October 21, 2010
Pablo Castillo, MD, PhD
Professor, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine
"Endocannabinoid-mediated plasticity: novel mechanisms and synaptic rules"
Endocannabinoids have emerged as the best example of retrograde signaling at central synapses. Typically, by targeting type 1 cannabinoid receptors, these small lipids can regulate transmitter release in a transient or consolidated manner. Dr. Castillo (Einstein, New York) will discuss key rules governing endocannabinoid-mediated synaptic plasticity, as well as novel forms of endocannabinoid signaling in the brain.
Host: Andres Barria
Wednesday - October 27, 2010
Special lecture: 2010 Lamport Lecture
Jennifer Lippincott-Schwartz, PhD
Chief of the Section on Organelle Biology in the Cell Biology and Metabolism Branch, NICHD, National Institutes of Health
"Breakthroughs in imaging using photoactivatable fluorescent protein technology"
Photoactivatable fluorescent proteins (PA-FPs) are molecules that switch to a new fluorescent state in response to activation to generate a high level of contrast. Several types of PA-FPs have been developed, including PA-FPs that fluoresce green or red, or convert from green to red in response to activating light. The optical ‘‘highlighting’’ capability of PA-FPs has led to the rise of novel imaging techniques providing important new biological insights. These range from in cellulo pulse-chase labeling for tracking subpopulations of cells, organelles or proteins under physiological settings, to super-resolution imaging of single molecules for determining intracellular protein distributions at nanometer precision. The use of PA-FPs in super-resolution imaging of single molecules is a rapidly emerging field of microscopy that improves the spatial resolution of light microscopy by over an order of magnitude (10-20 nm resolution). It is based on the controlled activation and sampling of sparse subsets of photoconvertible fluorescent molecules whose illumination centroids are fitted and then summed into a final super resolution image, revealing the complex distribution of dense populations of molecules within subcellular structures with nanometer precision. The full potential of PA-FPs in conventional, diffraction-limited and super-resolution imaging is only beginning to be realized. Here, I discuss the diverse array of PA-FPs available to researchers and the new imaging techniques they make possible for unraveling long-standing biological questions.
November 04, 2010
Johanna Montgomery, University of Auckland
"Postsynaptic density proteins as regulators of synaptic function and plasticity"
Long-term potentiation (LTP) and depression (LTD) are two major forms of synaptic plasticity expressed in the hippocampus. The induction and expression of synaptic plasticity are dependent on the NMDA and AMPA-type glutamate receptors respectively. The recruitment of receptors to synapses depends on their interaction with scaffold proteins at the postsynaptic density (PSD). SAP97 and PSD95 are central organizers of the PSD, simultaneously binding to receptors and to other synaptic scaffold or regulator proteins through numerous interaction domains. Alternative splicing of SAP97 transcripts gives rise to palmitoylated αSAP97 and L27-domain containing βSAP97 isoforms that differentially regulate the subsynaptic localization of GluR1 subunits of AMPA receptors. We have found that both α- and β- forms of SAP97 regulate synaptic plasticity via independent mechanisms. Examination of the surface pools of AMPARs and NMDARs indicates that αSAP97 selectively regulates the synaptic pool of AMPARs, whereas βSAP97 regulates the extrasynaptic pools of both AMPARs and NMDARs. Knockdown of βSAP97 rescues the synaptic localization of both AMPARs and NMDARs, showing that endogenous βSAP97 restricts glutamate receptor expression at excitatory synapses. Our data support a model wherein SAP97 isoforms can regulate the future ability of synapses to undergo plasticity by controlling the surface distribution of AMPARs and NMDARs.
Host: Ed Rubel
Co-hosting Department: Bloedel Research Center
November 18, 2010
Associate Professor, The Australian National University
"Cortical microcircuits for processing odors"
The piriform (or primary olfactory) cortex is a three-layered paleocortex that is thought to assemble "odor images" from the chemical components detected by olfactory receptor neurons in the nose. How the piriform cortex achieves this high-level synthetic task, despite its relatively simple architecture, is unknown. We are tackling this question by taking a bottom-up neurophysiological approach in brain slices. I will present our recent work on the major types of neurons in the piriform cortex and how they are wired into cortical microcircuits. Our findings will allow us to test ideas about the cellular processing that occurs in the piriform cortex when an animal sniffs an odor.
Host: Jane Sullivan
December 09, 2010
Professor, Washington State University
"Electrical and Vascular Markers of Sleep and Performance"
Increasing evidence points to the idea that any brain region that has been used more might need more sleep. This is particularly evident in rodents that use their whiskers in the dark, and visual system during the light; they exhibit greater amounts of slow wave activity in the respective brain regions. Such evidence may lead to a paradigm shift in sleep research to a more universal model of distributed sleep where the fundamental properties of sleep can be defined within the context of small neural units, but orchestrated by central mechanisms that help to consolidate sleep. We explored two physiological sleep markers that can be localized to cortical columns, namely, an electrical marker apparent as a change in the size and shape of an evoked response, and an evoked metabolic marker, evident as a change in the ability for the tissue vasculature to deliver blood to the activated tissue.
