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Complex behaviors arise from neural circuits that assemble from diverse cell types. Sleep is a conserved behavior essential for survival, yet little is known about how the nervous system generates neuron types of a sleep-wake circuit. Here, we focus on the specification of Drosophila 23E10-labeled dorsal fan-shaped body (dFB) long-field tangential input neurons that project to the dorsal layers of the fan-shaped body neuropil in the central complex. We use lineage analysis and genetic birth dating to identify two bilateral type II neural stem cells (NSCs) that generate 23E10 dFB neurons. We show that adult 23E10 dFB neurons express ecdysone-induced protein 93 (E93) and that loss of ecdysone signaling or E93 in type II NSCs results in their misspecification. Finally, we show that E93 knockdown in type II NSCs impairs adult sleep behavior. Our results provide insight into how extrinsic hormonal signaling acts on NSCs to generate the neuronal diversity required for adult sleep behavior. These findings suggest that some adult sleep disorders might derive from defects in stem cell-specific temporal neurodevelopmental programs. [Display omitted] • Sleep-regulating 23E10 dFB neurons originate from late larval type II NSCs • DL1 and DM1 type II NSCs specifically produce 23E10 dFB neurons • Ecdysone signaling in type II NSCs is essential for 23E10 dFB neuronal fate • E93 in type II NSCs regulates 23E10 dFB neuronal fate and sleep homeostasis Wani et al. identify NSCs that generate sleep-regulating 23E10 dFB neurons. They find that ecdysone signaling and E93 in type II NSCs are essential for proper 23E10 dFB neuronal fate. Disruption of E93 expression in type II NSCs causes sleep abnormalities, suggesting that developmental hormonal signaling is critical for adult sleep behavior. [ABSTRACT FROM AUTHOR]

Developing tissues are patterned in space and time; this enables them to differentiate their cell types and form complex structures to support different body plans. Although space and time are two independent entities, there are many examples of spatial patterns that originate from temporal ones. The most prominent example is the expression of the genes hunchback, Krüppel, pdm, and castor, which are expressed temporally in the neural stem cells of the Drosophila ventral nerve cord and spatially along the anteroposterior axis of the blastoderm stage embryo. In this Viewpoint, we investigate the relationship between space and time in specific examples of spatial and temporal patterns with the aim of gaining insight into the evolutionary history of patterning. [ABSTRACT FROM AUTHOR]

Neuroblasts in Drosophila divide asymmetrically, sequentially expressing a series of intrinsic factors to generate a diversity of neuron types. These intrinsic factors known as temporal factors dictate timing of neuroblast transitions in response to steroid hormone signaling and specify early versus late temporal fates in neuroblast neuron progeny. After completing their temporal programs, neuroblasts differentiate or die, finalizing both neuron number and type within each neuroblast lineage. From a screen aimed at identifying genes required to terminate neuroblast divisions, we identified Notch and Notch pathway components. When Notch is knocked down, neuroblasts maintain early temporal factor expression longer, delay late temporal factor expression, and continue dividing into adulthood. We find that Delta, expressed in cortex glia, neuroblasts, and after division, their GMC progeny, regulates neuroblast Notch activity. We also find that Delta in neuroblasts is expressed high early, low late, and is controlled by the intrinsic temporal program: early factor Imp promotes Delta, late factors Syp/E93 reduce Delta. Thus, in addition to systemic steroid hormone cues, forward lineage progression is controlled by local cell-cell signaling between neuroblasts and their cortex glia/GMC neighbors: Delta transactivates Notch in neuroblasts bringing the early temporal program and early temporal factor expression to a close.

During the development of the central nervous system (CNS), extremely large numbers of neurons are produced in a regular fashion to form precise neural circuits. During this process, neural progenitor cells produce different neurons over time due to their intrinsic gene regulatory mechanisms as well as extrinsic mechanisms. The Drosophila CNS has played an important role in elucidating the temporal mechanisms that control neurogenesis over time. It has been shown that a series of temporal transcription factors are sequentially expressed in neural progenitor cells and regulate the temporal specification of neurons in the embryonic CNS. Additionally, similar mechanisms are found in the developing optic lobe and central brain in the larval CNS. However, it is difficult to elucidate the function of numerous molecules in many different cell types solely by molecular genetic approaches. Recently, omics analysis using single-cell RNA-seq and other methods has been used to study the Drosophila nervous system on a large scale and is making a significant contribution to the understanding of the temporal mechanisms of neurogenesis. In this article, recent findings on the temporal patterning of neurogenesis and the contributions of cutting-edge technologies will be reviewed.

Proper functioning of the nervous system relies not only on the generation of a vast repertoire of distinct neural cell types but also on the precise neural circuitry within them. How the generation of highly diverse neural populations is regulated during development remains a topic of interest. Landmark studies in Drosophila have identified the genetic and temporal cues regulating neural diversity and thus have provided valuable insights into our understanding of temporal patterning of the central nervous system. The development of the Drosophila central complex, which is mostly derived from type II neural stem cell (NSC) lineages, showcases how a small pool of NSCs can give rise to vast and distinct progeny. Similar to the human outer subventricular zone (OSVZ) neural progenitors, type II NSCs generate intermediate neural progenitors (INPs) to expand and diversify lineages that populate higher brain centers. Each type II NSC has a distinct spatial identity and timely regulated expression of many transcription factors and mRNA binding proteins. Additionally, INPs derived from them show differential expression of genes depending on their birth order. Together type II NSCs and INPs display a combinatorial temporal patterning that expands neural diversity of the central brain lineages. We cover advances in current understanding of type II NSC temporal patterning and discuss similarities and differences in temporal patterning mechanisms of various NSCs with a focus on how cell-intrinsic and extrinsic hormonal cues regulate temporal transitions in NSCs during larval development. Cell extrinsic ligands activate conserved signaling pathways and extrinsic hormonal cues act as a temporal switch that regulate temporal progression of the NSCs. We conclude by elaborating on how a progenitor's temporal code regulates the fate specification and identity of distinct neural types. At the end, we also discuss open questions in linking developmental cues to neural identity, circuits, and underlying behaviors in the adult fly. [ABSTRACT FROM AUTHOR]

