Laurence O Trussell

Oregon Health and Science University, Portland, Oregon, United States

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Publications (76)672.86 Total impact

  • Pierre F Apostolides, Laurence O Trussell
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    ABSTRACT: Voltage-gated ion channels amplify, compartmentalize, and normalize synaptic signals received by neurons. We show that voltage-gated channels activated during subthreshold glutamatergic synaptic potentials in a principal cell generate an excitatory→inhibitory synaptic sequence that excites electrically coupled interneurons. In fusiform cells of the dorsal cochlear nucleus, excitatory synapses activate a TTX-sensitive Na(+) conductance and deactivate a resting Ih conductance, leading to a striking reshaping of the synaptic potential. Subthreshold voltage changes resulting from activation/deactivation of these channels subsequently propagate through gap junctions, causing slow excitation followed by inhibition in GABAergic stellate interneurons. Gap-junction-mediated transmission of voltage-gated signals accounts for the majority of glutamatergic signaling to interneurons, such that subthreshold synaptic events from a single principal cell are sufficient to drive spikes in coupled interneurons. Thus, the interaction between a principal cell's synaptic and voltage-gated channels may determine the spike activity of networks without firing a single action potential.
    Neuron 07/2014; · 15.77 Impact Factor
  • Pierre F Apostolides, Laurence O Trussell
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    ABSTRACT: The dorsal cochlear nucleus (DCN) is a cerebellum-like auditory brainstem region whose functions include sound localization and multisensory integration. While previous in vivo studies show that glycinergic and GABAergic inhibition regulate the response properties of several DCN cell types in response to sensory stimuli, data regarding the synaptic inputs onto DCN inhibitory interneurons remain limited. Using acute DCN slices from mice, we examined the properties of excitatory and inhibitory synapses onto the superficial stellate cell, a poorly understood cell type that provides inhibition to DCN output neurons (fusiform cells) as well as to local inhibitory interneurons (cartwheel cells). Excitatory synapses onto stellate cells activated both NMDA receptors and fast-gating, Ca(2+)-permeable AMPA receptors. Inhibition onto superficial stellate cells was mediated by glycine and GABAA receptors with different temporal kinetics. Paired recordings revealed that superficial stellate cells make reciprocal synapses and autapses, with a connection probability of ~18-20%. Unexpectedly, superficial stellate cells co-released both glycine and GABA, suggesting that co-transmission may play a role in fine-tuning the duration of inhibitory transmission.
    Journal of Neurophysiology 02/2014; · 3.30 Impact Factor
  • Pierre F Apostolides, Laurence O Trussell
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    ABSTRACT: The dorsal cochlear nucleus (DCN) integrates auditory and multisensory signals at the earliest levels of auditory processing. Proposed roles for this region include sound localization in the vertical plane, head orientation to sounds of interest, and suppression of sensitivity to expected sounds. Auditory and non-auditory information streams to the DCN are refined by a remarkably complex array of inhibitory and excitatory interneurons, and the role of each cell type is gaining increasing attention. One inhibitory neuron that has been poorly appreciated to date is the superficial stellate cell. Here we review previous studies and describe new results that reveal the surprisingly rich interactions that this tiny interneuron has with its neighbors, interactions which enable it to respond to both multisensory and auditory afferents.
    Frontiers in Neural Circuits 01/2014; 8:63. · 3.33 Impact Factor
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    Pierre F Apostolides, Laurence O Trussell
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    ABSTRACT: Electrical coupling of inhibitory interneurons can synchronize activity across multiple neurons, thereby enhancing the reliability of inhibition onto principal cell targets. It is unclear whether downstream activity in principal cells controls the excitability of such inhibitory networks. Using paired patch-clamp recordings, we show that excitatory projection neurons (fusiform cells) and inhibitory stellate interneurons of the dorsal cochlear nucleus form an electrically coupled network through gap junctions containing connexin36 (Cxc36, also called Gjd2). Remarkably, stellate cells were more strongly coupled to fusiform cells than to other stellate cells. This heterologous coupling was functionally asymmetric, biasing electrical transmission from the principal cell to the interneuron. Optogenetically activated populations of fusiform cells reliably enhanced interneuron excitability and generated GABAergic inhibition onto the postsynaptic targets of stellate cells, whereas deep afterhyperpolarizations following fusiform cell spike trains potently inhibited stellate cells over several hundred milliseconds. Thus, the excitability of an interneuron network is bidirectionally controlled by distinct epochs of activity in principal cells.
