Posters: Neuroscience Day 2026 | Edinburgh Neuroscience

Full poster titles and abstracts

#	Presenter	Presenter supervisor(s)	Affiliation	Poster title	Poster abstract (max 200 words)
1	Ross Lennen	Tracy Farr	Edinburgh Preclinical Imaging, INCR	Preclinical MRI Facility	A poster giving an overview of recent research projects (neuro and cardio) conducted on our Preclinical MRI Scanner and showcasing the capabilities of the Preclinical MRI Facility.
2	Adrian Thomson	Carmel Moran	Edinburgh Preclinical Imaging, INCR	Preclinical Ultrasound Facility	A poster giving an overview of recent research projects (neuro and cardio) conducted on our Preclinical Ultrasound Scanners and showcasing the capabilities of the Preclinical Ultrasound Facility.
3	Carlos Alcaide	Adriana Tavares	Edinburgh Preclinical Imaging, INCR	Preclinical PET Facility	A poster giving an overview of recent research projects (neuro and cardio) conducted on our Preclinical PET/CT and PET/MR Scanners and showcasing the capabilities of the Preclinical PET Facility.
4	Gianluca Destro	Adriana Tavares	Edinburgh Preclinical Imaging, INCR	Preclinical and Translational Radiochemistry	A poster giving an overview of the radiochemistry work performed to support radiotracer production and development for our preclinical PET research projects, showcasing the capabilities of the Preclinical Radiochemistry Department.
5	Jamie Elliott	Dr Sam Booker & Dr Claire Durrant	INCR	Seizure-like activity and inhibitory synaptic dysfunction in mouse hippocampal slice culture models of amyloid-β pathology	An early neuropathological feature of Alzheimer’s Disease (AD) is dysregulated excitation/inhibition (E/I) balance, the severity of which correlates with cognitive dysfunction. As AD progresses, E/I balance shifts towards excitation, contributing to epileptiform activity in up to half of AD patients. Post-mortem studies have identified that somatostatin-expressing inhibitory interneurons (SST INs), key regulators of E/I balance, are particularly vulnerable in AD brains. However, the early progression of early-stage E/I imbalance and SST IN dysfunction in AD is under-characterised. Here, we employ western blot and single-cell patch-clamp of CA1 pyramidal neurons (PNs) in hippocampal organotypic slice cultures (OSCs) generated from the APP/PS1 and APPNL-G-F models of amyloid-β pathology. In both OSC models, we identify E/I imbalance and increased seizure-like synaptic activity in CA1, which is not explained by excitatory neuron dysfunction or synapse loss. Next, using optogenetic tools to target SST INs, we examine inhibitory synaptic connectivity between SST INs and CA1 PNs in APPNL-G-F OSCs. We identify weakened inhibitory synapses between SST INs and CA1 PNs through OSC aging, which may arise from both pre-synaptic and post-synaptic dysfunction. Together, these results suggest that inhibitory synaptic dysfunction may contribute to E/I imbalance and seizure-like phenotypes in culture models of early amyloid-β pathology.
6	Gaia Brezzo	Barry McColl	INCR, UKDRI	Ontogeny dictates myeloid cell regional composition and survival following ischaemic stroke.	Cognitive impairment is a common and feared consequence of ischaemic stroke with no available treatments. Stroke triggers brain-wide altered myeloid cell profiles at the infarct site and in remote-but-connected brain areas. Determining whether composition and longevity of reactive brain‑resident and infiltrating myeloid cells differ at sites proximal and distal to the primary lesion could inform how brain‑wide connectivity and cognitive function are disrupted after stroke. We induced focal cortical stroke by middle cerebral artery occlusion in adult and aged Ms4a3CreRosaTdT mice, thereby enabling distinction of brain-immigrant GMP monocyte-derived (TdT+) cells from embryonic-derived brain-resident microglia (TdT-). scRNAseq and in situ profiling was conducted up to 3 months post-stroke. GMP monocyte-derived cells, many adopting a macrophage differentiation trajectory (MoDM), were restricted to the infarct area. Conversely, microglial reactivity was evident both local and remote to the infarct, each area defined by distinct spatiotemporal transcriptional states (e.g. cycling, inflammatory, endolysosomal). Lipid processing-enriched macrophages (e.g. Gpnmb, Plin2, Cd36, Trem2, Lpl) transitioned from a MoDM to microglial origin as injury resolution progressed. MoDMs did not engraft in the brain long-term, yet brain-wide reactive microglial populations persisted chronically. These results suggest that acute stroke causes long-lasting brain-wide effects on microglial states spatially linked to brain connectivity.
7	Amelia Beckett	Oliver Teenan, William Cawthorn, and Laura McCulloch	MScR Integrative Neuroscience, CIR, IRR	Investigating Neuro-Immune Signalling in Health, Ageing, and Disease	When the brain encounters stress, two major efferent pathways are activated: the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), driving glucocorticoid, adrenaline, and noradrenaline release to support short-term adaptation. In the spleen, these signals regulate immune cell trafficking, activation, and cytokine production. While acute activation is adaptive, chronic or dysregulated signalling contributes to persistent inflammation and immune dysfunction. However, how splenic neuroimmune signalling is remodelled across physiological stressors, and whether this differs by sex, remains unclear. This project hypothesises that ageing, stroke, and caloric restriction (CR) differentially remodel splenic neuroimmune signalling. Stroke is predicted to drive sustained SNS/HPA activation, ageing to reduce noradrenergic signalling and alter glucocorticoid sensitivity, and CR to induce a more regulated, adaptive profile with reduced stress-axis activity. qPCR analysis of β2-adrenergic and glucocorticoid receptor expression showed no significant differences between groups or sexes in whole spleen tissue. However, preliminary qPCR analysis of isolated lymphocytes revealed differential receptor expression in stroke, indicating cell-specific remodelling not detected at the tissue level. Glucocorticoid ELISA demonstrated significant increases in stroke and CR, but not ageing, further supporting distinct endocrine responses. Ongoing analyses will characterise catecholamine signalling and neuroimmune spatial organisation.
