Nicotinic recruitment of genetically-identified layer 1 interneurons in circuit function and memory

• Applicant: Professor Dr. Johannes Letzkus, Ph.D.
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Experimental and Theoretical Network Neuroscience
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450143268

The neocortex is 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. A key afferent pathway to neocortex that is critical for many higher cognitive functions such as attention, learning and memory is the cholinergic system. In addition, cholinergic dysfunctions have also been associated with several human brain disorders like Alzheimer’s disease and schizophrenia. Acetylcholine released by basal forebrain neurons has been shown to strongly affect a range of neocortical functions, including the intrinsic physiology of pyramidal neurons, synaptic transmission and plasticity, and local inhibitory interneurons. Interneurons in layer 1 of neocortex strongly express ionotropic, nicotinic acetylcholine receptors (nAChRs) at levels that are sufficient to elicit suprathreshold responses in rodents, and our recent work revealed that this feature is conserved in human neocortex. Moreover, previous work indicates that layer 1 interneurons can cause brief reductions of inhibition in pyramidal neurons, and this disinhibition has recently emerged as an important and widely observed mechanism influencing circuit function. Together, this indicates that nicotinic recruitment of layer 1 interneurons is likely a fundamentally important processing motif with a strong translational perspective, but very little is known about the mechanisms and consequences of this form of cholinergic circuit modulation, and how it combines with other effects of acetylcholine on the circuit. Here, we will employ the first selective genetic marker for layer 1 interneurons we have recently identified (Ndnf) to elucidate how nicotinic input to these cells in auditory cortex shapes their sensory responses, and the prominent learning-related plasticity of these interneurons in vivo. Moreover, we will determine how this manipulation in turn affects the function of the local circuit. To this end, we will establish and validate selective loss-of-function of nAChRs in Ndnf layer 1 interneurons, using genetically-modified mouse lines we have recently generated. We will focus on α7 and β2-containing receptors since they are expressed at high levels in both mouse and human layer 1 interneurons, and have been linked to cognitive functions and brain disorders. In combination with in vivo 2-photon calcium imaging, sensory stimulation and cortex-dependent associative conditioning, these experiments will for the first time reveal how cholinergic recruitment of a defined neocortical circuit element contributes to different brain functions. In addition to producing an understanding of this likely fundamentally important mechanism in mice, we expect that our insights will also be of relevance for elucidating the function of the healthy and diseased human brain.

• DFG Programme: Research Grants