• A community-maintained standard library of population genetic models

      Adrion, Jeffrey R.; Cole, Christopher B.; Dukler, Noah; Galloway, Jared G.; Gladstein, Ariella L.; Gower, Graham; Kyriazis, Christopher C.; Ragsdale, Aaron P.; Tsambos, Georgia; Baumdicker, Franz; et al. (ELIFE SCIENCES PUBLICATIONS LTD, 2020-06)
      The explosion in population genomic data demands ever more complex modes of analysis, and increasingly, these analyses depend on sophisticated simulations. Recent advances in population genetic simulation have made it possible to simulate large and complex models, but specifying such models for a particular simulation engine remains a difficult and error-prone task. Computational genetics researchers currently re-implement simulation models independently, leading to inconsistency and duplication of effort. This situation presents a major barrier to empirical researchers seeking to use simulations for power analyses of upcoming studies or sanity checks on existing genomic data. Population genetics, as a field, also lacks standard benchmarks by which new tools for inference might be measured. Here, we describe a new resource, stdpopsim, that attempts to rectify this situation. Stdpopsim is a community-driven open source project, which provides easy access to a growing catalog of published simulation models from a range of organisms and supports multiple simulation engine backends. This resource is available as a well-documented python library with a simple command-line interface. We share some examples demonstrating how stdpopsim can be used to systematically compare demographic inference methods, and we encourage a broader community of developers to contribute to this growing resource.
    • A causal role for right frontopolar cortex in directed, but not random, exploration

      Zajkowski, Wojciech K; Kossut, Malgorzata; Wilson, Robert C; Univ Arizona, Dept Psychol; Univ Arizona, Cognit Sci Program; University of Social Sciences and Humanities, Warsaw, Poland; Department of Psychology, University of Social Sciences and Humanities, Warsaw, Poland; Department of Psychology, University of Arizona, Tucson, United States (ELIFE SCIENCES PUBLICATIONS LTD, 2017-09-15)
      The explore-exploit dilemma occurs anytime we must choose between exploring unknown options for information and exploiting known resources for reward. Previous work suggests that people use two different strategies to solve the explore-exploit dilemma: directed exploration, driven by information seeking, and random exploration, driven by decision noise. Here, we show that these two strategies rely on different neural systems. Using transcranial magnetic stimulation to inhibit the right frontopolar cortex, we were able to selectively inhibit directed exploration while leaving random exploration intact. This suggests a causal role for right frontopolar cortex in directed, but not random, exploration and that directed and random exploration rely on (at least partially) dissociable neural systems.
    • Domain-swapped T cell receptors improve the safety of TCR gene therapy

      Bethune, Michael T; Gee, Marvin H; Bunse, Mario; Lee, Mark S; Gschweng, Eric H; Pagadala, Meghana S; Zhou, Jing; Cheng, Donghui; Heath, James R; Kohn, Donald B; et al. (ELIFE SCIENCES PUBLICATIONS LTD, 2016-11-08)
      T cells engineered to express a tumor-specific αβ T cell receptor (TCR) mediate anti-tumor immunity. However, mispairing of the therapeutic αβ chains with endogenous αβ chains reduces therapeutic TCR surface expression and generates self-reactive TCRs. We report a general strategy to prevent TCR mispairing: swapping constant domains between the α and β chains of a therapeutic TCR. When paired, domain-swapped (ds)TCRs assemble with CD3, express on the cell surface, and mediate antigen-specific T cell responses. By contrast, dsTCR chains mispaired with endogenous chains cannot properly assemble with CD3 or signal, preventing autoimmunity. We validate this approach in cell-based assays and in a mouse model of TCR gene transfer-induced graft-versus-host disease. We also validate a related approach whereby replacement of αβ TCR domains with corresponding γδ TCR domains yields a functional TCR that does not mispair. This work enables the design of safer TCR gene therapies for cancer immunotherapy.
    • Dreaming with hippocampal damage