8	Jamey Brewster	Cathy Abbott, Paul Donlin-Asp	INCR, SIDB	Establishing the mechanisms and functions of translation elongation factor isoform switching during neurodevelopment	eEF1A1 and eEF1A2 translation elongation factor isoforms are 92% similar and switch in expression during neurodevelopment. Prenatally, eEF1A1 is ubiquitously expressed; in postnatal brain, eEF1A1 is expressed in glia and axons, and eEF1A2 in neuronal cell bodies. Missense mutations in human eEF1A2 cause a neurodevelopmental disorder (NDD) defined by intractable epilepsy. Establishing the mechanisms governing eEF1A1 and eEF1A2 expression switching may inform genetic therapy for eEF1A2-related NDD. Since eEF1A1 and eEF1A2 3’UTRs are highly dissimilar, and eEF1A1 is enriched in the synaptic transcriptome and translatome, we hypothesise that local translation drives the sub-neuronal compartmentalisation of eEF1A isoforms. We employed RNA-fluorescence in situ hybridisation (RNA-FISH) to reveal that eEF1A1 RNAs are confined to white matter of adult mouse brain, whilst eEF1A2 transcripts are conversely enriched in neuronal cell bodies. In primary neurons, eEF1A1 RNAs are abundant in neurites at 3 days in vitro (DIV) and in axons and dendrites from DIV 7 – 21, whilst eEF1A2 transcripts increase in cell bodies from DIV 7 – 14. Using metabolic labelling with proximity ligation assay for eEF1A isoforms, we show that eEF1A1 specifically is highly translated in dendrites and axons. Our findings strongly suggest that eEF1A isoform compartmentalisation in neurons arises from local translation.
9	Rebekah J. White	Sebastian Greiss	INCR	Tissue-specific proteomics in C. elegans	Caenorhabditis elegans has been extremely valuable in both neuroscience and biogerontology. However, it is challenging to isolate individual tissues, meaning most proteome research explores changes at the whole-body level. We are therefore limited by the ability to study tissue-specific proteome changes. We are developing a robust tissue-specific labelling method for analysis of worm proteomes in a way that has not been possible before. This method will isolate a random sample of proteins in young and old worms for comparative analysis to enable us to determine which specific proteins are associated with the hallmarks of ageing in each tissue. Using genetic code expansion (GCE) technology, we will incorporate a non-canonical amino acid (ncAA) into proteins during translation. GCE traditionally utilises aminoacyl-tRNA-synthetase / tRNA pairs that do not cross-react with endogenous synthetases or tRNAs. Here, we will use tRNA variants that decode sense codons to stochastically label the proteome of tissues where the chosen synthetase/tRNA pair is expressed. We will incorporate ncAAs capable of Click chemistry into worm proteins, then introduce a tagged Click molecule to couple to the ncAA. This will allow us to rapidly and temporally label proteins produced at a chosen time in the desired tissue, and isolate these for further analysis such as mass spectrometry.
10	Yian Guan	Tracy Farr	INCR	Functional connectivity change following stroke in an ovine model.	Promoting recovery after stroke is an unmet need. Extending neuroimaging studies of post-stroke functional connectivity to animal models may help understand mechanisms underpinning plasticity. Twenty-four Merino sheep (2-3yrs, n=12 males and females) underwent middle cerebral artery occlusion and magnetic resonance imaging at baseline and 6 and 28 days post-stroke [resting state=TR/TE: 1590/31ms, 120 volumes]. Data was processed using the FMRIB Software Library and independent component analysis (ICA) generated resting state functional connectivity networks. Connectomes were visualized with BrainNet Viewer. ICA identified activity patterns comparable to the human default mode network at baseline. At 6 days post-stroke, activity within this network increased, while interhemispheric connectivity decreased. This somewhat normalized by 28 days. The connectomes also suggested functional connectivity increased after stroke. Bilateral brain regions with the highest nodal strength at baseline further increased at 6 days, but returned to comparable levels in the intact hemisphere by 28 days. Several lower-ranking subcortical regions showed increased nodal strength in the ischemic hemisphere at 6 days, this was accompanied by decreases in hindbrain structures. Our findings parallel clinical observations and suggest region-specific connectivity redistribution that contributes to post-stroke network re-organization.
11	Mengzhen Arthur Zhang	Prof Nathalie Rochefort	INCR	Reusable reduced-weight Neuropixels implant for stable chronic recordings in small adult mice	Conducting chronic, stable, large-scale in vivo electrophysiological recordings remains a challenge in systems neuroscience, especially for female mice which are usually smaller in size and lighter in weight. To improve inclusivity of female mice in longitudinal neurobehavioural studies using _Neuropixels_ probes, the chronic implant should not only allow long-term stable recordings and be reusable after explantation, but also the weight needs to be further reduced. Here, we present a reduced-weight version of Apollo Implant that inherits all advantages from the original design, and remains stable for weeks despite 20% reduction in weight. We tested this new implant in head-restricted female mice during passive visual stimulation viewing and active navigation in virtual reality. In both conditions, we acquired high-quality units across multiple brain regions for at least three weeks, and the total number stablise to around 100 after one week. Our reduced-weight version of _Apollo Implant_ improves inclusivity and flexibility in longitudinal experiments using Neuropixels without costing data quality.
