Developing 2-photon optical imaging for neural-network studies in medial entorhinal cortex of freely moving mice

Developing 2-photon optical imaging for neural-network studies in medial entorhinal cortex of freely moving mice

The medial entorhinal cortex (MEC) and the adjacent pre- and parasubiculum are thought to create an internal map of self-position that animals may use for goal-directed navigation. This map uses a set of functionally specific and largely non-overlapping cell types: grid cells, border cells, speed cells, object-vector cells, and head-direction cells. The presence of multiple distinct functional cell types, matched in specificity only by cell populations in some of the sensory and motor cortices, allows us to examine input-output transformations and computational algorithms in association cortices with unprecedented power and detail. In order to examine these algorithms, however, an obvious and crucial first step is to map the division of function across cells in anatomical space. This requires recording of hundreds of cells at the same time in freely-behaving animals exploring open spatial environments. Unfortunately the absence of appropriate methods for neural recording at the population level has so far prevented a clear understanding of the broader organization of multi-cell-type and multi-layer networks of MEC, at both micro and macro scales.  During my PhD, I invented a technique called “fast high-resolution miniaturized two-photon microscopy (FHIRM-TPM)”, which, through the use of a portable light-weight (2g) two-photon microscope, allows animals to move freely while large scale, single-cell-resolution calcium imaging is performed. In ANAT-MEC, I will refine this optical imaging method to study neural activity during spatial navigation in two-dimensional environments. I shall characterize in detail the anatomical organization of distinct cell types in MEC while mice engage in naturalistic, exploratory behavior in open spaces. Besides shedding light on this specific question, the project will – by developing a new technology - also open doors to unravel fundamental mechanisms of neural code formation in the mammalian space circuit.