Host: Eb Fetz
January 20, 2011
Assistant Professor, UW Dept. Biology
"The molecular and neural bases of scent and search behavior"
Chemical communication mediates a variety of critical biological processes. Sensory perception of chemical signals, for example, strongly influences reproduction, foraging, and immune function. In this talk, I will show that the physiological bases of olfactory navigation play important roles in regulating behavior and mediating biological interactions. I will illustrate this point with examples from 1) sperm chemosensory behavior, where molecular mechanisms mediating chemotactic behavior are important in fertilization, and 2) olfaction in insects, where odor preference and learning shape the selectivity of the olfactory system, which in turn mediates behavior. While these two sensory systems operate at different spatial scales, both employ similar behavioral search strategies (flux detection) as a means to locate odor sources. In studying these two systems, comparisons can be made to understand how chemical communication systems operate depending upon the environment in which they exist.
Host: Adrienne Fairhall
Tuesday - March 01, 2011
Special lecture: 2011 Hille Lecture
Professor and Director of the Membrane Biophysics Department, Max Planck Institute for Biophysical Chemistry
"Biophysics of Short-term Synaptic Plasticity"
3:30pm, Foege S-060
The term ‘synaptic plasticity’ describes the fact that connection strengths between the neurons of our brain change constantly in a use-dependent manner. These changes occur on many time scales and underly many of the computational capabilities of our brain. Molecular mechanisms for the fast forms, for so-called ‘short-term plasticity’, are still a matter of debate. The ‘Calyx of Held‘, a glutamatergic presynaptic terminal in the auditory pathway, is large enough that quantitative biophysical techniques, such as voltage clamp, Ca++ fluorimetry and Ca++ uncaging can be applied. Using these experimental tools, we have studied the role of Ca++ and other second messengers in neurotransmitter release and short-term synaptic plasticity (see E. Neher and T. Sakaba, 2008, Neuron 59, 861-872 for review). The lecture will cover a number of biophysically interesting aspects of neurotransmitter release, such as i) the amplitude and time-course of the ‘nanodomain Ca++ signal’ near open channels, which triggers release, ii) the depletion and refilling of synaptic vesicle pools, and iii) a discussion of the question what limits neurotransmitter release during episodes of high synaptic activity.
March 03, 2011
Alex Maier, National Institute of Mental Health
"Does activity in the primary visual cortex support perceptual experience?"
Primary visual cortex (V1) is one of the best studied structures of the primate brain and much of its functional properties are well understood, but whether its neural activity contributes to our conscious experience is a matter of long-standing debate. Using visual illusions such as perceptual suppression, in which a salient visual pattern escapes perception entirely, experimenters can ask if neural responses encode an observer’s perceptual interpretation or if they truthfully represent the physical structure of a stimulus instead. Single neuron recordings in macaque monkeys as well as neuroimaging studies in humans have successfully applied this paradigm to determine the extent to which activity in primary visual cortex reflects perceptual experience. However, while neurophysiological data from monkeys suggests that V1 neurons represent retinal input regardless of a subject’s perceptual state, human neuroimaging (fMRI) studies consistently demonstrate the presence of a strong perceptual signal. To understand the basis of this discrepancy, and to compare V1 signals directly during perceptual suppression, we conducted fMRI experiments and neuronal recordings in monkeys that were trained to indicate their perception during this visual illusion. Under conditions in which a stimulus was present but rendered perceptually invisible, we found a sharp divergence between single neuron responses and the hemodynamic fMRI responses in V1, resolving previously discrepant results. Yet, we also found a direct correlate of the perception-related fMRI response in the so-called local field potential (LFP), which might signify the presence of an unknown neural mechanism that correlates with the subject’s perceptual state. We have started to investigate the cellular basis of this signal by converting LFP into a measure of current flow across cellular membranes for the entire laminar structure of the cortical sheet. Using this technique, we have found a strong functional division between the upper and lower layers of V1, suggesting selective modulation by intrinsic connections, other cortical areas and subcortical structures, respectively. These findings, taken together, suggest that the perceptual outcome of visual stimulation is defined by a dynamic network spanning multiple cortical areas, including V1. Future work will determine the neural dynamics of inter-areal interactions underlying conscious perceptual experience.
