AMPK acts as a molecular trigger to coordinate glutamatergic signals and adaptive behaviours during acute starvation

Ahmadi, M. Amir; Roy, Richard

doi:10.7554/elife.16349

Cited by 30 publications

(48 citation statements)

References 76 publications

(182 reference statements)

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“…AMPK consists of a heterotrimeric complex that is activated by AMP and modulates diverse intercellular signaling pathways including mTOR, FoxO, and SIRT1[81]. Canonically, AMPK is activated during starvation and increases neuronal activity, though this effect varies by neuronal subtype [82,83] For example, in C. elegans , starvation-induced AMPK activation leads to inhibition of neurons that modulate local search behavior in response to food deprivation, while promoting activity in neurons that trigger dispersal behavior [84]. Here, we use a dominant negative variant of AMPK with a mutation in the catalytic domain of the alpha subunit to selectively disrupt AMPK function in Lk neurons [82].…”

Section: Discussionmentioning

confidence: 99%

A single pair of leucokinin neurons are modulated by feeding state and regulate sleep-metabolism interactions

Yurgel

Kakad

Zandawala

et al. 2018

Preprint

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1Dysregulation of sleep and feeding has widespread health consequences. Despite 2 extensive epidemiological evidence for interactions between sleep and metabolic 3 function, little is known about the neural or molecular basis underlying the integration of 4 these processes. Drosophila melanogaster potently suppress sleep in response to 5 starvation, and powerful genetic tools allow for mechanistic investigation of sleep-6 metabolism interactions. We have previously identified neurons expressing the 7 neuropeptide leucokinin (Lk) as being required for starvation-mediated changes in sleep. 8Here, we demonstrate an essential role for Lk neuropeptide in metabolic regulation of 9 sleep. Further, we find that the activity of Lk neurons is modulated by feeding state and 10 circulating nutrients, with reduced activity in response to glucose and increased activity 11 under starvation conditions. Both genetic silencing and laser-mediated microablation 12 localize Lk-mediated sleep regulation to a single pair of Lk neurons within the lateral 13 horn (LHLK) that project near primary sleep and metabolic centers of the brain. A 14 targeted screen identified a critical role for AMP-activated protein kinase (AMPK) in 15 starvation-modulated changes in sleep. Disruption of AMPK function in Lk neurons 16 suppresses sleep and increases LHLK activity in fed flies, phenocopying the starvation 17 state. Taken together, these findings localize feeding state-dependent regulation of 18 sleep to a single pair of neurons within the fruit fly brain and provide a system for 19 investigating the cellular basis of sleep-metabolism interactions. 20 21 Introduction 1 Dysregulation of sleep and feeding has widespread health consequences and reciprocal 2 interactions between these processes underlie a number of pathologies [1-4]. Sleep loss 3 correlates with increased appetite and insulin insensitivity, while short-sleeping 4 individuals are more likely to develop obesity, metabolic syndrome, type II diabetes, and 5 cardiovascular disease [1,3,4]. Although the neural basis for sleep regulation has been 6 studied in detail, little is known about how feeding state and changes in metabolic 7 function modulate sleep [5,6]. Understanding how sleep and feeding states are 8 integrated may provide novel insights into the co-morbidity of disorders linked to sleep 9 and metabolic regulation.10 Animals balance nutritional state and energy expenditure in order to achieve metabolic 11 homeostasis [7,8]. In both flies and mammals, diet potently affects sleep regulation, 12 strengthening the idea that sleep and metabolic state interact [5,6,9]. Starvation leads to 13 sleep loss, or disrupted sleep architecture, presumably to induce foraging behavior, 14 while high-calorie diets have complex effects on sleep depending on macronutrient 15 content [10-13]. Behavioral and physiological responses to changes in feeding state are 16 modulated both by cell autonomous nutrient centers in the brain that sense changes in 17 circulating nutrients and through communication b...

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Section: Discussionmentioning

confidence: 99%

A single pair of leucokinin neurons are modulated by feeding state and regulate sleep-metabolism interactions

Yurgel

Kakad

Zandawala

et al. 2018

Preprint

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“…Thereby AMPK has the potential to increase or decrease cell excitability, in a manner determined by both the cell-specific expression of its subunits and members of the ion channel superfamily, providing the capacity for system-level adjustments to whole-body metabolic status (Evans, 2006a). Expanding on this, evidence is emerging that AMPK may also directly phosphorylate and regulate enzymes key to transmitter biosynthesis (Zhang et al, 2018), receptors (Ahmadi and Roy, 2016), pumps and transporters (Schneider et al, 2015).…”

