Biology subjects

Jepson, J. E. C.

Publications and source records attributed to Jepson, J. E. C..

4 recordsLinked to original sources

bioRxiv2018

A sleep-regulatory circuit integrating circadian, homeostatic and environmental information in Drosophila

In the wild, when to go to sleep is a critical decision. Sleep onset is controlled by two processes: the circadian clock, and a homeostat measuring sleep drive [1, 2]. Environmental stimuli must also clearly intersect with the circadian clock and/or homeostat so that sleep is initiated only when appropriate. Yet how circadian, homeostatic and environmental cues are integrated at the circuit level is unclear. Recently, we found that DN1p clock neurons in Drosophila act to prolong morning wakefulness at elevated ambient temperatures [3]. Here we show that a subset of DN1p neurons exhibit temperature-sensitive increases in excitability, and define an output pathway linking DN1p neurons to downstream sleep-regulatory circuits. We show that DN1p neurons project axons to a subdomain of the Anterior Optic Tubercle (AOTU), and here make inhibitory synaptic connections with sleep-promoting tubercular-bulbar (TuBu) neurons. Using unbiased trans-synaptic labeling, we show that these TuBu neurons form synaptic connections with R-neurons innervating the ellipsoid body, subsets of which control homeostatic sleep drive [4]. DN1p excitability is clock-dependent, peaking in the late night and early morning [5]. Thus, integration of circadian and thermo-sensory information by DN1p neurons and subsequent inhibition of sleep-promoting TuBu neurons provides a mechanism by which an environmental stimulus can regulate sleep onset during a specific compartment of the day-night cycle. Furthermore, our results suggest that the AOTU functionally links circadian and sleep homeostat circuits in Drosophila.

neuroscience↗

bioRxiv2017

Neurocalcin acts in a clock- and light-modulated dopaminergic pathway to promote night sleep in Drosophila

Primary dystonia is a hyperkinetic movement disorder linked to altered dopaminergic signaling and synaptic plasticity in regions of the brain involved in motor control. Mutations in HPCA, encoding the neuronal calcium sensor Hippocalcin, are associated with primary dystonia, suggesting a function for Hippocalcin in regulating the initiation and/or maintenance of activity. However, such a role for Hippocalcin or Hippocalcin homologs has yet to be demonstrated in vivo. Here we investigate the cellular and organismal functions of the Drosophila Hippocalcin homolog Neurocalcin (NCA), and define a role for NCA in promoting sleep by suppressing nighttime hyperactivity. We show that NCA acts in a common pathway with the D1-type Dop1R1 dopamine receptor and facilitates sleep by inhibiting neurotransmitter release from a multi-component activity-promoting circuit. Our results suggest conserved roles for Hippocalcin homologs in modulating motor control through dopaminergic pathways, suppressing aberrant movements in humans and inappropriate nighttime locomotion in Drosophila.

neuroscience↗

bioRxiv2017

Mitochondrial impairment and rescue in riboflavin responsive neuropathy

Brown-Vialetto-Van Laere syndrome (BVVLS) represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter (RFVT) genes, SLC52A2 and SLC52A3, have recently been linked to BVVLS. However, the genetic frequency, neuropathology and downstream consequences of RFVT mutations have previously been undefined. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between RFVT mutations and BVVLS, identifying twenty-two pathogenic mutations in SLC52A2 and SLC52A3, fourteen of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column-medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain (ETC), we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. ETC complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila RFVT homologue revealed reduced levels of riboflavin, downstream metabolites, and ETC complex I activity. RFVT knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings indicate mitochondrial dysfunction as a downstream consequence of RFVT gene defects in BVVLS and validate riboflavin esters as a potential therapeutic strategy.

neuroscience↗

bioRxiv2016

Regulation of sleep plasticity by a thermo-sensitive circuit in Drosophila

Sleep is a highly conserved and essential behaviour in many species, including the fruit fly Drosophila melanogaster. In the wild, sensory signalling encoding environmental information must be integrated with sleep drive to ensure that sleep is not initiated during detrimental conditions. However, the molecular and circuit mechanisms by which sleep timing is modulated by the environment are unclear. Here we introduce a novel behavioural paradigm to study this issue. We show that in male fruit flies, onset of the daytime siesta is delayed by ambient temperatures above 29{degrees}C. We term this effect Prolonged Morning Wakefulness (PMW). We show that signalling through the TrpA1 thermo-sensor is required for PMW, and that TrpA1 specifically impacts siesta onset, but not night sleep onset, in response to elevated temperatures. We identify two critical TrpA1-expressing circuits and show that both contact DN1p clock neurons, the output of which is also required for PMW. Finally, we identify the circadian blue-light photoreceptor CRYPTOCHROME as a molecular regulator of PMW. We propose a model in which the Drosophila nervous system integrates information encoding temperature, light, and time to dynamically control when sleep is initiated. Our results provide a platform to investigate how environmental inputs co-ordinately regulate sleep plasticity.

neuroscience↗