Posts classified under: Joint Faculty

Research

The mind is thought to be the emergent property of the activities of ensembles of neurons. The nature of these emergent properties and how they arise are unknown. This is the focus of our research. In particular, our current research addresses the following fundamental questions in Neurophysics: 1. How is information about the physical world represented by ensembles of neurons? In particular, what are the neural mechanisms of perceiving space-time? 2. How do the neural representations evolve with learning? 3. What is the role of brain rhythms in learning and memory? 4. How does sleep influence learning? To address these questions we use both experimental and theoretical approaches as follows: 1. Develop hardware to measure and manipulate neural activity and behavior. 2. Measure the activity of ensembles of well isolated neurons from many hippocampal and neocortical areas simultaneously during learning and during sleep. 3. Develop data analysis tools to decipher the patterns of neural activity and field potentials, and their relationship to behavior. 4. Develop biophysical theories of synapses, neurons and neuronal networks that can explain these experimental finding, relate them to the underlying cellular mechanisms, and make experimentally testable predictions. The results would not only provide fundamental understanding of neural ensemble dynamics but also point to novel ways of treating learning and memory disorders.

Publications

Jason J. Moore, Pascal M. Ravassard, David Ho, Lavanya Acharya, Ashley L. Kees, Cliff Vuong, Mayanak R. Mehta.  Dynamics of Cortical Dendritic Membrane Potential and Spikes in Freely Behaving Cats.  Science, vol 335, issue 6331, 1281 (2017), 24 March 2017.

Acharya Lavanya, Aghajan Zahra M, Vuong Cliff, Moore Jason J, Mehta Mayank R Causal Influence of Visual Cues on Hippocampal Directional Selectivity Cell, 2016; 164(1-2): 197-207.

Mehta Mayank R From synaptic plasticity to spatial maps and sequence learning Hippocampus, 2015; 25(6): 756-62.

Aghajan Zahra M, Acharya Lavanya, Moore Jason J, Cushman Jesse D, Vuong Cliff, Mehta Mayank R Impaired spatial selectivity and intact phase precession in two-dimensional virtual reality Nature neuroscience, 2015; 18(1): 121-8.

Ravassard Pascal, Kees Ashley, Willers Bernard, Ho David, Aharoni Daniel, Cushman Jesse, Aghajan Zahra M, Mehta Mayank R Multisensory control of hippocampal spatiotemporal selectivity Science (New York, N.Y.), 2013; 340(6138): 1342-6.

Cushman Jesse D, Aharoni Daniel B, Willers Bernard, Ravassard Pascal, Kees Ashley, Vuong Cliff, Popeney Briana, Arisaka Katsushi, Mehta Mayank R Multisensory control of multimodal behavior: do the legs know what the tongue is doing? PloS one, 2013; 8(11): e80465.

Ghorbani Maryam, Mehta Mayank, Bruinsma Robijn, Levine Alex J Nonlinear-dynamics theory of up-down transitions in neocortical neural networks Physical review. E, Statistical, nonlinear, and soft matter physics, 2012; 85(2 Pt 1): 021908.

Ahmed Omar J, Mehta Mayank R Running speed alters the frequency of hippocampal gamma oscillations The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012; 32(21): 7373-83.

Hahn Thomas T G, McFarland James M, Berberich Sven, Sakmann Bert, Mehta Mayank R Spontaneous persistent activity in entorhinal cortex modulates cortico-hippocampal interaction in vivo Nature neuroscience, 2012; 15(11): 1531-8.

Resnik Evgeny, McFarland James M, Sprengel Rolf, Sakmann Bert, Mehta Mayank R The effects of GluA1 deletion on the hippocampal population code for position The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012; 32(26): 8952-68.

Mehta Mayank R Contribution of Ih to LTP, place cells, and grid cells Cell, 2011; 147(5): 968-70.

McFarland James M, Hahn Thomas T G, Mehta Mayank R Explicit-duration hidden Markov model inference of UP-DOWN states from continuous signals PloS one, 2011; 6(6): e21606.

Kumar Arvind, Mehta Mayank R Frequency-Dependent Changes in NMDAR-Dependent Synaptic Plasticity Frontiers in computational neuroscience, 2011; 5(5): 38.

Chen Zhiping, Resnik Evgeny, McFarland James M, Sakmann Bert, Mehta Mayank R Speed controls the amplitude and timing of the hippocampal gamma rhythm PloS one, 2011; 6(6): e21408.