12	Andrew Lau	Nathalie Rochefort	SIDB PhD Programme	Movie-trained transformer reveals novel response properties to dynamic stimuli in mouse visual cortex	Understanding how the brain encodes complex, dynamic visual stimuli remains a fundamental challenge in neuroscience. Here, we introduce ViV1T, a transformer based model trained on natural movies to predict neuronal responses in mouse primary visual cortex (V1). ViV1T outperformed state-of-the-art models in predicting responses to both natural and artificial dynamic stimuli, while requiring fewer parameters and reducing runtime. Despite being trained exclusively on natural movies, ViV1T accurately captured core V1 properties, including orientation and direction selectivity as well as contextual modulation, despite lacking explicit feedback mechanisms. ViV1T also revealed novel functional features. The model predicted a wider range of contextual responses when using natural and model-generated surround stimuli compared to traditional gratings, with novel model-generated dynamic stimuli eliciting maximal V1 responses. ViV1T also predicted that dynamic surrounds elicited stronger contextual modulation than static surrounds. Finally, the model identified a subpopulation of neurons that exhibit contrast-dependent surround modulation, switching their response to surround stimuli from inhibition to excitation when contrast decreases. These predictions were validated through semi-closed-loop in vivo recordings. Overall, ViV1T establishes a powerful, data-driven framework for understanding how brain sensory areas process dynamic visual information across space and time.
13	Anton Kinsler O'Sullivan	Professor Nathalie Rochefort	INCR	A novel projection from the Hypothalamic Supramammillary Nucleus to the Visual Cortex	Internal states such as hunger and arousal can influence visual processing. The hypothalamus regulates internal state, yet little is known about its relationship to the visual cortex. However, a direct neuronal projection from the hypothalamic Supramammillary Nucleus (SuM) to the primary visual cortex (V1) has been described. This study aims to characterise the cell types connecting SuM to V1, establish if a reciprocal V1 to SuM projection exists and investigate the wider connectome between the SuM and the isocortex. To test this, transgenic mice were used in combination with viral tracing and fluorescent antibodies. The majority of SuM-V1 projecting cells are homogenous, expressing Glutamate, GABA, NOS1 among other neurochemicals. Preliminary evidence shows no direct reciprocal projection from V1 to SuM, however the SuM receives inputs from higher order association cortices such as the Anterior Cingulate Cortex. Altogether, these results offer insights into the anatomy and connectivity between SuM, V1 and higher cortical areas, establishing a foundation for future work on the function of these connections with regard to integrating internal state with visual experience.
14	Mingshuai Zhu	Nathalie Rochefort	MScR Integrative Neuroscience	Impaired Neural Coding of Naturalistic Movie in Syngap1 HET mice	SYNGAP1 haploinsufficiency is a highly penetrant cause of Autism Spectrum Disorder (ASD) and Intellectual Disability (ID), yet its impact on cortical coding under naturalistic conditions remains unclear. Here, we investigated neural coding of dynamic visual stimuli in Syngap1 heterozygous (HET) mice using two-photon calcium imaging in primary visual cortex (V1) during natural movie presentation. Neural activity was mapped to stimulus features using a contrastive embedding approach (CEBRA) trained on DINO-based visual embeddings, enabling quantification of decoding accuracy as a measure of coding precision. We found that HET mice exhibit significantly impaired decoding accuracy compared to wild-type controls. This suggests a deficit in sustained encoding of complex visual information. Notably, administration of guanfacine, an α2A-adrenergic receptor agonist clinically used to treat ADHD, partially rescued decoding performance in HET mice, with the strongest effects observed during early stimulus processing. These findings indicate a temporal dissociation in coding deficits and support a role for noradrenergic modulation in stabilising cortical representations. Given the prevalence of atypical sensory processing in ASD and ID, our results provide a mechanistic link between SYNGAP1 mutations, neuromodulatory dysfunction, and impaired sensory coding. This work highlights the translational potential of targeting noradrenergic systems to restore circuit function in neurodevelopmental disorders.
15	Kellie Horan	Anna Williams, Don Mahad	Centre for Regenerative Medicine, IRR (PhD Regenerative Medicine)	Mitochondrial dynamics are selectively altered in parvalbumin neurons during grey matter demyelination	The quest for neuroprotective treatments in MS is key to avoid neurodegeneration. Demyelination of grey matter (GM) correlates with worsening disability. Some neurons, such as parvalbumin neurons (PV), are particularly vulnerable. They are highly myelinated and metabolically active, relying on mitochondrial oxidative phosphorylation. We hypothesised that unique changes in PV neuron mitochondria in response to demyelination underlie their selective vulnerability, and that manipulating this may identify neuroprotective targets. To test this, we used a mouse model of focal GM demyelination. We applied 3D-confocal microscopy to assess mitochondrial morphology, identifying increases in mitochondrial volume and branching only in PV neurons, suggesting cell-type-specific increases in mitochondrial fusion. Concordantly, we noted upregulation of mitochondrial fusion and downregulation of mitochondrial fission proteins, consistent with an early protective response. Conversely, in human post-mortem MS GM lesions, surviving PV neurons showed reduced mitochondrial size and a shift towards fission, suggesting temporal loss of this response in chronic demyelination. We manipulated mitochondrial dynamics first locally using a small molecule, and then cell-type-selectively using a Cre-dependent AAV approach in PV neurons. Overall, our findings suggest that temporal changes in mito-dynamics contribute to the selective vulnerability of PV neurons in MS and highlight mitochondrial pathways as potential neuroprotective targets.