      Spanò, Goffredina; Pizzamiglio, Gloria; McCormick, Cornelia; Clark, Ian A; De Felice, Sara; Miller, Thomas D; Edgin, Jamie O; Rosenthal, Clive R; Maguire, Eleanor A; Univ Arizona, Dept Psychol (ELIFE SCIENCES PUBLICATIONS LTD, 2020-06-08)
      The hippocampus is linked with both sleep and memory, but there is debate about whether a salient aspect of sleep - dreaming - requires its input. To address this question, we investigated if human patients with focal bilateral hippocampal damage and amnesia engaged in dreaming. We employed a provoked awakening protocol where participants were woken up at various points throughout the night, including during non-rapid eye movement and rapid eye movement sleep, to report their thoughts in that moment. Despite being roused a similar number of times, dream frequency was reduced in the patients compared to control participants, and the few dreams they reported were less episodic-like in nature and lacked content. These results suggest that hippocampal integrity may be necessary for typical dreaming to occur, and aligns dreaming with other hippocampal-dependent processes such as episodic memory that are central to supporting our mental life.
    • A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism

      Imler, Elliot; Pyon, Jin Sang; Kindelay, Selina; Torvund, Meaghan; Zhang, Yong-Quan; Chandra, Sreeganga S; Zinsmaier, Konrad E; Univ Arizona, Grad Interdisciplinary Program Neurosci; Univ Arizona, Dept Neurosci; Univ Arizona, Dept Mol & Cellular Biol, Undergrad Program Neurosci & Cognit Sci; et al. (ELIFE SCIENCES PUBLICATIONS LTD, 2019-10-30)
      The autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of CLN4 by expressing CLN4 mutant human CSPα (hCSPα) in Drosophila neurons. Similar to patients, CLN4 mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα accumulated abnormally, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructural examination revealed frequent abnormal membrane structures in axons and neuronal somata. The lethality, oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing endogenous wild type (WT) dCSP levels and enhanced by increasing WT levels. Furthermore, reducing the gene dosage of Hsc70 also attenuated CLN4 phenotypes. Taken together, we suggest that CLN4 alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.
    • A dynamic charge-charge interaction modulates PP2A:B56 substrate recruitment

      Wang, Xinru; Garvanska, Dimitriya H; Nasa, Isha; Ueki, Yumi; Zhang, Gang; Kettenbach, Arminja N; Peti, Wolfgang; Nilsson, Jakob; Page, Rebecca; Univ Arizona, Dept Chem & Biochem (ELIFE SCIENCES PUBLICATIONS LTD, 2020-03-20)
      The recruitment of substrates by the ser/thr protein phosphatase 2A (PP2A) is poorly understood, limiting our understanding of PP2A-regulated signaling. Recently, the first PP2A:B56 consensus binding motif, LxxIxE, was identified. However, most validated LxxIxE motifs bind PP2A: B56 with micromolar affinities, suggesting that additional motifs exist to enhance PP2A:B56 binding. Here, we report the requirement of a positively charged motif in a subset of PP2A:B56 interactors, including KIF4A, to facilitate B56 binding via dynamic, electrostatic interactions. Using molecular and cellular experiments, we show that a conserved, negatively charged groove on B56 mediates dynamic binding. We also discovered that this positively charged motif, in addition to facilitating KIF4A dephosphorylation, is essential for condensin I binding, a function distinct and exclusive from PP2A-B56 binding. Together, these results reveal how dynamic, charge-charge interactions fine-tune the interactions mediated by specific motifs, providing a new framework for understanding how PP2A regulation drives cellular signaling.
    • Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS

      Manzo, Ernesto; Lorenzini, Ileana; Barrameda, Dianne; O'Conner, Abigail G; Barrows, Jordan M; Starr, Alexander; Kovalik, Tina; Rabichow, Benjamin E; Lehmkuhl, Erik M; Shreiner, Dakotah D; et al. (ELIFE SCIENCES PUBLICATIONS LTD, 2019-06-10)
      Amyotrophic Lateral Sclerosis (ALS), is a fatal neurodegenerative disorder, with TDP-43 inclusions as a major pathological hallmark. Using a Drosophila model of TDP-43 proteinopathy we found significant alterations in glucose metabolism including increased pyruvate, suggesting that modulating glycolysis may be neuroprotective. Indeed, a high sugar diet improves locomotor and lifespan defects caused by TDP-43 proteinopathy in motor neurons or glia, but not muscle, suggesting that metabolic dysregulation occurs in the nervous system. Overexpressing human glucose transporter GLUT-3 in motor neurons mitigates TDP-43 dependent defects in synaptic vesicle recycling and improves locomotion. Furthermore, PFK mRNA, a key indicator of glycolysis, is upregulated in flies and patient derived iPSC motor neurons with TDP-43 pathology. Surprisingly, PFK overexpression rescues TDP-43 induced locomotor deficits. These findings from multiple ALS models show that mechanistically, glycolysis is upregulated in degenerating motor neurons as a compensatory mechanism and suggest that increased glucose availability is protective.
    • The host exosome pathway underpins biogenesis of the human cytomegalovirus virion

