FRIPROSJEKT-FRIPROSJEKT

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 published by the prestigious journal Cell Reports in 2022. In 2023, we identified a feature that enhances the ability of interneurons to separate different experiences during memory formation. In 2024, simulations in neuronal network models have identified the underlying mechanism. This theoretical analysis predicts that interneurons in the brain can help the discrimination between different memory representations by identifying subtle differences in the temporal structure of network activities. In the final stage this project, we are testing this prediction with an experimental approach. We are currently preparing a manuscript based on these results. In 2025, we found that inhibition of Martinotti cells enhances memory representations in a brain area-specific manner. The manuscript is in press in Nature Communications. Together, these results indicate that synaptic inhibition, which is generated by inhibitory neurons in the brain, does more than counterbalance synaptic excitation. Specifically, it organizes the processing and transmission of information in both spatial and temporal domains. By answering an important question: why the brain needs synaptic inhibition, the project has strong implications for understanding the design logic of neural circuits in the brain.

In terms of acquiring new knowledge, the project produced three actual outcomes at the cellular, circuit, and systems levels. First, we have identified several cellular mechanisms at interneuron dendrites and axons that allow these inhibitory neurons to organize cortical neuronal network activities with speed and temporal precision. Second, we have identified circuit mechanisms that allow interneurons to help neuronal networks in the hippocampus discriminate different input patterns. Such a feature may be important for the discrimination between different experiences during memory formation and retrieval. Third, we have found that inhibition of interneurons in the hippocampus and neocortex opens a window of opportunity for the formation of new memories. The outcomes have revealed a critical role of interneurons in cortical processing at both circuit and systems levels. These actual outcomes may lead to several potential outcomes. First, our results may have strong public health implications. Coherent neuronal network activities, which are organized by interneurons, play a key role in high-order cognition in the healthy brain. Conversely, brain diseases are often associated with abnormal neuronal network activities. The project has identified several interneuron specializations that allow these inhibitory cells to organize neuronal activities. These results may provide new therapeutic targets for combating brain disorders. Second, we are one of the very labs in the world that can perform high-quality electrophysiological recordings from interneuron dendrites and axons in the mammalian cortex. Our results have created a unique opportunity to construct realistic models for simulating interneuron functions at both cellular and network levels. By making these models accessible to the research community, this project may provide key building blocks for constructing large-scale models for in silico simulation of brain functions and brain diseases. These simulations may generate important theoretical predictions for designing future experiments for understanding the brain and identifying new therapeutic avenues for combating brain diseases. Our results have strong impacts on the advancement of scientific knowledge and research environments. Inhibitory interneurons contribute to only 20% of the total number of neurons in the cortical area, yet they are critical for high-order cognition. By identifying the role of interneurons in cortical processing and the underlying mechanisms, our results provide answers to an important question: why does the cortex need inhibitory interneurons? Consequently, they shed light on the design logic of neuronal circuits in the brain. In addition, the project has supported the development of brain imaging infrastructure at the University of Oslo. With the expertise gained from this project, a long-term vision is to establish a leading research specialized in studying the brain with a full-optical approach.

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.