Founded in 2001, the Department of Neurobiology at UMass Chan Medical School has evolved into a unique and integrated hub of investigators addressing fundamental problems in neurobiology, from single molecules to behavior, primarily using invertebrate model organisms. Combining cell biological, physiological and behavioral analyses with a critical interventionist angle afforded by cutting-edge genetic approaches, the Department aims to understand the complexity of brain development and function. Use the “UMass Chan Affiliation” Filter by Category in the left sidebar to see the publications produced by a specific lab.

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  • TIR-1/SARM1 inhibits axon regeneration and promotes axon degeneration

    Czech, Victoria L; O'Connor, Lauren C; Philippon, Brendan; Norman, Emily; Byrne, Alexandra B (2023-04-21)
    Growth and destruction are central components of the neuronal injury response. Injured axons that are capable of repair, including axons in the mammalian peripheral nervous system and in many invertebrate animals, often regenerate and degenerate on either side of the injury. Here we show that TIR-1/dSarm/SARM1, a key regulator of axon degeneration, also inhibits regeneration of injured motor axons. The increased regeneration in tir-1 mutants is not a secondary consequence of its effects on degeneration, nor is it determined by the NADase activity of TIR-1. Rather, we found that TIR-1 functions cell-autonomously to regulate each of the seemingly opposite processes through distinct interactions with two MAP kinase pathways. On one side of the injury, TIR-1 inhibits axon regeneration by activating the NSY-1/ASK1 MAPK signaling cascade, while on the other side of the injury, TIR-1 simultaneously promotes axon degeneration by interacting with the DLK-1 mitogen-activated protein kinase (MAPK) signaling cascade. In parallel, we found that the ability to cell-intrinsically inhibit axon regeneration is conserved in human SARM1. Our finding that TIR-1/SARM1 regulates axon regeneration provides critical insight into how axons coordinate a multidimensional response to injury, consequently informing approaches to manipulate the response toward repair.
  • Gliotransmission and adenosine signaling promote axon regeneration

    Wang, Fei; Ruppell, Kendra Takle; Zhou, Songlin; Qu, Yun; Gong, Jiaxin; Shang, Ye; Wu, Jinglin; Liu, Xin; Diao, Wenlin; Li, Yi; et al. (2023-04-06)
    How glia control axon regeneration remains incompletely understood. Here, we investigate glial regulation of regenerative ability differences of closely related Drosophila larval sensory neuron subtypes. Axotomy elicits Ca2+ signals in ensheathing glia, which activates regenerative neurons through the gliotransmitter adenosine and mounts axon regenerative programs. However, non-regenerative neurons do not respond to glial stimulation or adenosine. Such neuronal subtype-specific responses result from specific expressions of adenosine receptors in regenerative neurons. Disrupting gliotransmission impedes axon regeneration of regenerative neurons, and ectopic adenosine receptor expression in non-regenerative neurons suffices to activate regenerative programs and induce axon regeneration. Furthermore, stimulating gliotransmission or activating the mammalian ortholog of Drosophila adenosine receptors in retinal ganglion cells (RGCs) promotes axon regrowth after optic nerve crush in adult mice. Altogether, our findings demonstrate that gliotransmission orchestrates neuronal subtype-specific axon regeneration in Drosophila and suggest that targeting gliotransmission or adenosine signaling is a strategy for mammalian central nervous system repair.
  • Evidence for RNA or protein transport from somatic tissues to the male reproductive tract in mouse

