led by
Prof. Dr. Johannes Letzkus
Information about past experiences and current aims is a central element of all higher brain functions, but our understanding of such of internally-generated top-down signals in health and disease is limited. We use a combination of imaging, electrophysiology, cell-type specific targeting, optogenetics, viral tracing and behavior to dissect these mechanisms in the auditory cortex.
Research
Neocortex is the largest and most powerful area of the mammalian brain. This region has expanded and differentiated the most during evolution, mediates many of the capacities that distinguish humans from their closest relatives, and also plays a central role in many psychiatric disorders. All higher cognitive functions of the neocortex are enabled by bringing together two distinct streams of information: a ‘bottom-up’ stream carrying signals from the surrounding environment, and a ‘top-down’ stream that transmits internally-generated information encoding our previous experiences and current aims.
Whereas decades of work have addressed processing of sensory bottom-up information, our understanding of internally-generated information is still in its infancy.
Techniques
Our work aims to fill this gap by elucidating the mechanisms and consequences of top-down information processing in the auditory cortex. Using a combination of cutting-edge approaches (including 2-photon & 1-photon imaging, electrophysiology, optogenetics, viral tracing and computational analyses) together with behavioral paradigms, we address the following questions:
1) Which brain-wide afferents convey which type of top-down information to neocortex?
2) How are these top-down signals translated by local inhibitory interneurons to flexibly adjust circuit function?
3) Which aspects of information processing is subject to top-down modulation?
4) How does top-down information optimize brain function for complex, naturalistic behaviors?
5) How do perturbations of top-down processes contribute to brain disorders?
Publications
2024
- Hartung J, Schroeder A, . Layer 1 NDNF Interneurons are Specialized Top-Down Master Regulators of Cortical Circuits. bioRxiv
2023
- Schroeder A1,2, Pardi MB, Keijser J, Dalmay T, Groisman AI, Schuman E, Sprekeler H, Letzkus, JJ2,3 (2023). Inhibitory top-down projections from zona incerta mediate neocortical memory. Neuron, 11(5):727-738.e8.
- Pardi MB1, Schroeder A1, Letzkus JJ2 (2023). Probing top-down information in neocortical layer 1. Trends in Neurosciences, 46, 20-31.
2022
2021
2020
- Pardi MB1, Vogenstahl J, Dalmay T, Spano T, Pu D, Naumann LB, Sprekeler H, Letzkus JJ2 (2020). A thalamo-cortical top-down circuit for associative memory. Science, 370, 844-848. Highlighted by: Lewis S. (2020) Nature Reviews Neuroscience.
- Medina C1, de la Fuente V, tom Dieck S, Nassim-Assir, B, Dalmay T, Bartnik I, Lunardi P, de Oliveira Alvares L, Schuman EM, Letzkus JJ,Romano A2 (2020). LIMK, Cofilin 1 and actin dynamics involvement in fear memory processing. Neurobiology of Learning and Memory, 173, 107275.
2019
- Dalmay T1, Abs E1, Poorthuis RB, Hartung J, Pu D, Onasch S, Lozano YR, Signoret-Genest J, Tovote P, Gjorgjieva J, Letzkus JJ2,3 (2019). A critical role for neocortical processing of threat memory. Neuron, 104:1180-1194.
- Pardi MB1, Abs E, Letzkus JJ2,3 (2019). Disinhibition goes spatial. Neuron, 101:994-996.
2018
- Abs E1, Poorthuis RB1, Apelblat D, Muhammad K, Pardi MB, Enke L, Kushinsky D, Pu D, Eizinger MF, Conzelmann K-K, Spiegel I2, Letzkus JJ2,3 (2018) Learning-related plasticity in dendrite-targeting layer 1 interneurons. Neuron, 100:684-699. Highlighted by: Hou WH & Capogna M (2018) Neuron 100, 516-519.
- Poorthuis RB1, Muhammad K, Wang M, Verhoog MB, Junek S, Wrana A, Mansvelder HD, Letzkus JJ2,3 (2018) Rapid Neuromodulation of Layer 1 Interneurons in Human Neocortex. Cell Reports 23:951-958.
