Physiology and Biophysics

Seminars

Sep
25
Tue
2018
2018 Lamport Lecture – Richard Vallee @ HSB T-639
Sep 25 @ 4:00 pm – 5:00 pm
2018 Lamport Lecture

Cytoplasmic Dynein and Kinesins in Brain Development and Autophagy

Microtubule 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
Oct
4
Thu
2018
PBIO seminar series: Mohan Gupta @ G-328 H.S.B.
Oct 4 @ 9:30 am – 10:30 am
The role of microtubule-generated tension in accurate mitotic chromosome segregation Mohan ‘Moe’ Gupta, Ph.D. Assistant Professor Iowa State University Hosts: Linda Wordeman and Alex Paredez seminar abstract: To ensure genome stability in mitosis, the spindle assembly checkpoint (SAC) delays anaphase if sister chromosomes are not bound to microtubules from opposite spindle poles. Only in this configuration can dynamic microtubules produce tension across sister kinetochores. The interdependency between kinetochore-microtubule attachment and tension has proved challenging to elucidating the role(s) of tension at kinetochores. Thus, whether the SAC responds simply to kinetochore attachment status, or also to tension status remains obscure. Unlike higher eukaryotes, budding yeast kinetochores bind only one microtubule, simplifying the relationship between attachment and tension. To address the role of microtubule-generated tension in checkpoint signaling, we developed a Taxol-sensitive yeast model that allows tension to be reduced by microtubule stabilization in fully assembled spindles with attached kinetochores. Our results reveal that reducing tension on attached kinetochores delays anaphase onset. The tension-specific delay is transient relative to that imposed by kinetochores that are both unattached and tensionless. Furthermore, the mechanism requires only a subset of the core SAC proteins. Our results demonstrate that reduced tension generates a signal to delay anaphase that is temporally and mechanistically distinct from that characterized for unattached kinetochores.
Nov
8
Thu
2018
PBIO seminar series: Ellen Lumpkin @ G-328 H.S.B.
Nov 8 @ 9:30 am – 10:30 am
Exciting touch: Synaptic mechanisms in mamalian touch receptor
Ellen Lumpkin, Ph.D.
Associate Professor of Somatosensory Biology in Physiology & Cellular Biophysics and Dermatology
Columbia University
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.
Nov
15
Thu
2018
PBIO seminar series: Daniel Denman @ G-328 H.S.B.
Nov 15 @ 9:30 am – 10:30 am
Correlated spike time variability, population coding, and synchrony in the early visual system.
Daniel Denman, PhD
Allen Institute
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.
Nov
29
Thu
2018
PBIO seminar series: Luke Rice @ HSB G-328
Nov 29 @ 9:30 am – 10:30 am

Mechanism and regulation in microtubule dynamics

Luke 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.
Dec
6
Thu
2018
PBIO seminar series: EJ Chichilnisky @ G-328 H.S.B.
Dec 6 @ 9:30 am – 10:30 am
Toward a high-fidelity artificial retina
EJ Chichilnisky
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.
Dec
13
Thu
2018
PBIO seminar series: Michael Long @ G-328 H.S.B.
Dec 13 @ 9:30 am – 10:30 am

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.
Feb
21
Thu
2019
PBIO seminar series: Carlos Portera-Cailliau @ G-328 H.S.B.
Feb 21 @ 9:30 am – 10:30 am
Circuit Dysfunction Underlying Atypical Sensory Processing in Fragile X Syndrome Carlos Portera-Cailliau, M.D., Ph.D. Depts. of Neurology and Neurobiology David Geffen School of Medicine at UCLA Host: Andres Barria Abstract: To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we have adopted a symptom-to-circuit approach in the Fmr1-/- mouse model of Fragile X syndrome (FXS).  For example, using a go/no-go behavior task and in vivo 2-photon calcium imaging, we find that impaired visual discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons, and a decrease in the activity of parvalbumin (PV) interneurons in primary visual cortex.  Restoring visually evoked activity in PV cells in Fmr1-/-mice with a chemogenetic (DREADD) strategy was sufficient to rescue their behavioral performance.  Strikingly, human subjects with FXS exhibit similar impairments in visual discrimination as Fmr1-/- mice.  These results suggest that manipulating inhibition may help sensory processing in FXS.
Mar
14
Thu
2019
PBIO seminar series: Robert Fettiplace @ G-328 H.S.B.
Mar 14 @ 9:30 am – 10:30 am

THE CONTRIBUTIONS OF TMC1 TO TRANSDUCTION IN COCHLEAR HAIR CELLS

Robert Fettiplace, PhD Steenbock Professor of Neural and Behavioral Sciences

Department of Neuroscience University of Wisconsin-Madison

host: Peter Detwiler

Functional 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.
Mar
28
Thu
2019
PBIO seminar series: Darrin Brager @ T-639 H.S.B.
Mar 28 @ 9:30 am – 10:30 am

