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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Optical dissection of a cortical head direction circuit

Alternative title: Optisk disseksjon av en hoderetnings nervenettverk

Awarded: NOK 9.9 mill.

How do complex cognitive functions such as reasoning, memory and problem solving, emerge from the properties of neural circuits? To answer this question we must start perhaps by studying simple cognitive functions and tractable circuits. A basic cognitive function that is often taken for granted is our sense of direction. You become more aware of its function once you close your eyes and realize that you can still navigate your environment. In mammals, the so-called head direction cells (HD cells) form a neural substrate for this ability by firing when an animal is facing a specific direction. Thus these cells act like an internal compass. While HD cells have been discovered more than 30 years ago, how neural circuits give rise to cells with such properties remains unknown. New technological developments in our lab may now help to resolve this question. We have developed a microscope that enables monitoring the activity of thousands of neurons in a mouse brain while rotating the animal in an environment with visual cues. We have demonstrated that we can follow the activity of HD cells over many weeks and we will use this method to study HD cells in the cortex. We believe this method will help to resolve how circuits compute HD and will provide the neuroscience community with new capabilities for analyzing neural circuits. In the first year of the project, we have discovered that beside HD cells, there are also turn-selective cells in the same circuit. Moreover, some HD cells are also turn-selective. This is an interesting finding because decades-old models postulated the existence of these cells, which we now confirm experimentally. In the second and third year of the project, we have been consolidating our findings that there are angular head velocity cells in retrosplenial cortex. Moreover, we found that this cell type was much more widespread than previously thought. In the final period, we investigated what sensory modalities underlie the turn-selectivity of neuronal responses. We first established that most of these cells encode angular head velocity (AHV cells). Next, we found that these AHV cells depend on vestibular input or visual flow in a brain area-dependent manner. Finally, we generated a complete data set, wrote the manuscript and published this work.

Determining how our brain keeps track of head movements is essential for understanding two medical conditions that appear unrelated, vertigo and Alzheimer's disease. When you experience vertigo, you have the illusion that the world is moving while it is not. Nearly everyone is familiar with this experience. However, up to 10 % of Norwegians experience longer-lasting episodes, and this number increases to 30 % when you are older than 65 years. When you experience vertigo, something is wrong with either the vestibular apparatus or other brain areas responsible for sensing head movements. When you experience this, you understand why the vestibular apparatus is called the silent sense; In contrast to the other senses, for example, vision, you don't notice information from your vestibular apparatus until it is no longer functioning normally. It is silently working in the background to keep your balance and keep a stable representation of the world. While vertigo is a very common experience, we don't understand how our brain generates this illusion of a spinning world. This work, however, provides the first important fundament to answering this question which in turn could lead to better treatments. Importantly, because the vestibular apparatus also helps keep a stable representation of the world, it is also of key importance for orientation when trying to find your way home. Getting lost is an early symptom of Alzheimer's disease that afflicts about 60000 Norwegians and the same areas where neurons that keep track of head movements are the first to be affected by this disease. Altogether, these findings provide important new information to help solve several medical conditions.

How do complex cognitive functions such as reasoning, memory and problem solving, emerge from the properties of neural circuits? To answer this question we must start perhaps by studying simple cognitive functions and tractable circuits. A basic cognitive function that is often taken for granted is our sense of direction. You become more aware of its function once you close your eyes and realize that you can still navigate your environment. In mammals, the so-called head direction cells (HD cells) form a neural substrate for this ability by firing when an animal is facing a specific direction. Thus these cells act like an internal compass. While HD cells were discovered more than 30 years ago, how their directional tuning properties emerge from the underlying circuits is still unknown due to technical limitations. Capitalizing on recent technical developments in my lab, I propose a novel approach; 1) We will study HD cells in the retrosplenial cortex of mice. This is a superficial cortical circuit that has the important advantage of allowing easy access with powerful new optical methods to dissect circuit functions. 2) We developed a novel arena for rodents that is compatible with two-photon microscopy; It restrains the head, yet it allows controlled rotations in an environment with visual cues. We can image the activity of hundreds of neurons simultaneously with genetically encoded Ca2+ indicators while maintaining precise behavioral and sensory control. The arena is also sufficiently stable for in-vivo whole-cell patch-clamp recordings. The innovative methods that we developed and the choice of an accessible circuit, will allow us for the first time to determine HD tuning at every level of the neural circuit: somata, dendrites, dendritic spines and axons. We believe this will allow us to reveal how cortical circuits compute HD, and will provide the systems neuroscience community with new capabilities for cellular analysis of circuits.

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FRIMEDBIO-Fri prosj.st. med.,helse,biol

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