    Nature Neuroscience 11/2013; · 15.25 Impact Factor
  • Pierre F Apostolides, Laurence O Trussell
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    ABSTRACT: The release of neurotransmitter via the fusion of transmitter-filled, presynaptic vesicles is the primary means by which neurons relay information. However, little is known regarding the molecular mechanisms that supply neurotransmitter destined for vesicle filling, the endogenous transmitter concentrations inside presynaptic nerve terminals, or the dynamics of vesicle refilling after exocytosis. We addressed these issues by recording from synaptically coupled pairs of glycine/GABA coreleasing interneurons (cartwheel cells) of the mouse dorsal cochlear nucleus. We find that the plasma membrane transporter GlyT2 and the intracellular enzyme glutamate decarboxylase supply the majority of glycine and GABA, respectively. Pharmacological block of GlyT2 or glutamate decarboxylase led to rapid and complete rundown of transmission, whereas increasing GABA synthesis via intracellular glutamate uncaging dramatically potentiated GABA release within 1 min. These effects were surprisingly independent of exocytosis, indicating that prefilled vesicles re-equilibrated upon acute changes in cytosolic transmitter. Titration of cytosolic transmitter with postsynaptic responses indicated that endogenous, nonvesicular glycine/GABA levels in nerve terminals are 5-7 mm, and that vesicular transport mechanisms are not saturated under basal conditions. Thus, cytosolic transmitter levels dynamically set the strength of inhibitory synapses in a release-independent manner.
    Journal of Neuroscience 03/2013; 33(11):4768-81. · 6.91 Impact Factor
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    ABSTRACT: The properties of glycine receptors (GlyRs) depend upon their subunit composition. While the prevalent adult forms of GlyRs are heteromers, previous reports suggested functional α homomeric receptors in mature nervous tissues. Here we show two functionally different GlyRs populations in the rat medial nucleus of trapezoid body (MNTB). Postsynaptic receptors formed α1/β-containing clusters on somatodendritic domains of MNTB principal neurons, colocalizing with glycinergic nerve endings to mediate fast, phasic IPSCs. In contrast, presynaptic receptors on glutamatergic calyx of Held terminals were composed of dispersed, homomeric α1 receptors. Interestingly, the parent cell bodies of the calyces of Held, the globular bushy cells of the cochlear nucleus, expressed somatodendritic receptors (α1/β heteromers) and showed similar clustering and pharmacological profile as GlyRs on MNTB principal cells. These results suggest that specific targeting of GlyR β-subunit produces segregation of GlyR subtypes involved in two different mechanisms of modulation of synaptic strength.
    Journal of Neuroscience 11/2012; 32(47):17012-24. · 6.91 Impact Factor
  • Sidney P Kuo, Hsin-Wei Lu, Laurence O Trussell
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    ABSTRACT: Multiple classes of inhibitory interneurons shape the activity of principal neurons of the dorsal cochlear nucleus (DCN), a primary target of auditory nerve fibers in the mammalian brain stem. Feedforward inhibition mediated by glycinergic vertical cells (also termed tuberculoventral or corn cells) is thought to contribute importantly to the sound-evoked response properties of principal neurons, but the cellular and synaptic properties that determine how vertical cells function are unclear. We used transgenic mice in which glycinergic neurons express green fluorescent protein (GFP) to target vertical cells for whole cell patch-clamp recordings in acute slices of DCN. We found that vertical cells express diverse intrinsic spiking properties and could fire action potentials at high, sustained spiking rates. Using paired recordings, we directly examined synapses made by vertical cells onto fusiform cells, a primary DCN principal cell type. Vertical cell synapses produced unexpectedly small-amplitude unitary currents in fusiform cells, and additional experiments indicated that multiple vertical cells must be simultaneously active to inhibit fusiform cell spike output. Paired recordings also revealed that a major source of inhibition to vertical cells comes from other vertical cells.
