Vector coding in the entorhinal cortex

Nature is full of stationary and moving living organisms and objects. In this project, we want to understand how the brain encodes such objects by recording activity from nerve cells in the entorhinal cortex of freely moving mice or rats in environments that contain objects. The medial entorhinal cortex (MEC) is involved in the sense of place, and many MEC cells specialize in spatial navigation. The most well-known type of cell we found is the grid cell. These cells are proposed to function as a coordinate system that extends upon any surface with activity fields that are equally separated from each other, creating a tessellating hexagonal pattern. It is suggested that these cells provide the brain with spatial metric. Other cells map the head direction, the boundaries of the environment, and the speed of the subject. The newest discovery is of cells that map a specific direction and distance between the subject and an object. Since this can be described as a vector between the subject and the object, we decided to name these cells object vector (OV) cells. In this grant proposal we are interested in finding out whether there are specific features of the object that is eliciting an OV response, or whether OV cells are indifferent to the quality and appearance of the objects. In line with that, we want to explore whether motivation to explore the object will affect the expression of the OV response. We want also to understand what factors generate such cells; does the vector response for example depend on self-motion cues? And are OV cells clustered? Thus, we would like to describe and understand vector coding of position in the brain and how it is generated and compare it to other spatial coding systems.

The project has led to the following overall outcomes and impacts: - The project has identified which factors in the environment that OV cells use to anchor firing to given positions. - It has shown that cells in the hippocampus encode information about objects and that this primarily happens on the level of neuronal populations. - It has shown that OV cells are excitatory stellate or pyramidal cells in MEC and parasubiculum and that their anatomical location is different from that of grid cells. - It provides sufficient knowledge about OV cells to construct models of their formation and operation as well as their interactions with other functional cell types of the circuit. - It provides the breadth of data needed to construct new computational models for vectorial coding in MEC. - It is one of the first projects to use portable 2-photon microscopes to determine spatial coding mechanisms in widespread anatomical circuits. - It is one of the first projects to use Neuropixels silicon probes to record from hundreds of cells in MEC and hippocampus. The findings have inspired the design of studies searching for possible early functional markers of Alzheimer’s disease in human subjects, in collaboration with the K.G. Jebsen Centre for Alzheimer’s Disease. The first symptoms of Alzheimer's disease are often reduced sense of space and episodic memory, functions that are strongly dependent on the hippocampal formation and entorhinal cortex. Research at the Kavli Institute for Systems Neuroscience indicates that Alzheimer’s disease may start by slow degeneration of neural circuits for space and time. By identifying variables that control firing in OV cells, we prepare the ground for paradigms to distinguish modes of spatial mapping in humans in neuropsychological tests and functional MRI.

Much of what we know about high-level cortical neural coding has been obtained in the spatial mapping system of the entorhinal cortex. Until recently, this brain region was a blank spot on the brain’s functional map but today we know that it contains a number of computationally specialized cell types with dedicated roles in mapping of the local spatial environment: grid cells, head direction cells, border cells, and speed cells. Insights have been limited, however, by an almost exclusive reliance on recordings from rodents foraging in empty enclosures that are quite different from the richly populated, geometrically irregular environments of the natural world. We have recently tested mice in more complex environments - environments that contain discrete objects and so are different from the empty and open environments used to detect previous cell types. The tests showed that medial entorhinal cortex contains an abundant number of cells that use a vectorial code to represent location. These newly discovered cells - named object vector cells - fire at specific locations determined by distance and direction from discrete objects in the environment. Their combined firing can be used to infer location. In the present proposal, I wish to establish how vector coding enables spatial representation in the entorhinal-hippocampal spatial mapping system. We shall (i) identify the factors that cause object vector cells to fire to some objects and not to others, (ii) determine the sources of their metrics, and (iii) establish the morphological nature of object vector cells, their distribution in the network, and the relationship between object vector cells and cells with similar properties in other parts of the hippocampal-entorhinal system. Obtaining answers to these questions will significantly add to our understanding of the function of object vector cells in coding of space and their interaction with other elements of the space circuit.