      Turner, Declan L; Korneev, Denis V; Purdy, John G; de Marco, Alex; Mathias, Rommel A; Univ Arizona, Dept Immunobiol; Univ Arizona, BIO5 Inst (ELIFE SCIENCES PUBLICATIONS LTD, 2020-09-10)
      Human Cytomegalovirus (HCMV) infects over half the world's population, is a leading cause of congenital birth defects, and poses serious risks for immuno-compromised individuals. To expand the molecular knowledge governing virion maturation, we analysed HCMV virions using proteomics, and identified a significant proportion of host exosome constituents. To validate this acquisition, we characterized exosomes released from uninfected cells, and demonstrated that over 99% of the protein cargo was subsequently incorporated into HCMV virions during infection. This suggested a common membrane origin, and utilization of host exosome machinery for virion assembly and egress. Thus, we selected a panel of exosome proteins for knock down, and confirmed that loss of 7/9 caused significantly less HCMV production. Saliently, we report that VAMP3 is essential for viral trafficking and release of infectious progeny, in various HCMV strains and cell types. Therefore, we establish that the host exosome pathway is intrinsic for HCMV maturation, and reveal new host regulators involved in viral trafficking, virion envelopment, and release. Our findings underpin future investigation of host exosome proteins as important modulators of HCMV replication with antiviral potential.
    • An insect-like mushroom body in a crustacean brain

      Wolff, Gabriella Hannah; Thoen, Hanne Halkinrud; Marshall, Justin; Sayre, Marcel E; Strausfeld, Nicholas James; Univ Arizona, Sch Mind Brain & Behav, Dept Neurosci; Department of Biology, University of Washington, Seattle, United States; Sensory Neurobiology Group, University of Queensland, Brisbane, Australia; Sensory Neurobiology Group, University of Queensland, Brisbane, Australia; Department of Neuroscience, School of Mind, Brain and Behavior, University of Arizona, Tucson, United States; et al. (ELIFE SCIENCES PUBLICATIONS LTD, 2017-09-26)
      Mushroom bodies are the iconic learning and memory centers of insects. No previously described crustacean possesses a mushroom body as defined by strict morphological criteria although crustacean centers called hemiellipsoid bodies, which serve functions in sensory integration, have been viewed as evolutionarily convergent with mushroom bodies. Here, using key identifiers to characterize neural arrangements, we demonstrate insect-like mushroom bodies in stomatopod crustaceans (mantis shrimps). More than any other crustacean taxon, mantis shrimps display sophisticated behaviors relating to predation, spatial memory, and visual recognition comparable to those of insects. However, neuroanatomy-based cladistics suggesting close phylogenetic proximity of insects and stomatopod crustaceans conflicts with genomic evidence showing hexapods closely related to simple crustaceans called remipedes. We discuss whether corresponding anatomical phenotypes described here reflect the cerebral morphology of a common ancestor of Pancrustacea or an extraordinary example of convergent evolution.
    • Large-scale remodeling of a repressed exon ribonucleoprotein to an exon definition complex active for splicing