The ups and downs of HCN channels in Fragile X syndrome

Darrin H Brager

Senior Research Scientist, Lecturer Department of Neuroscience, Biology Instruction Office NOTE: location T-639
Apr
23
Tue
2019
PBIO seminar series: Trevor Lamb @ G-328 H.S.B.
Apr 23 @ 9:30 am – 10:30 am
Rod and cone phototransduction:  Molecular mechanism, quantitative model, and evolution of the genes Trevor Lamb Eccles Institute of Neuroscience, John Curtin School of Medical Research The Australian National University host: Peter Detwiler   Abstract: The first part of this presentation will outline our current understanding of the molecular basis of the phototransduction cascade in vertebrate rod and cone photoreceptors.  An overview will be given of the molecules that participate in activation, shut-off, and Ca-feedback regulation of the response to light.  Activation will be described in terms of the 2‑D diffusional encounters between molecules (rhodopsin, transducin, and the phosphodiesterase PDE6).  A recent discovery of considerable importance is that the PDE6 is only activated when it has two transducins bound; thus, the binding of a single transducin has negligible effect.  As a result, activation of the PDE6 is substantially immune to spontaneous thermal activation of transducin.  This new understanding has required the development of an updated quantitative model of phototransduction.  The revised model provides new insights into: (1) the nature of the single-photon event; (2) the existence of an additional delay in the onset phase of the rod response; and (3) the recovery of rods from bright flashes, and the nature of so-called ‘dominant time constants’ of recovery. The second part of the presentation will describe how the vertebrate phototransduction cascade evolved.  Around 600–700 million years ago, a simple chordate ancestor of ours possessed ciliary photoreceptor cells that probably used a single class of opsin that linked via a G‑protein cascade to cyclic nucleotide-gated ion channels, in a cascade bearing many similarities to that in present-day cones and rods.  As in the case of many other vertebrate features, an event (strictly, a pair of events) of monumental significance was the occurrence of two rounds of whole genome duplication (2R WGD), that led in principle to a quadruplication of every gene.  I will summarize analyses of the phylogeny (in extant species) of the genes for the proteins mediating phototransduction, and I will then describe analyses of gene synteny.  The combination of these approaches provides remarkable insights into the gene duplications (and losses) that occurred, prior to 2R WGD, during 2R WGD, and subsequently, that led to the emergence of distinct isoforms for rod and cone phototransduction proteins in present-day vertebrates.      
Apr
24
Wed
2019
2019 Hille Lecture – Bernardo Sabatini @ T-435, HSB
Apr 24 @ 11:30 am – 12:30 pm

“New twists on old synapses – multitransmitter neurons in the mammalian brain”

Bernardo Sabatini

Alice and Rodman W. Moorhead III Professor of Neurobiology, Harvard Medical School   time: 11:30Am location: T – 435

host: Stan Froehner

Seminar 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 .
May
16
Thu
2019
“Sex, drugs and funky rhythms” – Presented by Department of Physiology & Biophysics Lecture Series @ G-328 H.S.B.
May 16 @ 9:30 am – 10:30 am

Sex, drugs and funky rhythms

Colleen 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. 

May
23
Thu
2019
PBIO seminar series: Rachel Martin @ G-328 H.S.B.
May 23 @ 9:30 am – 10:30 am
What can we learn about protein solubility and aggregation from a cold fish?
Rachel Martin
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.  
Jun
6
Thu
2019
2019 Crill Lecture – Leslie B. Vosshall @ HSB T-625
Jun 6 @ 4:00 pm – 5:00 pm

Neurobiology of the World’s Most Dangerous Animal

Leslie B. Vosshall, Ph.D.

Robin Chemers Neustein Professor Head of the Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, NY

Seminar abstract:

My group is interested in the molecular neurobiology of mosquito host-seeking behavior. Female mosquitoes require a blood meal to complete egg development. In carrying out this innate behavior, mosquitoes spread dangerous infectious diseases such as malaria, dengue, Zika, chikungunya, and yellow fever. Humans attract mosquitoes via multiple sensory cues including emitted body odor, heat, and carbon dioxide in the breath. The mosquito perceives differences in these cues, both between and within species, to determine which animal or human to target for blood-feeding. We have developed CRISPR/Cas9 genome-editing in the Aedes aegypti mosquito with the goal of understand how sensory cues are integrated by the female mosquito to lead to host-seeking behavior. Some of the questions we are currently addressing are: Why are some people more attractive to mosquitoes than others? How do insect repellents work? How are multiple sensory cues integrated in the mosquito brain to elicit innate behaviors? How do female mosquitoes select a suitable body of water to lay their eggs? Recent advances from my group in analyzing the molecular biology of host-seeking behavior will be discussed. host: Stan Froehner  
Jul
23
Tue
2019
PBIO seminar series: Anne Carlson @ G-328 H.S.B.
Jul 23 @ 3:30 pm – 4:30 pm
“Keeping sperm out of a fertilized egg”   Anne E. Carlson, Ph.D. Assistant Professor Department of Biological Sciences University of Pittsburgh