Stanford Advisors

Lab Affiliations

  • Ben Barres, Barres Lab (9/1/2007)

All Publications

  • New tools for studying microglia in the mouse and human CNS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Bennett, M. L., Bennett, F. C., Liddelow, S. A., Ajami, B., Zamanian, J. L., Fernhoff, N. B., Mulinyawe, S. B., Bohlen, C. J., Adil, A., Tucker, A., Weissman, I. L., Chang, E. F., Li, G., Grant, G. A., Gephart, M. G., Barres, B. A. 2016; 113 (12): E1738-E1746
  • Microglia: Scapegoat, Saboteur, or Something Else? SCIENCE Aguzzi, A., Barres, B. A., Bennett, M. L. 2013; 339 (6116): 156-161


    Microglia are resident immune cells in the brain and spinal cord. These cells provide immune surveillance and are mobilized in response to disparate diseases and injuries. Although microglial activation is often considered neurotoxic, microglia are essential defenders against many neurodegenerative diseases. It also seems increasingly likely that microglial dysfunction can underlie certain neurological diseases without an obvious immune component.

    View details for DOI 10.1126/science.1227901

    View details for Web of Science ID 000313328200033

    View details for PubMedID 23307732

    View details for PubMedCentralID PMC4431634

  • Neurotoxic reactive astrocytes are induced by activated microglia. Nature Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W., Peterson, T. C., Wilton, D. K., Frouin, A., Napier, B. A., Panicker, N., Kumar, M., Buckwalter, M. S., Rowitch, D. H., Dawson, V. L., Dawson, T. M., Stevens, B., Barres, B. A. 2017; 541 (7638): 481-487


    Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases.

    View details for DOI 10.1038/nature21029

    View details for PubMedID 28099414

    View details for PubMedCentralID PMC5404890

  • Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility. Cell metabolism Valdearcos, M., Douglass, J. D., Robblee, M. M., Dorfman, M. D., Stifler, D. R., Bennett, M. L., Gerritse, I., Fasnacht, R., Barres, B. A., Thaler, J. P., Koliwad, S. K. 2017; 26 (1): 185–97.e3


    Dietary excess triggers accumulation of pro-inflammatory microglia in the mediobasal hypothalamus (MBH), but the components of this microgliosis and its metabolic consequences remain uncertain. Here, we show that microglial inflammatory signaling determines the immunologic response of the MBH to dietary excess and regulates hypothalamic control of energy homeostasis in mice. Either pharmacologically depleting microglia or selectively restraining microglial NF-κB-dependent signaling sharply reduced microgliosis, an effect that includes prevention of MBH entry by bone-marrow-derived myeloid cells, and greatly limited diet-induced hyperphagia and weight gain. Conversely, forcing microglial activation through cell-specific deletion of the negative NF-κB regulator A20 induced spontaneous MBH microgliosis and cellular infiltration, reduced energy expenditure, and increased both food intake and weight gain even in absence of a dietary challenge. Thus, microglial inflammatory activation, stimulated by dietary excess, orchestrates a multicellular hypothalamic response that mediates obesity susceptibility, providing a mechanistic rationale for non-neuronal approaches to treat metabolic diseases.

    View details for DOI 10.1016/j.cmet.2017.05.015

    View details for PubMedID 28683286

  • An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex. journal of neuroscience Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., Deng, S., Liddelow, S. A., Zhang, C., Daneman, R., Maniatis, T., Barres, B. A., Wu, J. Q. 2014; 34 (36): 11929-11947


    The major cell classes of the brain differ in their developmental processes, metabolism, signaling, and function. To better understand the functions and interactions of the cell types that comprise these classes, we acutely purified representative populations of neurons, astrocytes, oligodendrocyte precursor cells, newly formed oligodendrocytes, myelinating oligodendrocytes, microglia, endothelial cells, and pericytes from mouse cerebral cortex. We generated a transcriptome database for these eight cell types by RNA sequencing and used a sensitive algorithm to detect alternative splicing events in each cell type. Bioinformatic analyses identified thousands of new cell type-enriched genes and splicing isoforms that will provide novel markers for cell identification, tools for genetic manipulation, and insights into the biology of the brain. For example, our data provide clues as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation attributable to unique splicing of PKM2, the gene encoding the glycolytic enzyme pyruvate kinase. This dataset will provide a powerful new resource for understanding the development and function of the brain. To ensure the widespread distribution of these datasets, we have created a user-friendly website ( that provides a platform for analyzing and comparing transciption and alternative splicing profiles for various cell classes in the brain.

