Cytoplasmic Dynein and Kinesins in Brain Development and AutophagyMicrotubule Motor Proteins Are Involved in a Wide Range of cellular activities. Recent work in our lab has involved the role of the motor proteins in neuronal migration and neurogenesis in the developing brain. We have worked out mechanisms by which cytoplasmic dynein, its regulators Nde1 and Ndel1, and LIS1 and the kinesin Kif1a contribute to these functions as well as brain developmental disease. We have also found a new role for the dynein adaptor protein RILP as a master regulator of mTOR-dependent autophagy in neurons. Richard Vallee Professor of Pathology & Cell Biology Columbia University time: 4:00pm location: HSB, T-639 host: Stanley C. Froehner
Ellen Lumpkin, Ph.D.
Associate Professor of Somatosensory Biology in Physiology & Cellular Biophysics and Dermatology
host: John Tuthill
seminar abstract A rich variety of mechanosensitive cells trigger distinct skin sensations such as pressure, flutter and pain. A growing body of research indicates that epithelial cells play a key role in sensation by activating or modulating peripheral neurons in healthy skin. Dr. Lumpkin’s research aims to unveil how epithelial Merkel cells work in concert with the nervous system to generate different qualities of touch sensation. To tackle this question, her group uses neurophysiology, quantitative neuroanatomy, intersectional mouse genetics and optogenetics. Recently, they demonstrated that Merkel cells have dual roles in mechanosensation: they transduce sustained pressure, and amplify information transfer during dynamic touch, which encodes shapes and textures. The seminar will ocus on the molecular signaling mechanisms through which Merkel cells excite sensory neurons.
Daniel Denman, PhD
host: Adrienne Fairhall
Seminar abstract: In response to repeated presentation of the same stimulus, many visual neurons produce a variable number of spikes. This variability in spike count can be independent, correlated, or anti-correlated between pairs of neurons, and the implications of such correlations on sensory encoding have been extensively explored. In addition, spikes can also occur at variable times within the response (i.e., jitter, or spike time variability). While the magnitude of correlated spike count variability in spike count has been well-studied, the magnitude and sign of correlations in jitter, and any potential implications for visual coding, are not known. In this talk I will present measurements, using high-density electrophysiology (Neuropixels), of correlated jitter within small populations of 20-200 simultaneously recorded neurons across lateral geniculate nucleus and primary visual cortex. I will further discuss proposed mechanisms of correlated jitter and implications for potential and observed synchrony in visual cortical population responses.
Mechanism and regulation in microtubule dynamicsLuke Rice, Ph.D.
Associate Professor, Department of Biophysics, UT Southwestern Medical Center
host: Chip Asbury
Seminar abstract: Microtubules are dynamic polymers of αβ-tubulin that have essential roles in intracellular organization and chromosome segregation. The dynamic properties of MTs are central to their function, and they derive from the properties of individual tubulin subunits and their interactions within the MT lattice. Microtubule dynamics is a fascinating problem that tests our ability to integrate ‘one molecule at a time’ views of biochemistry and structure with lower-resolution measurements of collective behavior. My laboratory is focused on bridging this gap by discovering and quantifying the structural and molecular mechanisms that underlie microtubule dynamics and the action of regulatory factors. To provide a new way to study and perturb microtubule dynamics, my laboratory introduced methods for purifying recombinant αβ-tubulin on a scale that permits structural and biochemical studies. Our work draws on structural, biochemical, and reconstitution studies as well as computational simulations. I will present recent work from my group that is uncovering the mechanisms of XMAP215-family polymerases and CLASP-family rescue factors. These are two cellular factors that regulate microtubule dynamics in different ways despite sharing a common domain organization. At the end of my talk I will presenting ongoing collaborative work in which we are applying interferometric scattering microscopy to observe the microtubule growth at the level of individual αβ-tubulins.
John R. Adler Professor, Professor of Neurosurgery and of Ophthalmology and, by courtesy, of Electrical Engineering
host: Greg Horwitz
seminar abstract: Retinal prostheses represent an exciting development in science, engineering, and medicine – an opportunity to create devices that exploit our knowledge of neural circuitry in order to replace or even enhance visual function. However, although existing retinal prostheses demonstrate proof of principle in treating incurable blindness, they produce limited visual function. Some of the reasons for this can be understood based on the exquisitely precise and specific circuitry that mediates visual signaling in the retina. These considerations suggest that future devices may need to operate at single-cell, single-spike resolution in order to mediate naturalistic visual function. I will show large-scale multi-electrode recording and stimulation data from the primate retina indicating that, in many cases, such resolution is possible. I will also discuss cases in which it fails, and propose that we can substantially improve ariticial vision in such conditions by incorporating our knowledge of the visual system in bi-directional devices that adapt to the host neural circuity. Finally, I will discuss the potential implications for other neural interfaces of the future.
Uncovering circuit principles that enable robust behavioral sequences
Michael Long, PhD
Associate Professor, Neuroscience and Physiology
NYU, School of Medicine
host: Adrienne Fairhall
Abstract: For us to interact with the outside world, our brains must plan and dictate our actions and behaviors. In many cases, we learn to reproducibly execute a well-defined series of muscle movements to perform impressive feats, such as hitting a golf ball or playing the violin. How does the brain step through a reliable sequence of premotor commands for behavior? To address this issue, we study the cellular and circuit mechanisms that enable the production of the zebra finch song, a highly stable behavior executed with a high degree of precision. We use techniques ranging from 2-photon imaging, electron microscopy and in vivo recordings to test models of sequence generation at the circuit level. From this work, we can begin to understand the large-scale circuit motifs that underlie sequence generation across a variety of brain regions.
