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Department of Physiology and Biophysics

University of Colorado Department of Physiology and Biophysics
 

Achim Klug, PhD

Assistant Professor


 

Department of Physiology and Biophysics
University of Colorado School of Medicine

RC-1 North Tower 7120
Mail Stop F8307
Aurora, CO 80045
Tel (303) 724-4621
Fax (303) 724-4501

Lab Server (Intranet)
Curriculum Vitae​

E-mail:
Achim.Klug@ucdenver.edu


Graduate Programs:

Neuroscience
Biomedical Sciences​
MSTP​

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    Check out this interview about our work, which was recently published in International Innovation, the leading global dissemination resource for the wider scientific, technology and research communities, dedic​ated to disseminating the latest science, research and technological innovations on a global level. More information can be found at: www.researchmedia.eu (Click on thumbnail to download)

 

 

 


CURRENT RESEARCH

Topics the lab is interested in:

The computation and analysis of information that arrives from the outside world is an incredibly complex and fascinating task that our brains perform every day. How is, for example, a complicated, multi-frequency and constantly changing sound wave arriving at our ears converted and processed such that we can extract relevant pieces of information from it such as “The truck is approaching from the right, and it is coming fast”?​

The auditory system is a great model system to study sensory processing because a significant part of the computations in this system are performed by a series of distinct and anatomically separate brain areas (the auditory brain stem nuclei), and neurons in each of these nuclei perform a set of restricted integration steps – which are virtually identical among all the neurons in a given nucleus. Thus, the very complex question “how does the auditory system process information” can be broken down into many smaller and simpler questions such as “how does brain nucleus x process information”?

Specifically, our laboratory is interested in the brain nuclei that form the sound localization pathway. Sound localization is obviously a useful skill for a predator hunting prey, or a prey trying to avoid a predator. However, the same skill is also used by modern humans on a daily basis to isolate a sound source of interest from other sound sources that are active at the same time. The sound localization circuit separates these competing sound sources from each other and allows us to focus on the one we are interested in, while ignoring the others. Because of this skill we can, for example, have a conversation with somebody in a crowded bar and clearly understand what the person is saying - although many other people are talking at the same time and the music is playing as well.

Most of our laboratory’s current research revolves around a nucleus called the “medial nucleus of the trapezoid body” (MNTB). This nucleus provides fast and extremely well timed inhibition to other nuclei in the sound localization pathway, and has some extreme adaptations for speed and temporal fidelity. One of the most striking adaptations is the synapse that conveys excitatory inputs to MNTB neurons – the calyx of Held (images 1&2). 

Image 1
Four images of different calyces of Held. The calyx of Held (orange) is a type of giant synapse, which synapses onto MNTB neurons (green) and relays excitatory information to these neurons. The size of the synapse, its particular subcellular design, the location of ion channels, vesicles and receptors all contribute to the relaying of information across this synapse with extreme temporal precision. After receiving the excitatory inputs, the MNTB principal neurons (green) in turn send inhibitory outputs to a number of targets in the auditory brain stem and thus act as a master source of well-timed inhibition for the lower auditory system. Visualization of the calyx of Held via tracer injection (tetramethylrhodamine dextran) into the cochlear nucleus, MNTB neurons were labeled with fluorescent Nissl label. (Click on image to enlarge)


Image 2​

A small section of the medial nucleus of the trapezoid body (MNTB). Several MNTB principal neurons can be seen in red while synaptic inputs, mostly those belonging to the calyx of Held, are shown in green. Section was labeled with SV2 antibody (green) and fluorescent Nissl (red). (Click on image to enlarge)

The calyx of Held is giant synapse that carries a very large and well-timed incoming excitatory signal, which is converted into a well-timed outgoing inhibitory signal by the MNTB principal neuron. This inhibitory signal projects to other nuclei of the sound localization pathway, and participates in the computational process of sound localization, as well as in other tasks.

One of the projects we are pursuing is the question how this giant synapse performs when challenged with long streams of afferent information – as it typically occurs in real life situations. What are the rules of information processing at this synaptic station during biologically relevant activity?

