The hypothalamic NPVF circuit modulates ventral raphe activity during nociception

Madelaine, Romain; Lovett-Barron, Matthew; Halluin, Caroline; Andalman, Aaron S.; Jin, Lina; Skariah, Gemini; Leung, Louis C.; Burns, Vanessa M.; Mourrain, Philippe

doi:10.1038/srep41528

Cited by 19 publications

(22 citation statements)

References 30 publications

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“…In mammalian brains, npvf is highly enriched in the dorsomedial hypothalamus ( Hinuma et al, 2000 ; Liu et al, 2001 ; Ubuka et al, 2009 ). Similarly, using ISH we found that npvf is exclusively expressed in the zebrafish dorsomedial hypothalamus at 5 days post-fertilization (dpf) ( Figure 5A–C ), similar to previous observations ( Madelaine et al, 2017 ; Yelin-Bekerman et al, 2015 ). However, zebrafish larvae only have ~15 NPVF neurons per brain hemisphere, over an order of magnitude fewer than the number of NPVF neurons in mice ( Poling et al, 2012 ).…”

Section: Resultssupporting

confidence: 91%

“…We further identified a 4 kb genomic region directly 5’ to the npvf open reading frame that is sufficient to drive expression of enhanced green fluorescent protein (EGFP) specifically in npvf -expressing neurons, with 98 ± 1% (n = 12) of EGFP positive cells expressing npvf mRNA, and 97 ± 1% (n = 12) of npvf -positive cells expressing EGFP ( Figure 5B and C , Table 1 ). This neuronal population sends dense projections within the hypothalamus and to the raphe nuclei of the hindbrain ( Madelaine et al, 2017 ), and sparse projections to the forebrain, tectum, and spinal cord ( Figure 5—figure supplement 1 ), suggesting that it may regulate neurons in these regions ( Madelaine et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

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Genetic and neuronal regulation of sleep by neuropeptide VF

Lee

Andreev

Truong

et al. 2017

eLife

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Sleep is an essential and phylogenetically conserved behavioral state, but it remains unclear to what extent genes identified in invertebrates also regulate vertebrate sleep. RFamide-related neuropeptides have been shown to promote invertebrate sleep, and here we report that the vertebrate hypothalamic RFamide neuropeptide VF (NPVF) regulates sleep in the zebrafish, a diurnal vertebrate. We found that NPVF signaling and npvf-expressing neurons are both necessary and sufficient to promote sleep, that mature peptides derived from the NPVF preproprotein promote sleep in a synergistic manner, and that stimulation of npvf-expressing neurons induces neuronal activity levels consistent with normal sleep. These results identify NPVF signaling and npvf-expressing neurons as a novel vertebrate sleep-promoting system and suggest that RFamide neuropeptides participate in an ancient and central aspect of sleep control.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Genetic and neuronal regulation of sleep by neuropeptide VF

Lee

Andreev

Truong

et al. 2017

eLife

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“…These observations suggest that there are at least two functionally distinct neuronal populations among tph2 -expressing IRa neurons, consistent with studies of the mammalian RN that identified molecularly distinct sub-populations with distinct efferent projection patterns and functions (Huang et al, 2019; Ren et al, 2018; Ren et al, 2019). The NPVF neuron-induced inhibition of a sub-population of IRa neurons that we observed is consistent with a previous study which reported that optogenetic stimulation of NPVF neurons resulted in decreased GCaMP6s fluorescence in IRa neurons (Madelaine et al, 2017), although the effect was small and slow compared to our data. Further studies are needed to explore the molecular and functional diversity of RN neurons in zebrafish.…”

Section: Discussionsupporting

confidence: 93%

“…Overexpression of npvf or stimulation of npvf -expressing neurons results in increased sleep, whereas pharmacological inhibition of NPVF signaling or ablation of npvf -expressing neurons results in reduced sleep (Lee et al, 2017). While it is unknown how the NPVF system promotes sleep, these neurons densely innervate a region of the hindbrain that is consistent with the location of the RN (Lee et al, 2017; Madelaine et al, 2017). Because perturbations of the NPVF system and RN have similar effects on sleep, and processes of npvf -expressing neurons are found near the RN, we hypothesized that the NPVF system promotes sleep via the RN.…”

