Using wireless recording technologies to investigate cortical coherence in a mouse model of dementia

Many neuroscientists measure electrical signals in the brains of animals, such mice, in order to understand how the brain stores and processes information. This is often done whilst the mouse is conscious and exploring a maze which test different types of memory. We can also use this technology in mice which have been genetically altered to produce some of the symptoms of diseases such as Alzheimer's, to examine how the brain malfunctions in these conditions. Until recently the only way scientists have been able to do this is to attach a bundle of wires to the animals head whilst the animal is exploring the maze. This process inevitably produces a level of stress and discomfort to the animal and restricts its ability to move freely.

In this project, we aim to transfer the skills and knowledge associated with using a wireless recording system (called the 'TaiNi' system), from one of the developers (Eli Lilly) to academic groups based at the University of Exeter. The TaiNi system represents a step change in wireless recording technology for neuroscientists, since it is light enough to be easily carried by a mouse and yet powerful enough to transmit the complex neural signals to a nearby receiver for up to 72 hours at a time. These technological advancements mean that neuroscientists will be able to remotely monitor the electrical activity in a mouse brain, without the need to attach wires to the animal's head, substantially reducing the stress and discomfort associated with these types of experiment; therefore, this technology represents a significant welfare refinement for this type of experiment.

We will use the TaiNi system to examine communication between two brain regions that are thought to be important in the ability to remember and recognise familiar environments. This type of memory is severely impaired in people suffering from Alzheimer's disease, resulting in patients becoming lost and disorientated even in familiar places. Therefore, we will also examine communication between these brain regions in a mouse model of Alzheimer's disease.

These experiments will have two broad aims: firstly, the data gleaned from these studies will help explain the brain mechanisms underlying a devastating early symptom of dementia; and secondly, these studies will provide a 'proof of principal' that wireless recording technologies can be successfully deployed in mice. If successful in these aims, we will be in a position to contribute important information about how dementia affects the brain to the scientific and clinical dementia community. Furthermore, we will be able to provide guidance to other scientists wishing to use the TaiNi wireless recording system in their research.

Studying neuronal network and cellular level brain activity in animals that are behaving naturally is vital if we wish to understand the neural basis of complex behaviours. To achieve this neuroscientists employ in vivo electrophysiological techniques, which allow for the recording of emergent neuronal network oscillations and single unit activity. Until recently, the only feasible way of recording this activity in mice was to attach surgically implanted intracranial probes to physical wires. These physical wires produce shearing forces which ultimately impede movement and produce stress and discomfort in the animal. Recently, a lightweight, battery-powered wireless transmitter (TaiNi) has been developed for use in mice. By reducing stress and movement restriction associated with physical tethering, this technology represents a significant welfare refinement.

In this project, we will transfer the skills and knowledge associated with using the TaiNi system from one of the co-developers (Eli Lilly) to two academic groups. We have designed a short project which will provide proof of principal that wireless technologies can supersede our current tethered systems. In this project, we will examine the hypothesis that the retrosplenial cortex (RSC) provides associational information to the medial entorhinal cortex (MEC) in a contextual memory task. Using the TaiNi system, we will examine local field potential coherence between these two brain areas as mice explore novel and familiar environments. In more familiar environments, the relationship between running speed and network oscillations is enhanced, a form of plasticity which we hypothesise is driven by the RSC. Furthermore, we have preliminary evidence to suggest that this form of contextual memory-driven plasticity is impaired in a mouse model of Alzheimer's disease. Therefore, we will examine the hypothesis that impaired RSC-MEC interactions underlie these deficits in this neural correlate of spatial memory.

This proposal details the transfer of skills and knowledge on how to use a wireless in vivo electrophysiological system (referred to hereafter as the 'TaiNi system') from our partner, Eli Lilly, who co-developed the TaiNi system with researchers from Imperial College London, who have now created a spin-off company which began to distribute this system in December 2017. If this application is successful allows the deployment of the TaiNi system in the PI and Co-I's research groups (the 'end users'), this will provide both a significant refinement in the welfare of mice used for in vivo electrophysiology experiments.

In our current experimental set-up, when electrophysiological recordings are made from awake, behaving mice, the probe implanted in their brain is connected to the recording equipment via a long cable, in the 'tethered' system. Wired recording tethers produces a certain level of stress and discomfort, which the animal must acclimatise to. For example, the cables associated with transmitting the information from the neural implant to the recording devices often weigh more than the mouse itself. As a result, investigators usually counterbalance the recording cables to minimise associated shearing forces, but nevertheless there is likely to be a certain amount of discomfort and restriction of normal movement that results in less naturalistic behaviour. Switching to the wireless TaiNi system would represent a significant refinement in animal welfare, primarily because the shearing forces associated with physical wire tethers are eliminated. As discussed in the case for support, wireless systems allow mice to move more quickly and comfortably, and the display a much larger range of more naturalistic behaviours. In the end users' laboratories, we currently use 50 - 100 mice per annum for in vivo electrophysiology experiments, although this is set to increase as the Co-I only established his research group in 2016 and is currently undergoing a phase of rapid expansion.

In addition to the immediate refinement of the experience of up to 100 mice per annum in the end users' research groups, we estimate that 15 to 20 research groups in the UK are currently using in vivo electrophysiological recordings so if our plans to encourage wider adoption of this technology are successful, we estimate that this could lead to welfare refinements in up to 2000 mice in the UK each year. One of our main routes to realising this impact is through our partnership with other universities in the South West. The GW4 consortium (consisting of the Universities of Bath, Bristol, Cardiff and Exeter) are currently, in collaboration with NC3Rs, recruiting a 3Rs Research Manager who will be responsible for providing advice on 3Rs from the individual project level through to institutionally. A key part of their role will be to share knowledge of best practice; neurophysiology is a key strength across the GW4, so the NC3Rs research manager will be able to play a pivotal role in allowing the 3Rs impact of our work to be achieved rapidly and with no extra cost, providing a strong 'value-added' component to this research. The timeline for us realising the impact will likely be within the time-course of the project.