Interestingly, MNTB neurons not only receive the excitatory inputs from the calyx of Held, but substantial inhibitory inputs as well (image 3). In a second set of projects we are pursuing the question, what the functional role of these inhibitory inputs might be. Where do they originate, what type of information do they carry, and how do they interact with the excitatory currents?


Image 3
Inhibitory inputs to MNTB neurons. Other than the excitatory inputs discussed above, MNTB neurons receive substantial glycinergic inhibitory inputs as well. The section shown here was labeled with a glycine receptor antibody (red), which indicates locations on the neuron where inhibitory synapses might be located. MNTB principal cells (green) were labeled with fluorescent Nissl label. (Click on image to enlarge)

As mentioned above, the output of MNTB neurons integrates with excitatory projections from other sources in the actual process of sound localization. The localization of low frequency sounds and localization of high-frequency sounds is performed via different mechanisms and by two separate brain nuclei. Although the MNTB output controls both of these nuclei, we are mostly interested in the nucleus that performs low frequency localization, called medial superior olive (MSO). For many years, it was thought that the sound localization performed by MSO neurons is well understood, and that neural inhibition only plays a minor role in this localization process. However, more recent work suggests that fast inhibition, especially fast inhibition from the MNTB, may critically control the localization process at the MSO. We are testing this idea with a combination of optogenetics, in-vivo physiology and behavioral testing.

The sound localization nuclei participate not only in the pure process of sound localization, but also in the establishment of spatial channels. Being able to establish ‘channels of space’ from the incoming sound information, and being able to focus on a certain channel of interest, allows us to hear in an environment where many sound sources are active at the same time, or where background noise is present – for example the crowded bar on a Friday night. As people get older, they function progressively less well in that crowded bar, i.e. they have more and more trouble following a conversation when background noises are present. This condition, which is one form of age-related hearing loss (presbycusis), is very common and affects about half of the population by retirement age.

We would like to understand how fast inhibition in the auditory brain stem changes with age, and how these changes in fast inhibition are related to presbycusis. We study this question both in mice and humans with a combination of electrophysiology, hearing tests, and auditory brain stem response measurements. The clinical aspects of this project are performed in collaboration with Dr. Herman Jenkins, MD, and Dr. Kristin Uhler, PhD from the UCD Department of Otolaryngology.

Methods used in the lab:

Our laboratory uses a combination on in-vitro electrophysiology, in-vivo electrophysiology, anatomical and immunohistochemical methods, and optogenetics. In-vitro electrophysiology (patch clamp, image 4) is a great tool to study information processing in neurons on a cellular and subcellular level. We use patch clamp recordings to study synapses, ion channels, and the interaction of excitation and inhibition on a subcellular level. By contrast, in-vivo electrophysiology (extracellular recordings) allows us to study on a systems level, how sound information is processed (image 5, left device). Immunohistochemistry and neural tracing methods allow us to study the connections between different brain areas, and thus understand the ‘wiring’ of the auditory system. Viral manipulations and optogenetics allow us to manipulate neural circuits with light. We express novel, light sensitive, ion channels in auditory neurons, and then either turn off these cells with light (when an inhibitory protein, e.g. halorhodopsin, was expressed), or turn on the cells with light (when an excitatory protein, e.g. channelrhodopsin, was expressed). Light is delivered to deep brain nuclei via glass fibers that are connected to lasers or LEDs (image 5, right device). In order to understand, how light that is delivered by these fibers will spread in brain tissue, we also study the light scattering properties of brain tissue.



Image 4
Image of a typical patch clamp setup used to record currents from single neurons. The setup consists of a microscope located on an air table, a set of micromanipulators, and various electronic components. (Click on image to enlarge)
Image 5
Image of a multibarrel electrode (left) and a glass fiber implant (right). A match is also shown on the image for​​ size comparison. The multi barrel electrode consists of s single barrel recording electrode that can be used to record electrical activity from single neurons in-vivo. The attached multibarrel (in this case a 5 barrel unit) can be filled with various pharmacological agents (in most cases agonists and antagonists of excitatory or inhibitory receptors). The drugs can be iontophoresed on demand into the immediate vicinity of the neuron, thus activating or deactivating certain inputs that the neuron is receiving. The glass fiber tip can be implanted into the brain nucleus of interest and used to deliver light to this nucleus, also to manipulate the neural circuitry under investigation. (Click on image to enlarge)​
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Otto Albrecht
Graduate Student

E-mail: Otto.Albrecht@ucdenver.edu

Otto investigates the sources of inhibitory inputs to MNTB neurons, as well as their pattern of connectivity.

