Alison L. Barth
Maxwell H. and Gloria C. Connan Professor in the Life Sciences
Address:
159C Mellon Institute
Department of Biological Sciences
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4400 Fifth Avenue
Pittsburgh, PA 15213
Phone: 412-268-1198
Fax: 412-268-8423
Education
Postdoctoral Appointment, Stanford University School of Medicine
Research
How does experience shape the brain?
Research in the Barth Lab is focused on understanding how experience assembles and alters the properties of neural circuits in the cerebral cortex, in both normal and disease states. The lab has a specific focus on somatosensation in the mouse model system, where specific types of sensory input from the skin are used to drive neural activity to change the strength of synaptic connections and the firing output of cortical neurons. This neural plasticity can result in enhanced perceptual capabilities and influence subsequent learning. A detailed examination of how synapses are changed by experience is revealing fundamental principles about both perception and learning across many neural systems. In addition, researchers in the lab are using electrophysiological recordings, electron microscopy, and computational modeling to understand how functional networks are constructed and optimized in the neocortex. Experiments take advantage of transgenic mice to manipulate gene expression and label defined neural subsets and whole-cell recording and imaging to quantitate the electrical properties of cortical neurons. Ongoing projects include:
1. Algorithms for learning
How is information from the external world transformed by cortical circuits during both normal sensory processing as well as adaptively, during learning? Decades of research have focused on neural decoding – a stimulus focused-approach to estimate the probability or properties of a sensory stimulus from the pattern of spikes collected from increasingly large populations of neurons. In contrast, we are interested in neural algorithms: the small-scale, laminar and translaminar computations deployed by defined subtypes of neocortical neurons in the receipt and transfer of sensory input. This bottom-up approach seeks to identify biologically-grounded procedures by which neurons transform inputs to outputs, constrained by deep knowledge about the identity of molecularly-distinct subsets of neurons connected through highly-specified networks. Our experimental data drive predictions about how these processes can be altered during different brain states, such as attention, reward, or fatigue, as well as how they enable experience-dependent plasticity. Using state-of-the-art genetic tools for pathway-specific activation and cell-type specific electrophysiological recordings, we are developing insight into the low- and high-level computations that are carried out by increasingly large assemblies of neurons. We have identified critical cellular and synaptic control points, embedded in the 6-layered architecture of the circuit, that enable the cortical algorithm to adapt and change during behaviorally-relevant training. The sequence of these changes – which synapses, on which cells, in which layers - shed light onto how this neocortical circuit has become specialized for plasticity. Insights from biological systems can thus provide inspiration for engineered circuits for artificial intelligence.
2. High-throughput, fluorescence-based methods for synapse detection and connectomics
Anatomical methods for determining cell-type specific connectivity are essential to inspire and constrain our understanding of neural circuit function across development, during learning, and in disease states. We have developed new genetically-encoded reagents for fluorescence-synapse labeling and connectivity analysis in brain tissue that are designed for high-throughput, compartment-specific localization of synapses across diverse neuron types in the mammalian brain. High-resolution confocal image stacks of virally-transduced neurons can be used for 3D reconstructions of postsynaptic cells, automated detection of synaptic puncta, and multichannel fluorescence alignment of dendrites, synapses, and presynaptic neurites to assess cell-type specific connectivity. We are using these fluorescence-based reagents to quantitatively evaluate changes in synaptic connectivity during learning and in mouse models of neurological disorders such as Alzheimer’s and Parkinson’s disease. The vast number of fluorescently-labeled, input- and target-specified synapses we are collecting offers new and exciting opportunities for data analysis and machine learning.
3. Network assembly and optimization using principles of neural design
Neurons within the neocortex are connected in stereotyped ways to generate complex but reproducible patterns of activity. We are interested in how these principles enable effective information transfer and network plasticity. We are working with computer scientists to identify and adapt biological principles into engineered networks to inspire new architectures for information storage, working memory, and learning.
Publications
Barth, R.F., Buja, L.M., Barth, A.L., Carpenter, D.E., Parwani, A.V. A Comparison of the Clinical, Pathologic, Virologic, and Immunologic Features of SARS, MERS, and COVID-19 Viral Diseases.