Section: Introductionmentioning

confidence: 81%

Neuropeptide VF neurons promote sleep via the serotonergic raphe

Lee

Oikonomou

Cammidge

et al. 2019

Preprint

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15Although several sleep-regulating neurons have been identified, little is known about how they 16 interact with each other for sleep/wake control. We previously identified neuropeptide VF (NPVF) 17 and the hypothalamic neurons that produce it as a sleep-promoting system (Lee et al., 2017). 18Here we use zebrafish to describe a neural circuit in which neuropeptide VF (npvf)-expressing 19 neurons control sleep via the serotonergic raphe nuclei (RN), a hindbrain structure that promotes 20 sleep in both diurnal zebrafish and nocturnal mice. Using genetic labeling and calcium imaging, 21we show that npvf-expressing neurons innervate and activate serotonergic RN neurons. We 22 additionally demonstrate that optogenetic stimulation of npvf-expressing neurons induces sleep 23 in a manner that requires NPVF and is abolished when the RN are ablated or lack serotonin. 24Finally, genetic epistasis demonstrates that NPVF acts upstream of serotonin in the RN to 25 maintain normal sleep levels. These findings reveal a novel hypothalamic-hindbrain circuit for 26 sleep/wake control. 28While several sleep-and wake-promoting neuronal populations have been identified (reviewed in 30 (Bringmann, 2018; Liu and Dan, 2019; Saper and Fuller, 2017; Scammell et al., 2017)), 31 characterizing and understanding the functional and hierarchical relationships between these 32 populations is essential for understanding how the brain regulates sleep and wake states 33 (Oikonomou and Prober, 2017). Recent evidence from zebrafish and mice demonstrate that the 34 serotonergic raphe nuclei (RN) are critical for the initiation and maintenance of sleep (Oikonomou 35 et al., 2019), in contrast with previous models suggesting a wake-promoting role for the RN that 36 were largely based on their wake-active nature (Saper and Fuller, 2017; Scammell et al., 2017; 37Weber and Dan, 2016). In zebrafish, mutation of tryptophan hydroxylase 2 (tph2), which is 38 required for serotonin (5-HT) synthesis in the RN, results in reduced sleep, sleep depth, and 39 homeostatic response to sleep deprivation (Oikonomou et al., 2019). Pharmacological inhibition 40 of 5-HT synthesis or ablation of the RN also results in reduced sleep. Consistent with a sleep-41 promoting role for the raphe, optogenetic stimulation of raphe neurons results in increased sleep.42 Similarly, in mice, ablation of the RN results in increased wakefulness and an impaired 43 homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation of the RN at a 44 rate similar to their baseline pattern of activity induces NREM sleep. These complementary results 45 in zebrafish and mice (Oikonomou et al., 2019), along with classical ablation and pharmacological 46 studies (Ursin, 2008), indicate an evolutionarily conserved role for the serotonergic system in 47 promoting vertebrate sleep. However, it is unclear how the RN are themselves regulated to 48 promote sleep. 50Trans-synaptic retrograde viral tracing studies have identified substantial inputs to the RN from 51 hypothalamic ...

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“…The pixels containing the fish tail were determined in each frame of the tail monitoring videos using adaptive thresholding and blob detection algorithms in Scikit-image (van der Walt et al, 2014; Madelaine et al, 2017). Tail movements were identified by analyzing the number of tail-containing pixels that did not overlap between adjacent frames.…”

Section: Methodsmentioning

confidence: 99%

Ancestral Circuits for the Coordinated Modulation of Brain State

Lovett-Barron¹,

Andalman²,

Allen³

et al. 2017

Cell

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149

144

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SUMMARY Internal states of the brain profoundly influence behavior. Fluctuating states such as alertness can be governed by neuromodulation, but the underlying mechanisms and cell types involved are not fully understood. We developed a method to globally screen for cell types involved in behavior by integrating brain-wide activity imaging with high-content molecular phenotyping and volume registration at cellular resolution. We used this method (MultiMAP) to record from 22 neuromodulatory cell types in behaving zebrafish during a reaction-time task that reports alertness. We identified multiple monoaminergic, cholinergic, and peptidergic cell types linked to alertness and found that activity in these cell types was mutually correlated during heightened alertness. We next recorded from and controlled homologous neuromodulatory cells in mice; alertness-related cell-type dynamics exhibited striking evolutionary conservation and modulated behavior similarly. These experiments establish a method for unbiased discovery of cellular elements underlying behavior and reveal an evolutionarily conserved set of diverse neuromodulatory systems that collectively govern internal state.

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The hypothalamic NPVF circuit modulates ventral raphe activity during nociception

Cited by 19 publications

References 30 publications

Genetic and neuronal regulation of sleep by neuropeptide VF

Genetic and neuronal regulation of sleep by neuropeptide VF

Neuropeptide VF neurons promote sleep via the serotonergic raphe

Ancestral Circuits for the Coordinated Modulation of Brain State

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