THE CONTRIBUTIONS OF TMC1 TO TRANSDUCTION IN COCHLEAR HAIR CELLS
Robert Fettiplace, PhD Steenbock Professor of Neural and Behavioral SciencesDepartment of Neuroscience University of Wisconsin-Madison
host: Peter DetwilerFunctional mechanoelectrical transduction (MET) channels of cochlear hair cells require the presence of transmembrane channel-like protein isoforms TMC1 or TMC2. We show that TMCs distinctively influence channel properties. TMC1-dependent channels have larger single-channel conductance, faster adaptation and, in outer hair cells (OHCs), support a tonotopic apex-to-base gradient in channel conductance. The MET channel has a high permeability to calcium which is reduced in two different Tmc1 mutations associated with autosomal dominant deafness. Each MET channel complex exhibits multiple conductance states in ~50 pS increments, basal MET channels having more large-conductance levels. Using mice expressing fluorescently tagged TMCs, we show a three-fold increase in number of TMC1 molecules per stereocilium tip from cochlear apex to base, mirroring the channel conductance gradient in OHCs. The results suggest there are varying numbers of channels per MET complex, each requiring multiple TMC1 molecules, and together operating in a coordinated manner.
“New twists on old synapses – multitransmitter neurons in the mammalian brain”time: 11:30Am location: T – 435
host: Stan FroehnerSeminar Abstract: Neurons communicate via the release of neurotransmitters at synapses. It has been generally assumed that neurons in the mammalian brain utilize a single fast acting neurotransmitter and release the same substance at all of its synapses. I will present data from our laboratory and others that demonstrate a much higher complexity to neurotransmission. In older brain regions, such as the basal ganglia, many neurons release multiple small molecule neurotransmitters, such as GABA, glutamate, dopamine and acetylcholine, often targeting different cells with different transmitters. We find that in different classes of neurons, the release of collections of neurotransmitters serves different purpose, in some circuits acting as a substrate for plasticity and in others triggering cascades of synaptic signaling that evolve broad time scales. I will conclude by speculating about the contributions of multitransmitter neurons to the function of mammalian cortex and basal ganglia during learning .
Sex, drugs and funky rhythmsColleen E. Clancy, Ph.D. Professor of Physiology and Membrane Biology Professor of Pharmacology University of California, Davis host: Sharona Gordon Abstract:
Cardiotoxicity in the form of deadly abnormal rhythms is one of the most common and dangerous risks for drugs in development and clinical use. There is an urgent need for new approaches to screen and predict the effects of chemically similar drugs on the cardiac rhythm and to move beyond the QT interval as a diagnostic indicator for arrhythmia. To this end, we present a computational pipeline to predict cardiotoxicity over multiple temporal and spatial scales from the drug chemistry to the cardiac rhythm. We utilize predicted quantitative estimates of ion channel-drug interactions from our companion paper to simulate cardiotoxicity over multiple temporal and spatial scales from the drug chemistry to the cardiac rhythm.
Professor Departments of Chemistry and Molecular Biology & Biochemistry UC Irvine
host: Sharona Gordon
seminar abstract: The βγ-crystallin fold that is ubiquitous in the structural proteins of the vertebrate eye lens is an ancient structural motif found in diverse organisms from all three domains of life. In organisms without eyes, e.g. archaea, bacteria, tunicates, and sponges, βγ-crystallins serve as calcium-binding proteins. In vertebrates, they are primarily found in the eye lens, where they play an important role in controlling the refractive index gradient of this specialized tissue. The ubiquitous βγ-crystallins of the vertebrate lens are believed to have descended from an ancestral single-domain Ca2+-binding crystallin by a process that included gene duplication resulting in two copies of the double Greek key domain per chain, as well as selection for high refractive index. Because the lens has negligible protein turnover, the crystallins must remain stable and soluble for the lifetime of the organism despite their extremely high concentrations. In particular, we are interested in the resistance to phase separation of the cold-adapted crystallins of the Antarctic toothfish, Dissostichus mawsoni. The eye lens of D. mawsoni is evolutionarily adapted to function in the permanently sub-freezing waters of the Southern Ocean. This is in contrast to temperate and tropical fishes, and endothermic mammals, the lenses of which undergo liquid-liquid phase separation at low temperatures. Mammalian lenses phase separate at temperatures between 10 °C and 20 °C – well above the Antarctic’s sub-zero marine environment. The ability of the toothfish lens to maintain transparency in this frigid environment is particularly remarkable given that fish lenses have a high concentration of constituent proteins ≥1000 mg * mL-1). Recent work in my group focuses on testing the hypothesis that γ-crystallin isoform heterogeneity coupled with cold selective evolutionary pressures contribute to the clarity of the toothfish lens. We have measured the thermal stabilities and phase diagrams of seven key γ-crystallin lens proteins, and we are able to control the onset of liquid-liquid phase separation by introducing a small number of surface mutations. The implications of our findings with respect to the roles of frustration, ionic interactions, and protein flexibility liquid-liquid phase separation will be discussed.