Park, E., Audette, N.J. and Barth, A.L. Learning-dependent enhancement of persistent activity in the neocortex.
Kuljis, D.A., Micheva, K.D., Wegner, W., Bowman, R., LaBranche, M., Madison, D.V., Willig, K.I., and Barth, A.L. Gephyrin-lacking PV synapses on neocortical pyramidal neurons.
Bernhard, S.M., Lee, J., Erskine, A., Hires, S.A. and Barth, A.L. Automated home-cage training drives sensory association learning.
Bernhard, S.M., Lee, J., Zhu, M., Hsu, A., Erskine, A., Hires, S.A., and Barth, A.L. (2020). An automated homecage system for multiwhisker detection and discrimination learning in mice. BioRxiv 2020.04.27.063750.
Kuljis, D.A., Park, E., Myal, S.E., Clopath, C., and Barth, A.L. (2020). Transient and layer-specific reduction in neocortical PV inhibition during sensory association learning. BioRxiv 2020.04.24.059865.
Litvina, E., Adams, A., Barth, A.L., Bruchez, M.P., Carson, J., Dupre, K.B., Frank, L.M., Gates, K.M., Harris, K.M., Joo, H., Lichtman, J.W., Ramos, K.M., Sejnowski, T., Trimmer, J.S., White, S., Koroshetz, W. BRAIN Initiative: Cutting-edge tools and resources for the community.
Barth, A.L. and Ray, A. Progressive circuit changes during learning and disease.
Kuljis, D.A., Park, E., Telmer, C.A., Lee, J., Ackerman, D.S., Bruchez, M.P. and Barth, A.L. Fluorescence-based quantitative synapse analysis for cell-type specific connectomics.
Audette, N.J., Bernhard, S. M., Ray, A., Stewart, L.T., and Barth A.L. Rapid plasticity of higher-order thalamocortical inputs during sensory learning.
Reddy, J.W., Kimukin, I., Ahmed, Z., Stewart, L., Barth, A.L., Towe, E. and Chamanzar, M. High density, double-sided, flexible optoelectrical neural probes with embedded micro-LEDs.
Kuljis D.A., Zemoura K, Telmer C, Lee J, Park E, Xu W, Bruchez MP, and Barth AL. Quantitative synapse analysis for cell-type specific connectomics.
Beukema P, Cecil KL, Peterson E, Mann VR, Matsushita M, Takashima Y, Navlakha S, and Barth AL. TrpM8-mediated somatosensation in mouse neocortex.
Navlakha S, Bar-Joseph Z, and Barth AL. Network Design and the Brain.
Urban-Ciecko J, Jouhanneau JS, Myal SE, Poulet JFA, and Barth AL. Precisely Timed Nicotinic Activation Drives SST Inhibition in Neocortical Circuits.
Pratt CP, Kuljis DA, Homanics G, Dudem S, Hollywood MA, Barth AL, Bruchez MP. Tagging of endogenous BK channels with a fluorogen-activating peptide reveals β4-mediated control of channel clustering in cerebellum.
Lee J, Barth AL. Constructing the external world.
Audette NJ, Urban-Ciecko J, Matsushita M, Barth AL. POm thalamocortical input drives layer-specific microcircuits in somatosensory cortex.
Urban-Ciecko, J. and Barth A.L. Somatostatin neurons in cortical networks (2016)
Ye, L., Allen, W.F., Thompson, K.R., Tian, Q., Hsueh, B., Ramakrishnan, C., Wang A.-C., Jennings, J., Adhikari, A., Witten, I.B., Barth, A.L., Luo, L. Halpern C.H., McNab, J., and Deisseroth, K. Long-range wiring and molecular signatures of prefrontal cortex neuronal populations mediating positive or negative valence experience. (2016)
Barth A., Burkhalter A., Callaway E.M., Connors B.W., Cauli B., DeFelipe J., Feldmeyer D., Freund T., Kawaguchi Y., Kisvarday Z ., Kubota Y., McBain C., Oberlaender M., Rossier J., Rudy B., Staiger J.F., Somogyi P., Tamas G., Yuste R. Comment on "Principles of connectivity among morphologically defined cell types in adult neocortex". (2016) Science Sep 9;353(6304):1108.
