Matthew A. Xu-Friedman Neuronal Computation in the Auditory System Assistant Professor Ph.D. Cornell University (1997) Postdoctoral Work Harvard University (1997) Assistant Professor University at Buffalo (2004)

Address Information

Dr. Matthew A. Xu-Friedman
Department of Biological Sciences
661 Hochstetter Hall
State University of New York at Buffalo
Buffalo, NY 14260

(716) 645-4992
(716) 645-2975 (fax)

To send e-mail: mx@buffalo.edu

RESEARCH SUMMARY:

Many significant advances have been made in recent years in understanding the molecular and biophysical mechanisms underlying a wide range of channels, receptors, and modulators in the nervous system. However, much of this mechanistic work has been carried out in systems where the functional roles of individual cells are not well understood, such as cerebellum, cortex, hippocampus. Thus, very little is known how cellular properties influence neuronal function.

To address this issue, the lab uses the mammalian auditory brainstem as a model system. This system has been well studied in vivo, providing a great deal of information about the auditory pathways responsible for analyzing and localizing sounds. In addition, cells in the auditory pathway can also be studied in vitro, which allows detailed analyses of their cellular and synaptic properties. We apply in vitro methods to explain how cells in the auditory pathway can bring about the activity observed in vivo. This approach is valuable to neuroscience at large because the auditory system shares computational principles with the rest of the brain.

In addition, we are interested in synaptic structure, and how it contributes to synaptic physiology. For this we use serial electron microscopy and three-dimensional reconstructions to examine synapses in great detail, in order to explain how they behave in vitro.

Positions are available immediately for both postdocs and grad students in several projects in the lab. Please contact Dr. Xu-Friedman at mx@buffalo.edu for more information.

SELECTED PROJECTS:

A bushy cell of the anteroventral cochlear nucleus, labelled with Alexa488. The soma has a large dendrite projecting towards the bottom of the image, and the axon exits towards the top of the image. The soma diameter is ~12 µm

A sagittal slice of the cochlear nucleus, with the auditory nerve entering from the bottom right, the anteroventral cochlear nucleus in the top right, and the dorsal cochlear nucleus in the top left. Auditory nerve fibers (green) were labelled by injecting dextran-conjugated Alexa488 into the cochlea. They label frequency-specific bands in the AVCN. The molecular layer of the dorsal cochlear nucleus (red) is labelled with an antibody against the cannabinoid receptor CB1 (courtesy of Dr. Ken Mackie, UWash). Cell nuclei are labelled with a DAPI counterstain (blue). The scale bar is 200 µm.

Synaptic Physiology of the Auditory Brainstem

Bushy cell synaptic currents triggered by 100 Hz activity in the auditory nerve.
Synaptic currents depress considerably by the end of the train.

We are studying the synapse made by auditory nerve fibers onto bushy cells in the anteroventral cochlear nucleus, which is called the “endbulb of Held”. In response to high frequency activation, such as is found in vivo, synaptic currents change in size (see figure above). We want to understand what processes contribute to short-term changes in synaptic strength at the endbulb. There are many processes that could be involved, including presynaptic processes such as vesicle depletion and calcium channel inactivation, as well as postsynaptic processes such as desensitization and saturation. We use voltage clamp studies in brain slices as well as calcium imaging to investigate these processes. In addition, we use dynamic clamp to determine how these processes transform information as it is passed to the bushy cell.

Neuromodulation in the Auditory Brainstem

Bushy cell synaptic currents triggered by 100 Hz activity in the auditory nerve in the presence
of baclofen, a GABAB receptor agonist. The synapse changes from depressing to facilitating,
which could change its computational properties.

There are many neuromodulatory systems present in the cochlear nucleus, including GABAB and norepinephrine. We want to understand how modulatory systems affect different synapses within the cochlear nucleus. Neuromodulators can act presynaptically, to lower calcium influx and neurotransmitter release (see the effects of GABAB in the figure above), or postsynaptically to change resting potential or spike threshold. We want to understand how neuromodulators change the transfer of information by synapses in the cochlear nucleus. This work may provide insights into the functional roles of neuromodulators in other parts of the brain.

Synaptic Ultrastructure

A single release site made by a cerebellar mossy fiber onto a
granule cell dendrite. Vesicles are clustered around the presynaptic
active zone, across from the postsynaptic density.

Synapses are highly specialized structures. We use electron microscopy to study how structural features of synapses may underlie their physiological properties. In addition, we are developing techniques to better understand how single release sites are organized.

SELECTED PUBLICATIONS:
> For a Partial Listing of Publications click here <

• Radziwon KE, Stolzberg D, Salvi R, Xu-Friedman MA, and Dent ML (in press) Mouse audiograms using the psychophysical method of constant stimuli. J Comp Physiol A.

• Pliss L, Yang H, and Xu-Friedman MA (in press) Context-dependent effects of NMDA receptors on precise timing information at the endbulb of Held of the cochlear nucleus. J Neurophysiol.

• Yang H and Xu-Friedman MA (2009) Impact of synaptic depression on spike timing at the endbulb of Held. J Neurophysiol. 102: 1699-1710.

• Strenzke N, Chanda S, Kopp-Scheinpflug C, Khimich D, Reim K, Bulankina AV, Neef A, Wolf F, Brose N, Xu-Friedman MA, and Moser T (2009) Complexin-I is required for high-fidelity transmission at the endbulb of Held auditory synapse. J Neurosci. 29: 7991-8004.

• Yang H and Xu-Friedman MA (2008) Relative roles of different mechanisms of depression at the mouse endbulb of Held. J Neurophysiol 99, 2510-2521.

UB Links
Neuroscience Program http://www.smbs.buffalo.edu/neuroscience/
Center for Hearing and Deafness http://wings.buffalo.edu/faculty/research/chd/

Grants
R01 DC008125-01 “Information processing at auditory nerve synapses”
R03 DC007991-01 “Dynamics of information transfer at auditory nerve synapses”