    View details for DOI 10.1523/JNEUROSCI.1860-14.2014

    View details for PubMedID 25186741

    View details for PubMedCentralID PMC4152602

  • Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors NATURE Allen, N. J., Bennett, M. L., Foo, L. C., Wang, G. X., Chakraborty, C., Smith, S. J., Barres, B. A. 2012; 486 (7403): 410-?


    In the developing central nervous system (CNS), the control of synapse number and function is critical to the formation of neural circuits. We previously demonstrated that astrocyte-secreted factors powerfully induce the formation of functional excitatory synapses between CNS neurons. Astrocyte-secreted thrombospondins induce the formation of structural synapses, but these synapses are postsynaptically silent. Here we use biochemical fractionation of astrocyte-conditioned medium to identify glypican 4 (Gpc4) and glypican 6 (Gpc6) as astrocyte-secreted signals sufficient to induce functional synapses between purified retinal ganglion cell neurons, and show that depletion of these molecules from astrocyte-conditioned medium significantly reduces its ability to induce postsynaptic activity. Application of Gpc4 to purified neurons is sufficient to increase the frequency and amplitude of glutamatergic synaptic events. This is achieved by increasing the surface level and clustering, but not overall cellular protein level, of the GluA1 subunit of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) glutamate receptor (AMPAR). Gpc4 and Gpc6 are expressed by astrocytes in vivo in the developing CNS, with Gpc4 expression enriched in the hippocampus and Gpc6 enriched in the cerebellum. Finally, we demonstrate that Gpc4-deficient mice have defective synapse formation, with decreased amplitude of excitatory synaptic currents in the developing hippocampus and reduced recruitment of AMPARs to synapses. These data identify glypicans as a family of novel astrocyte-derived molecules that are necessary and sufficient to promote glutamate receptor clustering and receptivity and to induce the formation of postsynaptically functioning CNS synapses.

    View details for DOI 10.1038/nature11059

    View details for Web of Science ID 000305466800045

    View details for PubMedID 22722203

    View details for PubMedCentralID PMC3383085

  • A novel role for microglia in minimizing excitotoxicity BMC BIOLOGY Howe, M. L., Barres, B. A. 2012; 10


    Microglia are the abundant, resident myeloid cells of the central nervous system (CNS) that become rapidly activated in response to injury or inflammation. While most studies of microglia focus on this phenomenon, little is known about the function of 'resting' microglia, which possess fine, branching cellular processes. Biber and colleagues, in a recent paper in Journal of Neuroinflammation, report that ramified microglia can limit excitotoxicity, an important insight for understanding mechanisms that limit neuron death in CNS disease.

    View details for DOI 10.1186/1741-7007-10-7

    View details for Web of Science ID 000299827700002

    View details for PubMedID 22293401

    View details for PubMedCentralID PMC3269391

  • Mst3b, an Ste20-like kinase, regulates axon regeneration in mature CNS and PNS pathways NATURE NEUROSCIENCE Lorber, B., Howe, M. L., Benowitz, L. I., Irwin, N. 2009; 12 (11): 1407-1414


    Mammalian sterile 20-like kinase-3b (Mst3b, encoded by Stk24), regulates axon outgrowth in embryonic cortical neurons in culture, but its role in vivo and in neural repair is unknown. Here we show that Mst3b mediates the axon-promoting effects of trophic factors in mature rat retinal ganglion cells (RGCs) and dorsal root ganglion (DRG) neurons, and is essential for axon regeneration in vivo. Reducing Mst3b levels using short hairpin RNA prevented RGCs and DRG neurons from regenerating axons in response to growth factors in culture, as did expression of a kinase-dead Mst3b mutant. Conversely, expression of constitutively active Mst3b enabled both types of neurons to extend axons without growth factors. In vivo, RGCs lacking Mst3b failed to regenerate injured axons when stimulated by intraocular inflammation. DRG neurons regenerating axons in vivo showed elevated Mst3b activity, and reducing Mst3b expression attenuated regeneration and p42/44 MAPK activation. Thus, Mst3b regulates axon regeneration in both CNS and PNS neurons.