    Journal of Neurophysiology 05/2012; 108(4):1186-98. · 3.30 Impact Factor
  • Kevin J Bender, Laurence O Trussell
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    ABSTRACT: The action potential generally begins in the axon initial segment (AIS), a principle confirmed by 60 years of research; however, the most recent advances have shown that a very rich biology underlies this simple observation. The AIS has a remarkably complex molecular composition, with a wide variety of ion channels and attendant mechanisms for channel localization, and may feature membrane domains each with distinct roles in excitation. Its function may be regulated in the short term through the action of neurotransmitters, in the long term through activity- and Ca(2+)-dependent processes. Thus, the AIS is not merely the beginning of the axon, but rather a key site in the control of neuronal excitability.
    Annual Review of Neuroscience 03/2012; 35:249-65. · 20.61 Impact Factor
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    ABSTRACT: Minimally invasive measurements of neuronal activity are essential for understanding how signal processing is performed by neuronal networks. While optical strategies for making such measurements hold great promise, optical sensors generally lack the speed and sensitivity necessary to record neuronal activity on a single-trial, single-neuron basis. Here we present additional biophysical characterization and practical improvements of a two-component optical voltage sensor (2cVoS), comprised of the neuronal tracer dye, DiO, and dipicrylamine (DiO/DPA). Using laser spot illumination we demonstrate that membrane potential-dependent fluorescence changes can be obtained in a wide variety of cell types within brain slices. We show a correlation between membrane labeling and the sensitivity of the magnitude of fluorescence signal, such that neurons with the brightest membrane labeling yield the largest ΔF/F values per action potential (AP; ∼40%). By substituting a blue-shifted donor for DiO we confirm that DiO/DPA works, at least in part, via a Förster resonance energy transfer (FRET) mechanism. We also describe a straightforward iontophoretic method for labeling multiple neurons with DiO and show that DiO/DPA is compatible with two-photon (2P) imaging. Finally, exploiting the high sensitivity of DiO/DPA, we demonstrate AP-induced fluorescence transients (fAPs) recorded from single spines of hippocampal pyramidal neurons and single-trial measurements of subthreshold synaptic inputs to granule cell dendrites. Our findings suggest that the 2cVoS, DiO/DPA, enables optical measurements of trial-to-trial voltage fluctuations with very high spatial and temporal resolution, properties well suited for monitoring electrical signals from multiple neurons within intact neuronal networks.
    PLoS ONE 01/2012; 7(8):e41434. · 3.73 Impact Factor
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    ABSTRACT: Spontaneously active neurons typically fire either in a regular pattern or in bursts. While much is known about the subcellular location and biophysical properties of conductances that underlie regular spontaneous activity, less is known about those that underlie bursts. Here, we show that T-type Ca(2+) channels localized to the site of action potential initiation in the axon initial segment play a pivotal role in spontaneous burst generation. In auditory brainstem interneurons, axon initial segment Ca(2+) influx is selectively downregulated by dopaminergic signalling. This regulation has marked effects on spontaneous activity, converting the predominant mode of spontaneous activity from bursts to regular spiking. Thus, the axon initial segment is a key site, and dopamine a key regulator, of spontaneous bursting activity.
