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Achim E. Klug

TitleAssociate Professor
InstitutionUniversity of Colorado Denver - Anschutz Medical Campus
DepartmentSOM - Physiology

    Collapse Overview 
    Collapse overview
    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.

    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?

    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.

    Collapse Research 
    Collapse research activities and funding
    R01DC011582     (KLUG, ACHIM)Jul 1, 2011 - May 31, 2016
    The roles of GABAergic and glycinergic inhibition in the adult MNTB
    Role: Principal Investigator

    R01DC011555     (TOLLIN, DANIEL J)Dec 9, 2011 - Jun 30, 2022
    Developmental effects of early hearing loss on auditory information processing
    Role: Co-Principal Investigator

    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. McCullagh EA, McCullagh P, Klug A, Leszczynski JK, Fong DL. Effects of an Extended Cage-change Interval on Ammonia Levels and Reproduction in Mongolian Gerbils (Meriones unguiculatus). J Am Assoc Lab Anim Sci. 2017 Nov 01; 56(6):713-717. PMID: 29256365.
      View in: PubMed
    2. McCullagh EA, Salcedo E, Huntsman MM, Klug A. Tonotopic alterations in inhibitory input to the medial nucleus of the trapezoid body in a mouse model of Fragile X syndrome. J Comp Neurol. 2017 Nov 01; 525(16):3543-3562. PMID: 28744893.
      View in: PubMed
    3. Chen CH, McCullagh EA, Pun SH, Mak PU, Vai MI, Mak PI, Klug A, Lei TC. An Integrated Circuit for Simultaneous Extracellular Electrophysiology Recording and Optogenetic Neural Manipulation. IEEE Trans Biomed Eng. 2017 03; 64(3):557-568. PMID: 28221990.
      View in: PubMed
    4. Anna Dondzillo, Achim Klug, Tim C Lei. System and methods for conducting in vitro experiments. U.S. Patent Number 9458420. 2016.
    5. Albrecht O, Klug A. Laser-guided Neuronal Tracing In Brain Explants. J Vis Exp. 2015 Nov 25; (105). PMID: 26649948.
      View in: PubMed
    6. Dondzillo A, Quinn KD, Cruickshank-Quinn CI, Reisdorph N, Lei TC, Klug A. A recording chamber for small volume slice electrophysiology. J Neurophysiol. 2015 Sep; 114(3):2053-64. PMID: 26203105; PMCID: PMC4588903.
    7. Klug A, Albrecht O. Neural Circuits: Introducing Different Scales of Temporal Processing. Curr Biol. 2015 Jun 29; 25(13):R557-9. PMID: 26126280.
      View in: PubMed
    8. Mayer F, Albrecht O, Dondzillo A, Klug A. Glycinergic inhibition to the medial nucleus of the trapezoid body shows prominent facilitation and can sustain high levels of ongoing activity. J Neurophysiol. 2014 Dec 01; 112(11):2901-15. PMID: 25185813; PMCID: PMC4254873.
    9. Albrecht O, Dondzillo A, Mayer F, Thompson JA, Klug A. Inhibitory projections from the ventral nucleus of the trapezoid body to the medial nucleus of the trapezoid body in the mouse. Front Neural Circuits. 2014; 8:83. PMID: 25120436; PMCID: PMC4114201.
    10. Chen CH, Pun SH, Mak PU, Vai MI, Klug A, Lei TC. Circuit models and experimental noise measurements of micropipette amplifiers for extracellular neural recordings from live animals. Biomed Res Int. 2014; 2014:135026. PMID: 25133158; PMCID: PMC4123482.
    11. Al-Juboori SI, Dondzillo A, Stubblefield EA, Felsen G, Lei TC, Klug A. Light scattering properties vary across different regions of the adult mouse brain. PLoS One. 2013; 8(7):e67626. PMID: 23874433.
      View in: PubMed
    12. Dondzillo A, Thornton JL, Tollin DJ, Klug A. Manufacturing and using piggy-back multibarrel electrodes for in vivo pharmacological manipulations of neural responses. J Vis Exp. 2013 Jan 18; (71):e4358. PMID: 23354055; PMCID: PMC3582659.
    13. Klug A, Borst JG, Carlson BA, Kopp-Scheinpflug C, Klyachko VA, Xu-Friedman MA. How do short-term changes at synapses fine-tune information processing? J Neurosci. 2012 Oct 10; 32(41):14058-63. PMID: 23055473; PMCID: PMC3488594.
    14. Fischl MJ, Combs TD, Klug A, Grothe B, Burger RM. Modulation of synaptic input by GABAB receptors improves coincidence detection for computation of sound location. J Physiol. 2012 Jul 01; 590(13):3047-66. PMID: 22473782; PMCID: PMC3406390.
    15. Klug A. Short-term synaptic plasticity in the auditory brain stem by using in-vivo-like stimulation parameters. Hear Res. 2011 Sep; 279(1-2):51-9. PMID: 21640177.
      View in: PubMed
    16. Enes J, Langwieser N, Ruschel J, Carballosa-Gonzalez MM, Klug A, Traut MH, Ylera B, Tahirovic S, Hofmann F, Stein V, Moosmang S, Hentall ID, Bradke F. Electrical activity suppresses axon growth through Ca(v)1.2 channels in adult primary sensory neurons. Curr Biol. 2010 Jul 13; 20(13):1154-64. PMID: 20579880.
