Abstract: We seek to determine how physiological processes are integrated with the regulation of circadian rhythms and sleep. We recently identified a circadian rhythm of permeability in the blood brain barrier (BBB) of flies and mammals. In Drosophila, efflux transporters pump small lipophilic molecules, including xenobiotics, out of the brain during the daytime. Transporter activity is regulated by daily cycles of magnesium, which in turn are driven by rhythmic gap junction expression between two cell layers of the BBB. This mechanism confers circadian permeability onto many molecules, including the anti-epileptic phenytoin, which has time-of-day specific effects in a fly seizure model. I will discuss mechanisms underlying the rhythmic permeability of the mammalian BBB.
A recent screen of >12,000 lines that inducibly over-expressed random genes across the Drosophila genome in the nervous system identified a single sleep-promoting molecule: nemuri, an anti-microbial peptide. nemuri is induced by stress, which includes sleep deprivation and bacterial infection, and is capable of killing bacteria and driving sleep. Ongoing work examines the mechanisms that account for nemuri induction by stress.
Biography: Amita Sehgal is the John Herr Musser Professor of Neuroscience, an Investigator of the Howard Hughes Medical Institute, and Director of the Chronobiology and Sleep Institute at the University of Pennsylvania. She received her Ph.D. from the Weill Graduate School of Cornell University and conducted postdoctoral work with Michael Young at Rockefeller University. Sehgal is President-elect of the Society for Research on Biological Rhythms and a member of the US National Academy of Medicine (formerly the Institute of Medicine), the American Academy of Arts and Sciences, and the National Academy of Sciences.
For further information, please contact Fiona Woods at fiona.woods@cncb.ox.ac.uk
A potassium channel ß-subunit couples mitochondrial electron transport to sleep
Sleep, ageing and the fires of life
Sleep deprivation elevates mitochondrial reactive oxygen species in sleep-promoting neurons, which register this rise with the help of a redox-sensitive ion channel. The resulting changes in electrical excitability close a molecular feedback loop that leads to the induction of sleep.
It is no accident that oxygen tanks carry explosion hazard labels: uncontrolled combustion is dangerous.
Humans and animals face similar risks when they use the oxygen they breathe to convert food into energy. To contain these risks, food is combusted in specialised structures called mitochondria, which are present in virtually every cell. Mitochondrial combustion is tightly controlled but not failsafe. When a cell’s mitochondria are supplied with more fuel than the cell can use, the cell suffers ‘oxidative stress’.
Oxidative stress is believed to be a reason for why we age and a culprit for the degenerative diseases that blight our later years. Diets that restrict caloric intake may be beneficial because they limit the amount of fuel mitochondria can burn.
Writing in the journal Nature, the Miesenböck group now report that oxidative stress is also a root cause of sleep. The team studied the regulation of sleep in fruit flies. Each fly has around two dozen sleep-control neurons, brain cells that are also found in other animals and thought to exist in people. In previous research, Miesenböck’s team discovered that these sleep-control neurons act as an on–off switch: If the neurons are electrically active, the fly is asleep; when they are silent, the fly is awake.
Seoho Song, one of the two lead authors of the new study, says: ‘We decided to look for the signals that switch the sleep-control neurons on. We knew from our earlier work that a main difference between sleep and waking is how much electrical current flows through two ion channels, called Shaker and Sandman. During sleep, most of the current goes through Shaker.’
Ion channels generate and control the electrical impulses through which brain cells communicate.
‘This turned the big, intractable question “Why do we sleep?” into a concrete, solvable problem,’ says Song: ‘What causes the electrical current to flow through Shaker?’
The team found the answer in a component of the Shaker channel itself.
Lead author Anissa Kempf explains: ‘Suspended underneath the electrically conducting portion of Shaker is its β-subunit, like the gondola under a hot air ballon. A passenger in the gondola, the small molecule NADPH, flips back and forth between two chemical states; this regulates the Shaker current. The state of NADPH, in turn, reflects the degree of oxidative stress the cell has experienced. Sleeplessness causes oxidative stress, which drives the conversion.’
In a striking demonstration of this mechanism, a flash of light that flipped the chemical state of NADPH put flies to sleep.
