Neurons that make flies sleep

Sleep is known to be regulated by both intrinsic (what time is it?) and environmental factors (is it hot today?). How exactly these factors are integrated at the cellular level is a hot topic for investigation, given the prevalence of sleep disorders. Researchers in the Rosbash and Griffith labs are pursuing the question in the fruit fly Drosophila melanogaster, to take advantage of the genetic tools in the model system and the excellent understanding of circadian rhythms in the fly.

Like other animals, the fruit fly displays a robust activity/sleep pattern, which consists of a morning (M) activity peak, a middle-day siesta, an evening (E) activity peak and nighttime sleep. M and E peaks are controlled by different subgroups of circadian neurons such as wake-promoting M and E clock cells.

In a paper just published in Nature, Brandeis postdoctoral fellow Fang Guo and coworkers identify a small group of circadian neurons, a subset of the glutamatergic DN1 (gDN1s) cells, which have a critical role in both types of regulation. The authors manipulated the gDN1s activity by using recently developed optogenetics tools, and found activity of those neurons is both necessary and sufficient to promote sleep.

circadian-feedback

The cartoon model illustrates how the circadian neuron negative feedback set the timing of activity and siesta of Drosophila. The arousal-promoting M cells (sLNv) release pigment-dispersing factor (PDF) peptide to promote M activity at dawn. PDF peptide can activate gDN1s, which release glutamate to inhibit arousal-promoting M and E (LNds) cells and cause a middle-day siesta. At evening, the gDN1s activity is reduced to trough levels and release E cell activity from inhibition.

DN1s enhance baseline sleep by acting as feedback inhibitors of previously identified wake-promoting M and E clock cells, making them the first known sleep-promoting neurons in this circadian circuit. It is already known that M cell can activate gDN1s at dawn. Thus the daily activity-sleep pattern of Drosophila is timed by the circadian neuron negative feedback circuitry (see Figure).  More interestingly, by using in vivo calcium reporters, the authors reveal that the activity of the gDN1s is also shown to be sexually dimorphic, explaining the well-known difference in daytime sleep between males and females. DN1s also have a key role in mediating the effects of temperature on daytime sleep. The circadian and environmental responsiveness of gDN1s positions them to be key players in shaping sleep to the needs of the individual animal.

Authors on the paper include postdocs Guo, Junwei Yu and Weifei Luo, staff member Kate Abruzzi, and Brandeis graduate Hyung Jae Jung ’15 (Biology/HSSP).

Guo F, Yu J, Jung HJ, Abruzzi KC, Luo W, Griffith LC, Rosbash M. Circadian neuron feedback controls the Drosophila sleep-activity profile. Nature. 2016.

Fruit flies alter their sleep to beat the heat

Do you have trouble sleeping at night in the summer when it is really hot?

Does a warm sunny day make you want to take a nap?

You are not alone — fruit flies also experience changes in their sleep patterns when ambient temperature is high. In a new paper in Current Biology, research scientist Katherine Parisky and her co-workers from the Griffith lab show that hot temperatures cause animals to sleep more during the day and less at night, and then investigate the mechanisms governing the behavior.

The increase in daytime sleep is caused by a complex interplay between light and the circadian clock. The balance between daytime gains and nighttime losses at high temperatures is also influenced by homeostatic processes that work to keep total daily sleep amounts constant. This study shows how the nervous system deals with changes caused by environmental conditions to maintain normal operations.

Parisky KM, Agosto Rivera JL, Donelson NC, Kotecha S, Griffith LC. Reorganization of Sleep by Temperature in Drosophila Requires Light, the Homeostat, and the Circadian Clock. Curr Biol. 2016.

Hall, Rosbash and Young Share Shaw Prize in Life Science and Medicine

The 10th annual Shaw Prize in Life Science and Medicine has been awarded jointly to Michael Rosbash and Jeffrey Hall of Brandeis and Michael Young of Rockefeller University. The trio are once again being honored for their discovery of molecular mechanisms underlying circadian rhythms. Hall is Emeritus Professor of Biology at Brandeis, and Rosbash is Peter Gruber Endowed Chair in Neuroscience, Professor of Biology, and Howard Hughes Medical Institute Investigator.

The Shaw Prize, established under the auspices of Mr Run Run Shaw, honours individuals, regardless of race, nationality, gender and religious belief, who have achieved significant breakthrough in academic and scientific research or applications and whose work has resulted in a positive and profound impact on mankind. There are three annual prizes: Astronomy, Life Science and Medicine, and Mathematical Sciences, each bearing a monetary award of one million US dollars. The presentation ceremony is scheduled for Monday, 23 September 2013.

Update: There a couple of really nice videos on YouTube from the Pearl Report (TVB in Hong Kong) that discuss the science and the history behind this prize.

Hall, Rosbash, and Young share Wiley Prize

menetfig1The 12th annual Wiley Prize in Biomedical Sciences has been awarded jointly to Michael Rosbash and Jeffrey Hall of Brandeis and Michael Young of Rockefeller University. The trio are once again being honored for their work on the molecular mechanisms governing circadian rhythms (see more on this site)

It’s not all transcription! New insights on how biological rhythms are generated

Sleepy during the day? Hungry at night? You should check your biological clock!

