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Epilepsy is a complex brain disease, in which individuals are pre-disposed to show spontaneous seizures. Idiopathic epilepsy (IE) is classified as epilepsy of predominantly genetic or presumed genetic origin and in which there are no gross abnormalities of the structure of the brain nor other relevant underlying diseases causing seizure activity. IE is the most common chronic neurological condition in domestic dogs, estimated to affect 0.6% of dogs, but markedly higher in some breeds e.g. 17-33% in the Belgian Shepherd. Quality-of-life is also limited by side-effects of the currently used anti-epileptic drugs (AEDs), and quantity-of-life is potentially reduced due to an increased risk of premature death secondary to epilepsy. Further challenges faced by veterinarians treating dogs with epilepsy, and owners of affected dogs ARE (i) drug-resistance: a lack of response to currently available AEDs affecting up to 60-86% of treated dogs, and (ii) neurobehavioural changes comorbid with IE, which are poorly understood in dogs but highly prevalent in people with epilepsy. Our own studies have previously found that as few as 14% of dogs become seizure free on treatment, and increases in fear/anxiety and defensive aggression are seen following the onset of IE. These common features make the dog an ideal translational model for spontaneously occurring drug resistant epilepsy. It is clear that there is a need to gain a deeper understanding of IE in the dog to identify risk factors for (i) the development of IE, (ii) the lack of response to available AED therapies, (iii) the development of behavioural changes, and (iv) the interplay between these factors, so that future efforts to treat or prevent IE are targeted and effective. Genetic markers of both epilepsy and AED response have had limited success thus far, may be hard to interpret and account for only a limited proportion of susceptibility. In this study we instead investigate biochemical by-products of metabolic pathways (the 'metabolome') and the microorganisms living in association with the body (the 'microbiome') which reflects the interaction between an organism's genome and its environment and are a better potential indicator of observed characteristics, which can be potentially modified as treatment strategy. Although metabolomic markers of IE have not yet been found, profiles of anxiety have been identified in humans and mice. The microbiome has not yet been studied in IE development, but is involved in the metabolism of AEDs, and changes have been associated with anxiety levels through brain-gut interactions. This research programme will characterise types of disease presentation, the variation in behavioural characteristics, variation in metabolites in the metabolome, and differences in micro-organism populations in the microbiome in dogs with and without IE to identify novel biological markers of both the disease, drug response and behavioural signs (and associations between these factors) that could provide new perspectives on the underlying disease biology and provide new treatment targets. We will study these novel measures in two stages: firstly, a case-control study of breed and age-matched dogs with and without IE recruited from our hospital populations to directly compare profiles; secondly, a prospective cohort study of 5000 puppies from the South of England to identify physical and behavioural profiles measured before seizure onset that act as risk factors for IE development. Urine and faecal samples will be collected for metabolomic and microbiomic analysis. Behavioural testing will characterise aspects of the dogs' underlying affective state, to reveal whether IE and drug-resistance are associated with an underlying characteristic that predisposes individuals to perform anxiety-related behaviours. This novel and comprehensive approach is needed to unravel the mechanisms underlying IE, the occurrence of drug-resistance and behavioural abnormalities.