Drugs that change the chemistry of Shaker-bound NADPH in an analogous manner could be a powerful new type of sleeping pill. ‘Sleep disturbances are very common,’ says Miesenböck, ‘and sleeping pills are among the most commonly prescribed medicines. But existing drugs carry risks of confusion, forgetfulness and addiction. Targeting the mechanism we have discovered could possibly avoid some of these side effects.’
Mechanisms of sensory discrimination: Insights from Drosophila olfaction
Rumford Prize 2018
Gero Miesenböck is among the recipients of the 2018 Rumford Prize. He is honoured for the invention of optogenetics, along with colleagues responsible for subsequent refinements.
The Rumford Prize, awarded by the American Academy of Arts and Sciences, is one of the oldest scientific prizes in the United States. It recognises contributions to the fields of ‘heat and light’, widely interpreted. Previous recipients include Josiah Willard Gibbs, Albert Michelson, Thomas Edison, Enrico Fermi and George Wald.
Gero Miesenböck awarded an ERC Advanced Grant
Gero Miesenböck was awarded and ERC Advanced Grant to investigate the homeostatic regulation and biological function of sleep. The project will seek to identify the molecular changes that drive sleep-inducing neurons in the fly brain into the electrically active state.
Gero said: ‘I’m thrilled this worked out—especially since this may have been the last chance for UK residents to apply. The ERC is one of the very few funding agencies that understand “the usefulness of useless knowledge“, to quote Abraham Flexner’s famous argument for curiosity-driven research.’
The Somnostat
Hans-Ulrich Dodt
Abstract: Optics involving extremely long, thin sheets of light and a vastly increased Rayleigh range (achieved by breaking the diffraction limit of light sheets of low numerical aperture) allow an elegant application of ultramicroscopy to large samples, such as whole mouse brains or Drosophila. Due to the extremely low divergence of the light sheets, brains can be reconstructed from a single stack of optical sections with nearly isotropic resolution that reaches the single-spine level at higher magnification. Ultramicroscopy can be applied to samples of ever-increasing size. Large pieces of human tumors that have been cleared and stained by a new superfast clearing procedure can be imaged intraoperatively in three dimensions. Optically identified malignancies were subsequently confirmed by standard histological sectioning. We predict that ultramicroscopy of cleared tumors will play an increasingly important role in pathological diagnostics.
Biography: Hans-Ulrich Dodt studied medicine and physics at the Universities of Freiburg and Heidelberg. He was a postdoctoral fellow with Dieter Lux at the Max-Planck-Institute of Psychiatry and worked with Walter Zieglgänsberger on the development of infrared videomicroscopy. As a group leader in Munich, he began work on solvent-based tissue clearing methods in combination with light-sheet microscopy. In 2007 he was appointed to a Professorship of Bioelectronics at the Technical University of Vienna, where he holds a joint appointment at the Center for Brain Science of the Medical University
Lukas Sjulson
Abstract: Conditioned place preference (CPP) is a widely used model of addiction-related behavior whose underlying mechanisms are not understood. We used dual-site silicon optoprobe recordings in freely moving mice to examine interactions between the hippocampus and nucleus accumbens in cocaine CPP. We found that CPP was associated with recruitment of D2-positive nucleus accumbens medium spiny neurons to fire in the cocaine-paired location, and this recruitment was driven predominantly by selective strengthening of coupling with hippocampal place cells that encode the cocaine-paired location. These findings suggest that the synaptic potentiation in the accumbens caused by repeated cocaine administration preferentially affects inputs that were active at the time of drug exposure and provide a potential physiological mechanism by which drug use becomes associated with specific environmental contexts.
Biography:Luke Sjulson is Assistant Professor in the Departments of Psychiatry and Neuroscience at Albert Einstein College of Medicine. He studied neuroscience at Johns Hopkins before completing his MD at Cornell and his PhD at Sloan-Kettering and Yale in the laboratory of Gero Miesenbӧck, where he worked on the development of genetically-encoded voltage indicators. He then completed residency in adult psychiatry at NYU and a postdoctoral fellowship in the laboratories of Gordon Fishell and Gyӧrgy Buzsáki, where he studied the role of hippocampus-ventral striatum interactions in cocaine addiction. His research combines behavior, neurophysiology, optical techniques, and computational approaches to study the neural substrates of drug addiction, with the goal of developing novel treatments based on clinical neuromodulation.