The nervous system consists of a vast diversity of neurons and glia that are accurately assembled into functional circuits. What are the mechanisms that generate these diverse cell types? During development, an epithelial sheet with neurogenic potential is initially regionalised into spatially restricted domains of gene expression. From this, pools of neural stem cells (NSCs) with distinct molecular profiles and the potential to generate different neuron types, are specified. These NSCs then divide asymmetrically to self-renew and generate post-mitotic neurons or glia. As NSCs age, they experience transitions in gene expression, which further allows them to generate different neurons or glia over time. Versions of this general template of spatial and temporal patterning operate during the development of different parts of different nervous systems. Here, I cover our current knowledge of Drosophila brain and optic lobe development as well as the development of the vertebrate cortex and spinal cord within the framework of this above template. I highlight where our knowledge is lacking, where mechanisms beyond these might operate, and how the emergence of new technologies might help address unanswered questions. [ABSTRACT FROM AUTHOR]

The generation of neuronal diversity involves temporal patterning mechanisms by which a given progenitor sequentially produces multiple cell types. Several parallels are evident between the brain development programs of Drosophila and vertebrates, such as the successive emergence of specific cell types and the use of combinations of transcription factors to specify cell fates. Furthermore, cell-extrinsic cues such as hormones and signaling pathways have also been shown to be regulatory modules of temporal patterning. Recently, transcriptomic and epigenomic studies using large single-cell sequencing datasets have provided insights into the transcriptional dynamics of neurogenesis in the Drosophila and mammalian central nervous systems. We review these commonalities in the specification of neuronal identity and highlight the conserved or convergent strategies of brain development by discussing temporal patterning mechanisms found in flies and vertebrates. [ABSTRACT FROM AUTHOR]

A key problem in development is to understand how genes turn on or off at the right place and right time during embryogenesis. Such decisions are made by non-coding sequences called ‘enhancers.’ Much of our models of how enhancers work rely on the assumption that genes are activated de novo as stable domains across embryonic tissues. Such a view has been strengthened by the intensive landmark studies of the early patterning of the anterior-posterior (AP) axis of the Drosophila embryo, where indeed gene expression domains seem to arise more or less stably. However, careful analysis of gene expression patterns in other model systems (including the AP patterning in vertebrates and short-germ insects like the beetle Tribolium castaneum) painted a different, very dynamic view of gene regulation, where genes are oftentimes expressed in a wavelike fashion. How such gene expression waves are mediated at the enhancer level is so far unclear. Here, we establish the AP patterning of the short-germ beetle Tribolium as a model system to study dynamic and temporal pattern formation at the enhancer level. To that end, we established an enhancer prediction system in Tribolium based on time- and tissue-specific ATAC-seq and an enhancer live reporter system based on MS2 tagging. Using this experimental framework, we discovered several Tribolium enhancers, and assessed the spatiotemporal activities of some of them in live embryos. We found our data consistent with a model in which the timing of gene expression during embryonic pattern formation is mediated by a balancing act between enhancers that induce rapid changes in gene expression patterns (that we call ‘dynamic enhancers’) and enhancers that stabilize gene expression patterns (that we call ‘static enhancers’). However, more data is needed for a strong support for this or any other alternative models.

Temporal identity factors regulate competence of neural progenitors to generate specific cell types in a time-dependent manner, but how they operate remains poorly defined. In the developing mouse retina, the Ikaros zinc-finger transcription factor Ikzf1 regulates production of early-born cell types, except cone photoreceptors. In this study we show that, during early stages of retinal development, another Ikaros family protein, Ikzf4, functions redundantly with Ikzf1 to regulate cone photoreceptor production. Using CUT&RUN and functional assays, we show that Ikzf4 binds and represses genes involved in late-born rod photoreceptor specification, hence favoring cone production. At late stages, when Ikzf1 is no longer expressed in progenitors, we show that Ikzf4 re-localizes to target genes involved in gliogenesis and is required for Müller glia production. We report that Ikzf4 regulates Notch signaling genes and is sufficient to activate the Hes1 promoter through two Ikzf GGAA-binding motifs, suggesting a mechanism by which Ikzf4 may influence gliogenesis. These results uncover a combinatorial role for Ikaros family members during nervous system development and provide mechanistic insights on how they temporally regulate cell fate output. [ABSTRACT FROM AUTHOR]

This study contributes to research on the temporality in routines by proposing that action timing is a patterning mechanism, distinct from the sequence-based patterning that has been the focus of current research. We examine the effect of this mechanism by investigating how recurrent action timing—and its reproduction—affect the effectiveness of routine performance. We further theorize and show that multiplicity in the performative and the ostensive aspects of the routine influence the strength of timing-based patterning and its effects. We test our ideas using a unique dataset that tracks specific garbage collection actions and captures their precise timing, combined with corresponding data on customer complaints about missed collections. Our findings support our theoretical predictions and advance current understanding about different temporal patterning mechanisms in routines. [ABSTRACT FROM AUTHOR]

Amphibians, by virtue of their phylogenetic position, provide invaluable insights on nervous system evolution, development, and remodeling. The genetic toolkit for amphibians, however, remains limited. Recombinant adeno-associated viral vectors (AAVs) are a powerful alternative to transgenesis for labeling and manipulating neurons. Although successful in mammals, AAVs have never been shown to transduce amphibian cells efficiently. We screened AAVs in three amphibian species-the frogs Xenopus laevis and Pelophylax bedriagae and the salamander Pleurodeles waltl-and identified at least two AAV serotypes per species that transduce neurons. In developing amphibians, AAVs labeled groups of neurons generated at the same time during development. In the mature brain, AAVrg retrogradely traced long-range projections. Our study introduces AAVs as a tool for amphibian research, establishes a generalizable workflow for AAV screening in new species, and expands opportunities for cross-species comparisons of nervous system development, function, and evolution., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In the developing nervous system, neural stem cells (NSCs) use temporal patterning to generate a wide variety of different neuronal subtypes. In Drosophila, the temporal transcription factors, Hunchback, Kruppel, Pdm and Castor, are sequentially expressed by NSCs to regulate temporal identity during neurogenesis. Here, we identify a new temporal transcription factor that regulates the transition from the Pdm to Castor temporal windows. This factor, which we call Chronophage (or 'time-eater'), is homologous to mammalian CTIP1 (Bcl11a) and CTIP2 (Bcl11b). We show that Chronophage binds upstream of the castor gene and regulates its expression. Consistent with Chronophage promoting a temporal switch, chronophage mutants generate an excess of Pdm-specified neurons and are delayed in generating neurons associated with the Castor temporal window. In addition to promoting the Pdm to Castor transition, Chronophage also represses the production of neurons generated during the earlier Hunchback and Kruppel temporal windows. Genetic interactions with Hunchback and Kruppel indicate that Chronophage regulates NSC competence to generate Hunchback- and Kruppel-specified neurons. Taken together, our results suggest that Chronophage has a conserved role in temporal patterning and neuronal subtype specification. [ABSTRACT FROM AUTHOR]