Ahmed Omar J, Mehta Mayank R The hippocampal rate code: anatomy, physiology and theory Trends in neurosciences, 2009; 32(6): 329-38. Mehta Mayank R Cortico-hippocampal interaction during up-down states and memory consolidation Nature neuroscience, 2007; 10(1): 13-5.

Hahn Thomas T G, Sakmann Bert, Mehta Mayank R Differential responses of hippocampal subfields to cortical up-down states Proceedings of the National Academy of Sciences of the United States of America, 2007; 104(12): 5169-74.

Hoffman Kari L, Battaglia Francesco P, Harris Kenneth, MacLean Jason N, Marshall Lisa, Mehta Mayank R The upshot of up states in the neocortex: from slow oscillations to memory formation The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007; 27(44): 11838-41.

Hahn Thomas T G, Sakmann Bert, Mehta Mayank R Phase-locking of hippocampal interneurons’ membrane potential to neocortical up-down states Nature neuroscience, 2006; 9(11): 1359-61.

Mehta Mayank R Role of rhythms in facilitating short-term memory Neuron, 2005; 45(1): 7-9.

Mehta Mayank R Cooperative LTP can map memory sequences on dendritic branches Trends in neurosciences, 2004; 27(2): 69-72.

Petersen Carl C H, Hahn Thomas T G, Mehta Mayank, Grinvald Amiram, Sakmann Bert Interaction of sensory responses with spontaneous depolarization in layer 2/3 barrel cortex Proceedings of the National Academy of Sciences of the United States of America, 2003; 100(23): 13638-43.

Research

Astrocyte biology and biophysics. Astrocytes are a type of brain glial cell discovered by early neuroanatomists over a century ago. Captivated by their elaborate shapes, these pioneers documented the close spatial relationships between astrocytes and neurons. Subsequent work showed that fine astrocyte processes form connections with as many as 100,000 synapses and that individual astrocytes are tiled, as though they “know” not to invade each others territories. These studies raise the exciting possibility that individual astrocytes may regulate subsets of neurons and contribute to the operation of neuronal circuits. The lab seeks to investigate this possibility. ATP signaling. One reason the body can function in a regulated manner is due to the ability of cells to communicate with other cells in a precise way over different scales of time and distance. A major advance has been the realization that ATP, which is the energy source for reactions within cells, also plays major roles as a communicator between cells by activating P2X ion channels which are cell surface ATP receptors. By understanding P2X channel physiology in neurons and glia we seek to decipher how ATP shapes excitability and signaling over broad spatial and temporal scales.

Publications

Tong Xiaoping, Shigetomi Eiji, Looger Loren L, Khakh Baljit S Genetically encoded calcium indicators and astrocyte calcium microdomains The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry, 2013; 19(3): 274-91.

Shigetomi Eiji, Jackson-Weaver Olan, Huckstepp Robert T, O’Dell Thomas J, Khakh Baljit S TRPA1 channels are regulators of astrocyte basal calcium levels and long-term potentiation via constitutive D-serine release The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013; 33(24): 10143-53.

Shigetomi Eiji, Bushong Eric A, Haustein Martin D, Tong Xiaoping, Jackson-Weaver Olan, Kracun Sebastian, Xu Ji, Sofroniew Michael V, Ellisman Mark H, Khakh Baljit S Imaging calcium microdomains within entire astrocyte territories and endfeet with GCaMPs expressed using adeno-associated viruses The Journal of general physiology, 2013; 141(5): 633-47.

Hamby Mary E, Coppola Giovanni, Ao Yan, Geschwind Daniel H, Khakh Baljit S, Sofroniew Michael V Inflammatory mediators alter the astrocyte transcriptome and calcium signaling elicited by multiple G-protein-coupled receptors The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012; 32(42): 14489-510.

Khakh Baljit S, North R Alan Neuromodulation by extracellular ATP and P2X receptors in the CNS Neuron, 2012; 76(1): 51-69. E. Shigetomi, X. Tong, K. Kwan, D.P. Corey, & B.S. Khakh TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy via GAT-3 Nature Neuroscience, 2012; 15: 70-80.

Toulme Estelle, Khakh Baljit S Imaging P2X4 receptor lateral mobility in microglia: regulation by calcium and p38 MAPK The Journal of biological chemistry, 2012; 287(18): 14734-48.

Shigetomi Eiji, Tong Xiaoping, Kwan Kelvin Y, Corey David P, Khakh Baljit S TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3 Nature neuroscience, 2012; 15(1): 70-80.

Richler Esther, Shigetomi Eiji, Khakh Baljit S Neuronal P2X2 receptors are mobile ATP sensors that explore the plasma membrane when activated The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011; 31(46): 16716-30.