    Rinaldi, Vera; Messemer, Kathleen; Desevin, Kathleen; Sun, Fengyun; Berry, Bethany C; Kukreja, Shweta; Tapper, Andrew R; Wagers, Amy J; Rando, Oliver J (2023-03-27)
    The development of tools to manipulate the mouse genome, including knockout and transgenic technology, has revolutionized our ability to explore gene function in mammals. Moreover, for genes that are expressed in multiple tissues or at multiple stages of development, the use of tissue-specific expression of the Cre recombinase allows gene function to be perturbed in specific cell types and/or at specific times. However, it is well known that putative tissue-specific promoters often drive unanticipated 'off-target' expression. In our efforts to explore the biology of the male reproductive tract, we unexpectedly found that expression of Cre in the central nervous system resulted in recombination in the epididymis, a tissue where sperm mature for ~1-2 weeks following the completion of testicular development. Remarkably, we not only observed reporter expression in the epididymis when Cre expression was driven from neuron-specific transgenes, but also when Cre expression in the brain was induced from an AAV vector carrying a Cre expression construct. A surprisingly wide range of Cre drivers - including six different neuronal promoters as well as the adipose-specific Adipoq Cre promoter - exhibited off-target recombination in the epididymis, with a subset of drivers also exhibiting unexpected activity in other tissues such as the reproductive accessory glands. Using a combination of parabiosis and serum transfer experiments, we find evidence supporting the hypothesis that Cre may be trafficked from its cell of origin to the epididymis through the circulatory system. Together, our findings should motivate caution when interpreting conditional alleles, and suggest the exciting possibility of inter-tissue RNA or protein trafficking in modulation of reproductive biology.
  • Behavioral circatidal rhythms require Bmal1 in Parhyale hawaiensis

    Kwiatkowski, Erica R; Schnytzer, Yisrael; Rosenthal, Joshua J C; Emery, Patrick (2023-03-19)
    Organisms living in the intertidal zone are exposed to a particularly challenging environment. In addition to daily changes in light intensity and seasonal changes in photoperiod and weather patterns, they experience dramatic oscillations in environmental conditions due to the tides. To anticipate tides, and thus optimize their behavior and physiology, animals occupying intertidal ecological niches have acquired circatidal clocks. Although the existence of these clocks has long been known, their underlying molecular components have proven difficult to identify, in large part because of the lack of an intertidal model organism amenable to genetic manipulation. In particular, the relationship between the circatidal and circadian molecular clocks, and the possibility of shared genetic components, has been a long-standing question. Here, we introduce the genetically tractable crustacean Parhyale hawaiensis as a system for the study of circatidal rhythms. First, we show that P. hawaiensis exhibits robust 12.4-h rhythms of locomotion that can be entrained to an artificial tidal regimen and are temperature compensated. Using CRISPR-Cas9 genome editing, we then demonstrate that the core circadian clock gene Bmal1 is required for circatidal rhythms. Our results thus demonstrate that Bmal1 is a molecular link between circatidal and circadian clocks and establish P. hawaiensis as a powerful system to study the molecular mechanisms underlying circatidal rhythms and their entrainment.
  • Lipofuscin-like autofluorescence within microglia and its impact on studying microglial engulfment [preprint]

    Stillman, Jacob M; Lopes, Francisco M; Lin, Jing-Ping; Hu, Kevin; Reich, Daniel S; Schafer, Dorothy P (2023-03-01)
    Engulfment of cellular material and proteins is a key function for microglia, a resident macrophage of the central nervous system (CNS). Among the techniques used to measure microglial engulfment, confocal light microscopy has been used the most extensively. Here, we show that autofluorescence (AF), likely due to lipofuscin and typically associated with aging, can also be detected within microglial lysosomes in the young mouse brain by light microscopy. This lipofuscin-AF signal accumulates first within microglia and increases with age, but it is not exacerbated by amyloid beta-related neurodegeneration. We further show that this lipofuscin-AF signal within microglia can confound the interpretation of antibody-labeled synaptic material within microglia in young adult mice. Finally, we implement a robust strategy to quench AF in mouse, marmoset, and human brain tissue.
  • The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus

    Robert, Stephanie M; Reeves, Benjamin C; Kiziltug, Emre; Duy, Phan Q; Karimy, Jason K; Mansuri, M Shahid; Marlier, Arnaud; Allington, Garrett; Greenberg, Ana B W; DeSpenza, Tyrone; et al. (2023-02-16)
    The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.
  • Modulation of neuronal excitability by binge alcohol drinking