    The Journal of Physiology 11/2011; 590(Pt 1):109-18. · 4.38 Impact Factor
  • Laurence O. Trussell
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    ABSTRACT: This volume is an expression of the ongoing application of the concepts and ­techniques of cellular neurophysiology and cell biology to understanding auditory function. Embedded in this application is a story of the fruits of cross fertilization among scientific fields. Rather than apply traditional methods of neuroanatomy, in vivo extracellular recordings, or spike frequency analysis, many labs began asking questions such as what ion channels are expressed in auditory neurons? How do these channels determine the cellular response to sound? Beyond simply identifying which transmitters were expressed in different neurons, scientists explored the biophysical responses to those transmitters and related them to the response times of synapses.
    09/2011: pages 1-5;
  • Laurence O. Trussell
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    ABSTRACT: Most chapters in this volume address the function of the major excitatory synapses in the lower auditory pathways, with respect to coincidence detection, the ion channels that determine neuronal firing, and the control of excitation through modulation and plasticity. However, none of these processes can be understood at a functional level without considering synaptic inhibition. Indeed, inhibition through GABAergic and glycinergic interneurons is likely to play an essential role in controlling the excitation at every level of central auditory processing. The present chapter examines inhibitory interneurons in several contexts in order to illustrate the diversity of their cellular mechanisms and circuit-level function, with a focus on the auditory brainstem. The term “interneuron” is used loosely; in fact, inhibitory cells are so fundamental to auditory processing that individual neurons may act as both proper interneurons (intrinsic neurons, i.e., those inhibiting within a local circuit) and inhibitory projection neurons (inhibiting across brainstem nuclei or regions). After introducing the study of interneurons and their general function, the chapter examines two prominent examples from the cochlear nucleus and superior olivary complex, rather than provide an exhaustive summary of all known auditory interneurons. Then four aspects of interneuron physiology are explored: the control of the reversal potential for Cl−, the gating properties of the receptor-channel complex, the role of corelease of the transmitters GABA and glycine from interneuronal synapses; and, lastly, mechanisms for prolonging the action of the transmitter.
    09/2011: pages 165-185;
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    ABSTRACT: The amount of neurotransmitter stored in a single synaptic vesicle can determine the size of the postsynaptic response, but the factors that regulate vesicle filling are poorly understood. A proton electrochemical gradient (Δμ(H+)) generated by the vacuolar H(+)-ATPase drives the accumulation of classical transmitters into synaptic vesicles. The chemical component of Δμ(H+) (ΔpH) has received particular attention for its role in the vesicular transport of cationic transmitters as well as in protein sorting and degradation. Thus, considerable work has addressed the factors that promote ΔpH. However, synaptic vesicle uptake of the principal excitatory transmitter glutamate depends on the electrical component of Δμ(H+) (Δψ). We found that rat brain synaptic vesicles express monovalent cation/H(+) exchange activity that converts ΔpH into Δψ, and that this promotes synaptic vesicle filling with glutamate. Manipulating presynaptic K(+) at a glutamatergic synapse influenced quantal size, indicating that synaptic vesicle K(+)/H(+) exchange regulates glutamate release and synaptic transmission.
    Nature Neuroscience 08/2011; 14(10):1285-92. · 15.25 Impact Factor
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    Sidney P Kuo, Laurence O Trussell
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    ABSTRACT: Inhibitory interneurons across diverse brain regions commonly exhibit spontaneous spiking activity, even in the absence of external stimuli. It is not well understood how stimulus-evoked inhibition can be distinguished from background inhibition arising from spontaneous firing. We found that noradrenaline simultaneously reduced spontaneous inhibitory inputs and enhanced evoked inhibitory currents recorded from principal neurons of the mouse dorsal cochlear nucleus (DCN). Together, these effects produced a large increase in signal-to-noise ratio for stimulus-evoked inhibition. Surprisingly, the opposing effects on background and evoked currents could both be attributed to noradrenergic silencing of spontaneous spiking in glycinergic interneurons. During spontaneous firing, glycine release was decreased due to strong short-term depression. Elimination of background spiking relieved inhibitory synapses from depression and thereby enhanced stimulus-evoked inhibition. Our findings illustrate a simple yet powerful neuromodulatory mechanism to shift the balance between background and stimulus-evoked signals.
