Our ability to remember ‘where I put my car keys today’ as opposed to ‘where I put them yesterday’ depends on a computational process known as pattern separation. Pattern separation refers to the representation of highly similar memories in distinct ways so they can coexist without interference; and one of the first memory processes affected by ageing.
Pattern separation is a function of the hippocampal DG that comprises granule cells, mossy cells, and different types of interneurons. Mossy cells, in particular, are essential to pattern separation and key regulators of the balance between excitation and inhibition in DG circuitry.
In preliminary work, we have found that pattern separation memory deficits are linearly correlated with DG volume loss in the MRI scans of young epilepsy patients, and that the post-mortem brains of young epilepsy patients have fewer DG mossy cells, a pathological finding that is more typical of older adults.
Mossy cell death is known to be caused by seizure activity but may also lead to further disinhibition and hyperexcitability of the hippocampal DG in epilepsy patients. Hence, mossy cell death may be implicated in both the pathogenesis of recurrent seizures and the memory deficits that affect many patients with epilepsy.
Aims and objectives
Hypothesis: Epilepsy patients have pattern separation deficits because of the death of mossy cells from seizures.
Aim 1: To measure pattern separation in epilepsy patients using the mnemonic similarity task, a well-established behavioural test of pattern separation memory
Aim 2: To correlate the results of aim 1 with measurements of (a) DG volume from MRI scans, and (b) histopathological mossy cell density from surgical specimens (only patients who have temporal lobe epilepsy surgery)
Aim 3: To model the dynamics of pattern separation in the DG and use this to understand how seizures and mossy cell loss and lead to deficits
Methodology
50% of patients with drug-resistant epilepsy assessed by the Bristol epilepsy surgery services (>100 adults and >50 children annually) are eligible for surgery. Their standard assessment includes:
- EEG/video-telemetry
- 3T MRI head scans
- Neuropsychology work-up
In this research project (IRAS 229579 approved on 15 July 2022), the student will:
- recruit adults and children with temporal lobe (TLE) or generalised epilepsy (50 in each group)
- direct subjects to complete the online 10-15min Mnemonic Similarity Task (MST)
- ask subjects about their quality of life, epilepsy, and anti-epilepsy medications using online questionnaires in REDCap.
- histologically quantify different cell populations in the DG for those TLE patients who have surgery and ask these subjects to repeat the online MST and questionnaires when 3, 6 and 12 months have elapsed since their surgery (to determine how MST performance changes with seizure frequency in the post-operative period).
- correlate the results of the questionnaires, MST +/-histology with the MRI/EEG/neuropsychology results collected from subjects as part of their standard care.
- Develop a neural mass model of DG circuitry to model patient EEG data. The model will be used to predict the effect of mossy cell death and pharmacological agents, e.g., anti-epileptics, on pattern separation and epilepsy.
Apply for this project
This project will be based in Bristol Medical School - Translational Health Sciences.
Please contact [Email Address Removed] for further details on how to apply.
Apply now!
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