Skip to main content

Contribution of distinct pyramidal cell types in hippocampal area CA1 to episodic memory formation

Periodic Reporting for period 1 - CA1 layers (Contribution of distinct pyramidal cell types in hippocampal area CA1 to episodic memory formation)

Reporting period: 2016-06-01 to 2018-05-31

One central component of our lives is the ability to find our way around - to work, home, to our favourite restaurant - and to store the events that we experience at those places in our memory. It is known since the 1950s that damage to a collection of brain regions referred to as the hippocampal formation (HF) causes severe deficits in the ability to form new memories in both humans as well as lab animals, such as mice. The overall objective of this project was to elucidate how exactly individual components (or neuronal cell types) of the HF interact in order to create new memories. Performing electrophysiological experiments in genetically modified mice, we were able to demonstrate how different cell types in the HF and a structure referred to as the medial septum interact in order to create a brain clock – a signal which enables our brain to sort memories in the correct temporal order. In a separate project, we focused our investigation on the question of how neurons referred to as grid cells contribute to our ability to navigate. Grid cells are neurons which form a map of the environment and, based on theoretical grounds, were hypothesized to function as the brain’s GPS system. Their importance was recognized with the Nobel Prize 2013. We developed a technique that allowed us to selectively disrupt grid cells. Using this technique, we were able to investigate how grid cells contribute to the function of their communication patterns, and finally, we were the first to provide direct experimental evidence for the theory that grid cells are indeed important for our ability to navigate.

The HF is a vulnerable part of the brain and damage to its individual components is observed even in early stages of numerous neurological conditions such as stroke, epilepsy and Alzheimer's disease. Typical symptoms such as loss of memory and spatial navigation skills are likely due to such damage to the HF. The project described here provided us with more detailed information of how exactly the healthy HF functions. Understanding the exact processes of how memories are formed in the healthy brain will allow us to better understand what goes wrong in the diseased brain. This, in turn, will point us towards more directed strategies to slow down or prevent pathological memory loss and to improve memory function in patients with neurological conditions.
The hippocampal formation (HF) is the core of a memory system that is crucial for the formation of new episodic (unique event) memories in humans and lab animals such as rodents. These functions are thought to rely on a variety of specialized neural network computations: It is known, for example, that the hippocampus keeps track of the animal’s position in space, via the activation of place cells. A place cell is a neuron which increases its firing rate when the animal is in a specific location in space. Episodic memories are then formed by creating a joint representation of the animal’s current location and the events that occur at that location. Since the discovery of place cells in the 1970s, it is believed that place cell firing is generated by input from an upstream navigational system. The presence of such a navigational system was confirmed upon the recent discovery of multiple highly specialized cell types in the medial entorhinal cortex (MEC), the most prominent being grid cells. Grid cells are similar to place cells in that they form spatially selective firing fields (place fields). However, while place cell firing is confined to one to two place fields, grid cells form multiple firing fields that are arranged in equilateral triangular lattices. These firing patterns are thought to create a map like representation of the environment. In addition, the MEC contains head direction cells and speed cells which keep track of the animal’s running direction and speed, respectively. Together, these three cell types have all that is requires in order to accurately navigate through space. While the potential importance of place cells and grid cells was recognized by the Nobel Prize 2013, their function could not be experimentally evaluated due to the lack of tools that allow to manipulate individual functional cell types within the HF. We were able to overcome this obstacle by disrupting the normal development of grid cells in very young mice. This manipulation allowed us to experimentally test the long-standing theory that grid cells enable the animal to navigate through space through the generation of place cells in the hippocampus. To our surprise, we found that hippocampal place cells were able to keep track of the animal’s position in space, even when grid cells were abolished. The animal's ability to create shortcuts in order to navigate to a goal location, however, was nevertheless disrupted. Our results suggest that information about the current location of the animal can reach the hippocampus via routes that do not involve gird cells, and that this information is sufficient to keep track of the animal’s position in space. Behavioural tasks with high navigational demand, including the calculation of short cuts, in contrast, require computations performed by grid cells.

The formation of episodic memories does not only require the association of information about events and their places, but also that events are encoded in the correct temporal order. The temporal organization of information relies on the precise interplay between brain oscillations and the firing or individual neurons. The medial septum (MS) is a structure known to be a key generator of prominent brain oscillations referred to as the theta rhythm. How the individual cell types within the MS contribute to this function, however, remains unknown. Using patch clamp recordings and neuronal tracing techniques, the Monyer laboratory recently identified two distinct long-range-projecting GABAergic neuron (LRGN) types in the MS, which can be distinguished by their selective expression of parvalbumin (PV) and calbindin (CB) (Fuchs et al., 2016). These two cell types target specific cell types in the MEC and are ideally suited to coordinate distinct temporal computations in the MEC. We probed the function of these two LRGNs, using optogenetics and electrophysiological in vivo recordings in behaving mice. We found that the two cell types have distinct, and yet complementary functions: PV expressing LRGNs are important for the generation of the theta rhythm in the MEC, and thus for the generation of a clock-like signal for the coordination of memory components. CB expressing LRGNs, in turn, are not required to generate a clock-like signal, but instead organize the sequential firing of MEC neurons.

The results were presented at the Spring Hippocampal Research Conference 2017 in Taormina (Italy) as well as at the 11th Federation of European Neurocience Scoieties (FENS) 2018 in Berlin (Germany).
The techniques developed and scientific knowledge obtained during the project described above are currently being used as the basis for further projects, which will provide detailed insights into how the brain clock is disrupted in a mouse model of Alzheimer’s disease and mice that are addicted to alcohol. In addition, we are working on developing methods to test how impaired functions can be restored in the diseased brain - towards the long-term aim to develop strategies to alleviate symptoms of neurological diseases in humans.