      Wongpalee, Somsakul Pop; Vashisht, Ajay; Sharma, Shalini; Chui, Darryl; Wohlschlegel, James A; Black, Douglas L; Univ Arizona, Dept Basic Med Sci (ELIFE SCIENCES PUBLICATIONS LTD, 2016-11-24)
      Polypyrimidine-tract binding protein PTBP1 can repress splicing during the exon definition phase of spliceosome assembly, but the assembly steps leading to an exon definition complex (EDC) and how PTBP1 might modulate them are not clear. We found that PTBP1 binding in the flanking introns allowed normal U2AF and U1 snRNP binding to the target exon splice sites but blocked U2 snRNP assembly in HeLa nuclear extract. Characterizing a purified PTBP1-repressed complex, as well as an active early complex and the final EDC by SILAC-MS, we identified extensive PTBP1-modulated changes in exon RNP composition. The active early complex formed in the absence of PTBP1 proceeded to assemble an EDC with the eviction of hnRNP proteins, the late recruitment of SR proteins, and binding of the U2 snRNP. These results demonstrate that during early stages of splicing, exon RNP complexes are highly dynamic with many proteins failing to bind during PTBP1 arrest.
    • Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

      Chiao, Ying Ann; Zhang, Huiliang; Sweetwyne, Mariya; Whitson, Jeremy; Ting, Ying Sonia; Basisty, Nathan; Pino, Lindsay K.; Quarles, Ellen; Ngoc-Han Nguyen; Campbell, Matthew D.; et al. (ELIFE SCIENCES PUBLICATIONS LTD, 2020-07)
      Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. Improved diastolic function was concordant with increased phosphorylation of cMyBP-C Ser282 but was independent of titin isoform shift. Late-life viral expression of mitochondrial-targeted catalase (mCAT) produced similar functional benefits in old mice and SS-31 did not improve cardiac function of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. These results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and implicate mitochondrial energetics and redox signaling as therapeutic targets for cardiac aging.
    • Mesoscopic-scale functional networks in the primate amygdala

      Morrow, Jeremiah K.; Cohen, Michael X.; Gothard, Katalin M.; Univ Arizona, Dept Physiol (ELIFE SCIENCES PUBLICATIONS LTD, 2020-09)
      The primate amygdala performs multiple functions that may be related to the anatomical heterogeneity of its nuclei. Individual neurons with stimulus- and task-specific responses are not clustered in any of the nuclei, suggesting that single-units may be too-fine grained to shed light on the mesoscale organization of the amygdala. We have extracted from local field potentials recorded simultaneously from multiple locations within the primate (Macaca mulatta) amygdala spatially defined and statistically separable responses to visual, tactile, and auditory stimuli. A generalized eigendecomposition-based method of source separation isolated coactivity patterns, or components, that in neurophysiological terms correspond to putative subnetworks. Some component spatial patterns mapped onto the anatomical organization of the amygdala, while other components reflected integration across nuclei. These components differentiated between visual, tactile, and auditory stimuli suggesting the presence of functionally distinct parallel subnetworks.
    • Mushroom body evolution demonstrates homology and divergence across Pancrustacea

      Strausfeld, Nicholas James; Wolff, Gabriella Hanna; Sayre, Marcel Ethan; Univ Arizona, Sch Mind Brain & Behav, Dept Neurosci (ELIFE SCIENCES PUBLICATIONS LTD, 2020-03-03)
      Descriptions of crustacean brains have focused mainly on three highly derived lineages of malacostracans: the reptantian infraorders represented by spiny lobsters, lobsters, and crayfish. Those descriptions advocate the view that dome- or cap-like neuropils, referred to as 'hemiellipsoid bodies,' are the ground pattern organization of centers that are comparable to insect mushroom bodies in processing olfactory information. Here we challenge the doctrine that hemiellipsoid bodies are a derived trait of crustaceans, whereas mushroom bodies are a derived trait of hexapods. We demonstrate that mushroom bodies typify lineages that arose before Reptantia and exist in Reptantia thereby indicating that the mushroom body, not the hemiellipsoid body, provides the ground pattern for both crustaceans and hexapods. We show that evolved variations of the mushroom body ground pattern are, in some lineages, defined by extreme diminution or loss and, in others, by the incorporation of mushroom body circuits into lobeless centers. Such transformations are ascribed to modifications of the columnar organization of mushroom body lobes that, as shown in Drosophila and other hexapods, contain networks essential for learning and memory.
    • Origin of the mechanism of phenotypic plasticity in satyrid butterfly eyespots