Host: Stan Froehner
March 10, 2011
Yi Zhou, PhD, Johns Hopkins University
"The Cocktail Party Phenomenon - sound analysis from the perspective of single neurons"
One task routinely faced by the auditory system is the parsing of a mixture of sounds that overlap in frequency, location, and time. My research seeks to understand the neural mechanisms underlying sound processing in a noisy environment, the so-called “cocktail party phenomenon.” More specifically, how do single neurons process competing information produced by multiple sounds and how is this information represented in the neural responses. Based on results from electrophysiological studies in marmoset monkeys, I will show that, in the awake condition, the spatial-location and sound-level responses of auditory cortex neurons are modulated by inhibition. Functionally, inhibition prevents response summation when more than one sound is played, allows competition between spike-time patterns associated with different sounds, and increases the variability in the ensemble activity of neurons. This process demonstrates that multi-sound analysis is supported by inhibitory components in receptive field structures of cortical neurons. Future theory and experiments that study the variability information in ensemble neuronal responses will be critical for understanding the neural mechanisms of sound processing in a noise environment.
Host: Stan Froehner
March 17, 2011
Professor of Physiology, University of Wisconsin, Madison
"Prestin and cochlear amplification: the paradox of the outer hair cell membrane time constant"
Outer hair cells (OHCs) provide amplification in the mammalian cochlea using somatic force generation underpinned by voltage-dependent gating of the motor protein prestin. A problem with this mechanism is attenuation of the receptor potential at high frequencies by the OHC membrane RC filter with time constant, τm. We made recordings from OHCs in isolated cochleas of neonatal rats and gerbils and measured τm in cells at different locations corresponding to characteristic frequencies (CF) of 0.35 10 kHz. When hair bundles were exposed to endolymphatic Ca2+ (0.02 mM), about half the mechanotransducer (MT) channels opened at rest causing OHCs to depolarize to near 30 mV and, by activating a voltage-dependent K+ conductance, lowered τm. The opening of the MT channels in endolymph depended on using the appropriate intracellular calcium buffer which was estimated with perforated patch recordings as equivalent to 1 mM BAPTA. By inserting measured MT and K+ conductances into an equivalent electrical circuit, including an endolymphatic potential, we predicted the in vivo OHC resting potential across CFs was 40 mV and the membrane corner frequency (1/2 π τm0) roughly matched CF. We propose that minimal τm filtering in vivo ensures optimal activation of prestin by CF receptor potentials, thus removing a major argument against prestin underlying cochlear amplification.
Host: Peter Detwiler
March 24, 2011
Assistant Professor, University of Washington, Mechanical Engineering
"The Little Cell That Could Tug: Traction Forces, Intercellular Forces, and Mechanotransduction at the Cell-Matrix and Cell-Cell Interface."
Forces are essential for a cell’s ability to adhere, migrate, or contract. These forces are regulated by interactions between actin, myosin, and focal adhesion proteins, but mechanical factors such as stiffness, cell shape, adhesion area, and external stresses influence a cell’s ability to generate force. It has been difficult to characterize how cells sense and respond to mechanical factors because of shortcomings in the current techniques to control the cellular microenvironment. I will present the engineering approaches my lab uses to study cellular forces in response to mechanical factors. We focus on cell mechanics in the cardiovascular system and are specifically interested in the role that mechanical factors play in atherosclerosis and thrombosis. We use 1) arrays of micro- or nanoscale cantilever posts to measure cellular forces, 2) engineered system to control the mechanical forces acting on cells, and 3) computational approaches for image analysis and cell mechanics models. In my talk, I will highlight our recent work on how applied forces can regulate cytoskeletal tension through mechanotransduction. In multicellular structures like the endothelium, changes in cytoskeletal tension in individual cells affects the tugging force between cells. This tugging force, in turn, can affect the maintenance of the cell-cell contacts. Together these engineering approaches help advance a pathway towards understanding how cells operate in a physical world and how detection of mechanical changes can be early indicators of pathological conditions.
Host: Chip Asbury
March 31, 2011
Associate Clinical Professor, Washington State University - Vancouver
"Role of mu-opioid receptor desensitization in morphine tolerance: the presynaptic/postsynaptic paradox"
Our current work focuses on mechanisms of G-protein-coupled receptor (GPCR) modulation and changes in synaptic transmission associated with long-term opioid use. We have recently observed that the well-described opioid-induced desensitization of mu-opioid receptors does not occur at presynaptic GABAergic terminals indicating that regulatory mechanisms and potentially GPCR protein scaffolds are different at pre- and postsynaptic sites.
Host: Sharona Gordon
April 14, 2011
Hendrikje Nienborg, MD, PhD
Senior Research Associate, Salk Institute for Biological Studies
"Exploring the origin of decision related activity in early visual cortex."
