Brain Development: Why the young sleep longer
A transcription factor helps young flies to sleep longer by delaying the maturation of a neural network that controls sleep.
- Advanced Science Research Center, The Graduate Center, The City University of New York, United States
From absorbing new languages to mastering musical instruments, young children are wired to learn in ways that adults are not (Johnson and Newport, 1989). This ability coincides with periods of intense brain plasticity during which neurons can easily remodel their connections (Hubel and Wiesel, 1970). Many children are also scandalously good sleepers, typically getting several more hours of sleep per night than their parents (Jenni and Carskadon, 2007). As sleep deprivation has negative effects on learning and memory, learning like a child likely requires sleeping like one (Diekelmann and Born, 2010). Yet, how the ability to sleep for longer is synchronized with windows of high brain plasticity is not fully understood.
Sleep is deeply conserved through evolution, and examining how it develops in ‘simple organisms’ should provide fundamental insights relevant to humans. For instance, like human teenagers, one-day old Drosophila melanogaster flies sleep twice as much as mature adults, and disrupting the sleep of young flies has lasting effects on learning and behavior (Seugnet et al., 2011; Kayser et al., 2014). Now, in eLife, Matthew Kayser from the University of Pennsylvania and co-workers – including Leela Chakravarti Dilley as first author – report new regulatory mechanisms that promote sleep in young flies (Chakravarti Dilley et al., 2020).
The team started by searching for genes which, when knocked down, would reduce the difference in sleep duration between younger and older adult flies. A gene called pdm3 fit the bill by reducing sleep in juveniles. This gene codes for a transcription factor that belongs to a family known to regulate normal brain development. Chakravarti Dilley et al. further determined that pdm3 helps to establish correct sleep patterns for one-day-old flies during the pupal stage, when the relatively simple brain of a larva develops into the complex brain of the adult insect – a period of radical change that puts human puberty to shame.
Previous work on pdm3 mutants revealed aberrations in the way dopaminergic neurons reach and connect with neurons in the central complex, a region of the brain that is known to regulate sleep. There, the dopaminergic neurons encourage wakefulness by inhibiting cells called dFSB neurons, which promote sleep (Pimentel et al., 2016). In flies, the density of connections between dopaminergic and dFSB neurons normally increases over the first few days of adult life. Chakravarti Dilley et al. therefore explored whether pdm3 might regulate how dopaminergic neurons innervate the central complex. This revealed that when pdm3 was knocked down, one-day-old flies already showed levels of innervation that rivaled those seen in mature adults (Figure 1).
Figure 1
How the transcription factor pdm3 preserves high levels of sleep in young flies.
Expression of pdm3 during the pupal stage (top row) delays the innervation of the dFSB neurons (which promote sleep) by dopaminergic neurons (green) that encourage wakefulness. The progressive innervation of these neurons as the fly ages results in adult flies (dark) spending less time asleep than young flies (pale). Knock down of pdm3 (bottom row) results in premature innervation, leading to young flies spending much less time asleep. dFSB: dorsal fan-shaped body; DA: dopaminergic.
Given that pdm3 encodes a transcription factor, the team then searched for genes that regulate sleep and whose expression was altered by pdm3 being knocked down. These experiments suggested that pdm3 suppresses the expression of msp300, a gene from a family involved in synapse maturation. And indeed, knocking down both pdm3 and msp300 resulted in flies that developed normally in terms of sleep patterns and dopaminergic innervation of the central complex.
Perturbing neural development, especially during windows of high plasticity, can have a long-lasting impact on the ability for the brain to work properly (Marín, 2016). A lack of sleep could lead to such perturbations, as evidenced by the fact that disrupting sleep in early childhood or adolescence has long-term effects on behavior (Taveras et al., 2017; Roberts et al., 2009). Understanding how sleep is synchronized with periods of intense development may help to develop better therapeutic interventions that lessen long-term brain damage.