    Gimenez-Gomez, Pablo; Le, Timmy; Martin, Gilles E (2023-02-14)
    Drug use poses a serious threat to health systems throughout the world. The number of consumers rises every year being alcohol the drug of abuse most consumed causing 3 million deaths (5.3% of all deaths) worldwide and 132.6 million disability-adjusted life years. In this review, we present an up-to-date summary about what is known regarding the global impact of binge alcohol drinking on brains and how it affects the development of cognitive functions, as well as the various preclinical models used to probe its effects on the neurobiology of the brain. This will be followed by a detailed report on the state of our current knowledge of the molecular and cellular mechanisms underlying the effects of binge drinking on neuronal excitability and synaptic plasticity, with an emphasis on brain regions of the meso-cortico limbic neurocircuitry.
  • Neurexins in serotonergic neurons regulate neuronal survival, serotonin transmission, and complex mouse behaviors

    Cheung, Amy; Konno, Kotaro; Imamura, Yuka; Matsui, Aya; Abe, Manabu; Sakimura, Kenji; Sasaoka, Toshikuni; Uemura, Takeshi; Watanabe, Masahiko; Futai, Kensuke (2023-01-25)
    Extensive serotonin (5-hydroxytryptamine, 5-HT) innervation throughout the brain corroborates 5-HT's modulatory role in numerous cognitive activities. Volume transmission is the major mode for 5-HT transmission but mechanisms underlying 5-HT signaling are still largely unknown. Abnormal brain 5-HT levels and function have been implicated in autism spectrum disorder (ASD). Neurexin (Nrxn) genes encode presynaptic cell adhesion molecules important for the regulation of synaptic neurotransmitter release, notably glutamatergic and GABAergic transmission. Mutations in Nrxn genes are associated with neurodevelopmental disorders including ASD. However, the role of Nrxn genes in the 5-HT system is poorly understood. Here, we generated a mouse model with all three Nrxn genes disrupted specifically in 5-HT neurons to study how Nrxns affect 5-HT transmission. Loss of Nrxns in 5-HT neurons reduced the number of serotonin neurons in the early postnatal stage, impaired 5-HT release, and decreased 5-HT release sites and serotonin transporter expression. Furthermore, 5-HT neuron-specific Nrxn knockout reduced sociability and increased depressive-like behavior. Our results highlight functional roles for Nrxns in 5-HT neurotransmission, 5-HT neuron survival, and the execution of complex behaviors.
  • Viral Tracing Confirms Paranigral Ventral Tegmental Area Dopaminergic Inputs to the Interpeduncular Nucleus Where Dopamine Release Encodes Motivated Exploration

    Molas, Susanna; Zhao-Shea, Rubing; Freels, Timothy G; Tapper, Andrew R (2023-01-12)
    Midbrain dopaminergic (DAergic) neurons of the ventral tegmental area (VTA) are engaged by rewarding stimuli and encode reward prediction error to update goal-directed learning. However, recent data indicate that VTA DAergic neurons are functionally heterogeneous with emerging roles in aversive signaling, salience, and novelty, based in part on anatomic location and projection, highlighting a need to functionally characterize the repertoire of VTA DAergic efferents in motivated behavior. Previous work identifying a mesointerpeduncular circuit consisting of VTA DAergic neurons projecting to the interpeduncular nucleus (IPN), a midbrain area implicated in aversion, anxiety-like behavior, and familiarity, has recently come into question. To verify the existence of this circuit, we combined presynaptic targeted and retrograde viral tracing in the dopamine transporter-Cre mouse line. Consistent with previous reports, synaptic tracing revealed that axon terminals from the VTA innervate the caudal IPN; whereas, retrograde tracing revealed DAergic VTA neurons, predominantly in the paranigral region, project to the nucleus accumbens shell, as well as the IPN. To test whether functional DAergic neurotransmission exists in the IPN, we expressed the genetically encoded DA sensor, dLight 1.2, in the IPN of C57BL/6J mice and measured IPN DA signals in vivo during social and anxiety-like behavior using fiber photometry. We observed an increase in IPN DA signal during social investigation of a novel but not familiar conspecific and during exploration of the anxiogenic open arms of the elevated plus maze. Together, these data confirm VTA DAergic neuron projections to the IPN and implicate this circuit in encoding motivated exploration.
  • Presynaptic Gq-coupled receptors drive biphasic dopamine transporter trafficking that modulates dopamine clearance and motor function