A major effort in systems neuroscience is directed towards understanding the neural mechanisms of decision-making. Previous studies have demonstrated that during perceptual decision tasks, the activity of individual sensory neurons correlates with an animal’s perceptual decision, i.e. these sensory neurons show decision related activity. A widely held view explains this decision related activity as the causal effect of feed forward noise in sensory neurons on perceptual decisions. I will present evidence obtained from recordings in visual cortex of monkeys performing a visual discrimination task that challenges this view. It suggests that a component of decision related activity in visual neurons reflects top-down signals. Understanding the role of these top-down signals for perceptual decision making, and their interactions with feed forward sensory processing, will be greatly helped by combining optogenetic and viral vector based approaches to target circuit elements, such cortico-cortical feed-back. My current work uses these approaches to examine the role of inhibition on visual processing in the primary visual cortex of the awake monkey.
Host: Stan Froehner
April 28, 2011
Associate Professor, Northwestern University
"Regulation of HCN channels by the brain auxiliary subunit, TRIP8b"
HCN channels are critical for normal and abnormal brain function. The brain HCN channel auxiliary subunit, TRIP8b, interacts with HCN subunits at 2 distinct binding sites to control trafficking and gating of HCN channels. TRIP8b binds to the HCN subunit C-terminal tripeptides as well as directly with the cyclic nucleotide binding domains (CNBD). This talk will illustrate the mechanisms and functional importance of TRIP8b/HCN subunit interactions and discuss the behavioral outcomes of deletion of the gene encoding TRIP8b in mice.
Host: William N. Zagotta
May 12, 2011
Special lecture: 2011 Crill Lecture
Professor of Molecular & Cellular Physiology, Stanford University
"PROTEOMIC IMAGING TO DECODE MEMORY AND MIND: THE SYNAPTOME MEETS THE CONNECTOME"
I’ll describe my laboratory’s work with array tomography, a powerful new high-resolution proteomic imaging method we invented to explore the very-high-dimensional molecular architectures of brains, neurons and synapses. We are applying array tomography to define “synaptomes”, bodies of knowledge designed to add the molecular component annotation necessary for complete and useful neural circuit “connectomes”. We are concentrating especially on the search for patterns of change in synapse and circuit architectures associated with memory storage. I’ll also share some of the new glimpses array tomography provides of the really stunning beauty of brain circuitry. Background: The foundation of modern neuroscience is a consensus that neural network architectures completely determine all brain function, including memory and mind. Even in the simplest animal brains, however, neural networks are extremely complex, individually variable, and plastic. Although rapid progress in computation and imaging methods has greatly aided recent efforts, the goal of extracting neural circuit “wiring diagrams”, or “connectomes”, has remained elusive. Moreover, while it once seemed likely that wiring diagrams alone might suffice to constrain network function, this prospect has faded with growing recognition of the plasticity and proteomic diversity of individual neurons and their synapses. It has now become clear that neural network architectures must be defined with much finer granularity, extending down to the level of individual neural signaling proteins (e.g. ion channels, receptors, transporters, kinases, etc.). This moves the goalposts even further away. Fortunately, the rapid growth of available computation keeps alive the hope of grappling the brain’s seemingly astronomical complexity and eventually cracking the network architecture codes for behavior, memory, and mind.
Host: Stan Froehner
May 19, 2011
Assistant Professor, UCSD
"Genetic approaches to understanding how the visual systems works and wires up"
Host: Adrienne Fairhall
Co-hosting Department: Biological Structure
May 26, 2011
Assistant Professor, University of Washington
"Trafficking and Function of NMDA-receptors. A Tale of Two Receptors"
Glutamatergic synapses vary across brain regions in terms of properties and functions. A constant element in these synapses is the presence of NMDA-type glutamate receptors; a receptor that presumably does not participates in the transfer of information. Subunit composition of NMDARs in most brain regions changes throughout development in a process regulated by synaptic activity. We are interested in understanding how synaptic activity regulates the number and type of synaptic NMDARs and how NMDARs in turn contribute to define the properties and function of glutamatergic synapses.
Host: Stan Froehner
June 09, 2011
Michael Gutnick, Hebrew University
"Sodium Channels and Cortical Neuronal Excitability"
June 30, 2011
Joshua Dudman, Janelia Farm Research Campus
"Towards a functional architecture of the midbrain GABAergic circuits underlying appetitive conditioning in the mouse"
Dopaminergic neurons of the ventral midbrain are thought to play a crucial role in adaptive learning in vertebrates. Extracellular recordings from behaving animals have shown that individual dopamine neurons modulate their firing rate in response to novel appetitive and aversive stimuli as well as predictive stimuli. There are substantial complexities to the details of signaling by dopamine neurons and their relationship to behavior. We have focused on the role of local, putative GABAergic neurons in the control of dopamine neuron activity using both extracellular recordings from freely moving mice as well as circuit mapping in vitro. I will discuss our recent unpublished work that provides evidence that midbrain GABAergic neurons provide an important source of inhibition that is likely to, in part, determine the response of dopamine neurons to conditioned stimuli.
Host: Fred Rieke