Section: The Amp-activated Protein Kinasementioning

confidence: 99%

AMPK breathing and oxygen supply

Evans

2019

Respiratory Physiology & Neurobiology

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Regulation of breathing is critical to our capacity to accommodate deficits in oxygen availability and demand during, for example, sleep and ascent to altitude. Key to this are two reflex responses, hypoxic pulmonary vasoconstriction (HPV), which aids ventilation-perfusion matching at the lungs, and the hypoxic ventilatory response (HVR) which accelerates ventilation. In 2004 I proposed that HPV might be mediated by the AMP-activated protein kinase, which governs cell autonomous metabolic homeostasis. Pharmacological evidence was presented in support of this view, and the hypothesis extended to incorporate a role for AMPK in regulating carotid body afferent input responses during hypoxia and thus the HVR. The present article reviews our subsequent findings on these matters and those of others, which provide strong support for the view that AMPK mediates HPV. AMPK is also critical to the HVR, but against our expectations it is not required for carotid body activation during hypoxia. Contrary to current consensus in this respect, our findings suggest that AMPK deficiency blocks the HVR at the level of the brainstem, even when afferent input responses from the carotid body are normal. We have therefore revised our hypothesis on the HVR, now proposing that AMPK integrates local hypoxic stress at defined loci within the brainstem respiratory network with an index of peripheral hypoxic status, namely afferent chemosensory inputs. Nevertheless, in general outcomes are consistent with the original hypothesis, that the role of AMPK has evolved, through natural selection, to extend to the regulation of breathing, and thus oxygen and energy (ATP) supply to the whole body.

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“…Our results indicate that mgl-1 is necessary to generate local search. mgl-1 has been implicated in foodrelated physiological responses (Greer et al, 2008;Kang and Avery, 2009a, b), pharyngeal pumping (Dillon et al, 2015), and foraging (Ahmadi and Roy, 2016), making it a good entry point to circuit mechanisms related to food-related behaviors.…”

Section: Local Search Behavior In Wildtype C Elegansmentioning

confidence: 99%

“…Upon food removal, mgl-1 decreases pharyngeal pumping (feeding) (Dillon et al, 2015), promotes mobilization of fat stores downstream of TGF-β signaling (Greer et al, 2008), and modifies survival after starvation by regulating autophagy through action in AIY interneurons (Kang and Avery, 2009b). Its expression is regulated by AMPK and is dependent on satiety levels (Ahmadi and Roy, 2016). Identifying the cell typespecific readouts of MGL-1 action will provide a better understanding of conserved coordinated behavioral and physiological responses to changes in food availability.…”

Section: Glutamate and Mgl-1 Act At Multiple Time Scales After Food Rmentioning

confidence: 99%

“…Upon removal from food, C. elegans executes a stereotypical local search behavior in which it explores a small area by executing many random, undirected reversals and turns for about fifteen minutes. If it fails to find food, it transitions to a global search in which it explores larger areas by suppressing reorientations and executing long forward runs (Ahmadi and Roy, 2016;Calhoun et al, 2014;Gray et al, 2005;Hills et al, 2004;Salvador et al, 2014;Wakabayashi et al, 2004). The reorientations associated with local search in C. elegans are present in different patterns in other behaviors such as chemotaxis (Pierce-Shimomura et al, 1999) and aerotaxis (Hums et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Parallel multimodal circuits control an innate foraging behavior

López-Cruz

Pokala²,

Sordillo

et al. 2018

Preprint

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SUMMARYForaging strategies that enable animals to locate food efficiently are composed of highly conserved behavioral states with characteristic features. Here, we identify parallel multimodal circuit modules that control an innate foraging state --local search behavior --after food removal in the nematode Caenorhabditis elegans. Two parallel groups of chemosensory and mechanosensory glutamatergic neurons that detect food-related cues trigger local search by inhibiting separate integrating neurons through a metabotropic glutamate receptor, MGL-1. The chemosensory and mechanosensory modules are separate and redundant, as glutamate release from either can drive the full behavior. Spontaneous activity in the chemosensory module encodes information about the time since the last food encounter and correlates with the foraging behavior. In addition, the ability of the sensory modules to control local search is gated by the internal nutritional state of the animal. This multimodal circuit configuration provides robust control of an innate adaptive behavior.

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AMPK acts as a molecular trigger to coordinate glutamatergic signals and adaptive behaviours during acute starvation

Cited by 30 publications

References 76 publications

A single pair of leucokinin neurons are modulated by feeding state and regulate sleep-metabolism interactions

A single pair of leucokinin neurons are modulated by feeding state and regulate sleep-metabolism interactions

AMPK breathing and oxygen supply

Parallel multimodal circuits control an innate foraging behavior

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