Anna Dondzillo, PhD
Postdoctoral Fellow

E-mail: Anna.Dondzillo@ucdenver.edu

Anna characterizes the physiolog​ical properties of neurons in the ventral nucleus of trapezoid body (VNTB).


Former Lab Member

William (Billy) Kromka​
Undergraduate Research Assistant

E-mail: William.Kromka@colorado.edu

William (Billy) assists with immunohistochemical labeling as well as imaging.

Jennifer Thornton
Postdoctoral Fellow

E-mail: Jennifer.Thornton@ucdenver.edu

Jennifer investigates the integration of excitation and inhibition at the MNTB, as well as changes of MNTB derived inhibition with age.


Saif Al-juboori​

Master Student in Electrical Engineering

E-mail: Saif.Aljuboori@ucdenver.edu

Saif studies the scattering patterns of light delivered to brain tissue via glass fibers.

Florian Mayer
Graduate Student

E-mail: Florian.Mayer@ucdenver.edu

Florian works on the characterization of inhibitory inputs to neurons of the medial nucleus of the trapezoid body (MNTB).

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A. Dondzillo, J.L. Thornton, D.J. Tollin, and A. Klug: Manufacturing and Using Piggy-back Multibarrel Electrodes for In vivo Pharmacological Manipulations of Neural Responses. Journal of Visualized Experiments (Video Article) 71: e4358, 1-7, 2013.

A. Klug, J.G.G. Borst, B.A. Carlson, C. Kopp-Scheinpflug, V.A. Klyachko, and M.A. Xu-Friedman: How Do Short-Term Changes at Synapses Fine-Tune Information Processing? Journal of Neuroscience 32: 14058-14063, 2012.

M.J. Fischl, T.D. Combs, A. Klug, B. Grothe, and R.M. Burger:
Modulation of synaptic input by GABAB receptors improves coincidence detection for computation of sound location.
Journal of Physiology, published online, 10.1113/jphysiol.2011.226233, 2012.
See also associated Paper Highlight: M.T. Roberts and N.L. Golding: GABAB receptors sharpen tuning of a sound localization circuit. Journal of Physiology, in press.

A. Klug:
Short-term synaptic plasticity in the auditory brain stem by using in-vivo-like stimulation parameters.
Hearing Research 279:51-59, 2011.

J. Enes, N. Langwieser, J. Ruschel, M.M. Carballosa-Gonzalez, A. Klug, M.H. Traut, B. Ylera, S. Tahirovic, F. Hofmann, V. Stein, S. Moosmang, I.D. Hentall, and F. Bradke:
Electrical Activity Suppresses Axon Growth through Cav1.2 Channels in Adult Primary Sonsory Neurons.
Current Biology 20: 1154-1164, 2010.

A. Klug and B. Grothe:
Ethological Stimuli.
In: Palmer and Rees: The Oxford Handbook of Auditory Science: The Auditory Brain, pp 173-192.
Oxford University Press, England, 2010.
The handbook received the George Davey Howells Prize 2010 from London University and the Royal Society of Medicine for "Most distinguished published contribution to the advancement of Otolaryngology".

M. Ford, B. Grothe, and A. Klug:
Fenestration of the Calyx of Held Occurs Sequentially Along the Tonotopic Axis, Is Influenced by Afferent Activity, and Facilitates Glutamate Clearance.
Journal of Comparative Neurology 514: 92-106, 2009.

J. Hermann, B. Grothe, and A. Klug:
Modeling Short-Term Synaptic Plasticity at the Calyx of Held Using In Vivo-Like Stimulation Patterns.
Journal of Neurophysiology 101: 20-30, 2009.

