EducationPhD, University of California at Berkeley (1997)
Research in the lab centers around one overriding question: how does experience selectively activate and change neuronal properties? Although we are beginning to understand the neural basis for discrete behaviors in invertebrates, this question is exponentially more complex and challenging in vertebrates. In the mammalian cortex, complex behaviors and learning are mediated through the activity of hundreds of thousands -- if not millions -- of the trillions of neurons. Finding the right brain area, and indeed, the right neurons, is a critical step in enabling to identify the cellular and molecular basis for behavioral plasticity. We are addressing this question using a novel strain of transgenic mice that express GFP under the control of the c-fos promoter (fosGFP transgenic mice), coupling fluorescent gene expression to neural activity. This technique has allowed us to focus on changes occurring in the neurons that have initiated gene expression in response to in vivo experience. Once we know where in the brain to look, it becomes possible to ask highly sophisticated questions that bring together systems-level neuroscience, cellular electrophysiology, and molecular biology.
1. Identifying the plasticity transcriptome. It has long been recognized that learning requires the transcription of new genes, and there is abundant experimental evidence supporting a role for two transcription factors, CREB and zif268/egr-1, in initiating activity-dependent transcription. After identifying CREB and zif268 gene targets, we are now interested in how these targets are regulated by neuronal activity in seizure disorders and learning.
2. How do seizures alter programs of gene expression and alter neuronal excitability in cortical networks? Understanding how brain activity is abnormal after seizures can lead to the development of new anticonvulsant therapies. We have identified one new ion channel target that is functionally enhanced after seizures and can show that channel antagonists can block further seizures.
3. How does in vivo experience change synaptic and cellular responses? The somatosensory cortex of rodents contains a precise anatomical representation of the body surface, and it has long been know that over- or understimulation of some areas result in altered neuronal response properties. Using a single-whisker activation protocol in the fosGFP transgenic mice, we can show that some synapses are specifically altered by in vivo experience, and we are beginning to understand how previous synaptic modifications set the stage for future changes to occur, a process known as metaplasticity.
Audette NJ, Urban-Ciecko J, Matsushita M, Barth AL. POm thalamocortical input drives layer-specific microcircuits in somatosensory cortex. Cereb Cortex. 2017 Mar 10:1-17.
Barth A, Burkhalter A, Callaway EM, Connors BW, Cauli B, DeFelipe J, Feldmeyer D, Freund T, Kawaguchi Y, Kisvarday Z, Kubota Y, McBain C, Oberlaender M, Rossier J, Rudy B, Staiger JF, Somogyi P, Tamas G, Yuste R. Comment on "Principles of connectivity among morphologically defined cell types in adult neocortex". Science, 9 Sep 2016, 353(6304):1108
Urban-Ciecko, J and Barth AL. Somatostatin-expressing neurons in cortical networks. Nature Reviews Neuroscience, Jul 2016, 17(7):401-409.
Ye L, Allen WE, Thompson KR, Tian Q, Hsueh B, Ramakrishnan C, Wang A-C, Jennings JH, Adhikari A, Halpern CH, Witten IB, Barth AL, Luo L, McNab, JA, Deisseroth K. Wiring and molecular features of prefrontal ensembles representing distinct experiences. Cell, 16 June 2016, 165(7):1776-88.
Chandrasekaran S, Navlakha S, Audette NJ, McCreary DD, Suhan J, Bar-Joseph Z, and Barth AL. Unbiased, high-throughput electron microscopy analysis of experience-dependent synaptic changes in the neocortex. The Journal of Neuroscience, 16 Dec 2015, 35(50):16450-16462.
Cai X, Huang H, Kuzirian MS, Snyder LM, Matsushita M, Lee MC, Ferguson C, Homanics GE, Barth AL, and Ross SE. Generation of a KOR-Cre knockin mouse strain to study cells involved in kappa opioid signaling. Genesis, 17 Nov 2015 [Epub ahead of print]
Pratt CP, He J, Wang Y, Barth AL, and Bruchez MP. Fluorogenic Green-Inside Red-Outside (GIRO) Labeling Approach Reveals Adenylyl Cyclase-Dependent Control of BKα Surface Expression. Bioconjugate Chemistry, 16 Sep 2015, 26(9):1963-71.
Navlakha S, Barth AL, and Bar-Joseph Z. Decreasing-rate pruning optimizes the construction of efficient and robust distributed networks. PLoS Computational Biology, 28 July 2015, 11(7).
Urban-Ciecko J, Fanselow EF, and Barth AL. Neocortical somatostatin neurons reversibly silence excitatory transmission via GABAb receptors. Current Biology, 16 March 2015, 25, 1-10.
Glazewski S, Barth AL. Stimulus intensity determines experience-dependent modifications in neocortical neuron firing rates. European Journal of Neuroscience, Feb 2015, 41(4):410-9.
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