16	Julia van de Korput	David Lyons and Anna Williams	Translational Neuroscience PhD Program, INCR, IRR, MS Society Edinburgh Centre for MS Research	Myelin sheaths in the central nervous system can withstand damage and dynamically remodel	Myelin damage is a hallmark of several neurological disorders including Multiple Sclerosis (MS). While research predominantly addresses preventing demyelination and neurodegeneration, the early stages of acute myelin loss from axons remain poorly understood. Here we show that early damage in zebrafish and rodent demyelination models is characterized by myelin swelling. Using live imaging, we demonstrate that myelin swelling does not always lead to myelin loss, and that swellings can sometimes resolve, allowing sheaths to remodel. Increased neuronal activity during early demyelination exacerbates myelin damage, whereas reducing neuronal activity mitigates myelin swelling in both zebrafish and mice. In human MS tissue, myelin swelling is also dynamic, and prominent around active and chronic active lesions, supporting the idea that swellings represent an early stage of active demyelination prior to myelin loss. Ongoing investigations aim to examine how ion movement, fluid buffering and interactions with other cell types contribute to myelin swelling dynamics. Together, our data indicate that myelin swelling is a conserved feature of demyelination and that damage to myelin sheaths can resolve, opening opportunities for targeting human disease.
17	Jade Lucas	Bhuvaneish Selvaraj, Colin Smith, Siddharthan Chandran	UK DRI; Euan MacDonald Centre for Motor Neuron Disease Research; Anne Rowling Regenerative Neurology Clinic; INCR	Assessing the Cellular and Pathological Determinants of Disease Duration in ALS using Multiparametric Imaging Mass Cytometry analysis.	There is a marked, but underappreciated, heterogeneity in ALS disease duration. Despite the median survival of 3 years from symptom onset, 10 – 20% of people with ALS survive longer than 8 years (long survivors) and 10% of people live for less than two years (short survivors). Whilst clinical factors such as younger age-of-onset and bulbar site-of-onset are associated with long and short survival, respectively, the cellular and pathological factors determining the rate of disease progression remain poorly understood. Here, we have successfully established an Imaging Mass Cytometry (IMC) antibody panel of >30 markers enabling quantitative and spatially resolved analysis of the neurogliovascular unit and disease pathology in spinal cord and BA4 post-mortem tissue. Utilising this high-dimensional profiling technique on post-mortem tissue from 7 short sALS survivors, 6 long sALS survivors and 6 healthy controls, we have identified cellular and pathological features associated with disease duration in ALS. Preliminary analysis has highlighted a lower percentage of ChAT-positive cells in long survivors, suggesting that overall neuronal density may not correlate directly with survival. Additionally, we have identified alterations in other cell types, pointing towards glial or inflammatory contributions. Ongoing analysis using spatial and neighbourhood profiling will further elucidate the cellular interactions and microenvironments that distinguish long from short survivors. Combined with complementary snRNA-seq and bulk proteomics analysis, these insights may aid in identifying mechanisms of resilience and open new avenues for therapeutic intervention and prognostication.
18	Ruqi Zhang	Karen Horsburgh	INCR	Longitudinal two-photon imaging of microglia and microvasculature in mouse white matter in health and disease	Longitudinal two-photon imaging of microglia and microvasculature in mouse white matter in health and disease Ruqi Zhang1, Juraj Koudelka1,2, Giles Hardingham1,2, Emina Hayashida1, Eleni Papachristoforou1,2, Emily Schreurs1, Harris Papaonisiforou1, Owen Dando1,2, Sophie Calderwood1, Daniel Soong1, Barry McColl1,2, Axel Montagne1,2, Raj Kalaria3, Catherine Hall4, Jill Fowler1, Karen Horsburgh1 1Institue for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, UK. 2UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK. 3Translational and Clinical Research Institute, University of Newcastle, Newcastle Upon Tyne, UK. 4School of Psychology, University of Sussex, East Sussex, UK. Background: White matter (WM) abnormalities, caused by cerebral hypoperfusion, are a key characteristic of vascular cognitive impairment and dementia (VCID). Evidence implicates microglia in vascular-mediated white matter dysfunction. To investigate microglia-vascular interactions in white matter we developed a method to image using in vivo two-photon (2P) imaging and applied in a model of VCID. Methods: Subcortical cranial windows were implanted in Macgreen (CSF1REGFP/+) mice that underwent awake 2P imaging. Spectral confocal reflectance (SCoRe) microscopy was used to verify imaging in white matter. Red blood cell (RBC) velocity, vessel diameter, vascular density, microglial density, total microglial number, were quantified. The effect of bilateral carotid artery stenosis (BCAS), a model of VCID, on vascular and microglial measures was undertaken before and after BCAS (or sham) surgery using 2P imaging. Results: Vascular and microglial measures were stable (up to 10 weeks) after cranial window implantation in Macgreen (CSF1REGFP/+) mice. Following BCAS, RBC velocity decreased in white matter but unchanged in shams. Microglial numbers increased post- BCAS and related to reduced RBC velocity. Conclusions: A reliable and robust 2P method to measure subcortical white matter vascular and microglial metrics was established and the utility of this approach highlighted in a model of VCID.
19	Emily Payne	Sally Till	Wellcome Trust Translational Neuroscience	Behavioural measures of anxiety in rat models of Fragile X	Anxiety is a psychiatric condition with cognitive, behavioural, and physiological symptoms. Though anxiety is generally thought to be induced by external stressors, people with genetic neurodevelopmental disorders like Fragile X syndrome (FXS) are significantly more likely to develop anxiety. This leads to questions about how anxiety emerges in these populations, as they may have a genetic predisposition to anxiety, but they may also be exposed to environmental stressors from a young age. Using behavioural anxiety paradigms in rat models of FXS, I find that there may be an interaction between juvenile experience and genotype that shapes an animal’s behaviour as an adult. Wild-type animals tend to show greater modulation of behaviour with experience, while FXS model animals tend to be less affected by juvenile experiences. This may have implications for the importance of early development in shaping anxiety-like behaviours in adult animals.