Reeves AM, Shigetomi E, Khakh BS. Bulk loading of calcium indicator dyes to study astrocyte physiology: key limitations and improvements using morphological maps J Neurosci, 2011; 22: 9353-8.

Richler E, Shigetomi E, Khakh BS. Neuronal P2X2 Receptors Are Mobile ATP Sensors That Explore the Plasma Membrane When Activated J Neurosci, 2011; 31: 16716-30.

Reeves Alexander M B, Shigetomi Eiji, Khakh Baljit S Bulk loading of calcium indicator dyes to study astrocyte physiology: key limitations and improvements using morphological maps The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011; 31(25): 9353-8.

Shigetomi Eiji, Kracun Sebastian, Khakh Baljit S Monitoring astrocyte calcium microdomains with improved membrane targeted GCaMP reporters Neuron glia biology, 2010; 6(3): 183-91.

Shigetomi E, Kracun S, Sofroniew MV, Khakh BS. A genetically targeted optical sensor to monitor calcium signals in astrocyte processes Nature Neuroscience, 2010; 13: 759-66.

Shigetomi Eiji, Kracun Sebastian, Sofroniew Michael V, Khakh Baljit S A genetically targeted optical sensor to monitor calcium signals in astrocyte processes Nature neuroscience, 2010; 13(6): 759-66.

Toulme Estelle, Garcia Angie, Samways Damien, Egan Terrance M, Carson Monica J, Khakh Baljit S P2X4 receptors in activated C8-B4 cells of cerebellar microglial origin The Journal of general physiology, 2010; 135(4): 333-53.

Kracun Sebastian, Chaptal Vincent, Abramson Jeff, Khakh Baljit S Gated access to the pore of a P2X receptor: structural implications for closed-open transitions The Journal of biological chemistry, 2010; 285(13): 10110-21.

Kracun Sebastian, Chaptal Vincent, Abramson Jeff, Khakh Baljit S Gated access to the pore of a P2X receptor: structural implications for closed-open transitions The Journal of biological chemistry, 2010; 285(13): 10110-21.

Shigetomi Eiji, Khakh Baljit S Measuring near plasma membrane and global intracellular calcium dynamics in astrocytes Journal of visualized experiments : JoVE, 2009; 301(26): .

Singh Harpreet, Warburton Sarah, Vondriska Thomas M, Khakh Baljit S Proteomics to identify proteins interacting with P2X2 ligand-gated cation channels Journal of visualized experiments : JoVE, 2009; 301(27): .

Khakh Baljit S, Burnstock Geoffrey The double life of ATP Scientific American, 2009; 301(6): 84-90, 92.

Khakh Baljit S ATP-gated P2X receptors on excitatory nerve terminals onto interneurons initiate a form of asynchronous glutamate release Neuropharmacology, 2009; 56(1): 216-22.

Chaumont Severine, Compan Vincent, Toulme Estelle, Richler Esther, Housley Gary D, Rassendren Francois, Khakh Baljit S Regulation of P2X2 receptors by the neuronal calcium sensor VILIP1 Science signaling, 2008; 1(41): ra8.

E. Richler, S. Chaumont, E. Shigetomi, A. Sagasti & BS. Khakh. Tracking transmitter-gated P2X cation channel activation in vitro and in vivo, Nature Methods, 2008; 5: 87-93.

D.N. Bowser & BS. Khakh Two forms of astrocyte single vesicle exocytosis imaged with total internal reflection fluorescence microscopy, Proc Natl Acad Sci USA, 2007; 104: 485-91.

Khakh, B. S. North, R. A. P2X receptors as cell surface ATP sensors in health and disease, Nature, 2006; 442: 527-532. Khakh, B. S. Molecular physiology of P2X receptors and ATP signalling at synapses Nat Rev Neurosci, 2001; 2(3): 165-74.

Khakh, B.S. Zhou, X. Sydes, J. Galligan, J.J. Lester, H.A. State-dependent cross-inhibition between transmitter-gated cation channels, Nature, 2000; 406: 405-410.

Khakh, B.S. Lester, H.A. Dynamic Selectivity Filters in Ion Channels, Neuron, 1999; 23: 653-658.

Khakh, B.S. Bao, X. Labarca, C. Lester, H.A. Neuronal P2X receptor-transmitter-gated cation channels change their ion selectivity in seconds, Nat Neurosci, 1999; 2(4): 322-330.