The assembly of complex neural circuits requires that stem cells generate diverse types of neurons in the correct temporal order. Pioneering work in the Drosophila embryonic ventral nerve cord has shown that neural stem cells are temporally patterned by the sequential expression of rapidly changing transcription factors to generate diversity in their progeny. In recent years, a second temporal patterning mechanism, driven by the opposing gradients of the Imp and Syp RNA-binding proteins, has emerged as a powerful way to generate neural diversity. This long-range temporal patterning mechanism is utilized in the extended neural stem cell lineages of the postembryonic fly brain. Here, we review the role played by Imp and Syp gradients in several neural stem cell lineages, focusing on how they specify sequential neural fates through the post-transcriptional regulation of target genes, including the Chinmo and Mamo transcription factors. We further discuss how upstream inputs, including hormonal signals, modify the output of these gradients to couple neurogenesis with the development of the organism. Finally, we review the roles that the Imp and Syp gradients play beyond the generation of diversity, including the regulation of stem cell proliferation, the timing of neural stem cell lineage termination, and the coupling of neuronal birth order to circuit assembly. [ABSTRACT FROM AUTHOR]

Temporal patterning is an important mechanism for generating a great diversity of neuron subtypes from a seemingly homogenous progenitor pool in both vertebrates and invertebrates. Drosophila neuroblasts are temporally patterned by sequentially expressed Temporal Transcription Factors (TTFs). These TTFs are proposed to form a transcriptional cascade based on mutant phenotypes, although direct transcriptional regulation between TTFs has not been verified in most cases. Furthermore, it is not known how the temporal transitions are coupled with the generation of the appropriate number of neurons at each stage. We use neuroblasts of the Drosophila optic lobe medulla to address these questions and show that the expression of TTFs Sloppy-paired 1/2 (Slp1/2) is directly regulated at the transcriptional level by two other TTFs and the cell-cycle dependent Notch signaling through two cis-regulatory elements. We also show that supplying constitutively active Notch can rescue the delayed transition into the Slp stage in cell cycle arrested neuroblasts. Our findings reveal a novel Notch-pathway dependent mechanism through which the cell cycle progression regulates the timing of a temporal transition within a TTF transcriptional cascade.

The nervous system is one of the most sophisticated animal tissues, consisting of thousands of interconnected cell types. How the nervous system develops its diversity from a few neural stem cells remains a challenging question. Spatial and temporal patterning mechanisms provide an efficient model through which diversity can be generated. The molecular mechanism of spatiotemporal patterning has been studied extensively in Drosophila melanogaster , where distinct sets of transcription factors define the spatial domains and temporal windows that give rise to different cell types. Similarly, in vertebrates, spatial domains defined by transcription factors produce different types of neurons in the brain and neural tube. At the same time, different cortical neuronal types are generated within the same cell lineage with a specific birth order. However, we still do not understand how the orthogonal information of spatial and temporal patterning is integrated into the progenitor and post-mitotic cells to combinatorially give rise to different neurons. In this review, after introducing spatial and temporal patterning in Drosophila and mice, we discuss possible mechanisms that neural progenitors may use to integrate spatial and temporal information. We finally review the functional implications of spatial and temporal patterning and conclude envisaging how small alterations of these mechanisms can lead to the evolution of new neuronal cell types. [ABSTRACT FROM AUTHOR]

The nervous system is one of the most sophisticated animal tissues, consisting of thousands of interconnected cell types. How the nervous system develops its diversity from a few neural stem cells remains a challenging question. Spatial and temporal patterning mechanisms provide an efficient model through which diversity can be generated. The molecular mechanism of spatiotemporal patterning has been studied extensively in Drosophila melanogaster, where distinct sets of transcription factors define the spatial domains and temporal windows that give rise to different cell types. Similarly, in vertebrates, spatial domains defined by transcription factors produce different types of neurons in the brain and neural tube. At the same time, different cortical neuronal types are generated within the same cell lineage with a specific birth order. However, we still do not understand how the orthogonal information of spatial and temporal patterning is integrated into the progenitor and post-mitotic cells to combinatorially give rise to different neurons. In this review, after introducing spatial and temporal patterning in Drosophila and mice, we discuss possible mechanisms that neural progenitors may use to integrate spatial and temporal information. We finally review the functional implications of spatial and temporal patterning and conclude envisaging how small alterations of these mechanisms can lead to the evolution of new neuronal cell types.

During development, neural progenitors undergo temporal patterning as they age to sequentially generate differently fated progeny. Temporal patterning of neural progenitors is relatively well-studied in Drosophila. Temporal cascades of transcription factors or opposing temporal gradients of RNA-binding proteins are expressed in neural progenitors as they age to control the fates of the progeny. The temporal progression is mostly driven by intrinsic mechanisms including cross-regulations between temporal genes, but environmental cues also play important roles in certain transitions. Vertebrate neural progenitors demonstrate greater plasticity in response to extrinsic cues. Recent studies suggest that vertebrate neural progenitors are also temporally patterned by a combination of transcriptional and post-transcriptional mechanisms in response to extracellular signaling to regulate neural fate specification. In this review, we summarize recent advances in the study of temporal patterning of neural progenitors in Drosophila and vertebrates. We also discuss the involvement of epigenetic mechanisms, specifically the Polycomb group complexes and ATP-dependent chromatin remodeling complexes, in the temporal patterning of neural progenitors. [Display omitted] • TTF cascades and gradients of RNA-binding proteins regulate temporal patterning in Drosophila neuroblasts. • Vertebrate neural progenitors also undergo temporal patterning. • Single-cell RNA-sequencing is a powerful tool to study temporal patterning. • Chromatin modifiers and remodelers regulate temporal patterning of neural progenitors. [ABSTRACT FROM AUTHOR]

