Control of auditory cortex circuits by Ndnf layer 1 interneurons

• Applicant: Professor Johannes Letzkus, Ph.D.
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 427631082

Neocortex represents the largest and most powerful area of the human brain. This region has expanded and differentiated the most during mammalian evolution, mediates many of the capacities that distinguish humans from their closest relatives, and also plays a central role in many psychiatric disorders. One fundamental capacity that is enabled by neocortex is the brain’s enormous functional flexibility. This allows us for instance to focus our entire attention on a text, while still being able to react to relevant changes in our environment at any time, such as the ringing of our phone. Such behavioral adaptability in response to sudden changes is fundamentally important for survival in an unpredictable world, and our brain by far exceeds even the latest artificial intelligence algorithms in this capacity. Research over the last years has revealed that the functional flexibility of neuronal circuits is enabled to a large extent by inhibitory interneurons. These cells exert tight control over all computations of pyramidal neurons, which in turn instruct the individual’s behavior. Research on interneurons has received a strong impetus over the last years due to methodological developments that enable their efficient in vivo identification based on marker genes. However, we still lack selective markers for several relevant interneuron types. We have recently identified a novel marker gene (Ndnf) that for the first time enables selective targeting of layer 1 interneurons in both human and mouse neocortex. The aim of this proposal is to employ the genetically-modified mouse lines we have generated on this basis to elucidate how these novel Ndnf layer 1 interneurons affect the computations of auditory cortex circuits and endow them with flexibility. To this end we will combine optogenetic activity manipulations with patch-clamp electrophysiology in acute brain slices, and with large-scale extracellular recordings in the intact brain. These data will reveal for the first time how layer 1 interneurons control the function of the local network. The second part of the proposed work will use a recently developed genetic technique to identify subtypes of Ndnf interneurons, and to determine whether and how they differ in their control of the local circuit. To this end, we will employ targeting based on the intersection of Ndnf and an additional marker gene. In combination with optogenetics, electrophysiology, viral tracing, in vivo 2-photon imaging and behavioral training, this will produce a comprehensive, multidisciplinary understanding of the function of these subtypes. Taken together, this work will produce important insights on the function of a very little understood type of interneuron. Given that layer 1 is a major site in neocortex where internally-generated, top-down information is received, we expect these interneurons to contribute strongly to modulation of circuit function according to the current computational requirements of the animal.

• DFG Programme: Research Grants