Dopamine neurons promotes wakefulness via the DopR receptor in the Drosophila mushroom body

Driscoll, Margaret E.; Coleman, Victoria; McLaughlin, Morgan; Nguyen, Amanda; Sitaraman, Divya

doi:10.1101/2020.04.29.069229

Cited by 7 publications

(8 citation statements)

References 116 publications

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“…Dopaminergic neurons display varied levels of Rab10 even within a particular cluster [9]. Consequently, it is possible that the Rab10 GEFs, GAPs and effectors may also differ between the subsets of the dopaminergic neurons in the PAM, PPL1 and PPM3 neurons, the clusters that regulate the sleep-wake cycle [40,61,62] -indeed the three types of PAM neurons express a different subset of Rab10 interactors. Further, dLRRK is expressed in the dopaminergic neurons in the optic lobe, but not in the PAM neurons.…”

Section: Sleep/wake Cycles and Conditioned Courtship Memory Do Not Depend On An Interaction Between Rab10 And Lrrk2-g2019smentioning

confidence: 99%

Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

Fellgett

Middleton

Munns

et al. 2021

JPD

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Background: Inherited mutations in the LRRK2 protein are the common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. Objective: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. Methods: LRRK2-G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. Results: Rab10 loss-of-function rescued LRRK2-G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2-G2019S. Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. Conclusion: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease.

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Section: Sleep/wake Cycles and Conditioned Courtship Memory Do Not Depend On An Interaction Between Rab10 And Lrrk2-g2019smentioning

confidence: 99%

Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

Fellgett

Middleton

Munns

et al. 2021

JPD

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“…These MBON neurons are known to be required for behaviors that might compete with sleep, including avoidance of aversive stimuli, aversion to pathogen-infected food, ingestion, startle-induced locomotion, and memory for visual and olfactory cues (Al-Anzi and Zinn, 2018; Aso et al, 2014b; Kobler et al, 2020; Lewis et al, 2015; Owald et al, 2015; Sun et al, 2018; Yamazaki et al, 2018). For the γ5β′2a/β′2mp/β′2mp_bilateral MBONs, recruitment into the sleep circuitry likely also involves dopaminergic signaling since RNAi knockdown of the DopR1 and DopR2 dopamine receptors in these cells lead to an increase in nighttime sleep (Driscoll et al, 2020). Dopaminergic input to this subclass of MBONs was previously shown to be excitatory and wake-promoting (Sitaraman et al, 2015b).…”

Section: Discussionmentioning

confidence: 99%

Bantam regulates the adult sleep circuit in Drosophila

Hobin

Dorfman

Adel

et al. 2021

Preprint

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Sleep is a highly conserved feature of animal life characterized by dramatic changes in behavior, neural physiology and gene expression. The gene regulatory factors responsible for these sleep-dependent changes remain largely unknown. microRNAs are post-transcriptional modulators of gene expression which have been implicated in sleep regulation. Our previous screen identified 25 sleep-regulating microRNAs in Drosophila melanogaster, including the developmental regulator bantam (ban). Here we show that ban promotes early nighttime sleep through a population of glutamatergic neurons- the γ5β′2a/β′2mp/β′2mp_bilateral Mushroom Body Output Neurons (MBONs). We found that knockdown of ban in these neurons led to a reduction in early night sleep. The γ5β′2a/β′2mp/β′2mp_bilateral MBONs were previously shown to be wake-promoting, suggesting that ban acts to inhibit these neurons. GCaMP calcium imaging revealed that bantam inhibits the neural activity of the γ5β′2a/β′2mp/β′2mp_bilateral MBONs during the night but not the day. Blocking synaptic transmission in the γ5β′2a/β′2mp/β′2mp_bilateral MBONs rescued the effect of ban knockdown on sleep. Together these results suggest that ban promotes night sleep via the inhibition of the γ5β′2a/β′2mp/β′2mp_bilateral MBONs. RNAseq further revealed that bantam negatively regulates the wake-promoting mRNAs Kelch and CCHamide-2 receptor in the γ5β′2a/β′2mp/β′2mp_bilateral MBONs. These experiments establish bantam as an active regulator of sleep and neural activity within the fly brain.

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“…Dopaminergic mushroom body output neurons regulate sleep duration and sleep depth (Titos and Rogulja 2020). While dopaminergic signaling commonly functions to increase arousal (Driscoll et al 2020;Q. Liu et al 2012;Kume et al 2005;Li et al 2020), in this case the activity of the dopaminergic neurons leads to decreased responsiveness to external stimuli and thus suppresses sensory arousability (Titos and Rogulja 2020).…”

Section: It's Never That Simple How Does the Body Encode And Communicate The Absence Of Multiple Needs At Once To Drive Flexible Neural Smentioning

confidence: 99%

“…Dopaminergic mushroom body output neurons regulate sleep duration and sleep depth ( Titos and Dragana 2020 ). While dopaminergic signaling commonly functions to increase arousal ( Kume et al 2005 ; Liu et al 2012 ; Driscoll et al 2020 ; Li et al 2020), in this context, the activity of the dopaminergic neurons leads to decreased responsiveness to external stimuli and thus suppresses sensory arousability ( Titos and Dragana 2020 ). In this way, the dopaminergic neurons integrate input from the gut about nutrient and sleep states with external sensory stimuli, allowing the internal state of satiety to modulate the flies’ responsiveness to stimuli while asleep.…”

Section: Contextualizing Through Our Frameworkmentioning

confidence: 99%

Internal State: Dynamic, Interconnected Communication Loops Distributed Across Body, Brain, and Time

Kanwal

Coddington

Frazer

et al. 2021

Integrative and Comparative Biology

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Internal state profoundly alters perception and behavior. For example, a starved fly may approach and consume foods that it would otherwise find undesirable. A socially engaged newt may remain engaged in the presence of a predator, whereas a solitary newt would otherwise attempt escape. Yet, the definition of internal state is fluid and ill-defined. As an interdisciplinary group of scholars spanning five career stages (from undergraduate to full professor) and six academic institutions, we have come together in an attempt to provide an operational definition of internal state that could be useful in understanding behavior and the function of nervous systems, at timescales relevant to the individual. In this Perspective, we propose to define internal state through an integrative framework centered on dynamic and interconnected communication loops in and between the body and the brain. This framework is informed by a synthesis of historical and contemporary paradigms used by neurobiologists, ethologists, physiologists, and endocrinologists. We view internal state as composed of both spatially distributed networks (body-brain communication loops), and temporally distributed mechanisms that weave together neural circuits, physiology, and behavior. Given the wide spatial and temporal scales at which internal state operates—and therefore the broad range of scales at which it could be defined—we choose to anchor our definition in the body. Here we focus on studies that highlight body-to-brain signaling; body represented in endocrine signaling, and brain represented in sensory signaling. This integrative framework of internal state potentially unites the disparate paradigms often used by scientists grappling with body-brain interactions. We invite others to join us as we examine approaches and question assumptions to study the underlying mechanisms and temporal dynamics of internal state.

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Dopamine neurons promotes wakefulness via the DopR receptor in the Drosophila mushroom body

Cited by 7 publications

References 116 publications

Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

Bantam regulates the adult sleep circuit in Drosophila

Internal State: Dynamic, Interconnected Communication Loops Distributed Across Body, Brain, and Time

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