20	Scott Yun Ye	Rebecca Jordan	SIDB PhD Programme	LOCUS COERULEUS SIGNALS SIGNED VISUOMOTOR PREDICTION ERRORS THAT DEPEND ON TASK CONTEXT	The locus coeruleus (LC) is thought to dynamically regulate learning rates across the brain by signalling unexpected uncertainty – violations of predictions beyond the expected range. A possible way to compute unexpected uncertainty globally is via the summation of prediction errors across modalities, alongside a subtraction of the expected rate of error. Consistent with this idea, the LC displays prediction error-like responses to a variety of stimuli, including rewards and visuomotor mismatche s. If these responses result from computation of unexpected uncertainty, we expect that: 1) LC responses will generalise across modalities and increase when coincident errors occur, and 2) persistent increases in the ongoing rate of errors (i.e., high uncertainty) should become expected and have a subtractive influence on LC responses. We tested these ideas using fiber photometry recordings of LC calcium activity while mice were engaged in a range of different virtual reality (VR) paradigms. We found several phenomena in LC activity that are inconsistent with these predictions. First, LC responses to positive and negative visuomotor mismatch stimuli are heterogeneous across imaging sites. Second, increasing the uncertainty in visuomotor coupling results in a negligible short-term impact on LC mismatch responses. Finally, LC visuomotor mismatch responses are context-dependent, reducing in amplitude in the context of a spatial rewarded task. In sum, our results are inconsistent with the idea that the LC signals a global measure of unexpected uncertainty, and are more consistent with heterogeneous LC populations that signal signed prediction errors.
21	Johnny Tam	Suvankar Pal, Oliver Watts, Siddharthan Chandran	INCR	Beyond stealing cookies: validation of novel picture description and delayed recall task stimuli for automated cognitive assessment from speech	Background: Picture description tasks using the Cookie Theft image show limitations in repeatability and cultural acceptability. We developed a framework for multiple novel stimuli for this task, enhanced by a delayed recall component, tailored for automated speech assessment; and deployed in digital health observational studies. We report preliminary validation comparing the novel stimuli with the Cookie Theft picture. Methods: People living with Alzheimer’s disease (AD), mild cognitive impairment (MCI) and neurologically healthy controls completed the task using a smartphone app every 2 months over 2 years. Acoustic (eGeMAPSv02) and linguistic (spaCy) features were extracted. For delayed recall, distance metrics were calculated between features of the two recordings. Results: 98 participants (24 AD, 10 MCI, 64 controls) contributed 340 assessments. Novel stimuli elicited longer recordings (16.8 seconds, p<0.001), with no difference between new stimuli (p=0.61). Acoustic and linguistic features predicted cognitive status (impaired vs control, AUC 0.825, p=0.001) and diagnosis (AD vs MCI vs control, MAE 0.411, p=0.035). Novel stimuli outperformed the Cookie Theft Image in predicting cognitive status (AUC 0.906 vs 0.772). Jensen-Shannon distance of linguistic features predicted MoCA scores with MAE 3.829 (12.8% of range, 95%CI 2.848-4.580). Conclusions: Our findings support our novel stimuli as additions to the picture description task. The added delayed recall may boost performance by including a memory dimension. Our work paves way for accurate and scalable automated cognitive assessments using more sophisticated speech algorithms.
22	Tom Pratt	none	INCR	The 16p11.2 microdeletion enhances gene expression variability between human IPSC derived forebrain interneuron progenitor cells in culture.	The 574 kilobase pair 16p11.2 microdeletion raises a person’s odds for neurodevelopmental and energy balance conditions, particularly autism and obesity. There is considerable clinical heterogeneity and how much this reflects genetic versus environmental factors is unclear. Perturbation of interneurons is implicated in 16p11.2 phenotypes prompting investigation of how the 16p11.2 microdeletion impacts their development. We differentiate human induced pluripotent stem cells (IPSCs), isogenic except for heterozygous 16p11.2 microdeletion to minimise confounding effects of genetic background, to ventral telencephalic interneuron progenitor fate in 2D culture and use single cell RNA sequencing to obtain single cell transcriptome populations for comparative bioinformatics. Hundreds of transcripts are differentially expressed and many associate with cell signalling, chromatin, neurodevelopmental conditions including autism, and obesity. Pertinently, we find that transcript level variation is significantly greater in 16p11.2 heterozygous progenitors than their isogenic wild type counterparts and this holds for sets of genes comprising regulons, gene-sets functionally connected by transcription factor regulation, and for randomly selected gene-sets indicating that the 16p11.2 locus itself has a genome-wide property in stabilising transcription levels between cells. Regulons with greatest increased variation in 16p11.2 heterozygous progenitors exhibit strong enrichment for cell cycle related genes, resonating with our earlier finding of increased cell cycle variability between 16p11.2 heterozygous organoids, and many are regulated by transcription factors associated with autism and/or obesity enforcing the idea that unusual transcriptional variation itself contributes to phenotypes.
23	Samuel Heczko	Wai Kit (Calvin) Chan, David Price	Wellcome Translational Neuroscience Phd programme	Multiomic ATAC + RNA snSeq reveals Pax6 dependent chromatin accessibility modules	Knocking out the master transcription factor Pax6 leads to the neurogenesis of atypical inhibitory cells in the dorsal telencephalon, linking it to excitatory/inhibitory balance, relevant for multiple neurodevelopmental conditions. The imbalance stems from altered fate competence of neural progenitor radial glia (RG) cells. Here, we characterise the transcriptomic and chromatin accessibility programmes associated with the broadened differentiation potential. We generated an ATAC + RNA multiomic single-nuclei dataset from E14 conditional brain specific Pax6 knock-out (−/−, cKO) and control (+/−) mouse brains. Across three biological replicates, we obtained 33,117 high-quality, co-clustered, and annotated cells, including 8,321 RG cells. Multiomic analysis reveals a distinct phenotype across both data modalities, with the RNA phenotype closely mirroring previous work. Topic analysis of the ATAC data reveals sets of co-occurring DNA regions only available in control cells, and the lack of analogous order in the cKO cells. We characterise the motif content, nearby genes, and genomic locations of Pax6-dependent availability patterns. Moreover, we find a more spread-out distribution of ATAC features in cKO cells. Overall, our results demonstrate that Pax6 promotes synchrony in RG chromatin accessibility, and that its removal leads to disorder in transcriptional regulation, with specific DNA patterns particularly affected.
