Context-dependent spatially periodic activity in the human entorhinal cortex

The spatially periodic activity of grid cells in the entorhinal cortex (EC) of the rodent, primate, and human provides a coordinate system that, together with the hippocampus, informs an individual of its location relative to the environment and encodes the memory of that location. Among the most defining features of grid-cell activity are the 60 degrees rotational symmetry of grids and preservation of grid scale across environments. Grid cells, however, do display a limited degree of adaptation to environments. It remains unclear if this level of environment invariance generalizes to human grid-cell analogs, where the relative contribution of visual input to the multimodal sensory input of the EC is significantly larger than in rodents. Patients diagnosed with nontractable epilepsy who were implanted with entorhinal cortical electrodes performing virtual navigation tasks to memorized locations enabled us to investigate associations between grid-like patterns and environment. Here, we report that the activity of human entorhinal cortical neurons exhibits adaptive scaling in grid period, grid orientation, and rotational symmetry in close association with changes in environment size, shape, and visual cues, suggesting scale invariance of the frequency, rather than the wavelength, of spatially periodic activity. Our results demonstrate that neurons in the human EC represent space with an enhanced flexibility relative to neurons in rodents because they are endowed with adaptive scalability and context dependency

Interplay between astrocytic and neuronal networks during virtual navigation in the mouse hippocampus

Encoding of spatial information in hippocapal place cells is believed to contribute to spatial cognition during navigation. Whether the processing of spatial information is exclusively limited to neuronal cells or it involves other cell types, e.g. glial cells, in the brain is currently unknown. In this thesis work, I developed an analysis pipeline to tackle this question using statistical methods and Information Theory approaches. I applied these analytical tools to two experimental data sets in which neuronal place cells in the hippocampus were imaged using two-photon microscopy, while selectively manipulating astrocytic calcium dynamics with pharmacogenetics during virtual navigation. Using custom analytical methods, we observed that pharmacogenetic perturbation of astrocytic calcium dynamics, through clozapine-n-oxyde (CNO) injection, induced a significant increase in neuronal place field and response profile width compared to control conditions. The distributions of neuronal place field and response profile center were also significantly different upon perturbation of astrocytic calcium dynamics compared to control conditions. Moreover, we found contrasting effect of astrocytic calcium dynamics perturbation on neuronal content of spatial information in the two data sets. In the first data set, we found that CNO injection resulted in a significant increase in the average information content in all neurons. In the second data set, we instead found that mutual information values were not significantly different upon CNO application compared to controls. Although the presented results are still preliminary and more experiments and analyses are needed, these findings suggest that astrocytic calcium dynamics may actively control the way hippocampal neuronal networks encode spatial information during virtual navigation. These data thus suggest a complex and tight interplay between neuronal and astrocytic networks during higher cognitive functions

Exploring how spatial learning can affect the firing of place cells and head direction cells: the influence of changes in landmark configuration and the development of goal-directed spatial behaviour.

Rats learn to navigate to a specific location faster in a familiar environment (Keith and Mcvety 1988). It has been proposed that place learning does not require specific reward signals, but rather, that it occurs automatically. One of the strongest pieces of evidence for the automatic nature of place learning comes from the observation that place and head direction cells reference their receptive fields to prominent landmarks in an environment without needing a reward signal (O’Keefe and Conway 1978; Taube et al. 1990b). It has also been proposed that an allocentric representation of an environment would be bound to the landmarks with the greatest relative stability to guide its orientation (O’Keefe and Nadel 1978). The first two parts of this thesis explore whether place and head direction cells automatically use the most coherent landmarks for orientation. Head direction cells have been shown to orient their preferred firing directs coherently when being exposed to conflicting landmarks in an environment (Yoganarasimha et al. 2006). A model of head direction cells was thus used to explore the necessary mechanisms required to implement an allocentric system that selects landmarks based on their relative stability. We found that the simple addition of Hebbian projections combined with units representing the orientation of landmarks to the head direction cell system is sufficient for the system to exhibit such a capacity. We then recorded both entorhinal head direction cells and CA1 place cells and at the same time subjected the rats to repeated experiences of landmark conflicts. During the conflicts a subset of landmarks always maintained a fixed relative relationship with each other. We found that the visual landmarks retained their ability to control the place and head direction cells even after repeated experience of conflict and that the simultaneously recorded place cells exhibited coherent representations between conflicts. However, the ’stable landmarks’ did not show significantly greater control over the place and head direction cells when comparing to the unstable landmarks. This argues against the hypothesis that the relative stability between landmarks is encoded automatically. We did observe a trend that, with more conflict experience, the ’stable landmarks’ appeared to exert greater control over the cells. The last part of the thesis explores whether goal sensitive cells (Ainge et al. 2007a) discovered from CA1 of hippocampus are developed due to familiarity with the environment or from the demands for rats to perform a win-stay behaviour. We used the same win-stay task as in Ainge et al. and found that there were few or no goal sensitive cells on the first day of training. Subsequent development of goal sensitive activity correlated significantly with the rat’s performance during the learning phase of the task. The correlation provides support to the hypothesis that the development of goal sensitive cells is associated to the learning of the win-stay task though it does not rule out the possibility that these goal sensitive cells are developed due to the accumulated experience on the maze. In summary, this thesis explores what kind of spatial information is encoded by place and head direction cells and finds that relative stability between landmarks without a reward signal is not automatically encoded. On the other hand, when additional information is required to solve a task, CA1 place cells adapt their spatial code to provide the necessary information to guide successful navigation