As in every organism, humans are exposed to daily variations of their environment. There is obviously the day/night cycle, but significant variations of temperature and humidity also occur in temperate regions of the globe. To survive to these environmental changes, organisms have evolved so that their biology, biochemistry, physiology and behavior are rhythmically regulated on a 24hr-basis. Humans are no exception, and most (if not all) of our biological functions are set to function optimally at the most appropriate time of the day. For example, the physiology of muscle cells is rhythmic so that their capacity of coping with physical activity is maximal during the day.

A lot of progress has been made over the last two decades to uncover the molecular underpinnings of circadian (for circa, about and dies, day) rhythms. To keep the story short, in all eukaryotes the circadian system relies on transcriptional feedback loops that operate at the level of individual cells (see figure 1). In mammals, these loops are composed of the two transcription factors CLK and BMAL1, which act as a heterodimeric complex to activate the expression of the transcriptional repressors Period (Per1, Per2 and Per3) and Cryptochrome (Cry1 and Cry2). When expressed, these repressor proteins are post-translationally modified (e.g., phosphorylation) and feedback to inhibit the transcriptional activity of CLK:BMAL1. As a result, transcription of Per and Cry genes is shut-off. The progressive degradation of the PER and CRY proteins then leads to a new cycle of CLK:BMAL1-mediated transcription. Importantly, these transcriptional oscillations regulate the rhythmic expression of a large fraction of the transcriptome (up to 10-15% of all mRNAs). These output genes, also called “clock-controlled genes”, are rhythmically regulated in a tissue-specific manner, and are responsible for the daily oscillations of biological functions.

As in other biological systems, it is generally assumed that daily variations of mRNA levels are a direct consequence of transcription regulation. However, there is growing evidence that post-transcriptional events such as mRNA splicing, polyadenylation, nuclear export and half-life also contribute to changes in the amount of mRNA expressed by particular genes. Such post-transcriptional processes are known to have a role in other areas of cell biology but until very recently this had not been studied in detail at a genome-wide level.

This is the question addressed by Jerome Menet, Joseph Rodriguez, Katharine Abruzzi and Michael Rosbash, in a paper recently published at eLife (Menet et al., 2012). The authors directly assayed rhythmic transcription by measuring the amount of nascent RNA being produced at a given time, six times a day, across all the genes in mouse liver cells using a high-throughput sequencing approach called Nascent-Seq (see figure 2). They compared this with the amount of liver mRNA expressed at six time points of the day. Although the authors found that many genes exhibit rhythmic mRNA expression in the mouse liver, about 70% of them did not show comparable transcriptional rhythms. Post-transcriptional regulations have therefore a major role in the circadian system of mice. Interestingly, similar experiments performed by Joe Rodriguez in the Rosbash lab using Drosophila as the model system led to the same conclusions, suggesting that the contribution of post-transcriptional events to the generation of circadian rhythms is common to all animals (Rodriguez et al., in press).

To assess the contribution of the core molecular clock to genome-wide transcriptional rhythms, Menet et al. also examined how rhythmic CLK:BMAL1 DNA binding directly affects the transcription of its target genes. They found that although maximal binding occurs at an apparently uniform phase, the peak transcriptional phases of CLK:BMAL1 target genes are heterogeneous, which indicates a disconnect between CLK:BMAL1 DNA binding and its transcriptional output.

The data taken together reveal novel regulatory features of rhythmic gene expression and illustrate the potential of Nascent-Seq as a genome-wide assay technique for exploring a range of questions related to gene expression and gene regulation.

Menet JS, Rodriguez J, Abruzzi KC, Rosbash M. Nascent-Seq Reveals Novel Features of Mouse Circadian Transcriptional Regulation. elife. 2012;1:e00011. doi: 10.7554/eLife.00011.

Rodriguez J, Tang CHA, Khodor YL, Vodala S, Menet JS, Rosbash M. Post-transcriptional events regulate genome-wide rhythmic gene expression in Drosophila. Proc Natl Acad Sci U S A. (In press).

Massry Prize for Hall, Rosbash, and Young

Brandeis scientists Michael Rosbash and Jeff Hall, along with Michael Young (Rockefeller Univ.) will receive the 2012 Massry Prize, according to Brandeis NOW. The prize, established in 1996 by the Meira and Shaul G. Massry Foundation,   honors “outstanding contributions to the biomedical sciences and the advancement of health“. This trio of researchers has garnered several prizes already for their contributions to understanding the mechanisms underlying circadian rhythms.

The winners will receive the prize and present lectures on October 29, 2012 at the University of Southern California.

There will be a couple of opportunities to hear Michael Rosbash talk about circadian rhythms locally, first at the Inaugural Lecture for the Gruber chair on Thursday, then at the Brandeis Café Science fall season opener on October 1.

 

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