24	Khalid Salamat	Fiona Houston	The Roslin Institute	Identification and validation of novel blood-based biomarkers for monitoring progression of prion disease	One of the major challenges in controlling infectious prion diseases is the prolonged asymptomatic incubation period, during which onward transmission can occur. Reliable diagnostic assays for detecting infection in accessible samples (e.g., blood, urine) during preclinical stages remain lacking. Most current approaches target misfolded prion protein (PrPSc) as a surrogate marker. This study aimed to identify and validate novel blood-based protein biomarkers associated with early prion disease pathogenesis. Using archived blood samples from orally infected sheep with BSE, we used mass spectrometry to identify differentially expressed proteins in pooled plasma collected at the midpoint of incubation. Selected candidates, including those reported in literature, were validated using semi-quantitative Western blotting. Age-related expression changes were first assessed in longitudinal samples from healthy controls. Candidate proteins were then analysed in orally infected sheep (n = 9) at three stages: pre-infection, mid-incubation (12 months post-infection), and clinical disease, relative to age-matched controls. Our study demonstrates the potential for using proteomic approaches to identify novel biomarkers of prion disease in an unbiased manner. Identification of novel biomarkers will not only aid the development of tests for early diagnosis of prion diseases, but can also facilitate the development and early deployment of potential treatments.
25	Shahd Qutifan	Ross Jones, Tom Gillingwater	PhD of Anatomical Sciencies	Comparative Ultrastructure of the NMJ in Humans and Mice using TEM	The neuromuscular junction (NMJ) is the synaptic connection between the terminal end of a lower motor neuron and a skeletal muscle fibre. At this specialized synapse, the motor neuron action potential is converted to skeletal muscle fibre contraction. The morphology and physiology of the NMJ is known to be altered in neuromuscular pathologies and in variety of stressors such as inactivity. However, the human NMJ is still relatively underexplored compared to other species, such as rodents, and the ultrastructure of the human NMJ is even less quantified. Here, we have undertaken a comprehensive study of the ultrastructure of the human NMJ using transmission electron microscopy (TEM) and compared it to that of the mouse NMJ, one of the most well-studied of mammalian synapses. This work presents our reference data to date.
26	Laura Bayón Cordero	David Lyons	INCR	Astrocyte-oligodendrocyte interactions in the regulation of myelin damage	Myelin disruption is the defining feature of demyelinating diseases such as multiple sclerosis (MS), but little is known about the mechanisms driving progression from myelin damage to complete loss. In the central nervous system, astrocytes communicate with oligodendrocytes through direct intercellular coupling and may be key to preserve myelin integrity. This project aims to investigate how astrocyte-oligodendrocyte interactions influence myelin damage progression using high-resolution live imaging in zebrafish genetic models of demyelination. Astrocytes establish close contacts with myelin sheaths in the zebrafish spinal cord and maintain these interactions upon demyelination. Notably, our findings show that individual astrocytes undergo dynamic changes during early demyelination. We observed an increased presence of transient swellings in astrocytes near disrupted myelin, suggesting an active role in buffering ions or fluid from damaged sheaths. Based on these results, we will focus on the role of gap junction-mediated communication between astrocytes and oligodendrocytes after myelin damage. Using fluorescent transgenic reporters for connexin 43 (astrocytes) and connexin 47 (oligodendrocytes), we will track gap junction distribution and assess their contribution to myelin integrity through pharmacological disruption. This work will define the relevance of astrocyte support to oligodendrocytes during early myelin damage and identify novel targets to prevent myelin loss.
27	Inés Jiménez Pulido	Lida Zoupi and Rafael Almeida	INCR, EastBIO	Development of a genetic toolkit to modulate vertebrate myelination in a neuron subtype-specific manner	In the central nervous system, oligodendrocytes wrap axons of certain neuron subtypes with a specialised cell membrane, myelin. Myelin insulates the axons, enabling saltatory conduction of action potentials; other roles of myelin include ion buffering, trophic support, and the transfer of antioxidant molecules to the underlying myelinated axon. Interestingly, the pattern of distribution of myelin varies across neurons, suggesting that myelination might affect neuronal integrity and function in a subtype-specific manner. To date, however, modulations affect myelination and/or oligodendrocyte development as a whole, affecting multiple neuron subtypes at once. We therefore have little insight into the regulatory properties of myelin for individual subtypes in vivo. To study this, we first need to modulate the myelination of only specific axons in an otherwise intact central nervous system. With this aim, we are selectively overexpressing in our neurons of interest molecules that have been previously shown to inhibit myelination. We use the Gal4-UAS system in zebrafish and the Cre-loxP system in mice. We are quantifying the degree of myelin inhibition provided by each candidate molecule to then assess the health and function of axons with modulated myelin. This will enable us to characterise the role of myelin on specific neuronal subtypes.
28	Phoebe Lyster-Binns	Dr Rafael Almeida	INCR	Glial paranodal protein dynamics during myelin development in vivo	A key component of the axon-myelin interface are paranodes where glial neurofascin 155 (NF155) binds axonal contactin 1 and caspr to adhere myelin to the underlying axon. While the axonal components are well studied, the regulation of the only glial component, NF155, during myelination remains unclear. To investigate its dynamics and regulatory mechanisms, we engineered novel knock-in zebrafish tagging endogenous nfascb, the homologue of NF155, with GFP. Longitudinal in vivo imaging revealed nfascb clusters at the edges of myelin sheaths as soon as they form. Once established, there is little change in the size and density of the clusters over time. Remarkably, despite this stability, there is continued nfascb delivery to paranodes, suggesting the clusters remain dynamic as sheaths grow. To identify novel regulators of nfascb dynamics, we are now using GFP based pull-down proteomics. Our work reveals unexpected paranode dynamics during myelin development.
