amino acids (EAAs)4. This suggests that food selection is geared towards achieving the target amount of a particular macronutrient with assistance of the EAA-specific hunger-driven response, which is poorly understood. Here we show in Drosophila that a microbiome-gut-brain axis detects a deficit of EAAs and stimulates a compensatory appetite for EAAs. We found that the neuropeptide CNMamide (CNMa)5 was highly induced in enterocytes of the anterior midgut during protein deprivation. Silencing of the CNMa-CNMa receptor axis blocked the EAA-specific hunger-driven response in deprived flies. Furthermore, gnotobiotic flies bearing an EAA-producing symbiotic microbiome exhibited a reduced appetite for EAAs. By contrast, gnotobiotic flies with a mutant microbiome that did not produce leucine or other EAAs showed higher expression of CNMa and a greater compensatory appetite for EAAs. We propose that gut enterocytes sense the levels of diet- and microbiome-derived EAAs and communicate the EAA-deprived condition to the brain through CNMa.
PMID: 33953396
ISSN: 1476-4687
CID: 4878582

Identification and characterization of GAL4 drivers that mark distinct cell types and regions in the Drosophila adult gut

Lim, Seung Yeon; You, Hyejin; Lee, Jinhyeong; Lee, Jaejin; Lee, Yoojin; Lee, Kyung-Ah; Kim, Boram; Lee, Ji-Hoon; Jeong, JiHyeon; Jang, Sooin; Kim, Byoungsoo; Choi, Hyungjun; Hwang, Gayoung; Choi, Min Sung; Yoon, Sung-Eun; Kwon, Jae Young; Lee, Won-Jae; Kim, Young-Joon; Suh, Greg S B
The gastrointestinal tract in the adult Drosophila serves as a model system for exploring the mechanisms underlying digestion, absorption and excretion, stem cell plasticity, and inter-organ communication, particularly through the gut-brain axis. It is also useful for studying the cellular and adaptive responses to dietary changes, alterations in microbiota and immunity, and systematic and endocrine signals. Despite the various cell types and distinct regions in the gastrointestinal tract, few tools are available to target and manipulate the activity of each cell type and region, and their gene expression. Here, we report 353 GAL4 lines and several split-GAL4 lines that are expressed in enteric neurons (ENs), progenitors (ISCs and EBs), enterocytes (ECs), enteroendocrine cells (EEs), or/and other cell types that are yet to be identified in distinct regions of the gut. We had initially collected approximately 600 GAL4 lines that may be expressed in the gut based on RNA sequencing data, and then crossed them to UAS-GFP to perform immunohistochemistry to identify those that are expressed selectively in the gut. The cell types and regional expression patterns that are associated with the entire set of GAL4 drivers and split-GAL4 combinations are annotated online at (K-Gut Project). This GAL4 resource can be used to target specific populations of distinct cell types in the fly gut, and therefore, should permit a more precise investigation of gut cells that regulate important biological processes.
PMID: 33326321
ISSN: 1563-5260
CID: 4726662

Signal Amplification in Drosophila Olfactory Receptor Neurons

Kim, Byoung Soo; Suh, Greg S B
Olfactory receptor neurons (ORNs) transform scant chemical inputs into significant neural signals. This transformation requires signal amplification. In this issue of Neuron, Ng et al. (2019) identified a mechanism by which the signals evoked by pheromones are amplified in the ORNs that selectively promote courtship behavior in Drosophila.
PMID: 31805260
ISSN: 1097-4199
CID: 4221052

A glucose-sensing neuron pair regulates insulin and glucagon in Drosophila

Oh, Yangkyun; Lai, Jason Sih-Yu; Mills, Holly J; Erdjument-Bromage, Hediye; Giammarinaro, Benno; Saadipour, Khalil; Wang, Justin G; Abu, Farhan; Neubert, Thomas A; Suh, Greg S B
Although glucose-sensing neurons were identified more than 50 years ago, the physiological role of glucose sensing in metazoans remains unclear. Here we identify a pair of glucose-sensing neurons with bifurcated axons in the brain of Drosophila. One axon branch projects to insulin-producing cells to trigger the release of Drosophila insulin-like peptide 2 (dilp2) and the other extends to adipokinetic hormone (AKH)-producing cells to inhibit secretion of AKH, the fly analogue of glucagon. These axonal branches undergo synaptic remodelling in response to changes in their internal energy status. Silencing of these glucose-sensing neurons largely disabled the response of insulin-producing cells to glucose and dilp2 secretion, disinhibited AKH secretion in corpora cardiaca and caused hyperglycaemia, a hallmark feature of diabetes mellitus. We propose that these glucose-sensing neurons maintain glucose homeostasis by promoting the secretion of dilp2 and suppressing the release of AKH when haemolymph glucose levels are high.
PMID: 31645735
ISSN: 1476-4687
CID: 4163012

Rapid, biphasic CRF neuronal responses encode positive and negative valence

Kim, Jineun; Lee, Seongju; Fang, Yi-Ya; Shin, Anna; Park, Seahyung; Hashikawa, Koichi; Bhat, Shreelatha; Kim, Daesoo; Sohn, Jong-Woo; Lin, Dayu; Suh, Greg S B
Corticotropin-releasing factor (CRF) that is released from the paraventricular nucleus (PVN) of the hypothalamus is essential for mediating stress response by activating the hypothalamic-pituitary-adrenal axis. CRF-releasing PVN neurons receive inputs from multiple brain regions that convey stressful events, but their neuronal dynamics on the timescale of behavior remain unknown. Here, our recordings of PVN CRF neuronal activity in freely behaving mice revealed that CRF neurons are activated immediately by a range of aversive stimuli. By contrast, CRF neuronal activity starts to drop within a second of exposure to appetitive stimuli. Optogenetic activation or inhibition of PVN CRF neurons was sufficient to induce a conditioned place aversion or preference, respectively. Furthermore, conditioned place aversion or preference induced by natural stimuli was significantly decreased by manipulating PVN CRF neuronal activity. Together, these findings suggest that the rapid, biphasic responses of PVN CRF neurons encode the positive and negative valences of stimuli.
PMID: 30833699
ISSN: 1546-1726
CID: 3723962