    Neuron 07/2011; 71(2):306-18. · 15.77 Impact Factor
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    Hai Huang, Laurence O Trussell
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    ABSTRACT: Little is known about which ion channels determine the resting electrical properties of presynaptic membranes. In recordings made from the rat calyx of Held, a giant mammalian terminal, we found resting potential to be controlled by KCNQ (Kv7) K(+) channels, most probably KCNQ5 (Kv7.5) homomers. Unlike most KCNQ channels, which are activated only by depolarizing stimuli, the presynaptic channels began to activate just below the resting potential. As a result, blockers and activators of KCNQ5 depolarized or hyperpolarized nerve terminals, respectively, markedly altering resting conductance. Moreover, the background conductance set by KCNQ5 channels, together with Na(+) and hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, determined the size and time course of the response to subthreshold stimuli. Signaling pathways known to directly affect exocytic machinery also regulated KCNQ5 channels, and increase or decrease of KCNQ5 channel activity controlled release probability through alterations in resting potential. Thus, ion channel determinants of presynaptic resting potential also control synaptic strength.
    Nature Neuroscience 01/2011; 14(7):840-7. · 15.25 Impact Factor
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    Kevin J Bender, Laurence O Trussell
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    ABSTRACT: There is a growing appreciation of synaptic plasticity in the early levels of auditory processing, and particularly of its role in inhibitory circuits. Synaptic strength in auditory brainstem and midbrain is sensitive to standard protocols for induction of long-term depression, potentiation, and spike-timing-dependent plasticity. Differential forms of plasticity are operative at synapses onto inhibitory versus excitatory neurons within a circuit, and together these could serve to tune circuits involved in sound localization or multisensory integration. Such activity-dependent control of synaptic function in inhibitory neurons may also be expressed after hearing loss and could underlie persistent neuronal activity in patients with tinnitus. This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'.
    Neuropharmacology 12/2010; 60(5):774-9. · 4.11 Impact Factor
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    Kevin J Bender, Christopher P Ford, Laurence O Trussell
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    ABSTRACT: Action potentials initiate in the axon initial segment (AIS), a specialized compartment enriched with Na(+) and K(+) channels. Recently, we found that T- and R-type Ca(2+) channels are concentrated in the AIS, where they contribute to local subthreshold membrane depolarization and thereby influence action potential initiation. While periods of high-frequency activity can alter availability of AIS voltage-gated channels, mechanisms for long-term modulation of AIS channel function remain unknown. Here, we examined the regulatory pathways that control AIS Ca(2+) channel activity in brainstem interneurons. T-type Ca(2+) channels were downregulated by dopamine receptor activation acting via protein kinase C, which in turn reduced neuronal output. These effects occurred without altering AIS Na(+) or somatodendritic T-type channel activity and could be mediated by endogenous dopamine sources present in the auditory brainstem. This pathway represents a new mechanism to inhibit neurons by specifically regulating Ca(2+) channels directly involved in action potential initiation.