During the approximately 5 days of Drosophila neurogenesis (late embryogenesis to the beginning of pupation), a limited number of neural stem cells produce approximately 200,000 neurons comprising hundreds of cell types. To build a functional nervous system, neuronal types need to be produced in the proper places, appropriate numbers, and correct times. We discuss how neural stem cells (neuroblasts) obtain so-called area codes for their positions in the nervous system (spatial patterning) and how they keep time to sequentially produce neurons with unique fates (temporal patterning). We focus on specific examples that demonstrate how a relatively simple patterning system (Notch) can be used reiteratively to generate different neuronal types. We also speculate on how different modes of temporal patterning that operate over short versus long time periods might be linked. We end by discussing how specification programs are integrated and lead to the terminal features of different neuronal types. [ABSTRACT FROM AUTHOR]

The cerebellum is a conserved structure of the vertebrate brain involved in the timing and calibration of movements. Its function is supported by the convergence of fibers from granule cells (GCs) and inferior olive neurons (IONs) onto Purkinje cells (PCs). Theories of cerebellar function postulate that IONs convey error signals to PCs that, paired with the contextual information provided by GCs, can instruct motor learning. Here, we use the larval zebrafish to investigate (1) how sensory representations of the same stimulus vary across GCs and IONs and (2) how PC activity reflects these two different input streams. We use population calcium imaging to measure ION and GC responses to flashes of diverse luminance and duration. First, we observe that GCs show tonic and graded responses, as opposed to IONs, whose activity peaks mostly at luminance transitions, consistently with the notion that GCs and IONs encode context and error information, respectively. Second, we show that GC activity is patterned over time: some neurons exhibit sustained responses for the entire duration of the stimulus, while in others activity ramps up with slow time constants. This activity could provide a substrate for time representation in the cerebellum. Together, our observations give support to the notion of an error signal coming from IONs and provide the first experimental evidence for a temporal patterning of GC activity over many seconds., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Prat et al.)

The developing central nervous system (CNS) is particularly prone to malignant transformation, but the underlying mechanisms remain unresolved. However, periods of tumor susceptibility appear to correlate with windows of increased proliferation, which are often observed during embryonic and fetal stages and reflect stereotypical changes in the proliferative properties of neural progenitors. The temporal mechanisms underlying these proliferation patterns are still unclear in mammals. In Drosophila, two decades of work have revealed a network of sequentially expressed transcription factors and RNA-binding proteins that compose a neural progenitor-intrinsic temporal patterning system. Temporal patterning controls both the identity of the post-mitotic progeny of neural progenitors, according to the order in which they arose, and the proliferative properties of neural progenitors along development. In addition, in Drosophila, temporal patterning delineates early windows of cancer susceptibility and is aberrantly regulated in developmental tumors to govern cellular hierarchy as well as the metabolic and proliferative heterogeneity of tumor cells. Whereas recent studies have shown that similar genetic programs unfold during both fetal development and pediatric brain tumors, I discuss, in this Review, how the concept of temporal patterning that was pioneered in Drosophila could help to understand the mechanisms of initiation and progression of CNS tumors in children.

Temporal patterning of neural progenitors leads to the sequential production of diverse neurons. To understand how extrinsic cues influence intrinsic temporal programs, we studied Drosophila mushroom body progenitors (neuroblasts) that sequentially produce only three neuronal types: γ, then α’β’, followed by αβ. Opposing gradients of two RNA-binding proteins Imp and Syp comprise the intrinsic temporal program. Extrinsic activin signaling regulates the production of α’β’ neurons but whether it affects the intrinsic temporal program was not known. We show that the activin ligand Myoglianin from glia regulates the temporal factor Imp in mushroom body neuroblasts. Neuroblasts missing the activin receptor Baboon have a delayed intrinsic program as Imp is higher than normal during the α’β’ temporal window, causing the loss of α’β’ neurons, a decrease in αβ neurons, and a likely increase in γ neurons, without affecting the overall number of neurons produced. Our results illustrate that an extrinsic cue modifies an intrinsic temporal program to increase neuronal diversity.

Multipotent retinal progenitor cells (RPCs) generate various cell types in a precise chronological order, but how exactly cone photoreceptor production is restricted to early stages remains unclear. Here, we show that the POU-homeodomain factors Pou2f1/Pou2f2, the homologs of Drosophila temporal identity factors nub/pdm2, regulate the timely production of cones inmice. Forcing sustained expression of Pou2f1 or Pou2f2 in RPCs expands the period of cone production, whereas misexpression in late-stage RPCs triggers ectopic cone production at the expense of late-born fates. Mechanistically, we report that Pou2f1 induces Pou2f2 expression, which binds to a POUmotif in the promoter of the rod-inducing factor Nrl to repress its expression. Conversely, conditional inactivation of Pou2f2 in RPCs increases Nrl expression and reduces cone production. Finally, we provide evidence that Pou2f1 is part of a cross-regulatory cascade with the other temporal identity factors Ikzf1 and Casz1. These results uncover Pou2f1/2 as regulators of the temporal window for cone genesis and, given their widespread expression in the nervous system, raise the possibility of a general role in temporal patterning. [ABSTRACT FROM AUTHOR]

Proper neural function depends on the correct specification of individual neural fates, controlled by combinations of neuronal transcription factors. Different neural types are sequentially generated by neural progenitors in a defined order, and this temporal patterning process can be controlled by Temporal Transcription Factors (TTFs) that form temporal cascades in neural progenitors. The Drosophila medulla, part of the visual processing center of the brain, contains more than 70 neural types generated by medulla neuroblasts which sequentially express several TTFs, including Homothorax (Hth), eyeless (Ey), Sloppy paired 1 and 2 (Slp), Dichaete (D) and Tailless (Tll). However, it is not clear how such a small number of TTFs could give rise to diverse combinations of neuronal transcription factors that specify a large number of medulla neuron types. Here we report how temporal patterning specifies one neural type, the T1 neuron. We show that the T1 neuron is the only medulla neuron type that expresses the combination of three transcription factors Ocelliless (Oc or Otd), Sox102F and Ets65A. Using CRISPR-Cas9 system, we show that each transcription factor is required for the correct morphogenesis of T1 neurons. Interestingly, Oc, Sox102F and Ets65A initiate expression in neurons beginning at different temporal stages and last in a few subsequent temporal stages. Oc expressing neurons are generated in the Ey, Slp and D stages; Sox102F expressing neurons are produced in the Slp and D stages; while Ets65A is expressed in subsets of medulla neurons born in the D and later stages. The TTF Ey, Slp or D is required to initiate the expression of Oc, Sox102F or Ets65A in neurons, respectively. Thus, the neurons expressing all three transcription factors are born in the D stage and become T1 neurons. In neurons where the three transcription factors do not overlap, each of the three transcription factors can act in combination with other neuronal transcription factors to specify different neural fates. We show that this way of expression regulation of neuronal transcription factors by temporal patterning can generate more possible combinations of transcription factors in neural progeny to diversify neural fates. • A combination of three transcription factors controls T1 neuron morphogenesis. • Temporal Transcription Factors in neuroblasts control expression of neuronal TFs. • Temporal progression of neuroblasts generates different transcription factor codes. [ABSTRACT FROM AUTHOR]