J. Hermann, M. Pecka, H. von Gersdorff, B. Grothe, and A. Klug:
Synaptic Transmission at the Calyx of Held Under In Vivo-Like Activity Levels.
Journal of Neurophysiology 98: 807-820, 2007.
See also associated Editorial Focus: E. Neher: Short-Term Plasticity Turns Plastic.
Journal of Neurophysiology 98: 577-578, 2007.

M. Pecka, T.P. Zahn, B. Saunier-Rebori, I. Siveke, F. Felmy, L. Wiegrebe, A. Klug, G.D. Pollak, and B. Grothe:
Inhibiting the Inhibition: A Neuronal Network for Sound Localization in Reverberant Environments.
Journal of Neuroscience 27: 1782-1790, 2007.

A. Klug and L.O. Trussell:
Activation and deactivation of voltage-dependent K+ channels during synaptically-driven action potentials in the MNTB.
Journal of Neurophysiology 96: 1547-1555, 2006.

A. Klug, E. E. Bauer, J. T. Hanson, and G. D. Pollak:
Processing of species specific vocalizations in the auditory brainstem and midbrain of Mexican free tailed bats
(Tadarida brasiliensis).
In: J.S. Kanwal and G. Ehret, (eds.): Behavior and Neurodynamics for Auditory Communication, pp 132-155.
Cambridge University Press, Cambridge, England, 2006.

T.J. Park, A. Klug, M. Holinstat, and B. Grothe:
Interaural Level Difference Processing in the Lateral Superior Olive and the Inferior Colliculus.
Journal of Neurophysiology 92: 289-301, 2004.

G.D. Pollak, A. Klug, and E.E. Bauer:
Processing and Representation of Species-Specific Communication Calls in the Auditory System of Bats.
International Review of Neurobiology 56: 83-121, 2003.

G.D. Pollak, R.M. Burger, and A. Klug:
Dissecting the circuitry of the auditory system.
Trends in Neurosciences 26: 33-39, 2003.

E.E. Bauer, A. Klug, and G.D. Pollak:
Spectral Determination of Responses to Species-Specific Calls in the Dorsal Nucleus of the Lateral Lemniscus.
Journal of Neurophysiology 88: 1955-1967, 2002.

A. Klug, E.E. Bauer, J.T. Hanson, L. Hurley, J. Meitzen, and G.D. Pollak:
Response Selectivity for Species-Specific Calls in the Inferior Colliculus of Mexican Free-Tailed Bats is Generated by Inhibition.
Journal of Neurophysiology 88: 1941-1954, 2002.

G.D. Pollak,​ R.M. Burger, T.J. Park, A. Klug, and E.E. Bauer:
Roles of inhibition for transforming binaural properties in the brainstem auditory system.
Hearing Research 168: 60-78, 2002.

A. Klug, A. Khan, R.M. Burger, E.E. Bauer, L.M. Hurley, L. Yang, B. Grothe, M.B. Halvorsen, and T.J. Park:
Latency as a Function of Intensity in Auditory Neurons: Influences of Central Processing.
Hearing Research 148: 107-123, 2000.

E.E. Bauer, A. Klug, and G.D. Pollak:
Features of Contralaterally Evoked Inhibition in the Inferior Colliculus.
Hearing Research 141: 80-96, 2000. A.

A. Klug, E.E. Bau­er, and G.D. Pol­lak:
Mul­ti­ple Com­po­nents of Ip­si­lat­er­al­ly Evo­ked In­hi­bi­tion in the In­fe­rior Col­li­cu­lus.
Jour­nal of Neu­ro­phy­sio­lo­gy 82: 593-610, 1999.

J.P. Os­wald, A. Klug, and T.J. Park:
In­ter­au­ral In­ten­si­ty Dif­fe­ren­ce Pro­ces­sing in Au­di­to­ry Mid­brain Neu­rons: Ef­fects of a Tran­sient Ear­ly In­hi­bi­to­ry In­put.
Jour­nal of Neu­ro­scien­ce 19: 1149-1163, 1999.

