研究成果

Technical advances in visualizing neural network activity:

The invention of two-photon calcium imaging by W. Denk and collaborators opened up a new research avenue in neuroscience, known as “optophysiology”. Initially, this technique blossomed by applications to in vitro preparations, as efficient ways of loading calcium indicators into living brains were missing. This changed dramatically when Konnerth´s group introduced what is now familiar to neuroscientists as ”multi-cell bolus loading” (MCBL; Stosiek et al., 2003). This simple but ingenious bulk-loading technique allowed to visualize activity patterns in large nerve cell ensembles to characterize “network activity” at cellular resolution. By now, MCBL and/or population imaging involving genetically-endcoded calcium sensors has spread to essentially all in vivo calcium imaging labs.

Seminal insights into brain functions:

Konnerth´s techniques were used by his lab and many others (too many to cite here) to gain seminal insights into brain development and disease, and into the mechanisms of sensory processing in the mammalian cortex.

(1) Development and disease:

How does the developing brain acquire the ability to respond to specific properties of the environment (such as the directionally of moving visual stimuli)? Konnerth´s group showed that many aspects of this development are independent of exposure to external stimuli. Rather, brain-intrinsic processes underlie the emergence of such response patterns (Rochefort et al., 2009, 2011). Another milestone was the investigation of network dysfunction in disease models. In Alzheimer´s disease (AD) the brain´s ability to appropriately respond to specific stimuli is lost. Konnerth and colleagues showed that this is not solely due to the loss of network activity, as it is generally assumed, but may relate to the presence of “hyperactive” cells (Busche et al., 2008). This discovery might also explain why AD is often remarkably associated with epilepsy. Recently, Konnerth and colleagues decisively advanced our understanding of the mechanisms underlying the hyperactivity in AD. First, they identified distinct stages of decline in sensory cortical performance in vivo as a function of the increased amyloid-beta load (Grienberger et al., 2012). Then, using a new approach of high-resolution two-photon imaging of the hippocampus in vivo (Busche et al., 2012), they demonstrated that hyperactivity is a very early functional impairment in AD and that soluble Abeta, rather than the plaques themselves, as initially assumed, is crucial for neuronal hyperactivity. These discoveries have profound implications for understanding AD pathogenesis and indicate strategies for novel pharmacological treatments of this devastating disease.

(2) Sensory processing:

In a tour-de-force combination of the MCBL, in vivo electrophysiology, and high-speed imaging in the visual system of living mice (Jia et al., 2010), Konnerth´s group could answer a question that has preoccupied systems neuroscientists since the pioneering work of Hubel and Wiesel: Do neurons that respond best to stimuli with a specific orientation receive inputs that already show this selectivity? The results are remarkable; it appears that even highly orientation-selective cells receive excitatory inputs of many orientations. The important implication is that orientation-selectivity is computed by single cortical neurons. Konnerth and colleagues refined this approach to achieve what can be considered the ultimate in optophysiological resolution, namely measuring the sensory tuning curves of single synapses in auditory cortex neurons (Chen et al., 2011). The basis of the technical advance was the development of a new and highly sensitive two-photon imaging method termed LOTOS (low-power temporal oversampling) (see details in Chen et al., 2012). By using LOTOS within the mouse vibrissal cortex in vivo, they demonstrated that, in the topographically well-organized macroscopic cellular structure of barrel columns, the dendritic organization of single-spine synaptic inputs is surprisingly unstructured (Varga et al., 2012). Taken together, this work provides definitive evidence that in vivo tuning in neighboring spines is described best by a “salt-and-pepper” pattern. These reports represent major steps forward in neuroscience. They serve as the starting point for studies focusing on subcellular mechanisms that underlie feature-specific responsiveness of neurons in the mammalian cortex.

2022 TUM Emeritus of Excellence

2017 Senior Research Professorship of the non-profit Hertie Foundation

2015 The Brain Prize, Grete Lundbeck European Brain Research Prize

2012 Advanced Grant of the European Research Council

2007 Carl-von-Linde Fellow at the TUM Institute for Advanced Study

2006 Heinz Maier-Leibnitz Medal of the TUM

2001 Max Planck Research Prize

2001 Gottfried Wilhelm Leibniz Prize of the German Research Foundation DFG

1997 Feldberg Prize of the Foundation for Anglo-German Scientific Exchange

1. Chen Y, Kloos M, Varga Z, Zhang Y, Piro I, Sato TK, Sakmann B, Nelken I, Konnerth A. (2026) Thalamic activation of the visual cortex at the single-synapse level. Science 391, 1349-1354.

2. Zott B, Simon MM, Hong W, Unger F, Chen-Engerer HJ, Frosch MP, Sakmann B, Walsh DM, Konnerth A (2019) A vicious cycle of amyloid β-dependent neuronal hyperactivation. Science 365, 559–565.

3. Grienberger C, Chen X, Konnerth A (2014) NMDA receptor-dependent multi-dendrite Ca2+ spikes required for hippocampal burst firing in vivo. Neuron 81, 1274–1281.

4. Busche MA, Chen X, Henning HA, Reichwald J, Staufenbiel M, Sakmann B, Konnerth A (2012) Critical role of soluble amyloid-ß for early hippocampal hyperactivity in a mouse model of Alzheimer´s disease. Proc Nat Acad Sci USA 109, 8740-8745.

5. Chen X, Leischner U, Rochefort NL, Nelken I, Konnerth A (2011) Functional mapping of single spines in cortical neurons in vivo. Nature 475, 501-505.

6. Jia H, Rochefort N, Chen X, Konnerth A (2010) Dendritic organization of sensory input to cortical neurons in vivo. Nature 464, 1307-1312.

7. Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, Staufenbiel M, Konnerth A, Garaschuk O (2008) Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer's Disease. Science 321, 1686-1689.

8. Stosiek C, Garaschuk O, Holthoff K, Konnerth A (2003) ‘In vivo’ two-photon calcium imaging of neuronal networks. Proc Nat Acad Sci USA 100, 7319-7324.