Neuropeptide VF neurons promote sleep via the serotonergic raphe

Abstract

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 ...

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

“…Observational studies have shown that lifestyle-related risk factors, like alcohol consumption, smoking, diabetes, hypertension, cerebrovascular disease, stress, anxiety, depression, and sleep-wake dysfunction are statistical contributors to the emergence and severity of AD-type dementia. 168,169,177,178 NSS integrity is tightly linked to many of these risk factors, including sleep-wake dysfunction, [179][180][181][182] stress, [183][184][185] depression, 186,187 drug abuse, 188,189 eating disorder, 190 and diabetes. 191,192 Therefore, it is reasonable to expect that positive lifestyle changes may galvanize NSS resilience to AD.…”