T.J. Park, A. Klug, J.P. Oswald, and B. Grothe:
A Novel Circuit in the Batʼs Midbrain Recruits Neurons into Sound Localization Processing.
Naturwissenschaften 85: 176-179, 1998.

A. Klug, T.J. Park, and G.D. Pol­lak:
Gly­ci­ne and GA­BA In­fluen­ce Bi­nau­ral Pro­ces­sing in the In­fe­rior Col­li­cu­lus of the Mu­sta­che Bat.
Jour­nal of Neu­ro­phy­sio­lo­gy 74: 1701-1713, 1995.


Grants and Awards (selection):​​

​2012-2013

​Team Award​
​UC Center for Neuroscience & CCTSI/CTSA
"Developing​​​ a treatment for presbycusis by reversing age-related changes in fast inhibitory projections".
Role: Co-PI (with Dr. Herman Jenkins, Otolaryn​​gology)​​

2011-2016​​

R01 DC 11582 ​​
NIH (National Institutes of Health)
“The role of GABAergic and glycinergic inhibition to MNTB neurons”.
Role: PI

​2007 – 2008

​Sachbeihilfe KL1842/1-2 (Research Grant)
DFG (German Research Council)
Verarbeitung komplexer Informationsströme in der Calyx-von-Held-Synapse (Processing of complex information streams in the calyx of Held synapse)
Role: PI

​2005 – 2007

Sachbeihilfe KL1842/1-1 (Research Grant)
DFG (German Research Council)
Verarbeitung komplexer Informationsströme in der Calyx-von-Held-Synapse (Processing of complex information streams in the calyx of Held synapse)
Role: PI ​

​2004

Münchner Universitätsgesellschaft e.V.
(equipment grant)
Role: PI

​1998

Society for General Physioiogists
(award in recognition of outstanding academic performance during MBL’s “Neural Systems and Behavior” Course)

​1998

​Herbert W. Rand Fellowship
Marine Biological Laboratory, Woods Hole
(fellowship for MBL’s ”Neural Systems and Behavior” course)

​1995

Grass Foundation Fellowship, Cornell University
(fellowship for Cornell´s “Shoals Marine Laboratory”)

​1993 - 1994

Study Abroad Fellowship, University of Würzburg, Germany

​1990 - 1995

Hanns-Seidel-Foundation, Munich, Germany
(full scholarship providing total cost of education & salary for duration of undergraduate studies)​

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The lab is involved in a number of technology transfer projects involving neuroscience related research tools, which are in various stages of completion. For more information, please check out the external links provided below.

1. Optogenetics APP

Light delivery to deep brain areas is becoming increasingly more important, as more and more tools to optically manipulate neural activity become available. Especially the currently evolving field of optogenetics provides very powerful and elegant ways to control neural activity with light. However, to take advantage of these tools in-vivo, correct and controlled light delivery to deep brain areas needs to be accomplished.

Optogenetics is a tool which aids an investigator in estimating the required optical power for a given in-vivo experiment involving optogenetics or any other experimental approach that includes light delivery to deep brain areas via optical fibers. Different brain areas have different optical properties, which determine how light scatters and distributes in the brain tissue, once it exits the optical fiber. To estimate the amount of light required for a given experimental design, knowledge about the specific scattering properties of the brain region, the wavelength of the light, the specific opsin to be used, as well as the properties of the optical fiber are required.

We created a computer program that computes the required optical power for a given in-vivo experiment based on these various parameters, and suggests an optical power value for a particular experimental situation. The program models the maximal depth at which effective excitation of the opsin can be expected.
At this point, the program is available as a Mac iOS APP which can be run on iPhones, iPads, and certain iPods. Versions for other operating systems are in progress.

APP Website:
www.optogeneticsapp.com

The APP is distributed by Popneuron Limited, under license from the University of Colorado.
www.popneuron.com ​​​​​​

2. Tricky2See

An advanced method to analyze neuroscience research data. The beta version can be accessed here:

(internal link, password protected):
www.tricky2see.com