- Mager T1, Lopez de la Morena D1, Senn V, Schlotte J, A DE, Feldbauer K, Wrobel C, Jung S, Bodensiek K, Rankovic V, Browne L, Huet A, Juttner J, Wood PG, Letzkus JJ, Moser T2, Bamberg E2 (2018) High frequency neural spiking and auditory signaling by ultrafast red-shifted optogenetics. Nature Commun. 9:1750.
2015
- Letzkus JJ1,2, Wolff SB, Luthi A2,3 (2015) Disinhibition, a Circuit Mechanism for Associative Learning and Memory. Neuron 88:264-276.
- Karadottir RT1,2, Letzkus JJ2, Mameli M2, Ribeiro C2 (2015) Your ticket to independence: a guide to getting your first principal investigator position. Eur J Neurosci 42:2372-2379.
2014
- Wolff SB1, Grundemann J1, Tovote P, Krabbe S, Jacobson GA, Muller C, Herry C, Ehrlich I, Friedrich RW, Letzkus JJ2, Luthi A2 (2014) Amygdala interneuron subtypes control fear learning through disinhibition. Nature 509:453-458.
- Highlighted by: Ozawa T & Johansen JP (2014) Current Biology 24, R690-693.
- Senn V1, Wolff SB1, Herry C, Grenier F, Ehrlich I, Grundemann J, Fadok JP, Muller C, Letzkus JJ, Luthi A2 (2014) Long-range connectivity defines behavioral specificity of amygdala neurons. Neuron 81:428-437.
- Poorthuis RB1, Enke L1, Letzkus JJ2 (2014) Cholinergic circuit modulation through differential recruitment of neocortical interneuron types during behaviour. The Journal of Physiology 592:4155-4164.
2011
- Letzkus JJ1,2, Wolff SB1, Meyer EM, Tovote P, Courtin J, Herry C, Luthi A2 (2011) A disinhibitory microcircuit for associative fear learning in the auditory cortex. Nature 480:331-335. Highlighted by: Flight MH (2011). Nat Rev Neurosci 13, 72.
- Kampa BM1, Gundlfinger A, Letzkus JJ, Leibold C (2011) Circuit mechanisms of memory formation. Neural Plast 2011:494675.
2010
- Ciocchi S1, Herry C1, Grenier F, Wolff SB, Letzkus JJ, Vlachos I, Ehrlich I, Sprengel R, Deisseroth K, Stadler MB, Muller C, Luthi A2 (2010) Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468:277-282.
- Froemke RC1,2, Letzkus JJ, Kampa BM, Hang GB, Stuart GJ (2010) Dendritic synapse location and neocortical spike-timing-dependent plasticity. Front Synaptic Neurosci 2:29.
- Herry C1, Ferraguti F, Singewald N, Letzkus JJ, Ehrlich I, Luthi A2 (2010) Neuronal circuits of fear extinction. Eur J Neurosci 31:599-612.
2008
2007
- Kole MH1, Letzkus JJ1, Stuart GJ2 (2007) Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy. Neuron 55:633-647.
- Letzkus JJ1, Kampa BM, Stuart GJ2 (2007) Does spike timing-dependent synaptic plasticity underlie memory formation? Clin Exp Pharmacol Physiol 34:1070-1076.
- Kampa BM1,2, Letzkus JJ, Stuart GJ (2007) Dendritic mechanisms controlling spike-timing-dependent synaptic plasticity. Trends Neurosci 30:456-463.
2006
- Letzkus JJ1, Kampa BM, Stuart GJ2 (2006) Learning rules for spike timing-dependent plasticity depend on dendritic synapse location. J. Neurosci. 26:10420-10429.
- Kampa BM1,2, Letzkus JJ, Stuart GJ (2006) Cortical feed-forward networks for binding different streams of sensory information. Nature Neurosci. 9:1472-1473.
- Kampa BM1, Letzkus JJ, Stuart GJ2 (2006) Requirement of dendritic calcium spikes for induction of spike-timing-dependent synaptic plasticity. The Journal of Physiology 574:283-290.
- Davie JT1, Kole MH, Letzkus JJ, Rancz EA, Spruston N, Stuart GJ, Hausser M2 (2006) Dendritic patch-clamp recording. Nature Protocols 1:1235-1247.
2004
2003