Chandrasekaran, S., Navlakha, S., Audette, N.J., McCreary, D., Souhan, J., Bar-Joseph, Z., and Barth, A.L. Unbiased, high-throughput analysis of experience-dependent changes in synaptic density in somatosensory cortex. (2015)
Pratt, C.P., He, J., Wang, Y., Barth, A.L., and Bruchez, M.P. Fluorogenic Green-Inside Red -Outside (GIRO) labeling reveals kinase-dependent control of BKalpha surface expression. (2015)
Cai, X., Huang, H., Kuzirian, M.S., Snyder, L.M., Matsushita, M., Lee, M.C., Furguson, C., Homanics, G.E., Barth, A.L., and Ross, S.E. Generation of a KOR-Cre knockin mouse strain to study cells involved in kappa opioid signaling (2015) [Epub ahead of print]
Navlakha, S., Barth, A.L.*, and Bar-Joseph, Z.* Synapse pruning rates optimize construction of efficient and robust networks. (2015) *indicates co-corresponding authors
Urban-Ciecko, J., Fanselow, E.E., and Barth, A.L. Neocortical somatostatin neurons reversibly silence excitatory transmission via GABAb receptors (2015)
Glazewski, S. and Barth, A.L. Stimulus intensity determines experience-dependent modifications in neocortical neuron firing rates. (2015)
Urban-Ciecko, J., Wen, J.A., Parekh, P.K., and Barth, A.L. Experience-dependent regulation of presynaptic NMDARs enhances neurotransmitter release at neocortical synapses. (2014)
Jouhanneau, J.S., Ferrarese, L., Estabanez L., Audette N., Brecht, M., Barth, A.L., and Poulet, J.F.A. Cortical cfos expression reveals broad receptive field excitatory neurons targeted by POm. (2014)
Czajkowski, R., Jayaprakash, B., Wiltgen, B., Rogerson, T., Karlsson, M.G., Barth, A.L., Trachtenberg, J., and Silva, A.J. Encoding and storage of spatial information in the retrosplenial cortex (2014)
Barth, A.L. and Kuhlman, S.J. The many layers of specification and plasticity in the neocortex. (2013)
Navlakha, S., Suhan, J., Barth, A.L., and Bar-Joseph, Z. A high-throughput machine learning framework to detect synapses in electron microscopy images. (2013) Proc. of the 21st Intl. Conf. on Intelligent Systems for Molecular Biology and 12th European Conf. on Computational Biology (ISMB/ECCB).
Wen, J.A. and Barth, A.L. Initiation, labile, and stabilization phases of experience-dependent plasticity at neocortical synapses. (2013)
Benedetti, B.L.*, Takashima, Y.*, Wen, J.A., Urban-Ciecko, J., and Barth, A.L. Asymmetric wiring of layer 2/3 neurons drives sparse and reliable firing during neocortical development. (2012) [Epub ahead of print] *these authors contributed equally to this work.
Poulet, J.F.A. and Barth, A.L. Experimental evidence for sparse firing in the neocortex. (2012)
Wen, J.A. and Barth A.L. Synaptic lability after experience-dependent plasticity is not mediated by calcium-permeable AMPARs. (2012)
Shruti, S., Urban-Ciecko, J, Fitzpatrick, J., Brenner, R., Bruchez, M., and Barth, A.L. The brain-specific beta 4 subunit downregulates BK channel cell surface expression. (2012)
Barth, A.L. AC-1 and synaptic development. (2012)
Ly, C., Melman, T. Barth, A.L. and Ermentrout, G.B. Phase-resetting curve determines how BK currents affect neuronal firing. (2011)
Wen, J.A. and Barth, A.L. Input-specific critical periods for experience-dependent plasticity in layer 2/3 pyramidal neurons. (2011)
Yassin, L., Benedetti, B.L., Jouhanneau, J.-S., Wen, J.A., Poulet, J.F.A. and Barth A.L. An embedded subnetwork of highly active neurons in the neocortex. (2010)