Finalist post-graduate research student (completed Sept '19, pre-viva), School of Life Sciences

Main supervisor: Prof. Bruno Frenguelli

Secondary supervisors: Dr Daniel Hebenstreit; Dr Mark Wall; Dr Elliot Ludvig

Summary:

Over the course of my PhD, I have investigated one of the molecular pathways hypothesised to underlie activity-dependent changes occurring within the mammalian hippocampus. Combining electrophysiological, histological, behavioural, transcriptomic and bioinformatic techniques, I have investigated the role of MSK1, a nuclear kinase, in in regulating the hippocampal response to environmental enrichment and in transducing external neurotrophic signals. I am currently awaiting my thesis viva, and am now working at a recovery clinic, where i deliver psycho-educational seminars to support client self-determination and volition, and am working on facilitating the introduction of neurofeedback techniques and technology to promote engagement and long-term support with new recovery methodologies.

Research Abstract:

Title: Investigation of Mitogen- and Stress Activated Kinase 1 Function in the Molecular Mechanisms of Experience-Dependent Synaptic Plasticity.

To date, pharmaceutical therapies have been largely unsuccessful at ameliorating or preventing the effects of dementia-related neurodegeneration. Environmental enrichment (increased social contact and cognitive engagement with surroundings) has however been shown to be effective at stimulating neurogenesis and improving cognitive function in many animal models. The molecular mechanism of this improvement is currently not fully characterised, but could aid understanding molecular changes during memory formation, and how to boost this process. The Frenguelli lab have found evidence that mitogen- and stress-activated kinase 1 (MSK1) has a regulatory role upon learning and memory in response to environmental stimuli, acting through CREB phosphorylation and histone H3 phosphorylation. CREB is an evolutionarily conserved transcription factor controlling the expression of genes affecting memory formation through the modulation of synaptic stability. Using mouse models of a kinase-inactive form of MSK1 displaying a deficit in basal synaptic transmission and CREB phosphorylation activity, the aim of this project is to further characterise the role MSK1 plays in modulating cognitive responses to environmental enrichment. Three main approaches were pursued to characterise hippocampal differences underlying the response to either standard housing and enriched environment housing, with and without normal MSK1 function:

High-throughput RNA-sequencing of mouse hippocampi and subsequent bioinformatic analysis in order to elucidate the role this regulatory kinase may play in the gene transcription in response to enrichment;

Electrophysiological recordings in order to further charcterise pre- and post-synaptic differences in CA1 hippocampal transmission, and simultaneously fill neurons for future staining and 3D-morphological reconstruction. Enrichment is known to modulate neuronal morphology, promoting larger, more complex dendritic trees.

Behavioural experiments to characterise MSK1s role in modulating the response to enrichment. Enrichment is known to modulate the hippocampus-dependent behaviours of object-location novelty, sociability preference and social novelty. The role of MSK1 in mediating these activities will be determined to relate a macroscopic phenotype to cellular and molecular changes observed.

This combination of methods should provide novel insight into both the transcriptomic and molecular effects of activity-dependent MSK1-dependent learning and memory within the hippocampus.

Publications:

Daumas S, Hunter CJ, Mistry RB, et al. "The Kinase Function of MSK1 Regulates BDNF Signaling to CREB and Basal Synaptic Transmission, But Is Not Required for Hippocampal Long-Term Potentiation or Spatial Memory." eNeuro. 2017;4(1):ENEURO.0212-16.2017. doi:10.1523/ENEURO.0212-16.2017.

Background to my research: The Hippocampus (With Pictures!)

My research at the University of Warwick focuses on the hippocampus, an area in the brain that deals with episodic memory consolidation (the who, the what and the why associated with our memory recall) and spatial memory. To illustatrate this: London taxi cab drivers who deal everyday with navigating the city's labyrinth of roads (relying on spatial memory) have significantly larger hippocampi than that of the average person. Conversely, one of the most famous cases of long-term memory loss (memory consolidation) was that of a patient called H.M.. H.M. had large parts of his hippocampus removed surgically to try to cure his epilepsy; the surgery was successful, but left him with an inability to store information from his short-term memory as long-term memories - meaning he could only remember things for a few hours!

Below is a graphic model of the human brain recreated from MRI data. only one hemisphere (half) of the cortex is shown, exposing the left-hand side of the hippocampus (in red).

(Credit: Daniel Cooper and Equinox Graphics Ltd. 2017)

The Hippocampus contains many neurons (the cells within the brain that transmit information) that are connected together to form a network. The way this netowrk is connected affects the way information received from sensory organs and the rest of the cortex is processed - the same information can be interpretted differently by different networks, leading to different outputs, and the way your hippocampus is connected changes over time and circumstance in a process known as neuronal plasticity. This network can be very complex, with many different connections, as can be seen in the below cut view "inside" the tube of the red hippocampus above.

(Credit: Daniel Cooper and Equinox Graphics Ltd. 2017)

By studying how these networks change at the molecular protein level, drug intervention and therapeutic targetting can become a reality. First however, the basic underlying mechanisms encoding memory must be understood, which in a very small way, is what my research with Prof. Frenguelli is attempting to do.

As well as my research work, I also enjoy making 3D images and animations of biological processes in collaboration with Equinox Graphics Ltd.. A small collection of the images I have produced with them and Prof. Frenguelli are below:

"Biological Warfare": An Illustration showing T-cells (blue, right-bottom) being bound by IgG antibodies (yellow) at the PD-L1 receptor as part of monoclonal antibody therapy. This prevents the T-cells from binding to the cancerous cells (red fleshy wall to the left) expressing the receptor ligand, and telling the T-cell that the cancer cells are harmless - This leads to increased T-cell agression towards the cancer. Produced in collaboration with Astrazeneca for Pint of Science, Cambridge.

(Credit: Daniel Cooper and Equinox Graphics Ltd. 2017)

Basic synaptic network. Dendritic spines (Blobs within the picture) are shown projecting from dendrites (the tentacles covered in blobs) where they can form new synaptic connections between axons (smooth tentacles) and dendrites, chemically connecting neurons together.

(Credit: Daniel Cooper and Equinox Graphics Ltd. 2017)

Sofware Literacy:

- AutoDesk Maya, Luxology Modo – Commercial 3D Modelling Software

- CorelDraw, Photoshop and After Effects

- Programming experience using MatLab and R languages.

Daniel Cooper

d dot d dot cooper at warwick dot ac dot uk