Complex behaviors depend on the precise developmental specification of neuronal circuits, but the relationship between genetic programs for neural development, circuit structure, and behavioral output is often unclear. The central complex (CX) is a conserved sensory-motor integration center in insects, which governs many higher-order behaviors and largely derives from a small number of type II neural stem cells (NSCs). Here, we show that Imp, a conserved IGF-II mRNA-binding protein expressed in type II NSCs, plays a role in specifying essential components of CX olfactory navigation circuitry. We show the following: (1) that multiple components of olfactory navigation circuitry arise from type II NSCs. (2) Manipulating Imp expression in type II NSCs alters the number and morphology of many of these circuit elements, with the most potent effects on neurons targeting the ventral layers of the fan-shaped body (FB). (3) Imp regulates the specification of Tachykinin-expressing ventral FB input neurons. (4) Imp is required in type II NSCs for establishing proper morphology of the CX neuropil structures. (5) Loss of Imp in type II NSCs abolishes upwind orientation to attractive odor while leaving locomotion and odor-evoked regulation of movement intact. Taken together, our findings establish that a temporally expressed gene can regulate the expression of a complex behavior by developmentally regulating the specification of multiple circuit components and provides a first step toward a developmental dissection of the CX and its roles in behavior. [Display omitted] • Drosophila olfactory navigation circuit components are derived from type II NSCs • The dorsolateral type II NSC cell generates ventral FB odor-encoding input neurons • Imp governs specification and identity of the olfactory navigation circuit elements • Loss of Imp in type II NSCs impairs upwind orientation during olfactory navigation Hamid et al. describe the lineages of olfactory navigation circuit elements in Drosophila and show that stem cell-specific RNA-binding protein, Imp, regulates the specification and morphology of multiple circuit elements, specifically in the central complex. Imp regulates upwind orientation in response to odor. [ABSTRACT FROM AUTHOR]

It is still unclear what drives progression of childhood tumors. During Drosophila larval development, asymmetrically-dividing neural stem cells, called neuroblasts, progress through an intrinsic temporal patterning program that ensures cessation of divisions before adulthood. We previously showed that temporal patterning also delineates an early developmental window during which neuroblasts are susceptible to tumor initiation (Narbonne-Reveau et al., 2016). Using single-cell transcriptomics, clonal analysis and numerical modeling, we now identify a network of twenty larval temporal patterning genes that are redeployed within neuroblast tumors to trigger a robust hierarchical division scheme that perpetuates growth while inducing predictable cell heterogeneity. Along the hierarchy, temporal patterning genes define a differentiation trajectory that regulates glucose metabolism genes to determine the proliferative properties of tumor cells. Thus, partial redeployment of the temporal patterning program encoded in the cell of origin may govern the hierarchy, heterogeneity and growth properties of neural tumors with a developmental origin.

How circuits assemble starting from stem cells is a fundamental question in developmental neurobiology. We test the hypothesis that, in neuronal stem cells, temporal transcription factors predictably control neuronal terminal features and circuit assembly. Using the Drosophila motor system, we manipulate expression of the classic temporal transcription factor Hunchback (Hb) specifically in the NB7-1 stem cell, which produces U motor neurons (MNs), and then we monitor dendrite morphology and neuromuscular synaptic partnerships. We find that prolonged expression of Hb leads to transient specification of U MN identity, and that embryonic molecular markers do not accurately predict U MN terminal features. Nonetheless, our data show Hb acts as a potent regulator of neuromuscular wiring decisions. These data introduce important refinements to current models, show that molecular information acts early in neurogenesis as a switch to control motor circuit wiring, and provide novel insight into the relationship between stem cell and circuit.

Translating advances in cancer research to clinical applications requires better insight into the metabolism of normal cells and tumour cells in vivo. Much effort has focused on understanding how glycolysis and oxidative phosphorylation (OxPhos) support proliferation, while their impact on other aspects of development and tumourigenesis remain largely unexplored. We found that inhibition of OxPhos in neural stem cells (NSCs) or tumours in the Drosophila brain not only decreases proliferation, but also affects many different aspects of stem cell behaviour. In NSCs, OxPhos dysfunction leads to a protracted G1/S-phase and results in delayed temporal patterning and reduced neuronal diversity. As a consequence, NSCs fail to undergo terminal differentiation, leading to prolonged neurogenesis into adulthood. Similarly, in brain tumours inhibition of OxPhos slows proliferation and prevents differentiation, resulting in reduced tumour heterogeneity. Thus, in vivo, highly proliferative stem cells and tumour cells require OxPhos for efficient growth and generation of diversity.

Neurons originate from neural stem cells and then synapse with stereotyped partners to form neuronal circuits. Recent findings indicate that several molecular mechanisms generating neuronal identity can rewire neuronal connectivity in the Drosophila brain when genetically manipulated. In this review, I discuss how mechanisms generating neuronal identity could activate molecular pathways essential for circuit formation and function. Next, I propose that the central complex of Drosophila, an ancient and highly conserved brain region essential for locomotor control and navigation, is an excellent model system to further explore mechanisms linking circuit development to circuit function.

