Martinotti cells: from subcellular properties to behavior

This project aims to answer a long-standing question in neuroscience: how does the activity of nerve cells inside the brain produce meaningful behavior? The cortex in the mammalian brain plays a key role in sensory and motor functions. While sensory functions give us the ability to see, hear and feel inputs from the surrounding environment, motor functions generate goal-directed voluntary movements of body parts. Furthermore, the cortical network makes important contributions to a wide range of high order cognitive functions, for example, decision making, learning and memory. These complex neural functions depend on the activity of millions of nerve cells inside the massive cortical neuronal network. Technical advances in the past decade have provided neuroscientists the opportunity to record and manipulate the activity of nerve cells during behavior in a highly cell type-specific manner. In this project, scientists at the University of Oslo (UIO) will take advantage of these technical innovations to determine the role of Martinotti cells in sensory perception. These cells represent a major type of inhibitory nerve cells in the cortical network. Although the research on Martinotti cells began more century ago following their initial discovery by the Italian neuroanatomist Carlo Martinotti in 1889, the function of this specific type of inhibitory cells is unclear. Interesting questions, such as how Martinotti cells determine the perception of visual, auditory and touch information in the cortex, remain to be answered. To address these questions, two UIO research groups will combine their strength and use the latest generation of molecular, anatomical, optical, electrophysiological and computational modeling tools to study Martinotti cell functions in the sensory cortex at synaptic, circuit and behavior levels. In the first year, we have developed a behaviour task for mice that probes their ability to distinguish sensory stimuli in a working memory task. We have performed the first in-vivo imaging experiments in mouse lines that allow us to record the activity from Martinotti cells specifically. Tools are being developed to establish a pipeline from acquiring the data with two-photon microscopy, to analyze data with advanced analysis methods. In 2020, we have identified an mechanism which contributes to the fast signaling in interneuron axons. These results were published in the prestigious journal Nature Communications and have strong implications for understanding brain signaling. In 2021, we identified a mechanism in interneuron dendrites that contributes to high-frequency network oscillations in the brain, which play a key role in high-order cognitive functions. These results have been been published by the prestigious journal Cell Reports in 2022. In 2023, we identified a mechanism that enhances the ability of interneurons to separate different experiences during memory formation. We have presented our results in the 2023 Society for Neuroscience meeting, and we are using this result to write a manuscript.

A major challenge in modern neuroscience is to determine how complex brain functions may emerge from the activity of its elemental components. This proposal represents an ambitious, yet feasible plan to meet this challenge. Specifically, we will combine cutting-edge subcellular electrophysiological, optical imaging and modeling techniques to investigate the role of Martinotti cells, a key type of inhibitory neurons in the cerebral cortex, in sensory processing. With the long-term goal of revealing the cellular and circuit substrate of sensory representation in the brain, this project will shed light on the general mechanisms by which neural circuits in the mammalian brain operate. Moreover, the project will allow us to build a platform at the University of Oslo (UIO) on which long-standing questions in the field can be addressed with technical innovations. In line with the strategic goal of the Toppforsk program, this groundbreaking project will enable the PIs to reach their full potential to obtain a consolidator (or an advanced) grant from the European Research Council. To achieve the goal, the project will combine the expertise and skills of an international research network that includes two research groups at the UIO and several leading scientists in Europe and the US.