Research

Dr. Glanzman is interested in the cell biology of learning and memory in simple organisms. In our research we use two animals, the marine snail Aplysia californica, and the zebrafish (Danio rerio). Work on Aplysia: This invertebrate has a comparatively simple nervous system (~ 20,000 neurons) that provides a valuable experimental model for understanding the cellular mechanisms that underlie simple forms of learning, such as habituation, sensitization, and classical conditioning. Another experimental advantage of Aplysia is that sensory and motor neurons that mediate specific reflexes of the animal can be placed into dissociated cell culture where they will reform their synaptic connections. These in vitro sensorimotor synapses are extremely useful for cellular and molecular studies of short- and long-term learning-related synaptic plasticity. Currently, my laboratory is investigating the mechanisms that underlie the persistence of memory: how are memories maintained in our brains over long periods of time? Two phenomena related to memory persistence that have attracted significant interest in recent years are memory reconsolidation and memory erasure. Regarding memory reconsolidation, it has been found that when a long-term memory is reactivated through a reminder stimulus the memory becomes temporarily labile; during this period the memory can be permanently lost by various treatments, such as protein synthesis inhibition, until it reconsolidates and is once more stable. Memories can also be lost, apparently permanently, if a specific kinase, known as PKM, is inhibited. This suggests that the activity of PKM is critical for the maintenance of long-term memories. We are currently performing studies on Aplysia to try to unravel the mechanisms that underlie memory reconsolidation and memory erasure. These studies should provide insights into how memories persist. They may also facilitate treatments for such disorders of long-term memory as posttraumatic stress disorder (PTSD). Work on the zebrafish: The zebrafish has significant advantages for genetic and molecular studies of behavior, including studies of learning and memory. The zebrafish is amenable to both forwards and reverse genetics. Furthermore, although it is a vertebrate with a complex vertebrate nervous system, it possesses reflexive behaviors that are mediated by relatively simple neural circuits in the spinal cord and brainstem. Finally, zebrafish larvae are transparent, which facilitates the use of imaging techniques to study learning-related neural activity within the intact animal. We are interested in the neural basis of nonassociative and associative behavioral modification of the startle reflex.

Publications

Roberts Adam C, Bill Brent R, Glanzman David L Learning and memory in zebrafish larvae Frontiers in neural circuits, 2013; 7: 126.

Glanzman David L PKM and the maintenance of memory F1000 biology reports, 2013; 5: 4.

Glanzman David L David L. Glanzman Current biology : CB, 2012; 22(21): R895-7. Cai Diancai, Pearce Kaycey, Chen Shanping, Glanzman David L Reconsolidation of long-term memory in Aplysia Current biology : CB, 2012; 22(19): 1783-8.

Glanzman David L Behavioral neuroscience: no easy path from genes to cognition Current biology : CB, 2012; 22(9): R302-4.

Glanzman David L Olfactory habituation: fresh insights from flies Proceedings of the National Academy of Sciences of the United States of America, 2011; 108(36): 14711-2.

Cai Diancai, Pearce Kaycey, Chen Shanping, Glanzman David L Protein kinase M maintains long-term sensitization and long-term facilitation in aplysia The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011; 31(17): 6421-31.

Roberts Adam C, Reichl Jun, Song Monica Y, Dearinger Amanda D, Moridzadeh Naseem, Lu Elaine D, Pearce Kaycey, Esdin Joseph, Glanzman David L Habituation of the C-start response in larval zebrafish exhibits several distinct phases and sensitivity to NMDA receptor blockade PloS one, 2011; 6(12): e29132.

Issa Fadi A, O’Brien Georgeann, Kettunen Petronella, Sagasti Alvaro, Glanzman David L, Papazian Diane M Neural circuit activity in freely behaving zebrafish (Danio rerio) The Journal of experimental biology, 2011; 214(Pt 6): 1028-38.

Glanzman David L Common mechanisms of synaptic plasticity in vertebrates and invertebrates Current biology : CB, 2010; 20(1): R31-6.

Glanzman David L Ion pumps get more glamorous Nature neuroscience, 2010; 13(1): 4-5.

Esdin Joseph, Pearce Kaycey, Glanzman David L Long-term habituation of the gill-withdrawal reflex in aplysia requires gene transcription, calcineurin and L-type voltage-gated calcium channels Frontiers in behavioral neuroscience, 2010; 4(1): 181.

Glanzman David L Habituation in Aplysia: the Cheshire cat of neurobiology Neurobiology of learning and memory, 2009; 92(2): 147-54.

