Cell and systems analysis of spatial and episodic memory
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
I aim to understand how we find remember where things are and the things that happen to us in everyday life. I aim to do this by understanding how the actions of neurons in different parts of the brain enable these functions, including using computers to see how neurons can work together as well as experiments involving data from single cells, functional neuroimaging and studying patients with specific brain damage. To perform realistic experiments I will use recent advances in virtual reality to provide controlled situations in which to do these things. This is important for the following reasons.
Diagnosing a neurological disease and monitoring its progress often depends on being able to measure its effect on behaviour. Many neurological conditions affect our ability find our way around and to remember things, e.g. Alzheimer‘s disease - the most common form of dementia. Where brain surgery may be required (as in some cases of intractable epilepsy) it is also useful to be able to tell which part rain is affected using behavioural tests, and imaging techniques. At a more basic level, understanding how the neurons and neural systems work will aid the development of new medicines. This type of basic research can also have unforeseen knock-on effects: aiding scientific discoveries in related fields such as pharmacology, computer science, engineering.
Diagnosing a neurological disease and monitoring its progress often depends on being able to measure its effect on behaviour. Many neurological conditions affect our ability find our way around and to remember things, e.g. Alzheimer‘s disease - the most common form of dementia. Where brain surgery may be required (as in some cases of intractable epilepsy) it is also useful to be able to tell which part rain is affected using behavioural tests, and imaging techniques. At a more basic level, understanding how the neurons and neural systems work will aid the development of new medicines. This type of basic research can also have unforeseen knock-on effects: aiding scientific discoveries in related fields such as pharmacology, computer science, engineering.
Technical Summary
Memory is a fundamental property of human existence, and memory impairments in
common conditions such as dementia, stroke or epilepsy are among the most debilitating
of cognitive deficits. Recent molecular and pharmacological advances in memory research, understood at the physiological level, may be hard to translate into treatments for cognitive deficits without models that integrate between neuronal/synaptic levels and cognitive/behavioural levels in a systematic manner. I aim to provide such an integrated understanding, via a programme that combines experiments at neuronal, systems and behavioural levels, and integrates the result within a computational model of the neural systems underlying memory. A key aim is to be able to relate findings from one field (e.g. physiology) to findings in another (e.g. neuropsychology) with explicit quantitative models which can generate critical new predictions and tests.
My previous MRC work developed a quantitative understanding of spatial memory, focused on the hippocampus and related temporal and parietal systems, by combining single unit and EEG recording in freely moving rats with fMRI of healthy humans, and neuropsychological testing of patients with focal brain lesions, performing tasks within virtual reality. I propose to build on this successful platform in three ways: i) To apply the approach to clinical conditions affecting hippocampal-dependent memory: enhanced detection of early Alzheimer‘s disease; characterization of the functional and structural sequeli of a specific form of limbic encephalitis; and detection of right hippocampal damage in a clinical setting; ii) To strengthen links from cellular physiology to behaviour/symptoms, by studying: the relationship of single unit activity to expression of Alzheimer-like symptoms in a mouse model, and to blockade of long-term potentiation in hippocampal region CA3 in rodents; the relationship of single-unit activity recorded intracranially in humans to spatial memory performance. iii) To extend the approach to include large-scale temporal dynamics of neural activity, by recording EEG in rodents, intra-cranially in patients, and MEG in healthy volunteers. Basic-science objectives include: identifying the functional role of the hippocampus and prefrontal cortex in spatial memory; extending our computational model of memory to verbal sequences and further development of the links between the cellular, systems and behavioural data on memory. Clinical implications include: increased ability to relate observations (in health or disease) or manipulations (e.g. genetic or pharmacological) at the level of neuronal/ synaptic physiology (as in the rodent studies) or systems (as in EEG, MEG, MRI or lesions) to specific behaviour/ symptoms in memory (e.g. pattern completion, generalisation to a shifted viewpoint) and vice versa.
common conditions such as dementia, stroke or epilepsy are among the most debilitating
of cognitive deficits. Recent molecular and pharmacological advances in memory research, understood at the physiological level, may be hard to translate into treatments for cognitive deficits without models that integrate between neuronal/synaptic levels and cognitive/behavioural levels in a systematic manner. I aim to provide such an integrated understanding, via a programme that combines experiments at neuronal, systems and behavioural levels, and integrates the result within a computational model of the neural systems underlying memory. A key aim is to be able to relate findings from one field (e.g. physiology) to findings in another (e.g. neuropsychology) with explicit quantitative models which can generate critical new predictions and tests.
My previous MRC work developed a quantitative understanding of spatial memory, focused on the hippocampus and related temporal and parietal systems, by combining single unit and EEG recording in freely moving rats with fMRI of healthy humans, and neuropsychological testing of patients with focal brain lesions, performing tasks within virtual reality. I propose to build on this successful platform in three ways: i) To apply the approach to clinical conditions affecting hippocampal-dependent memory: enhanced detection of early Alzheimer‘s disease; characterization of the functional and structural sequeli of a specific form of limbic encephalitis; and detection of right hippocampal damage in a clinical setting; ii) To strengthen links from cellular physiology to behaviour/symptoms, by studying: the relationship of single unit activity to expression of Alzheimer-like symptoms in a mouse model, and to blockade of long-term potentiation in hippocampal region CA3 in rodents; the relationship of single-unit activity recorded intracranially in humans to spatial memory performance. iii) To extend the approach to include large-scale temporal dynamics of neural activity, by recording EEG in rodents, intra-cranially in patients, and MEG in healthy volunteers. Basic-science objectives include: identifying the functional role of the hippocampus and prefrontal cortex in spatial memory; extending our computational model of memory to verbal sequences and further development of the links between the cellular, systems and behavioural data on memory. Clinical implications include: increased ability to relate observations (in health or disease) or manipulations (e.g. genetic or pharmacological) at the level of neuronal/ synaptic physiology (as in the rodent studies) or systems (as in EEG, MEG, MRI or lesions) to specific behaviour/ symptoms in memory (e.g. pattern completion, generalisation to a shifted viewpoint) and vice versa.