    Kearney, Patrick J; Bolden, Nicholas C; Kahuno, Elizabeth; Conklin, Tucker L; Martin, Gilles E; Lubec, Gert; Melikian, Haley E (2023-01-12)
    Extracellular dopamine (DA) levels are constrained by the presynaptic DA transporter (DAT), a major psychostimulant target. Despite its necessity for DA neurotransmission, DAT regulation in situ is poorly understood, and it is unknown whether regulated DAT trafficking impacts dopaminergic signaling and/or behaviors. Leveraging chemogenetics and conditional gene silencing, we found that activating presynaptic Gq-coupled receptors, either hM3Dq or mGlu5, drove rapid biphasic DAT membrane trafficking in ex vivo striatal slices, with region-specific differences between ventral and dorsal striata. DAT insertion required D2 DA autoreceptors and intact retromer, whereas DAT retrieval required PKC activation and Rit2. Ex vivo voltammetric studies revealed that DAT trafficking impacts DA clearance. Furthermore, dopaminergic mGlu5 silencing elevated DAT surface expression and abolished motor learning, which was rescued by inhibiting DAT with a subthreshold CE-158 dose. We discovered that presynaptic DAT trafficking is complex, multimodal, and region specific, and for the first time, we identified cell autonomous mechanisms that govern presynaptic DAT tone. Importantly, the findings are consistent with a role for regulated DAT trafficking in DA clearance and motor function.
  • A comparative analysis of microglial inducible Cre lines [preprint]

    Faust, Travis E; Feinberg, Philip A; O'Connor, Ciara; Kawaguchi, Riki; Chan, Andrew; Strasburger, Haley; Masuda, Takahiro; Amann, Lukas; Knobeloch, Klaus-Peter; Prinz, Marco; et al. (2023-01-09)
    Cre/LoxP technology has revolutionized genetic studies and allowed for spatial and temporal control of gene expression in specific cell types. The field of microglial biology has particularly benefited from this technology as microglia have historically been difficult to transduce with virus or electroporation methods for gene delivery. Here, we interrogate four of the most widely available microglial inducible Cre lines. We demonstrate varying degrees of recombination efficiency and spontaneous recombination, depending on the Cre line and loxP distance. We also establish best practice guidelines and protocols to measure recombination efficiency in microglia, which could be extended to other cell types. There is increasing evidence that microglia are key regulators of neural circuit structure and function. Microglia are also major drivers of a broad range of neurological diseases. Thus, reliable manipulation of their function in vivo is of utmost importance. Identifying caveats and benefits of all tools and implementing the most rigorous protocols are crucial to the growth of the field of microglial biology and the development of microglia-based therapeutics.
  • Cell-specific effects of the sole C. elegans Daughterless/E protein homolog, HLH-2, on nervous system development

    Masoudi, Neda; Schnabel, Ralf; Yemini, Eviatar; Leyva-Díaz, Eduardo; Hobert, Oliver (2023-01-03)
    Are there common mechanisms of neurogenesis used throughout an entire nervous system? We explored to what extent canonical proneural class I/II bHLH complexes are responsible for neurogenesis throughout the entire Caenorhabditis elegans nervous system. Distinct, lineage-specific proneural class II bHLH factors are generally thought to operate via interaction with a common, class I bHLH subunit, encoded by Daughterless in flies, the E proteins in vertebrates and HLH-2 in C. elegans. To eliminate function of all proneuronal class I/II bHLH complexes, we therefore genetically removed maternal and zygotic hlh-2 gene activity. We observed broad effects on neurogenesis, but still detected normal neurogenesis in many distinct neuron-producing lineages of the central and peripheral nervous system. Moreover, we found that hlh-2 selectively affects some aspects of neuron differentiation while leaving others unaffected. Although our studies confirm the function of proneuronal class I/II bHLH complexes in many different lineages throughout a nervous system, we conclude that their function is not universal, but rather restricted by lineage, cell type and components of differentiation programs affected.
  • Binge alcohol drinking alters the differential control of cholinergic interneurons over nucleus accumbens D1 and D2 medium spiny neurons

