Biology subjects

Miesenboeck, G.

Publications and source records attributed to Miesenboeck, G..

4 recordsLinked to original sources

bioRxiv2024

A half-centre oscillator encodes sleep pressure

Oscillatory neural dynamics are an inseparable part of mammalian sleep. Characteristic rhythms are associated with different sleep stages and variable levels of sleep pressure, but it remains unclear whether these oscillations are passive mirrors or active generators of sleep. Here we report that sleep-control neurons innervating the dorsal fan-shaped body of Drosophila (dFBNs) produce slow-wave activity (SWA) in the delta frequency band (0.2-2 Hz) that is causally linked to sleep. The dFBN ensemble contains rhythmic cells whose membrane voltages oscillate in anti-phase between hyperpolarized DOWN and depolarized UP states releasing bursts of action potentials. The oscillations rely on direct interhemispheric competition of two inhibitory half-centers connected by glutamatergic synapses. Interference with glutamate release from dFBNs disrupts SWA and baseline as well as rebound sleep, while the optogenetic replay of SWA (with the help of intersectional, dFBN-restricted drivers) induces sleep. dFBNs generate SWA throughout the sleep-wake cycle-- despite a mutually antagonistic flip-flop arrangement with arousing dopaminergic neurons--but adjust its power to sleep need via an interplay of sleep history-dependent increases in excitability and homeostatic depression of their efferent synapses, as we demonstrate transcriptionally, structurally, functionally, and with a simple computational model. The oscillatory format permits a durable encoding of sleep pressure over long time scales but requires downstream mechanisms that convert the amplitude-modulated periodic signal into binary sleep-wake states.

neuroscience↗

bioRxiv2024

Sleep pressure accumulates in a voltage-gated lipid peroxidation memory

Voltage-gated potassium (KV) channels contain cytoplasmic {beta}-subunits whose aldo-keto reductase activity is required for the homeostatic regulation of sleep. Here we show that Hyperkinetic, the {beta}-subunit of the KV1 channel Shaker in Drosophila, forms a dynamic lipid peroxidation memory. Information is stored in the oxidation state of Hyperkinetics nicotinamide adenine dinucleotide phosphate (NADPH) cofactor, which changes when lipid-derived carbonyls, such as 4-oxo-2-nonenal or an endogenous analog generated by illuminating a membrane-bound photosensitizer, abstract an electron pair. NADP+ remains locked in the active site of KV{beta} until membrane depolarization permits its release and replacement with NADPH. Sleep-inducing neurons use this voltage-gated oxidoreductase cycle to encode their recent lipid peroxidation history in the collective binary states of their KV{beta}-subunits; this biochemical memory influences--and is erased by--spike discharges driving sleep. The presence of a lipid peroxidation sensor at the core of homeostatic sleep control suggests that sleep protects neuronal membranes against oxidative damage. Indeed, brain phospholipids are depleted of vulnerable polyunsaturated fatty acyl chains after enforced waking, and slowing the removal of their carbonylic breakdown products increases the demand for sleep.

neuroscience↗

bioRxiv2024

Mitochondrial origins of the pressure to sleep

To obtain a comprehensive, unbiased view of molecular changes in the brain that may underpin the need for sleep, we have characterized the transcriptomes of single cells isolated from rested and sleep-deprived flies. Transcripts upregulated after sleep deprivation, in sleep-control neurons projecting to the dorsal fan-shaped body (dFBNs) but not ubiquitously in the brain, encode almost exclusively proteins with roles in mitochondrial respiration and ATP synthesis. These gene expression changes are accompanied by mitochondrial fragmentation, enhanced mitophagy, and an increase in the number of contacts between mitochondria and the endoplasmic reticulum, creating conduits for the replenishment of peroxidized lipids. The morphological changes are reversible after recovery sleep and blunted by the installation of an electron overflow in the respiratory chain. Inducing or preventing mitochondrial fission or fusion in dFBNs alters sleep and the electrical properties of sleep-control cells in opposite directions: hyperfused mitochondria increase, whereas fragmented mitochondria decrease, neuronal excitability and sleep. ATP levels in dFBNs rise after enforced waking because of diminished ATP consumption during the arousal-mediated inhibition of these neurons, which predisposes them to heightened oxidative stress. Consistent with this view, uncoupling electron flux from ATP synthesis relieves the pressure to sleep, while exacerbating mismatches between electron supply and ATP demand (by powering ATP synthesis with a light-driven proton pump) promotes sleep. Sleep, like ageing, may be an inescapable consequence of aerobic metabolism.

neuroscience↗

bioRxiv2020

Changes in presynaptic gene expression during homeostatic compensation at a central synapse

Homeostatic matching of pre- and postsynaptic function has been observed in many species and neural structures, but whether transcriptional changes contribute to this form of trans-synaptic coordination remains unknown. To identify genes whose expression is altered in presynaptic neurons as a result of perturbing postsynaptic excitability, we applied a transcriptomics-friendly, temperature-inducible Kir2.1-based activity clamp at the first synaptic relay of the Drosophila olfactory system, a central synapse known to exhibit trans-synaptic homeostatic matching. Twelve hours after adult-onset suppression of activity in postsynaptic antennal lobe projection neurons, we detected changes in the expression of many genes in the third antennal segment, which houses the somata of presynaptic olfactory receptor neurons. These changes affected genes with roles in synaptic vesicle release and synaptic remodeling, including several genes implicated in homeostatic plasticity at the neuromuscular junction. At 48 hours and beyond, the transcriptional landscape was tilted toward proteostasis, energy metabolism, and cellular stress defenses, indicating that the system had been pushed to its homeostatic limits. Our data provide insights into the nature of homeostatic compensation at a central synapse and identify many genes engaged in synaptic homeostasis. The presynaptic transcriptional response to genetically targeted postsynaptic perturbations could be exploited for the construction of novel connectivity tracing tools. Significance StatementHomeostatic feedback mechanisms adjust intrinsic and synaptic properties of neurons to keep their average activity levels constant. We show that, at a central synapse in the fruit fly brain, these mechanisms include changes in presynaptic gene expression that are instructed by an abrupt loss of postsynaptic excitability. The trans-synaptically regulated genes have roles in synaptic vesicle release and synapse remodeling; protein synthesis, folding, and degradation; and energy metabolism. Our analysis suggests that similar homeostatic machinery operates at peripheral and central synapses, identifies some of its components, and potentially opens new opportunities for the development of connectivity-based gene expression systems.

neuroscience↗