      Bhardwaj, Shivam; Jolander, Lim Si-Hui; Wenk, Markus R; Oliver, Jeffrey C; Nijhout, H Frederik; Monteiro, Antonia; Univ Arizona, Off Digital Innovat & Stewardship (ELIFE SCIENCES PUBLICATIONS LTD, 2020-02-11)
      Plasticity is often regarded as a derived adaptation to help organisms survive in variable but predictable environments, however, we currently lack a rigorous, mechanistic examination of how plasticity evolves in a large comparative framework. Here, we show that phenotypic plasticity in eyespot size in response to environmental temperature observed in Bicyclus anynana satyrid butterflies is a complex derived adaptation of this lineage. By reconstructing the evolution of known physiological and molecular components of eyespot size plasticity in a comparative framework, we showed that 20E titer plasticity in response to temperature is a pre-adaptation shared by all butterfly species examined, whereas expression of EcR in eyespot centers, and eyespot sensitivity to 20E, are both derived traits found only in a subset of species with eyespots.
    • Overtone focusing in biphonic tuvan throat singing

      Bergevin, Christopher; Narayan, Chandan; Williams, Joy; Mhatre, Natasha; Steeves, Jennifer K. E.; Bernstein, Joshua G. W.; Story, Brad; Univ Arizona, Speech Language & Hearing Sci (ELIFE SCIENCES PUBLICATIONS LTD, 2020-02-17)
      Khoomei is a unique singing style originating from the republic of Tuva in central Asia. Singers produce two pitches simultaneously: a booming low-frequency rumble alongside a hovering high-pitched whistle-like tone. The biomechanics of this biphonation are not well-understood. Here, we use sound analysis, dynamic magnetic resonance imaging, and vocal tract modeling to demonstrate how biphonation is achieved by modulating vocal tract morphology. Tuvan singers show remarkable control in shaping their vocal tract to narrowly focus the harmonics (or overtones) emanating from their vocal cords. The biphonic sound is a combination of the fundamental pitch and a focused filter state, which is at the higher pitch (1-2 kHz) and formed by merging two formants, thereby greatly enhancing sound-production in a very narrow frequency range. Most importantly, we demonstrate that this biphonation is a phenomenon arising from linear filtering rather than from a nonlinear source.
    • Personality links with lifespan in chimpanzees

      Altschul, Drew M; Hopkins, William D; Herrelko, Elizabeth S; Inoue-Murayama, Miho; Matsuzawa, Tetsuro; King, James E; Ross, Stephen R; Weiss, Alexander; Univ Arizona, Dept Psychol (ELIFE SCIENCES PUBLICATIONS LTD, 2018-10-09)
      Life history strategies for optimizing individual fitness fall on a spectrum between maximizing reproductive efforts and maintaining physical health over time. Strategies across this spectrum are viable and different suites of personality traits evolved to support these strategies. Using data from 538 captive chimpanzees (Pan troglodytes) we tested whether any of the dimensions of chimpanzee personality - agreeableness, conscientiousness, dominance, extraversion, neuroticism, and openness - were associated with longevity, an attribute of slow life history strategies that is especially important in primates given their relatively long lives. We found that higher agreeableness was related to longevity in males, with weaker evidence suggesting that higher openness is related to longer life in females. Our results link the literature on human and nonhuman primate survival and suggest that, for males, evolution has favored the protective effects of low aggression and high quality social bonds.
    • Rats exhibit similar biases in foraging and intertemporal choice tasks

      Kane, Gary A; Bornstein, Aaron M; Shenhav, Amitai; Wilson, Robert C; Daw, Nathaniel D; Cohen, Jonathan D; Univ Arizona, Dept Psychol, Cognit Sci Program (ELIFE SCIENCES PUBLICATIONS LTD, 2019-09-18)
      Animals, including humans, consistently exhibit myopia in two different contexts: foraging, in which they harvest locally beyond what is predicted by optimal foraging theory, and intertemporal choice, in which they exhibit a preference for immediate vs. delayed rewards beyond what is predicted by rational (exponential) discounting. Despite the similarity in behavior between these two contexts, previous efforts to reconcile these observations in terms of a consistent pattern of time preferences have failed. Here, via extensive behavioral testing and quantitative modeling, we show that rats exhibit similar time preferences in both contexts: they prefer immediate vs. delayed rewards and they are sensitive to opportunity costs of delays to future decisions. Further, a quasi-hyperbolic discounting model, a form of hyperbolic discounting with separate components for short- and long-term rewards, explains individual rats’ time preferences across both contexts, providing evidence for a common mechanism for myopic behavior in foraging and intertemporal choice.
    • Signal categorization by foraging animals depends on ecological diversity