    Kolpakova, Jenya; van der Vinne, Vincent; Gimenez-Gomez, Pablo; Le, Timmy; Martin, Gilles E (2022-12-15)
    Animals studies support the notion that striatal cholinergic interneurons (ChIs) play a central role in basal ganglia function by regulating associative learning, reward processing, and motor control. In the nucleus accumbens (NAc), a brain region that mediates rewarding properties of substance abuse, acetylcholine regulates glutamatergic, dopaminergic, and GABAergic neurotransmission in naïve mice. However, it is unclear how ChIs orchestrate the control of these neurotransmitters/modulators to determine the synaptic excitability of medium spiny neurons (MSNs), the only projecting neurons that translate accumbens electrical activity into behavior. Also unknown is the impact of binge alcohol drinking on the regulation of dopamine D1- and D2 receptor-expressing MSNs (D1- and D2-MSNs, respectively) by ChIs. To investigate this question, we optogenetically stimulated ChIs while recording evoked and spontaneous excitatory postsynaptic currents (sEPSCs) in nucleus accumbens core D1- and D2-MSN of ChAT.ChR2.eYFPxDrd1.tdtomato mice. In alcohol-naïve mice, we found that stimulating NAc ChIs decreased sEPSCs frequency in both D1- and D2-MSNs, presumably through a presynaptic mechanism. Interestingly, ChI stimulation decreased MSN synaptic excitability through different mechanisms in D1- vs. D2-MSNs. While decrease of ChI-mediated sEPSCs frequency in D1-MSNs was mediated by dopamine, the same effect in D2-MSNs resulted from a direct control of glutamate release by ChIs. Interestingly, after 2 weeks of binge alcohol drinking, optogenetic stimulation of ChIs enhanced glutamate release in D1-MSNs, while its effect on D2-MSNs remained unchanged. Taken together, these data suggest that cholinergic interneurons could be a key target for regulation of NAc circuitry and for alcohol consumption.
  • Deconstructing the Nervous System: Transcriptional Mechanisms Sculpting Neuronal Connectivity in C. elegans

    Alexander, Kellianne (2022-12-08)
    An important step in brain development is the active remodeling of neural circuits, however the molecular mechanisms directing circuit refinement and their timing are not fully understood. Defects in synaptic refinement has been linked with several neuropsychiatric disorders, yet we have an incomplete understanding of the molecular mechanisms involved. In this thesis I am investigating synaptic remodeling using the motor circuit of the nematode Caenorhabditis elegans as a model. A subset of GABAergic motor neurons, the dorsal D-class (DD) neurons, undergo an interesting form of remodeling where the axonal and dendritic domains switch during circuit development. This process requires eliminating juvenile synaptic connections and forming new synaptic contacts to establish the adult circuit. In this work, I identify a conserved transcriptional regulator, DVE-1, that directs the elimination of synaptic inputs onto remodeling C. elegans GABAergic neurons. Dorsally localized juvenile acetylcholine receptor clusters and apposing presynaptic cholinergic vesicle clusters that are normally eliminated during wild type maturation, persist into adulthood in dve-1 mutants. Failure in synapse elimination leads to altered motor function, specifically a turning bias during movement, indicating that altered synaptic activity impacts mature circuit function in dve-1 mutants. Furthermore, I investigated DVE-1 transcriptional regulation of synapse elimination. DVE-1 is localized to GABAergic neuron nuclei prior to remodeling and disruption of DVE-1 nuclear localization impairs synapse elimination, suggesting cell-autonomous regulation of synapse elimination. Transcriptome analysis of dve-1 mutants identified striking changes in GABA neuron expressed genes governing cytoskeletal organization and proteostasis, suggesting DVE-1 promotes synapse elimination through transcriptional regulation of these pathways. Temporally regulated expression of the Ig domain protein OIG-1 stabilizes synapses prior to remodeling. Synapse elimination occurs precociously in oig-1 mutants, but is delayed in oig-1;dve-1 double mutants, suggesting that mature connectivity is sculpted through the convergence of constitutive DVE-1-regulated pro-degenerative mechanisms and parallel-acting temporally regulated maintenance processes. Further, I investigated the role of a downstream target of DVE-1 revealed from my transcriptome analysis, calcineurin B/cnb-1. I find that cnb-1 acts cell-autonomously to promote synapse elimination. Together my work begins to uncover a previously unknown transcriptional network driving synaptic refinement and expect that ongoing studies of transcriptional control of synapse elimination by DVE-1 will illuminate conserved genetic mechanisms controlling synapse removal during circuit development.
  • Investigating the Molecular Mechanisms of Toxicity in Mouse Models of Frontotemporal Dementia