    View details for DOI 10.1038/nn.2414

    View details for Web of Science ID 000271194100013

    View details for PubMedID 19855390

    View details for PubMedCentralID PMC2770175

  • Differential activation of cAMP response element binding protein in discrete nucleus accumbens subregions during early and late cocaine sensitization BEHAVIORAL NEUROSCIENCE Brenhouse, H. C., Howe, M. L., Stellar, J. R. 2007; 121 (1): 212-217


    The present study examined the differential cocaine-induced activation of the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) throughout discrete zones of analysis of the nucleus accumbens (NAc) in rats. CREB-dependent gene transcription, which may underlie long-lasting drug-induced changes in behavior and the subjective effects of cocaine, varies depending on the stage of drug exposure or withdrawal and the cell population involved. Using immunohistochemistry, the authors analyzed changes in CREB phosphorylation in the NAc after 5 days of cocaine, a short or long drug-free period, and a subsequent challenge injection. The NAc shell was separated into 5 zones of analysis previously defined by neurochemistry and connectivity. Repeated cocaine resulted in CREB phosphorylation in all analyzed subregions of the NAc excluding the most ventrolateral region of the shell 2 weeks after cessation of repeated cocaine, but rats challenged after 2 drug-free days yielded a more localized activation of CREB in the 3 most dorsomedial zones of the shell. The temporal and anatomical determinants of cocaine-induced CREB activity may indicate functional differences among NAc shell subregions and suggest the involvement of CREB in early and late cocaine effects.

    View details for DOI 10.1037/0735-7044.121.1.212

    View details for Web of Science ID 000244287300020

    View details for PubMedID 17324065

  • Transcription factor IIA tau is associated with undifferentiated cells and its gene expression is repressed in primary neurons at the chromatin level in vivo STEM CELLS AND DEVELOPMENT Howe, M. L., Mehmud, Z. F., Saha, S., Buratovich, M., Stutius, E. A., Schmidt, H. D., Lenon, A. L., Reddicks, C., Ivanov, G. S., Przyborski, S. A., Ozer, J. S. 2006; 15 (2): 175-190


    The levels of General Transcription Factor (TF) IIA were examined during mammalian brain development and in rat embryo fibroblasts and transformed cell lines. The large TFIIA subunit paralogues alphabeta and tau are largely produced in unsynchronized cell lines, yet only TFIIA alphabeta is observed in a number of differentiated tissue extracts. Steady-state protein levels of the TFIIA tau, alphabeta, and gamma subunits were significantly reduced when human embryonal (ec) and hepatic carcinoma cell lines were stimulated to differentiate with either all-trans-retinoic acid (ATRA) or sodium butyrate. ATRA-treated NT2-ec cells required replating to induce a neuronal phenotype and loss of detectable TFIIA tau and gamma proteins. High levels of TFIIA tau, alphabeta, and gamma and Sp factors were identified in extracts from human fetal and rat embryonic day-18 brains, but not in human and rat adult brain extracts. A high histone H3 Lys9/Lys4 methylation ratio was observed in the TFIIA tau promoter of primary hippocampal neurons from day-18 rat embryos, suggesting that repressive epigenetic marks of chromatin prevent TFIIA tau from being transcribed in neurons. We conclude that TFIIA tau is associated with undifferentiated cells during development, yet is down-regulated at the chromatin level upon cellular differentiation.

    View details for Web of Science ID 000237416700004

    View details for PubMedID 16646664