Neurons originate from neural stem cells and then synapse with stereotyped partners to form neuronal circuits. Recent findings indicate that several molecular mechanisms generating neuronal identity can rewire neuronal connectivity in the Drosophila brain when genetically manipulated. In this review, I discuss how mechanisms generating neuronal identity could activate molecular pathways essential for circuit formation and function. Next, I propose that the central complex of Drosophila , an ancient and highly conserved brain region essential for locomotor control and navigation, is an excellent model system to further explore mechanisms linking circuit development to circuit function. [ABSTRACT FROM AUTHOR]

Development relies on the exquisite control of both the timing and the levels of gene expression to achieve robust developmental transitions. How cis - and trans -acting factors control both aspects simultaneously is unclear. We show that transcriptional pulses of the temporal patterning microRNA (miRNA) lin-4 are generated by two nuclear hormone receptors (NHRs) in C. elegans , NHR-85 and NHR-23, whose mammalian orthologs, Rev-Erb and ROR, function in the circadian clock. Although Rev-Erb and ROR antagonize each other to control once-daily transcription in mammals, NHR-85/NHR-23 heterodimers bind cooperatively to lin-4 regulatory elements to induce a single pulse of expression during each larval stage. Each pulse's timing, amplitude, and duration are dictated by the phased expression of these NHRs and the C. elegans Period ortholog, LIN-42, that binds to and represses NHR-85. Therefore, during nematode temporal patterning, an evolutionary rewiring of circadian clock components couples the timing of gene expression to the control of transcriptional dosage. [Display omitted] • lin-4 miRNA transcription is highly dynamic, with ∼100 min pulses per larval stage • NHR-85/NHR-23 heterodimers bind cooperatively to the upstream lin-4 enhancers • The duration of NHR-85/NHR-23 dimerization controls lin-4 transcriptional dynamics • LIN-42 binds directly to NHR-85 to dynamically modulate lin-4 transcriptional dosage Kinney, Sahu, et al. report that genes implicated in mammalian circadian transcription are rewired in C. elegans to generate the oscillatory transcriptional patterns of miRNAs that program temporal patterning during post-embryonic development. This gene regulatory network directly controls lin-4 gene dosage in the heterochronic pathway, maintaining developmental robustness. [ABSTRACT FROM AUTHOR]

Bats emit biosonar pulses in complex temporal patterns that change to accommodate dynamic surroundings. Efforts to quantify these patterns have included analyses of inter-pulse intervals, sonar sound groups, and changes in individual signal parameters such as duration or frequency. Here, the similarity in temporal structure between trains of biosonar pulses is assessed. The spike train similarity space (SSIMS) algorithm, originally designed for neural activity pattern analysis, was applied to determine which features of the environment influence temporal patterning of pulses emitted by flying big brown bats, Eptesicus fuscus. In these laboratory experiments, bats flew down a flight corridor through an obstacle array. The corridor varied in width (100, 70, or 40 cm) and shape (straight or curved). Using a relational point-process framework, SSIMS was able to discriminate between echolocation call sequences recorded from flights in each of the corridor widths. SSIMS was also able to tell the difference between pulse trains recorded during flights where corridor shape through the obstacle array matched the previous trials (fixed, or expected) as opposed to those recorded from flights with randomized corridor shape (variable, or unexpected), but only for the flight path shape in which the bats had previous training. The results show that experience influences the temporal patterns with which bats emit their echolocation calls. It is demonstrated that obstacle proximity to the bat affects call patterns more dramatically than flight path shape.

Highlights • Temporal patterning of neurogenesis orchestrates the production and wiring of neurons. • The fly visual system contains many examples of temporal patterning and neural wiring. • Mechanisms of temporal patterning of nervous systems may be evolutionarily conserved. Abstract During neural development, a wide variety of neurons are produced in a highly coordinated manner and form complex and highly coordinated neural circuits. Temporal patterning of neuron type specification plays very important roles in orchestrating the production and wiring of neurons. The fly visual system, which is composed of the retina and the optic lobe of the brain, is an outstanding model system to study temporal patterning and wiring of the nervous system. All of the components of the fly visual system are topographically connected, and each ommatidial unit in the retina corresponds to a columnar unit in the optic lobe. In the retina, the wave of differentiation follows the morphogenetic furrow, which progresses in a posterior-to-anterior direction. At the same time, differentiation of the optic lobe also accompanies the wave of differentiation or temporally coordinated neurogenesis. Thus, temporal patterning plays important roles in establishing topographic connections throughout the fly visual system. In this article, we review how neuronal differentiation and connectivity are orchestrated in the fly visual system by temporal patterning mechanisms. [ABSTRACT FROM AUTHOR]

Bats emit biosonar pulses in complex temporal patterns that change to accommodate dynamic surroundings. Efforts to quantify these patterns have included analyses of inter- pulse intervals, sonar sound groups, and changes in individual signal parameters such as duration or frequency. Here, the similarity in temporal structure between trains of biosonar pulses is assessed. The spike train similarity space (SSIMS) algorithm, originally designed for neural activity pattern analysis, was applied to determine which features of the environment influence temporal patterning of pulses emitted by flying big brown bats, Eptesicus fuscus. In these laboratory experiments, bats flew down a flight corridor through an obstacle array. The corridor varied in width (100, 70, or 40 cm) and shape (straight or curved). Using a relational point-process framework, SSIMS was able to discriminate between echolocation call sequences recorded from flights in each of the corridor widths. SSIMS was also able to tell the difference between pulse trains recorded during flights where corridor shape through the obstacle array matched the previous trials (fixed, or expected) as opposed to those recorded from flights with randomized corridor shape (variable, or unexpected), but only for the flight path shape in which the bats had previous training. The results show that experience influences the temporal patterns with which bats emit their echolocation calls. It is demonstrated that obstacle proximity to the bat affects call patterns more dramatically than flight path shape. [ABSTRACT FROM AUTHOR]

Drosophila neuroblasts are an excellent model for investigating how neuronal diversity is generated. Most brain neuroblasts generate a series of ganglion mother cells (GMCs) that each make two neurons (type I lineage), but 16 brain neuroblasts generate a series of intermediate neural progenitors (INPs) that each produce 4-6 GMCs and 8-12 neurons (type II lineage). Thus, type II lineages are similar to primate cortical lineages, and may serve as models for understanding cortical expansion. Yet the origin of type II neuroblasts remains mysterious: do they form in the embryo or larva? If they form in the embryo, do their progeny populate the adult central complex, as do the larval type II neuroblast progeny? Here, we present molecular and clonal data showing that all type II neuroblasts form in the embryo, produce INPs and express known temporal transcription factors. Embryonic type II neuroblasts and INPs undergo quiescence, and produce embryonic-born progeny that contribute to the adult central complex. Our results provide a foundation for investigating the development of the central complex, and tools for characterizing early-born neurons in central complex function. [ABSTRACT FROM AUTHOR]