      Kikuchi, David William; Dornhaus, Anna; Gopeechund, Vandana; Sherratt, Thomas N; Univ Arizona, Dept Ecol & Evolutionary Biol (ELIFE SCIENCES PUBLICATIONS LTD, 2019-04-25)
      Warning signals displayed by defended prey are mimicked by both mutualistic (Mullerian) and parasitic (Batesian) species. Yet mimicry is often imperfect: why does selection not improve mimicry? Predators create selection on warning signals, so predator psychology is crucial to understanding mimicry. We conducted experiments where humans acted as predators in a virtual ecosystem to ask how prey diversity affects the way that predators categorize prey phenotypes as profitable or unprofitable. The phenotypic diversity of prey communities strongly affected predator categorization. Higher diversity increased the likelihood that predators would use a 'key' trait to form broad categories, even if it meant committing errors. Broad categorization favors the evolution of mimicry. Both species richness and evenness contributed significantly to this effect. This lets us view the behavioral and evolutionary processes leading to mimicry in light of classical community ecology. Broad categorization by receivers is also likely to affect other forms of signaling.
    • Specific Eph receptor-cytoplasmic effector signaling mediated by SAM-SAM domain interactions

      Wang, Yue; Shang, Yuan; Li, Jianchao; Chen, Weidi; Li, Gang; Wan, Jun; Liu, Wei; Zhang, Mingjie; Univ Arizona, Ctr Biomed Informat & Biostat (ELIFE SCIENCES PUBLICATIONS LTD, 2018-05-11)
      The Eph receptor tyrosine kinase (RTK) family is the largest subfamily of RTKs playing critical roles in many developmental processes such as tissue patterning, neurogenesis and neuronal circuit formation, angiogenesis, etc. How the 14 Eph proteins, via their highly similar cytoplasmic domains, can transmit diverse and sometimes opposite cellular signals upon engaging ephrins is a major unresolved question. Here, we systematically investigated the bindings of each SAM domain of Eph receptors to the SAM domains from SHIP2 and Odin, and uncover a highly specific SAM SAM interaction-mediated cytoplasmic Eph-effector binding pattern. Comparative X-ray crystallographic studies of several SAM SAM heterodimer complexes, together with biochemical and cell biology experiments, not only revealed the exquisite specificity code governing Eph/effector interactions but also allowed us to identify SAMD5 as a new Eph binding partner. Finally, these Eph/effector SAM heterodimer structures can explain many Eph SAM mutations identified in patients suffering from cancers and other diseases.
    • A Toll-receptor map underlies structural brain plasticity

      Li, Guiyi; Forero, Manuel G; Wentzell, Jill S; Durmus, Ilgim; Wolf, Reinhard; Anthoney, Niki C; Parker, Mieczyslaw; Jiang, Ruiying; Hasenauer, Jacob; Strausfeld, Nicholas James; et al. (ELIFE SCIENCES PUBLICATIONS LTD, 2020-02-18)
      Experience alters brain structure, but the underlying mechanism remained unknown. Structural plasticity reveals that brain function is encoded in generative changes to cells that compete with destructive processes driving neurodegeneration. At an adult critical period, experience increases fiber number and brain size in Drosophila. Here, we asked if Toll receptors are involved. Tolls demarcate a map of brain anatomical domains. Focusing on Toll-2, loss of function caused apoptosis, neurite atrophy and impaired behaviour. Toll-2 gain of function and neuronal activity at the critical period increased cell number. Toll-2 induced cycling of adult progenitor cells via a novel pathway, that antagonized MyD88-dependent quiescence, and engaged Weckle and Yorkie downstream. Constant knock-down of multiple Tolls synergistically reduced brain size. Conditional over-expression of Toll-2 and wek at the adult critical period increased brain size. Through their topographic distribution, Toll receptors regulate neuronal number and brain size, modulating structural plasticity in the adult brain.