Quantifying the molecular response to memory retrieval and its genetic association with schizophrenia
Deficits in the molecular mechanisms of memory are thought to be central to the psychiatric pathology associated with schizophrenia. New methods now allow us to explore deeper into the molecular dynamics of memory and refine our understanding of the impacts from schizophrenia. This interdisciplinary project aims to profile neuronal gene expression required for memory retrieval and extinction, and determine the molecular pathways of relevance to schizophrenia.
Evidence from genomic studies of schizophrenia indicates that genes with synaptic functions involved in learning and memory are central to the pathology of the disorder (1). However, our current understanding of the specific genes and transcripts responsible for these processes is limited by a lack of cell-specific data from high-throughput sequencing methods. By establishing which neuronal genes are particularly important for different phases of learning and memory, we will be able to refine the biology implicated in schizophrenia pathology in view of designing improved treatments. Different profiles of gene expression are evoked by the acquisition, consolidation, retrieval and extinction of memories. Some evidence suggests that genes responsible for memory extinction may be particularly associated with schizophrenia (2). Furthermore, abnormalities in this type of inhibitory learning have been reported in patients (3) and may contribute to the development and persistence of psychotic and cognitive symptoms in the condition.
Our proposal provides an opportunity for a PhD student to work on an interdisciplinary project aiming to refine the neuronal gene expression profiles associated with the retrieval and extinction of contextual fear memory. The work will build on a strong foundation of research into memory, transcriptomics and psychiatric disorders by the supervisory team and their experienced lab groups.
The first objective will be to model the molecular response to contextual fear conditioning and profile the neuronal-specific transcriptome following memory retrieval and extinction. The student will use mice with neuronal-specific genetically tagged ribosomes to conduct a fear conditioning paradigm and extract ribosome-bound RNA from excitatory neurons during critical phases of memory retrieval and extinction. They will then use nextgeneration RNA sequencing, bioinformatics and supercomputing to compare these molecular profiles, and study their implications in the context of human co-expression profiles and patient genomics. These steps will afford the student freedom to use the data in pursuit of additional goals of primary interest to them. This may include comparison with published datasets of gene expression associated with specific plasticity processes such as long-term potentiation, or tests for enrichment of genetic association with a range of psychiatric disorders related to schizophrenia.
The student may choose to take advantage of existing links with other academic institutions during the optimisation of methods for ribosome profiling and transcriptome analysis, which may include short research visits within the UK or abroad. Together with opportunities to attend national and international conferences on psychiatric genomics, this will allow them to begin establishing a network of collaborators and a wider awareness of current work in the field.
Academic criteria: Applicants should possess a minimum of an upper second-class Honours degree, master's degree, or equivalent in a relevant subject.
English requirements: Applicants whose first language is not English must meet the minimum University requirements (e.g. 6.5 IELTS)
How to Apply
A list of all the projects and how to apply is available on our website at gw4biomed.ac.uk. You may apply for up to 2 projects.
Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’.
Please complete the online application form by 5.00pm on Wednesday, 2nd November 2022. If you are shortlisted for interview, you will be notified by Friday 16th December 2022. Interviews will be held virtually on 25th and 26th January 2023.
For informal enquiries, please contact [Email Address Removed]
For project-related queries, please contact the respective supervisors listed on the projects.