References
-
The memory function of sleepNature Reviews Neuroscience 11:114–126.https://doi.org/10.1038/nrn2762
-
The period of susceptibility to the physiological effects of unilateral eye closure in kittensThe Journal of Physiology 206:419–436.https://doi.org/10.1113/jphysiol.1970.sp009022
-
Sleep behavior and sleep regulation from infancy through adolescence: normative aspectsSleep Medicine Clinics 2:321–329.https://doi.org/10.1016/j.jsmc.2007.05.001
-
Sleepless in adolescence: prospective data on sleep deprivation, health and functioningJournal of Adolescence 32:1045–1057.https://doi.org/10.1016/j.adolescence.2009.03.007
Article and author information
Author details
Publication history
Copyright
© 2020, Chowdhury and Shafer
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,935
- views
-
- 157
- downloads
-
- 2
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Brain Development: Why the young sleep longer
eLife 9:e56833.
https://doi.org/10.7554/eLife.56833
Further reading
-
- Genetics and Genomics
Recent studies have revealed a role for zinc in insulin secretion and glucose homeostasis. Randomized placebo-controlled zinc supplementation trials have demonstrated improved glycemic traits in patients with type II diabetes (T2D). Moreover, rare loss-of-function variants in the zinc efflux transporter SLC30A8 reduce T2D risk. Despite this accumulated evidence, a mechanistic understanding of how zinc influences systemic glucose homeostasis and consequently T2D risk remains unclear. To further explore the relationship between zinc and metabolic traits, we searched the exome database of the Regeneron Genetics Center-Geisinger Health System DiscovEHR cohort for genes that regulate zinc levels and associate with changes in metabolic traits. We then explored our main finding using in vitro and in vivo models. We identified rare loss-of-function (LOF) variants (MAF <1%) in Solute Carrier Family 39, Member 5 (SLC39A5) associated with increased circulating zinc (p=4.9 × 10-4). Trans-ancestry meta-analysis across four studies exhibited a nominal association of SLC39A5 LOF variants with decreased T2D risk. To explore the mechanisms underlying these associations, we generated mice lacking Slc39a5. Slc39a5-/- mice display improved liver function and reduced hyperglycemia when challenged with congenital or diet-induced obesity. These improvements result from elevated hepatic zinc levels and concomitant activation of hepatic AMPK and AKT signaling, in part due to zinc-mediated inhibition of hepatic protein phosphatase activity. Furthermore, under conditions of diet-induced non-alcoholic steatohepatitis (NASH), Slc39a5-/- mice display significantly attenuated fibrosis and inflammation. Taken together, these results suggest SLC39A5 as a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD) due to metabolic derangements including T2D.
-
- Developmental Biology
- Genetics and Genomics
Repurposing of pleiotropic factors during execution of diverse cellular processes has emerged as a regulatory paradigm. Embryonic development in metazoans is controlled by maternal factors deposited in the egg during oogenesis. Here, we explore maternal role(s) of Caspar (Casp), the Drosophila orthologue of human Fas-associated factor-1 (FAF1) originally implicated in host-defense as a negative regulator of NF-κB signaling. Maternal loss of either Casp or it’s protein partner, transitional endoplasmic reticulum 94 (TER94) leads to partial embryonic lethality correlated with aberrant centrosome behavior, cytoskeletal abnormalities, and defective gastrulation. Although ubiquitously distributed, both proteins are enriched in the primordial germ cells (PGCs), and in keeping with the centrosome problems, mutant embryos display a significant reduction in the PGC count. Moreover, the total number of pole buds is directly proportional to the level of Casp. Consistently, it’s ‘loss’ and ‘gain’ results in respective reduction and increase in the Oskar protein levels, the master determinant of PGC fate. To elucidate this regulatory loop, we analyzed several known components of mid-blastula transition and identify the translational repressor Smaug, a zygotic regulator of germ cell specification, as a potential critical target. We present a detailed structure-function analysis of Casp aimed at understanding its novel involvement during PGC development.