Scholars of Roman archaeology, epigraphy, and history are increasingly discussing urban maintenance and waste disposal, but the impact of these phenomena on the archaeological record remains largely understudied. The presence of waste disposal systems in Roman towns entails that a large part of what was discarded was periodically removed from the urban area. This in turn implies that whole historical periods may be underrepresented by the finds recovered within the city. This aspect can be apprehended through the post-excavation analysis of the House of Titus Macer in Aquileia, whose mid-imperial phase, during which the domus was inhabited and regularly maintained, is poorly represented. What has been observed suggests that great caution must be exercised when using data collected within urban sites to draw conclusions on ancient economic trends. To tackle this problem, our research agendas should target large extra moenia dumps more frequently. [ABSTRACT FROM AUTHOR]

We discuss three empirical findings that we think any theory attempting to integrate interval timing with associative learning concepts will need to address. These empirical phenomena all come from studies that combine peak timing procedures with reinforcer devaluation or conditional discrimination tasks commonly employed, respectively, in interval timing or associative learning research traditions. The three phenomena we discuss include: (1) the observation that disruptions in reward identity encoding have little to no impact on the encoding of reward time in the peak procedure (Delamateret al., 2018), (2) the findings that organisms tend to average their time estimates when presented with a stimulus compound consisting of separately learned stimuli indicating short or long reward times but that such temporal averaging, itself, is sensitive to post-conditioning selective reward devaluation, and (3) that rats can learn a temporal patterning task in which two stimuli presented independently indicate one time to reward availability while their compound indicates another. We review our prior results and present new findings illustrating these three phenomena and we discuss the special challenges they pose for cascade theories of timing, for multiple-oscillator models, and for any approach that attempts to integrate interval timing and associative models. We close by illustrating some ways in which multi-layer connectionist network models might begin to address some of our key findings. We believe this will require an approach that includes separate mechanisms that code for reward identity and time, but that does so in a way that permits for integration between the two systems. • We address 3 important phenomena in the study of associative learning and timing processes. • Reward identity disruptions do not impact reward timing, suggesting the two are separable. • Temporal averaging is flexibly adjusted by post-training selective reward devaluation. • Temporal patterning discriminations can be learned and reversed. • Multi-layered connectionist modeling approaches may help integrate the results from associative learning and interval timing paradigms. [ABSTRACT FROM AUTHOR]

Transitions in competence underlie the ability of CNS progenitors to generate a diversity of neurons and glia. Retinal progenitor cells in mouse generate early-born cell types embryonically and late-born cell types largely postnatally. We find that the transition from early to late progenitor competence is regulated by Jarid2. Loss of Jarid2 results in extended production of early cell types and extended expression of early progenitor genes. Jarid2 can regulate histone modifications, and we find reduction of repressive mark H3K27me3 on a subset of early progenitor genes with loss of Jarid2 , most notably Foxp1. We show that Foxp1 regulates the competence to generate early-born retinal cell types, promotes early and represses late progenitor gene expression, and is required for extending early retinal cell production after loss of Jarid2. We conclude that Jarid2 facilitates progression of retinal progenitor temporal identity by repressing Foxp1 , which is a primary regulator of early temporal patterning. [Display omitted] • Loss of Jarid2 delays retinal progenitor early- to late-identity transition • Jarid2 mediates H3K27me3 deposition and repression of early genes including Foxp1 • Foxp1 regulates the timing of early retinal cell production • Foxp1 is an effector of Jarid2 -mediated temporal patterning Temporal patterning of neural progenitors is essential to generate neuronal diversity. Zhang et al. find that Jarid2 facilitates retinal progenitor temporal identity transition via H3K27me3 deposition and repression of early genes, most notably Foxp1. They find that Foxp1 is an effector of Jarid2 in regulating timing of retinal neurogenesis. [ABSTRACT FROM AUTHOR]

How axon guidance pathways are utilized in coordination with temporal and spatial patterning of neural progenitors to regulate neuropil assembly is not well understood. We study this question in the Drosophila medulla using the transmedullary (Tm) projection neurons that target lobula through the inner optic chiasm (IOC). We demonstrate that the Netrin pathway plays multiple roles in guidance of Tm axons and that temporal patterning of medulla neuroblasts determines pioneer versus follower Tm neurons during this process. Loss of Frazzled (Fra) in early-born pioneer Tm neurons leads to IOC defects, while loss of Fra from follower neurons does not affect the IOC. In the follower projection neurons, Fra is required in other targeting steps including lobula branch extension and layer-specific targeting. Furthermore, different from other identified scenarios of Netrin/Fra involved axon guidance in Drosophila , we demonstrate that diffusible Netrin is required for the correct axon targeting and optic lobe organization. [Display omitted] • Netrin pathway has multiple roles in guidance of fly medulla visual projection axons • Early-born Tm neurons require Fra/Netrin signaling to pioneer the targeting path • Fra functions in lobula branch extension of TmY3 and layer-specific targeting of Tm3 • Diffusible Netrin is required for axon targeting of fly medulla projection neurons Zhang et al. find that Netrin pathway plays multiple roles in axon targeting of Drosophila medulla projection neurons. It is required in pioneer projection neurons to establish the targeting path and has additional roles in the stepwise targeting of specific projection neurons. Diffusability of Netrin is required in this process. [ABSTRACT FROM AUTHOR]

Complex behaviors depend on the precise developmental specification of neuronal circuits, but the relationship between genetic prograssms for neural development, circuit structure, and behavioral output is often unclear. The central complex (CX) is a conserved sensory-motor integration center in insects that governs many higher order behaviors and largely derives from a small number of Type II neural stem cells. Here, we show that Imp, a conserved IGF-II mRNA-binding protein expressed in Type II neural stem cells, specifies components of CX olfactory navigation circuitry. We show: (1) that multiple components of olfactory navigation circuitry arise from Type II neural stem cells and manipulating Imp expression in Type II neural stem cells alters the number and morphology of many of these circuit elements, with the most potent effects on neurons targeting the ventral layers of the fan-shaped body. (2) Imp regulates the specification of Tachykinin expressing ventral fan-shaped body input neurons. (3) Imp in Type II neural stem cells alters the morphology of the CX neuropil structures. (4) Loss of Imp in Type II neural stem cells abolishes upwind orientation to attractive odor while leaving locomotion and odor-evoked regulation of movement intact. Taken together, our work establishes that a single temporally expressed gene can regulate the expression of a complex behavior through the developmental specification of multiple circuit components and provides a first step towards a developmental dissection of the CX and its roles in behavior.