Villareal Greg, Li Quan, Cai Diancai, Fink Ann E, Lim Travis, Bougie Joanna K, Sossin Wayne S, Glanzman David L Role of protein kinase C in the induction and maintenance of serotonin-dependent enhancement of the glutamate response in isolated siphon motor neurons of Aplysia californica The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009; 29(16): 5100-7.

Bedi Supinder S, Cai Diancai, Glanzman David L Effects of axotomy on cultured sensory neurons of aplysia: long-term injury-induced changes in excitability and morphology are mediated by different signaling pathways Journal of neurophysiology, 2008; 100(6): 3209-24.

Fulton Daniel, Condro Michael C, Pearce Kaycey, Glanzman David L The potential role of postsynaptic phospholipase C activity in synaptic facilitation and behavioral sensitization in Aplysia Journal of neurophysiology, 2008; 100(1): 108-16.

Glanzman DL New tricks for an old slug: The critical role of postsynaptic mechanisms in learning and memory in Aplysia, Prog. Brain Res, 2008; 169C: 277-292.

Glanzman David L New tricks for an old slug: the critical role of postsynaptic mechanisms in learning and memory in Aplysia Progress in brain research, 2008; 169(12): 277-92.

Glanzman David L Octopus conditioning: a multi-armed approach to the LTP–learning question Current biology : CB, 2008; 18(12): R527-30.

Cai Diancai, Chen Shanping, Glanzman David L Postsynaptic regulation of long-term facilitation in Aplysia Current biology : CB, 2008; 18(12): 920-5.

Villareal Greg, Li Quan, Cai Diancai, Glanzman David L The role of rapid, local, postsynaptic protein synthesis in learning-related synaptic facilitation in aplysia Current biology : CB, 2007; 17(23): 2073-80.

Jami SA, Wright WG, Glanzman DL. Differential classical conditioning of the gill-withdrawal reflex in Aplysia recruits both NMDA receptor-dependent enhancement and NMDA receptor-dependent depression of the reflex, J Neurosci, 2007; 27(12): 3064-8. Download

Glanzman, D. L Simple minds: the neurobiology of invertebrate learning and memory, Invertebrate Neurobiology, 2007; 347-380.

Villareal G, Li Q, Cai D, Glanzman DL The role of rapid, local, postsynaptic protein synthesis in learning-related synaptic facilitation in Aplysia, Curr. Biol, 2007; 17(23): 2073-2080. Download

Jami Shekib A, Wright William G, Glanzman David L Differential classical conditioning of the gill-withdrawal reflex in Aplysia recruits both NMDA receptor-dependent enhancement and NMDA receptor-dependent depression of the reflex The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007; 27(12): 3064-8.

Glanzman DL. The cellular mechanisms of learning in Aplysia: of blind men and elephants, Biol Bull, 2006; 210(3): 271-9. Download

Glanzman David L The cellular mechanisms of learning in Aplysia: of blind men and elephants The Biological bulletin, 2006; 210(3): 271-9. Li Q,

Roberts AC, Glanzman DL. Synaptic facilitation and behavioral dishabituation in Aplysia: dependence on release of Ca2+ from postsynaptic intracellular stores, postsynaptic exocytosis, and modulation of postsynaptic AMPA receptor efficacy, J Neurosci, 2005; 25(23): 5623-37. Download

Li Quan, Roberts Adam C, Glanzman David L Synaptic facilitation and behavioral dishabituation in Aplysia: dependence on release of Ca2+ from postsynaptic intracellular stores, postsynaptic exocytosis, and modulation of postsynaptic AMPA receptor efficacy The Journal of neuroscience : the official journal of the Society for Neuroscience, 2005; 25(23): 5623-37.

Roberts AC, Glanzman DL. Learning in Aplysia: looking at synaptic plasticity from both sides, Trends Neurosci, 2003; 26(12): 662-70. Download Ezzeddine Y, Glanzman DL. Prolonged habituation of the gill-withdrawal reflex in Aplysia depends on protein synthesis, protein phosphatase activity, and postsynaptic glutamate receptors, J Neurosci, 2003; 23(29): 9585-94. Download

Chitwood RA, Li Q, Glanzman DL. Serotonin facilitates AMPA-type reponses in isolated siphon motor neurons of Aplysia in culture, J Physiol, 2001; 534(Pt 2): 501-10. Download

Murphy GG, Glanzman DL. Cellular analog of differential classical conditioning in Aplysia: disruption by the NMDA receptor antagonist DL-2-amino-5-phosphonovalerate, J Neurosci, 1999; 19(23): 10595-602. Download