Thalamic place cells: where, how and why

Elucidating how the brain makes, stores and updates "knowledge" is a key challenge in biology. A fundamental type of knowledge is spatial memory, formed by the hippocampus and its surrounding network and underpinning both spatial behaviours and memory for life events. Failure of the hippocampal system leads to profound disorientation and amnesia, as in Alzheimer's dementia. Spatial knowledge is supported in the hippocampus by place cells (PCs), each of which becomes active in certain places in the environment. PCs provide both a self-location signal and also an index of where, in the brain, associated information is stored as memories. Evidence suggests that some of the brain indexing function may take place during restfulness and non-dreaming (slow-wave) sleep. Waking movement, resting and sleep are distinguished by concurrent brain oscillatory patterns. The most prominent, theta, is found throughout the hippocampal network during active sensory processing. The PC signal in hippocampus is formed by combining complex multi-sensory signals with previously acquired memory. Given this complexity, we were recently surprised to discover place cells in a deeper and simpler brain structure, the AV nucleus of the anterior thalamus, which has completely different inputs. This is now the fourth thalamic region in which PCs have been reported and so we think these neurons are an important part of the spatial memory system. Relatedly, damage to anterior thalamus has long been associated with profound amnesia. Thalamus also has a critical role in organising brain activity patterns during sleep. Putting this information together, our guiding hypothesis is that the PCs in thalamus work together with those in hippocampus to help organise the memory indexing process. As a first step to addressing this hypothesis we plan to investigate how these neurons work together by combining the expertise of PI Jeffery in neuronal recording in awake animals, and Co-I Craig in cellular anatomy and manipulation. Both investigators have independently been researching thalamic interactions with hippocampus, and will join forces to answer the following questions: Where are thalamic place cells found and what are their characteristics? From where do they acquire their spatial and temporal signals? Might they have a role in spatial memory processing? Aim 1 will map the location of thalamic place cells and systematically document their properties to determine their similarities and differences, with respect to each other and to hippocampal place cells. It will characterise the spatial properties of their activity and also timing relative to the hippocampal theta rhythm. These investigations will show how the signal in thalamus is related to that in hippocampus and perhaps provide clues to the direction of flow of the place signals in the network. Aim 2 extends this by deploying a combination of anatomical tracing, activity suppression and neuronal recording in order to discover the source of the thalamic place and theta signals. Aim 3 investigates activity of thalamic PCs during rest and sleep, to determine whether thalamic PCs reactivate during rest/sleep as hippocampal place cells do, and if so, how this correlates with contemporaneous activity in both hippocampus and neocortex. These experiments will add greatly to our understanding of hippocampal-thalamic interactions, and potentially identify thalamus as a crucial player in the hippocampal-neocortical interaction that underlies memory storage. This would be important not just for basic science but also for medicine and industry.