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The Homeostatic Regulation and Biological Function of Sleep

The Homeostatic Regulation and Biological Function of Sleep

Objective

Sleep is vital and universal, but its biological function remains unknown. This project will seek to understand why we need to sleep by studying how the brain responds to sleep loss. My previous work in Drosophila showed that rising sleep pressure activates two dozen sleep-inducing neurons in the dorsal fan-shaped body (dFB) of the central complex. Sleep need is encoded in the electrical excitability of these neurons, which fluctuates because two potassium conductances, voltage-gated Shaker and the leak channel Sandman, are modulated antagonistically. As a consequence, dFB neurons are electrically silent during waking and persistently active during sleep. The key open question addressed in this project is the nature of the molecular changes that drive dFB neurons into the electrically active state. My preliminary data point to two dFB-intrinsic transducers of sleep pressure. First, the Shaker β subunit Hyperkinetic responds via a bound nicotinamide cofactor to oxidative by-products of mitochondrial electron transport, revealing a potential connection between energy metabolism, oxidative stress, and sleep, three processes implicated independently in lifespan, aging, and disease. To strengthen this connection, we will monitor sleep and the biophysics of dFB neurons after perturbing mitochondrial respiration or cellular redox chemistry and vice versa. Second, Rho GTPases relay currently unknown signals to the machinery responsible for the regulated endocytosis of Sandman, whose extraction from the plasma membrane is a prerequisite for switching the sleep-promoting activity of dFB neurons on. To identify these signals, we will investigate cell-autonomous, synaptic, and non-synaptic mechanisms of GTPase control. Because clear parallels exist between dFB neurons and sleep-active neurons in the mammalian hypothalamus, mechanistic insights that can currently be gained only in Drosophila are expected to have broad validity for understanding sleep and its disruptions.
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Host institution

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD

Address

Wellington Square University Offices
Ox1 2jd Oxford

United Kingdom

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 2 374 999

Beneficiaries (1)

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THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD

United Kingdom

EU Contribution

€ 2 374 999

Project information

Grant agreement ID: 832467

Status

Grant agreement signed

  • Start date

    1 October 2019

  • End date

    30 September 2024

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 2 374 999

  • EU contribution

    € 2 374 999

Hosted by:

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD

United Kingdom