    Neuron 11/2010; 68(3):500-11. · 15.77 Impact Factor
  • Michael T Roberts, Laurence O Trussell
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    ABSTRACT: In the outer layers of the dorsal cochlear nucleus, a cerebellum-like structure in the auditory brain stem, multimodal sensory inputs drive parallel fibers to excite both principal (fusiform) cells and inhibitory cartwheel cells. Cartwheel cells, in turn, inhibit fusiform cells and other cartwheel cells. At the microcircuit level, it is unknown how these circuit components interact to modulate the activity of fusiform cells and thereby shape the processing of auditory information. Using a variety of approaches in mouse brain stem slices, we investigated the synaptic connectivity and synaptic strength among parallel fibers, cartwheel cells, and fusiform cells. In paired recordings of spontaneous and evoked activity, we found little overlap in parallel fiber input to neighboring neurons, and activation of multiple parallel fibers was required to evoke or alter action potential firing in cartwheel and fusiform cells. Thus neighboring neurons likely respond best to distinct subsets of sensory inputs. In contrast, there was significant overlap in inhibitory input to neighboring neurons. In recordings from synaptically coupled pairs, cartwheel cells had a high probability of synapsing onto nearby fusiform cells or other nearby cartwheel cells. Moreover, single cartwheel cells strongly inhibited spontaneous firing in single fusiform cells. These synaptic relationships suggest that the set of parallel fibers activated by a particular sensory stimulus determines whether cartwheel cells provide feedforward or lateral inhibition to their postsynaptic targets.
    Journal of Neurophysiology 11/2010; 104(5):2462-73. · 3.30 Impact Factor
  • Sidney P Kuo, Laurence O Trussell
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    ABSTRACT: A new study by Yao et al. in the current issue of Cell proposes that a novel vesicular protein, dubbed Flower, regulates endocytosis by controlling presynaptic Ca(2+) levels. This finding is intriguing not only for its implications for vesicle cycling, but also for the multitude of Ca(2+)-dependent processes at play in presynaptic nerve terminals.
    Neuron 09/2009; 63(5):566-7. · 15.77 Impact Factor
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    Yuil Kim, Laurence O Trussell
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    ABSTRACT: Cartwheel cells are glycinergic auditory interneurons which fire Na(+)- and Ca(2+)-dependent spike bursts, termed complex spikes, and which synapse on both principal cells and one another. The reversal potential for glycine (E(gly)) can be hyperpolarizing or depolarizing in cartwheel cells, and many cells are even excited by glycine. We explored the role of spike activity in determining E(gly) in mouse cartwheel cells using gramicidin perforated-patch recording. E(gly) was found to shift toward more negative potentials after a period of complex spiking or Ca(2+) spiking induced by depolarization, thus enhancing glycine's inhibitory effect for approximately 30 s following cessation of spiking. Combined perforated patch electrophysiology and imaging studies showed that the negative E(gly) shift was triggered by a Ca(2+)-dependent intracellular acidification. The effect on E(gly) was likely caused by bicarbonate-Cl(-) exchanger-mediated reduction in intracellular Cl(-), as H(2)DIDS and removal of HCO(3)(-)/CO(2) inhibited the negative E(gly) shift. The outward Cl(-) flux underlying the negative shift in E(gly) opposed a positive shift triggered by passive Cl(-) redistribution during the depolarization. Thus, a Ca(2+)-dependent mechanism serves to maintain or enhance the strength of inhibition in the face of increased excitatory activity.
    Journal of Neuroscience 09/2009; 29(37):11495-510. · 6.91 Impact Factor

Publication Stats

4k Citations
672.86 Total Impact Points

Institutions

  • 2000–2014
    • Oregon Health and Science University
      Portland, Oregon, United States
  • 2009
    • Oregon Medical Research Center
      Portland, Oregon, United States
  • 2007
    • Rosalind Franklin University of Medicine and Science
      • Cell Biology and Anatomy
      North Chicago, IL, United States
  • 2006
    • Ludwig-Maximilian-University of Munich
      • Department of Neuroradiology
      München, Bavaria, Germany
  • 1992–2002
    • University of Wisconsin–Madison
      Madison, Wisconsin, United States
  • 1989
    • Washington University in St. Louis
      • Department of Anatomy and Neurobiology
      Saint Louis, MO, United States
  • 1988
    • University of Washington Seattle
      • Department of Neurology
      Seattle, WA, United States
  • 1987–1988
    • University of California, Los Angeles
      Los Angeles, California, United States