29	Sophie Siems	Rafael Almeida	INCR	How does paranodal adhesion mediate myelin formation and repair ?	Accurate myelination is crucial for efficient neuronal circuit function, as the amount and distribution of myelin around an axon directly influence neurotransmission. This is especially evident in multiple sclerosis (MS), where regenerated myelin sheaths are often thinner, shorter, or misdirected, failing to support normal nerve function. However, the molecular mechanisms regulating myelin growth and repair remain poorly understood. Recent studies suggest that adhesion proteins at the axon-myelin interface regulate myelin growth and targeting, as their disruption produces myelin defects similar to those in MS. Yet, how these proteins are dynamically regulated to ensure accurate myelination is unknown. To address this, we developed a reporter knock-in zebrafish for nfascb (nfascb-EGFP), a critical myelin adhesion protein. This model allows real-time visualisation of endogenous nfascb at single-cell resolution and reveals nfascb clusters at the edges of mature myelin sheaths. In addition to visualising endogenous proteins, we used nfascb-EGFP fish to identify nfascb binding partners via ex vivo immunoprecipitation. In parallel, we established a zebrafish line that enables proximity labeling of GFP-tagged proteins in oligodendrocytes. Combined with our nfascb-GFP line, this approach allows us to identify molecular interactors of nfascb in vivo that may serve as key regulators of adhesion formation, and thereby support accurate myelin growth and repair.
30	Yann A. Dubos	Dr. Rafael G. Almeida	INCR	How do axons release neurotransmitters away from synapses?	It is well-established that synapses are specialised sites of neurotransmitter release. Nonetheless, some neurons release neurotransmitters from sites lacking pre-synaptic specialisations (asynaptic neurotransmission), for example along the axon trunk of glutamatergic upper motor neurons. Previous work suggests this axonal neurotransmission signals to nearby glia, challenging the notion that neurotransmission is confined to rapid, point-to-point “wiring.” How axons regulate neurotransmitter vesicle fusion at appropriate times and places remains unknown. I hypothesise that, like synaptic release, asynaptic axonal neurotransmitter release is regulated by calcium and mediated by SNARE proteins, but that there exist differences in the protein isoforms and/or calcium sources involved. Understanding these putative differences in release mechanisms would enable us to manipulate one or the other communication axis specifically, in turn clarifying their respective circuit functions. Here, I describe a non-invasive, in vivo imaging-based approach to tackling this question. Leveraging advances in genetically encoded fluorescent reporters and the zebrafish model, I can simultaneously observe synaptic and asynaptic neurotransmission, in real-time and at single-neuron resolution, within functional and intact circuits. Combining this with pharmacological and genetic manipulation of candidate regulators of axonal neurotransmitter release, I aim to shed light on the various means neurons use to communicate with their neighbouring cells.
31	Katy Marshall-Phelps	Rafael Almeida	ONCR	In vivo mapping of neurotransmitter release along myelinated CNS axons	Synaptic neurotransmission is essential for neuronal communication and circuit function. However, neurons can release neurotransmitters outside of conventional synapses, including along axons. The significance of this axonal release remains unclear, although emerging evidence suggests an important role in how neurons communicate with glia. Using zebrafish, we have optimised two genetically encoded fluorescent reporters to visualise neurotransmitter release along myelinated axons in vivo. Using an extracellular glutamate sensor (iGluSnFR4s) and reporter of synaptic vesicle release (SypHy), we show that glutamate release occurs not only at synapses but also frequently along myelinated axons. Axonal glutamate transients exhibit distinct kinetics compared to synaptic events, with lower frequencies and reduced peak amplitudes, indicating mechanistic differences between synaptic and axonal modes of release. Spatial analyses reveal a significant enrichment of vesicle fusion at nodes of Ranvier, the unmyelinated gaps between adjacent myelin sheaths, suggesting that axonal neurotransmission is spatially organised rather than stochastic. Together, our findings identify axonal neurotransmitter release as a common and spatially patterned feature of myelinated axons, supporting a role in local neuron-glia signalling.
32	Eleni Tsoukala	Lida Zoupi	INCR, SIDB	Fragile X messenger ribonucleoprotein is dispensable for developmental myelination and axonal function in the corpus callosum	Fragile X syndrome (FXS) is a prevalent syndromic neurodevelopmental disorder, caused by loss of functional fragile X messenger ribonucleoprotein (FMRP), encoded by the fragile messenger ribonucleoprotein 1 (Fmr1) gene. FMRP is expressed in neurons and all glial cells, including oligodendrocytes. Oligodendrocytes produce myelin, a membrane that ensheathes the axons, enabling fast transmission of neuronal signals (action potentials, APs), through the formation of the nodes of Ranvier. The AP conduction velocity (CV) is affected by both axonal and myelin properties. We and others have previously shown impaired myelination in FXS, but the functional implications are unknown. We hypothesized that FMRP is important for myelination and axonal function, predicting that its loss would result in myelination impairments and decreased action potential conduction velocity (AP CV). Using histological and ultrastructural techniques, we assessed developmental myelination in FXS (Fmr1 KO) rats. We also used compound action potential recordings to assess axonal function. Our findings showed that the abundance of myelinated axons, myelin thickness, and axonal diameter were unaffected in Fmr1 KO rats. Additionally, the length of the nodes of Ranvier and AP CV were comparable between genotypes. Overall, our findings suggest that FMRP is dispensable for typical developmental myelination and function.