      View in: PubMed
    17. Achim Klug and Benedikt Grothe. Ethological Stimuli. Oxford Handbook of Auditory Science: The Auditory Brain. Edited by: A Rees and A Palmer. 2010.
    18. Ford MC, Grothe B, Klug A. Fenestration of the calyx of Held occurs sequentially along the tonotopic axis, is influenced by afferent activity, and facilitates glutamate clearance. J Comp Neurol. 2009 May 01; 514(1):92-106. PMID: 19260071.
      View in: PubMed
    19. Hermann J, Grothe B, Klug A. Modeling short-term synaptic plasticity at the calyx of Held using in vivo-like stimulation patterns. J Neurophysiol. 2009 Jan; 101(1):20-30. PMID: 18971300.
      View in: PubMed
    20. Hermann J, Pecka M, von Gersdorff H, Grothe B, Klug A. Synaptic transmission at the calyx of Held under in vivo like activity levels. J Neurophysiol. 2007 Aug; 98(2):807-20. PMID: 17507501.
      View in: PubMed
    21. Pecka M, Zahn TP, Saunier-Rebori B, Siveke I, Felmy F, Wiegrebe L, Klug A, Pollak GD, Grothe B. Inhibiting the inhibition: a neuronal network for sound localization in reverberant environments. J Neurosci. 2007 Feb 14; 27(7):1782-90. PMID: 17301185.
      View in: PubMed
    22. Klug A, Trussell LO. Activation and deactivation of voltage-dependent K+ channels during synaptically driven action potentials in the MNTB. J Neurophysiol. 2006 Sep; 96(3):1547-55. PMID: 16775198.
      View in: PubMed
    23. Achim Klug, Eric Bauer, Joshua Hanson, and George D Pollak. In: Behavior and Neurodynamics for Auditory Communication. Cambridge University Press, Edited by: JS Kanwal and G Ehret. Processing of Species-Specific Vocalizations in the Auditory Brainstem and Midbrain of Mexican Free-Tailed Bats (Tadarida brasiliensis). 2006.
    24. Park TJ, Klug A, Holinstat M, Grothe B. Interaural level difference processing in the lateral superior olive and the inferior colliculus. J Neurophysiol. 2004 Jul; 92(1):289-301. PMID: 15056693.
      View in: PubMed
    25. Pollak GD, Klug A, Bauer EE. Processing and representation of species-specific communication calls in the auditory system of bats. Int Rev Neurobiol. 2003; 56:83-121. PMID: 14696311.
      View in: PubMed
    26. Pollak GD, Burger RM, Klug A. Dissecting the circuitry of the auditory system. Trends Neurosci. 2003 Jan; 26(1):33-9. PMID: 12495861.
      View in: PubMed
    27. Klug A, Bauer EE, Hanson JT, Hurley L, Meitzen J, Pollak GD. Response selectivity for species-specific calls in the inferior colliculus of Mexican free-tailed bats is generated by inhibition. J Neurophysiol. 2002 Oct; 88(4):1941-54. PMID: 12364520.
      View in: PubMed
    28. Bauer EE, Klug A, Pollak GD. Spectral determination of responses to species-specific calls in the dorsal nucleus of the lateral lemniscus. J Neurophysiol. 2002 Oct; 88(4):1955-67. PMID: 12364521.
      View in: PubMed
    29. Pollak GD, Burger RM, Park TJ, Klug A, Bauer EE. Roles of inhibition for transforming binaural properties in the brainstem auditory system. Hear Res. 2002 Jun; 168(1-2):60-78. PMID: 12117510.
      View in: PubMed
    30. Klug A, Khan A, Burger RM, Bauer EE, Hurley LM, Yang L, Grothe B, Halvorsen MB, Park TJ. Latency as a function of intensity in auditory neurons: influences of central processing. Hear Res. 2000 Oct; 148(1-2):107-23. PMID: 10978829.
      View in: PubMed
    31. Bauer EE, Klug A, Pollak GD. Features of contralaterally evoked inhibition in the inferior colliculus. Hear Res. 2000 Mar; 141(1-2):80-96. PMID: 10713497.
      View in: PubMed
    32. Klug A, Bauer EE, Pollak GD. Multiple components of ipsilaterally evoked inhibition in the inferior colliculus. J Neurophysiol. 1999 Aug; 82(2):593-610. PMID: 10444659.
      View in: PubMed
    33. Oswald JP, Klug A, Park TJ. Interaural intensity difference processing in auditory midbrain neurons: effects of a transient early inhibitory input. J Neurosci. 1999 Feb 01; 19(3):1149-63. PMID: 9920676.
      View in: PubMed
    34. Park TJ, Klug A, Oswald JP, Grothe B. A novel circuit in the bat's midbrain recruits neurons into sound localization processing. Naturwissenschaften. 1998 Apr; 85(4):176-9. PMID: 9618688.
      View in: PubMed
    35. Klug A, Park TJ, Pollak GD. Glycine and GABA influence binaural processing in the inferior colliculus of the mustache bat. J Neurophysiol. 1995 Oct; 74(4):1701-13. PMID: 8989406.
      View in: PubMed
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