Final Report Summary - INTRASPACE (An intracellular approach to spatial coding in the hippocampus)
Humans as many other animals from birds to insects are able to orient themselves and navigate in familiar environments. But unlike other species, navigation in humans is flexible, meaning that we are able to take shortcut or make detours when necessary. This ability is thought to rely on the activity of cells in the hippocampal formation, an ensemble of brain structures in the medial temporal lobe in humans. At the core of this network, the hippocampus is important both for spatial navigation and for episodic memory (the memory of our everyday life events). In rodents exploring a new environment, a small ensemble of excitatory cells in the hippocampus, called place cells, will be active in specific locations (their place field) while the majority of hippocampal excitatory cells remain silent. This specific neuronal assembly is thought to represent a cognitive map, a mental representation of that environment, which will be stored in long-term memory, allowing flexible spatial navigation. Understanding the mechanisms involved in the selection of which cell will be part of a given assembly in a particular environment (also called the allocation process) is important to understand the formation of spatial maps and episodic memories. This question is at the core of the InstraSpace project. The ability of a given cell to map an environment could be in part rigidly pre-determined even before spatial exploration (Dragoi and Tonegawa., 2011; Epsztein et al., 2011), maybe based on its initial level of intrinsic cellular excitability (Lee et al., 2012). Cells with a high level of intrinsic excitability before exploring a new environment are more likely to be active in that environment compared to less excitable cells. Intrinsic neuronal excitability is set by the expression and distribution of voltage-gated channels in a particular cell, which will increase or decrease its ability to respond to incoming synaptic inputs. Intrinsic excitability is difficult to study with classical techniques used to probe neuronal activity in navigating animals (extracellular recordings). The aim of this project is to take advantage of newly developed techniques to perform intracellular recordings in navigating animals (Lee et al., 2006; Harvey et al., 2009; Lee, Epsztein and Brecht, 2009; Lee et al., 2014) to better understand the link between intrinsic excitability and the allocation process. These recordings allow us to directly stimulate a given cell and record its firing output thus assessing their input/output function and to inject pharmacological agents in order to induce long-term modifications of its intrinsic excitability.
In a first part of the project we wanted to see whether a specific level of intrinsic excitability is permanently attached to a given cell or whether a regulatory mechanism might exist. This question was motivated by observation that cells ensembles vary between different environments. In vitro studies had described long-term plasticity of intrinsic excitability in the hippocampus but we did not whether these mechanisms might be observed in the intact brain in vivo. Using stimulations applied via the patch-pipette we were able to induce a fast and long-lasting decrease in excitability and investigate some induction and expression mechanisms. We propose that this mechanism will prevent the same cells from always being activated thus reducing memory interference. Along the same line we wanted to see if the link between intrinsic excitability and allocation is still observed when animal explore a familiar environment. We thus used intracellular recordings to probe input/ouput function of CA1 pyramidal cells as mice explore virtual reality environment. We observe that cells with a high level of excitability tend to get hyperpolarized during movement suggesting that they are not involved in coding during spatial navigation. This result support our hypothesis of a switch from intrinsic to synaptic mechanisms of place cells activation with familiarization of an environment. This result was further confirmed using two-photon calcium imaging in navigating animals (in collbaoration with the Cossart lab).
In a second part of the project we wanted to see whether the recruitment rule based on intrinsic excitability differed in other part of the hippocampal formation and we started to correlate the level of intrinsic excitability and the recruitment probability of cells in upstream parts of the hippocampal formation.
In a third and last part of the project we wanted to understand the mechanisms behind changes in the coding of place cells that are observed when changes occur in a familiar environment, which is closer to our everyday experience. We often take the same streets to go from home to work but the parked cars have changed, the people in the street are different, the trees have lost their leaves during winter yet we can always find our way. For this we made use of virtual reality to be able to modify instantaneously and in a controlled way the explored environments. The use of virtual reality allowed us to reveal the importance of proximal visual landmarks for the accurate coding of space. We also found that modulating these landmarks could profoundly modify the coding of a familiar environment a process called remapping. The intracellular mechanisms behind these changes were investigated with whole-cell patch clamp recordings.
Overall this project aims at revealing the cellular mechanisms involved in the formation of spatial memories, which allow us to navigate. This essential function is impaired in several neurological diseases such as Alzheimer disease and temporal lobe epilepsy.
In a first part of the project we wanted to see whether a specific level of intrinsic excitability is permanently attached to a given cell or whether a regulatory mechanism might exist. This question was motivated by observation that cells ensembles vary between different environments. In vitro studies had described long-term plasticity of intrinsic excitability in the hippocampus but we did not whether these mechanisms might be observed in the intact brain in vivo. Using stimulations applied via the patch-pipette we were able to induce a fast and long-lasting decrease in excitability and investigate some induction and expression mechanisms. We propose that this mechanism will prevent the same cells from always being activated thus reducing memory interference. Along the same line we wanted to see if the link between intrinsic excitability and allocation is still observed when animal explore a familiar environment. We thus used intracellular recordings to probe input/ouput function of CA1 pyramidal cells as mice explore virtual reality environment. We observe that cells with a high level of excitability tend to get hyperpolarized during movement suggesting that they are not involved in coding during spatial navigation. This result support our hypothesis of a switch from intrinsic to synaptic mechanisms of place cells activation with familiarization of an environment. This result was further confirmed using two-photon calcium imaging in navigating animals (in collbaoration with the Cossart lab).
In a second part of the project we wanted to see whether the recruitment rule based on intrinsic excitability differed in other part of the hippocampal formation and we started to correlate the level of intrinsic excitability and the recruitment probability of cells in upstream parts of the hippocampal formation.
In a third and last part of the project we wanted to understand the mechanisms behind changes in the coding of place cells that are observed when changes occur in a familiar environment, which is closer to our everyday experience. We often take the same streets to go from home to work but the parked cars have changed, the people in the street are different, the trees have lost their leaves during winter yet we can always find our way. For this we made use of virtual reality to be able to modify instantaneously and in a controlled way the explored environments. The use of virtual reality allowed us to reveal the importance of proximal visual landmarks for the accurate coding of space. We also found that modulating these landmarks could profoundly modify the coding of a familiar environment a process called remapping. The intracellular mechanisms behind these changes were investigated with whole-cell patch clamp recordings.
Overall this project aims at revealing the cellular mechanisms involved in the formation of spatial memories, which allow us to navigate. This essential function is impaired in several neurological diseases such as Alzheimer disease and temporal lobe epilepsy.