The neocortex is unique to mammals and its evolutionary origin is still highly debated. The neocortex is generated by the dorsal pallium ventricular zone, a germinative domain that in reptiles give rise to the dorsal cortex. Whether this latter allocortical structure contains homologues of all neocortical cell types it is unclear. Recently we described a population of DCX+/Tbr1+ cells that is specifically associated with the layer II of higher order areas of both the neocortex and of the more evolutionary conserved piriform cortex. In a reptile similar cells are present in the layer II of the olfactory cortex and the DVR but not in the dorsal cortex. These data are consistent with the proposal that the reptilian dorsal cortex is homologous only to the deep layers of the neocortex while the upper layers are a mammalian innovation. Based on our observations we extended these ideas by hypothesizing that this innovation was obtained by co-opting a lateral and/or ventral pallium developmental program. Interestingly, an analysis in the Allen brain atlas revealed a striking similarity in gene expression between neocortical layers II/III and piriform cortex. We thus propose a model in which the early neocortical column originated by the superposition of the lateral olfactory and dorsal cortex. This idea is consistent with previous hypotheses that the peri-allocortex (i.e insular and perirhinal cortex) may represent the more ancient neocortical part. Our model may have also interesting implications in the study of sensory processing in both neocortex and piriform cortex. The great advances in deciphering the molecular logic of the amniote pallium developmental programs will hopefully enable to directly test our hypotheses in the next future.

The neocortex is unique to mammals and its evolutionary origin is still highly debated. The neocortex is generated by the dorsal pallium ventricular zone, a germinative domain that in reptiles give rise to the dorsal cortex. Whether this latter allocortical structure contains homologs of all neocortical cell types it is unclear. Recently we described a population of DCX+/Tbr1+ cells that is specifically associated with the layer II of higher order areas of both the neocortex and of the more evolutionary conserved piriform cortex. In a reptile similar cells are present in the layer II of the olfactory cortex and the DVR but not in the dorsal cortex. These data are consistent with the proposal that the reptilian dorsal cortex is homologous only to the deep layers of the neocortex while the upper layers are a mammalian innovation. Based on our observations we extended these ideas by hypothesizing that this innovation was obtained by co-opting a lateral and/or ventral pallium developmental program. Interestingly, an analysis in the Allen brain atlas revealed a striking similarity in gene expression between neocortical layers II/III and piriform cortex. We thus propose a model in which the early neocortical column originated by the superposition of the lateral olfactory and dorsal cortex. This model is consistent with the fossil record and may account not only for the topological position of the neocortex, but alsofor its basic cytoarchitectural and hodological features. This idea is also consistent with previous hypotheses that the peri-allocortex represents the more ancient neocortical part. The great advances in deciphering the molecular logic of the amniote pallium developmental programs will hopefully enable to directly test our hypotheses in the next future. [ABSTRACT FROM AUTHOR]

It is essential that individuals diagnosed to have an auditory processing problem (APD) be provided appropriate management in order to overcome their difficulty to the maximum extent possible. The positive impact of training on individuals with APD has been demonstrated in studies carried outside India as well as within India. In India, studies on the management of APD have primarily focused on deficit specific therapy. These studies have demonstrated positive outcomes for therapy provided for auditory processes such as auditory integration, auditory separation / closure training, temporal integration, and temporal patterning. Deficit specific training has been noted to be useful not only in children but also in older adults with APD. Along with such training, the use of compensatory and coping strategies is recommended to help individuals with APD deal with difficulties faced in day-to-day situations. The article provides an overview of the studies carried out in India regarding APD management. [ABSTRACT FROM AUTHOR]

The brain areas that endow insects with the ability to see consist of remarkably complex neural circuits. Reiterated arrays of many diverse neuron subtypes are assembled into modular yet coherent functional retinotopic maps. Tremendous progress in developing genetic tools and cellular markers over the past years advanced our understanding of the mechanisms that control the stepwise production and differentiation of neurons in the visual system of Drosophila melanogaster. The postembryonic optic lobe utilizes at least two modes of neurogenesis that are distinct from other parts of the fly central nervous system. In the first optic ganglion, the lamina, neuroepithelial cells give rise to precursor cells, whose proliferation and differentiation depend on anterograde signals from photoreceptor axons. In the second optic ganglion, the medulla, the coordinated activity of four signaling pathways orchestrates the gradual conversion of neuroepithelial cells into neuroblasts, while a specific cascade of temporal identity transcription factors controls subtype diversification of their progeny. [ABSTRACT FROM AUTHOR]

Whether subjects with insomnia exhibit good sleep on some interval basis is unclear. Prior research suggests that patients with insomnia are highly variable with respect to night-to-night sleep continuity, that more than 40% of patients exhibit temporal patterning of good sleep, and that nearly 90% of patients exhibit better than average sleep following 1 to 3 nights of relatively poor sleep. The aim of the present study was to replicate and extend the above-noted findings utilizing: (i) a large sample studied over an extended time interval (ii) absolute standards for 'good' and 'poor' sleep; and (iii) a formal statistical methodology to assess temporal patterning and the association of time in bed with bout duration of poor or average sleep. Thirty-three subjects with insomnia and 33 good sleepers completed sleep diaries over the course of 110 days. It was found that subjects with insomnia (compared to good sleepers) had more poor nights (e.g. about 39 versus 7% of the assessed nights), a higher probability of a having a poor night on any given occasion (60% greater probability than good sleepers) and more consecutive nights of poor sleep between good sleep nights (median bout duration of approximately three versus one night). Lastly, it was found that (as would be predicted by both the Spielman model and the two-process model) time in bed moderated bout duration in the insomnia group. That is, longer times in bed were associated with longer bouts of poor sleep. [ABSTRACT FROM AUTHOR]

While the growth of the developing brain is known to be well-protected compared to other organs in the face of nutrient restriction (NR), careful analysis has revealed a range of structural alterations and long-term neurological defects. Yet, despite intensive studies, little is known about the basic principles that govern brain development under nutrient deprivation. For over 20 years, Drosophila has proved to be a useful model for investigating how a functional nervous system develops from a restricted number of neural stem cells (NSCs). Recently, a few studies have started to uncover molecular mechanisms as well as region-specific adaptive strategies that preserve brain functionality and neuronal repertoire under NR, while modulating neuron numbers. Here, we review the developmental constraints that condition the response of the developing brain to NR. We then analyze the recent Drosophila work to highlight key principles that drive sparing and plasticity in different regions of the central nervous system (CNS). As simple animal models start to build a more integrated picture, understanding how the developing brain copes with NR could help in defining strategies to limit damage and improve brain recovery after birth. [ABSTRACT FROM AUTHOR]