Communicating the nutritional value of sugar inDrosophila

Abu, Farhan; Wang, Justin G; Oh, Yangkyun; Deng, Jingjing; Neubert, Thomas A; Suh, Greg S B
Sweet-insensitiveDrosophilamutants are unable to readily identify sugar. In presence of wild-type (WT) flies, however, these mutant flies demonstrated a marked increase in their preference for nutritive sugar. Real-time recordings of starved WT flies revealed that these flies discharge a drop from their gut end after consuming nutritive sugars, but not nonnutritive sugars. We proposed that the drop may contain a molecule(s) named calorie-induced secreted factor (CIF), which serves as a signal to inform other flies about its nutritional value. Consistent with this, we observed a robust preference of flies for nutritive sugar containing CIF over nutritive sugar without CIF. Feeding appears to be a prerequisite for the release of CIF, given that fed flies did not produce it. Additionally, correlation analyses and pharmacological approaches suggest that the nutritional value, rather than the taste, of the consumed sugar correlates strongly with the amount (or intensity) of the released CIF. We observed that the release of this attractant signal requires the consumption of macronutrients, specifically nutritive sugars and l-enantiomer essential amino acids (l-eAAs), but it is negligibly released when flies are fed nonnutritive sugars, unnatural d-enantiomer essential amino acids (d-eAAs), fatty acids, alcohol, or salts. Finally, CIF (i) is not detected by the olfactory system, (ii) is not influenced by the sex of the fly, and (iii) is not limited to one species ofDrosophila.
PMID: 29507251
ISSN: 1091-6490
CID: 2975122

Drosophila SLC5A11 Mediates Hunger by Regulating K+ Channel Activity

Park, Jin-Yong; Dus, Monica; Kim, Seonil; Abu, Farhan; Kanai, Makoto I; Rudy, Bernardo; Suh, Greg S B
Hunger is a powerful drive that stimulates food intake. Yet, the mechanism that determines how the energy deficits that result in hunger are represented in the brain and promote feeding is not well understood. We previously described SLC5A11-a sodium/solute co-transporter-like-(or cupcake) in Drosophila melanogaster, which is required for the fly to select a nutritive sugar over a sweeter nonnutritive sugar after periods of food deprivation. SLC5A11 acts on approximately 12 pairs of ellipsoid body (EB) R4 neurons to trigger the selection of nutritive sugars, but the underlying mechanism is not understood. Here, we report that the excitability of SLC5A11-expressing EB R4 neurons increases dramatically during starvation and that this increase is abolished in the SLC5A11 mutation. Artificial activation of SLC5A11-expresssing neurons is sufficient to promote feeding and hunger-driven behaviors; silencing these neurons has the opposite effect. Notably, SLC5A11 transcript levels in the brain increase significantly when flies are starved and decrease shortly after starved flies are refed. Furthermore, expression of SLC5A11 is sufficient for promoting hunger-driven behaviors and enhancing the excitability of SLC5A11-expressing neurons. SLC5A11 inhibits the function of the Drosophila KCNQ potassium channel in a heterologous expression system. Accordingly, a knockdown of dKCNQ expression in SLC5A11-expressing neurons produces hunger-driven behaviors even in fed flies, mimicking the overexpression of SLC5A11. We propose that starvation increases SLC5A11 expression, which enhances the excitability of SLC5A11-expressing neurons by suppressing dKCNQ channels, thereby conferring the hunger state.
PMID: 27397890
ISSN: 1879-0445
CID: 2180102

Humidity Sensing in Drosophila

Enjin, Anders; Zaharieva, Emanuela E; Frank, Dominic D; Mansourian, Suzan; Suh, Greg S B; Gallio, Marco; Stensmyr, Marcus C
Environmental humidity influences the fitness and geographic distribution of all animals [1]. Insects in particular use humidity cues to navigate the environment, and previous work suggests the existence of specific sensory mechanisms to detect favorable humidity ranges [2-5]. Yet, the molecular and cellular basis of humidity sensing (hygrosensation) remains poorly understood. Here we describe genes and neurons necessary for hygrosensation in the vinegar fly Drosophila melanogaster. We find that members of the Drosophila genus display species-specific humidity preferences related to conditions in their native habitats. Using a simple behavioral assay, we find that the ionotropic receptors IR40a, IR93a, and IR25a are all required for humidity preference in D. melanogaster. Yet, whereas IR40a is selectively required for hygrosensory responses, IR93a and IR25a mediate both humidity and temperature preference. Consistent with this, the expression of IR93a and IR25a includes thermosensory neurons of the arista. In contrast, IR40a is excluded from the arista but is expressed (and required) in specialized neurons innervating pore-less sensilla of the sacculus, a unique invagination of the third antennal segment. Indeed, calcium imaging showed that IR40a neurons directly respond to changes in humidity, and IR40a knockdown or IR93a mutation reduced their responses to stimuli. Taken together, our results suggest that the preference for a specific humidity range depends on specialized sacculus neurons, and that the processing of environmental humidity can happen largely in parallel to that of temperature.
PMID: 27161501
ISSN: 1879-0445
CID: 2107522

Interoceptive sugar sensing by the brain [Meeting Abstract]

Dus, Monica; Lai, Jason; Mills, Holly; Oh, Yangkyun; Suh, Greg S. B.
ISSN: 0379-864x
CID: 2308002