    Daly, Luke R (2022-11-28)
    Frontotemporal Dementia (FTD) is the most common form of presenile dementia and is characterized by impaired cognitive function, behavioral changes, or non-fluent speech aphasia. The most common genetic cause of FTD is a hexanucleotide GGGGCC (G4C2) repeat expansion in the C9orf72 gene (C9orf72-HRE). This thesis outlines a series of in vivo and in vitro experiments undertaken to investigate the molecular mechanisms of toxicity contributing to FTD pathogenesis. In my efforts to characterize the neuroinflammation observed in our Poly(Glycine-Arginine) mouse model of FTD, I found Fkbp5 - a gene our lab previously identified as a modulator of Poly(GR) toxicity - to be significantly downregulated in the cortex of Poly(GR) animals relative to controls. Published RNA sequencing data suggests that Fkbp5 is most highly expressed in microglia of the mammalian brain. However, despite its importance in a variety of neurological disorders, very little is known about the specific role fkbp5 plays in microglia. Data presented in this thesis implicate Fkbp5 as an important modulator of neuroinflammatory signaling and Poly(GR) toxicity. Here, I outline the breeding scheme I devised to generate a novel genetic tool to further untangle the role Fkbp5 may be playing in neuroinflammation and C9orf72 pathogenesis. In additional efforts to investigate the molecular underpinnings of C9orf72 pathology, I contributed to the characterization of a novel AAV9 model of C9orf72-HRE developed by our collaborators at SUNY Upstate Medical University.
  • Neuronal signal-regulatory protein alpha drives microglial phagocytosis by limiting microglial interaction with CD47 in the retina

    Jiang, Danye; Burger, Courtney A; Akhanov, Viktor; Liang, Justine H; Mackin, Robert D; Albrecht, Nicholas E; Andrade, Pilar; Schafer, Dorothy P; Samuel, Melanie A (2022-11-14)
    Microglia utilize their phagocytic activity to prune redundant synapses and refine neural circuits during precise developmental periods. However, the neuronal signals that control this phagocytic clockwork remain largely undefined. Here, we show that neuronal signal-regulatory protein alpha (SIRPα) is a permissive cue for microglial phagocytosis in the developing murine retina. Removal of neuronal, but not microglial, SIRPα reduced microglial phagocytosis, increased synpase numbers, and impaired circuit function. Conversely, prolonging neuronal SIRPα expression extended developmental microglial phagocytosis. These outcomes depended on the interaction of presynaptic SIRPα with postsynaptic CD47. Global CD47 deficiency modestly increased microglial phagocytosis, while CD47 overexpression reduced it. This effect was rescued by coexpression of neuronal SIRPα or codeletion of neuronal SIRPα and CD47. These data indicate that neuronal SIRPα regulates microglial phagocytosis by limiting microglial SIRPα access to neuronal CD47. This discovery may aid our understanding of synapse loss in neurological diseases.
  • The homeodomain transcriptional regulator DVE-1 directs a program for synapse elimination during circuit remodeling [preprint]