Animals can modify the shape and mass of their individual limb bones to accommodate both habitual and new, imposed mechanical forces. This is perhaps best exemplified by the increases in bone mass that are seen in the dominant, serving arm of tennis players versus their non-serving, ball-throwing arm - we term the process by which these changes are achieved mechano-adaptation. If we understood the way such mechano-adaptive increases in bone mass were coordinated, we would be able to mimic them and, thus, alleviate any decreases in bone mass that places specific regions of bones at risk of fracture. This risk of fracture is very obvious in ageing bones, which fail to exhibit the capacity for such structural modification in response to imposed forces. There are massive, often hidden, consequences of such failure to adapt, which are increasing dramatically with enhanced longevity and lifestyle choices - the costs to health and society are huge. There is one main reason why we don't understand how bone mechano-adaptation is coordinated. The reason is that until now we have not been able to match microscopic level bone bending in response to imposed forces with the precise location of the ensuing structural increases in bone formation. We have recently made three advances that now make this possible. We have developed: i) a non-surgical model for imposing controllable forces to the tibia in living mice, ii) a means of measuring the extent of bending over the entire surface of small bones, and iii) recently acquired a machine that allows a precise microscopic 3D analysis of where bone is actively being formed. This creates a unique and timely opportunity. It was previously thought that mechano-adaptive processes acted to minimise the 'greatest' bending. We have generated pilot data that have allowed us to predict that, in contrast, bones adapt in order to minimise the 'steepest' local bending gradients on their surface. To test this we will bend some bones in mature mice that we know will adapt by increasing bone formation. To test whether steep bending gradients 'drive' formation we will: i) measure the bending pattern to generate a 'contour map' across the tibial bone surface, while it is being exposed to mechanical forces; ii) produce a 3D picture of the entire tibia describing exactly where bone formation takes place; iii) explore the overall changes in tibial structure by high-power 3D X-ray imaging, and iv) create virtual, digital computer images of the changes induced by these mechanical forces. These studies will determine which specific mechanical force is responsible for promoting bone formation and whether this occurs where bending gradients are indeed steepest. This will be useful if it can be used to modify bones which fail to fulfil their structural load-bearing role, as in ageing. Our pilot data from aged mouse bone are therefore crucial as they show that bending gradients appear less 'steep'; the general magnitude of bending engendered by force increases and the steepest gradients are consequently less severe. Using the methods described above as well as measures of bone quality and cellular responses to mechanical stimulation, we will explore if tibiae in aged mice exhibit a reduced cellular sensitivity to bending forces and/or a reduced mechanical stimulus capable of promoting adaptation. Our pilot studies have also shown that aged mouse bones do not exhibit mechano-adaptation and, intriguingly, that this can be restored to aged bones by prior imposition of a prolonged period without habitual use. We propose to explore the factors that change with this restoration, in the hope that we can identify how to kick-start mechano-adaptation in aged bones and thus alleviate the risk of fracture. Defining the drivers of adaptive increases in new bone formation in a precise 3D manner will also allow future studies to pinpoint the cellular events that are necessary to coordinate mechano-adaptation.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Aquaculture is a large field, with many species of fish and crustaceans being consumed in the UK. Five billion prawns and other decapod crustaceans imported into the UK annually (Crustacean Compassion, 2023) and 400 billion shrimp are farmed in total globally each year (Shrimp Welfare Project, 2023). Consequently, this project focuses on shrimp farming and its relationship with environmental degradation in India. There is little scholarship on this field; most of research is being conducted by NGOs and would benefit from greater academic input. However, despite the lack of attention on the welfare of shrimp and other invertebrates, decapod crustaceans are now legally recognised as sentient by the UK Government through the Animal Welfare (Sentience) Act 2022 after recommendations from Birch et al. (2021). Therefore, the government now has an obligation to ensure that that the 40,000 tonnes of shrimp consumed in the UK each year by retail shoppers alone (Pegg, 2019) are sourced from farms with acceptable welfare standards. Indeed, shrimp are such a large part of the UK diet that they comprise around a fifth of the total value of seafood imports into the UK (Pegg, 2019). Given that welfare in shrimp is not yet fully understood, scholars currently closely conflate environmental conditions and welfare in shrimp farms (Lewit- Mendes, Saugh & Boddy, 2022). Mangroves are commonly cleared to make way for shrimp farms, however, they are vital in creating a sustainable and liveable ecosystem for the shrimp, and there are increasing calls for integrated shrimp-mangrove aquaculture, or silvofisheries, to allow for food production whilst also largely maintaining ecosystem function (McSherry et al., 2023; Ahmed, Thompson & Glaser, 2018). The lack of knowledge on crustacean welfare means it is imperative to not only maintain but also improve mangrove ecosystems and prepare them for the changes that climate change will bring. Further scholarship on producers and the relationship between their livelihoods and mangroves is also warranted.