    Alexander, Kellianne D; Ramachandran, Shankar; Biswas, Kasturi; Lambert, Christopher M; Russell, Julia; Oliver, Devyn B; Armstrong, William; Rettler, Monika; Doitsidou, Maria; Bénard, Claire; et al. (2022-11-10)
    An important step in brain development is the remodeling of juvenile neural circuits to establish mature connectivity. The elimination of juvenile synapses is a critical step in this process; however, the molecular mechanisms directing synapse elimination activities and their timing are not fully understood. We identify here a conserved transcriptional regulator, DVE-1, that shares homology with mammalian special AT-rich sequence-binding (SATB) family members and directs the elimination of juvenile synaptic inputs onto remodeling C. elegans GABAergic neurons. Dorsally localized juvenile acetylcholine receptor clusters and apposing presynaptic sites are eliminated during maturation of wild type GABAergic neurons but persist into adulthood in dve-1 mutants. The persistence of juvenile synapses in dve-1 mutants does not impede synaptic growth during GABAergic remodeling and therefore produces heightened motor connectivity and a turning bias during movement. DVE-1 is localized to GABAergic nuclei prior to and during remodeling and DVE-1 nuclear localization is required for synapse elimination to proceed, consistent with DVE-1’s function as a transcriptional regulator. Pathway analysis of DVE-1 targets and proteasome inhibitor experiments implicate transcriptional control of the ubiquitin-proteasome system in synapse elimination. Together, our findings demonstrate a new role for a SATB family member in the control of synapse elimination during circuit remodeling through transcriptional regulation of ubiquitin-proteasome signaling. Contributions Summary KDA generated strains, transgenic lines, molecular constructs, confocal microscopy images and analysis, performed optogenetic behavioral experiments, photoconversion experiments, modencode ChIP-seq analysis and pathway analysis. SR performed all calcium imaging experiments/analysis and conducted single worm tracking. KB performed all Bortezomib inhibitor experiments and analysis. CL generated most vectors and constructs. JR assisted with generation of CRISPR/Cas9 generated strains. WA and MR assisted with aldicarb behavioral assay. DO assisted with EMS screen and isolation of dve-1 mutant. CB and MD aided in CloudMap bioinformatic analysis of the uf171 mutant. MMF and KDA designed and interpreted results of all experiments and wrote the manuscript.
  • Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans

    Hernandez-Cravero, Bruno; Gallino, Sofia; Florman, Jeremy; Vranych, Cecilia; Diaz, Philippe; Elgoyhen, Ana Belén; Alkema, Mark J; de Mendoza, Diego (2022-11-08)
    The nematode Caenorhabditis elegans requires exogenous cholesterol to survive and its depletion leads to early developmental arrest. Thus, tight regulation of cholesterol storage and distribution within the organism is critical. Previously, we demonstrated that the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) plays a key role in C. elegans since it modulates sterol mobilization. However, the mechanism remains unknown. Here we show that mutations in the ocr-2 and osm-9 genes, coding for transient receptors potential V (TRPV) ion channels, dramatically reduce the effect of 2-AG in cholesterol mobilization. Through genetic analysis in combination with the rescue of larval arrest induced by sterol starvation, we found that the insulin/IGF-1signaling (IIS) pathway and UNC-31/CAPS, a calcium-activated regulator of neural dense-core vesicles release, are essential for 2-AG-mediated stimulation of cholesterol mobilization. These findings indicate that 2-AG-dependent cholesterol trafficking requires the release of insulin peptides and signaling through the DAF-2 insulin receptor. These results suggest that 2-AG acts as an endogenous modulator of TRPV signal transduction to control intracellular sterol trafficking through modulation of the IGF-1 signaling pathway.
  • Microglia states and nomenclature: A field at its crossroads

    Paolicelli, Rosa C; Sierra, Amanda; Stevens, Beth; Tremblay, Marie-Eve; Aguzzi, Adriano; Ajami, Bahareh; Amit, Ido; Audinat, Etienne; Bechmann, Ingo; Bennett, Mariko; et al. (2022-11-02)
    Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.
  • Microglia are SYK of Aβ and cell debris

    Schafer, Dorothy P; Stillman, Jacob M (2022-10-27)
    During neurodegenerative disease, resident CNS macrophages termed "microglia" assume a neuroprotective role and engulf toxic protein aggregates and cell debris. In this issue of Cell, two groups independently show how spleen tyrosine kinase (SYK) acts downstream of microglial surface receptors to propagate this neuroprotective program in vivo.

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