33	Paul Rignanese	Peter Kind	OpenSourceNeuro	Spikeling : An open-source hardware implementation of spiking neurons for neuroscience teaching	Hands-on electrophysiology is foundational to neuroscience education, yet access remains uneven due to cost, logistical hurdles, and limited availability of biological preparations. Spikeling is an open-source neurophysiology teaching platform that makes electrophysiology concepts accessible, reproducible, and adaptable in university courses through a configurable hardware–software system. A central goal is to operationalize open science in teaching and method development. By releasing hardware designs, firmware, and analysis tools under open licenses, Spikeling enables transparent inspection of assumptions, replication across institutions, and community-driven improvement. This openness is particularly important in academia, where reproducibility, methodological literacy, and equitable access to research-grade concepts are increasingly recognized as core educational outcomes. In teaching settings, Spikeling supports inquiry-based laboratory activities that bridge theory and practice. Students can explore excitability, thresholds, adaptation, and input–output relationships; implement stimulus paradigms; and export recordings for quantitative analysis—mirroring the logic of patch-clamp–style experiments without the logistical barriers of live preparations. Instructors can tailor activities from introductory neurophysiology to advanced computational neuroscience modules, while the open design encourages learners to interrogate and modify the system itself as part of the scientific process. By lowering barriers and making methods transparent, Spikeling strengthens both neuroscience training and open research culture.
34	Jessica Willshaw	Patricio Opazo	UK DRI	Combining miniscope and two-photon microscopy to investigate the physiological role of dendritic spine loss and compensation in hippocampal place cells in vivo	Alzheimer’s disease (AD) is characterised by synapse loss which strongly correlates with cognitive decline, however the neuroprotective mechanisms implemented by the brain to compensate for this loss are unknown. In the lab, we recently developed tools to artificially eliminate dendritic spines and identified a two-stage structural synaptic compensatory response: the enlargement of surviving spines followed by the regeneration of new spines. The aim of this project is therefore to determine the physiological relevance of synaptic compensation in freely moving animals. To that end, here we present a novel hybrid imaging approach that combines one-photon miniscope calcium imaging to identify active place cells in CA1 during spatial behaviour, with benchtop two-photon microscopy for high-resolution imaging of dendritic spines in the same neurons. These techniques can be used to visualise and eliminate dendritic spines in the brain which will allow us to investigate the effects of synaptic loss and compensation on the function of behaviourally relevant neurons in the context of AD models.
35	Laura Oliveira	Lida Zoupi	INCR	Myelination deficits in the somatosensory cortex of Fmr1 KO mice	Fragile X Syndrome (FXS) is a neurodevelopmental disorder resulting from the lack of the protein FMRP due to the transcriptional silencing of the FMR1 gene. FXS is one of the leading single gene causes of autism. Individuals present with intellectual disability, autism, sensory hypersensitivities and epilepsy amongst other comorbidities. FMRP is ubiquitously expressed throughout the brain. Neuronal defects have been widely studied in rodent models of FXS, with neuronal excitability and network dysfunction in the somatosensory cortex contributing to altered sensory processing in FXS. Myelin is an insulating membrane formed by oligodendrocytes that ensures the fast and efficient transmission of neuronal signals. Whilst altered myelination has been reported in FXS individuals, rodent models and iPSC-derived oligodendrocyte cultures, the contribution of oligodendrocytes to sensory phenotypes in FXS is unknown. I have assessed oligodendrocyte lineage cell numbers and myelination in the somatosensory cortex of the Fmr1 knock-out mouse. I have found a 29% reduction in mature oligodendrocytes and a 17% increase in oligodendrocyte precursor cells in Fmr1 KO relative to wild-type mice, which was accompanied by a 40% reduction in myelination. Ongoing experiments aim to establish if the observed myelination phenotype and well-known neuronal function defects can be recovered by pro-myelinating drugs.
36	Uffaq Mastoor	Jay Shetty, Susana R. Louros, Javier Escudero, Catherine Crompton	Translational Neuroscience PhD programme	Prognostic value of Interictal Epileptiform Discharges on EEG for Neurodevelopmental outcomes in Early-Onset Epilepsy: A Systematic Review	Background: Children with early-onset epilepsy (seizure onset ≤5 years) are at elevated risk of adverse neurodevelopmental outcomes, including cognitive impairment, intellectual disability, and autism spectrum features. Seizure burden alone provides limited prognostic information. Interictal epileptiform discharges (IEDs), spike or sharp-wave complexes occurring between clinical seizures on electroencephalography (EEG), are common in paediatric epilepsy and may reflect brain network instability relevant to neurodevelopment. Whether interictal EEG features recorded in early childhood are associated with long-term neurodevelopmental outcomes remains unclear. Methods: A systematic review was conducted in accordance with a prospectively registered protocol (PROSPERO: CRD420251162420) and reported per PRISMA 2020 guidelines. MEDLINE, Embase, PubMed, PsycINFO, and Scopus were searched from 1966 to October 2025. Longitudinal studies examining interictal EEG features in children with epilepsy onset ≤5 years, with neurodevelopmental outcomes assessed ≥12 months after baseline EEG, were eligible. Risk of bias was assessed using QUIPS; certainty of evidence using GRADE. Results: Of 1,613 records identified, four longitudinal studies met inclusion criteria (epilepsy contexts: infant-onset focal epilepsy, Sturge–Weber syndrome, epileptic encephalopathies, cryptogenic generalised epilepsies). Across all four studies, greater severity or disruption of interictal EEG activity showed a directional association with poorer neurodevelopmental outcomes. All four studies were rated at moderate to high risk of bias. Certainty of evidence was low to very low across all outcome domains. Conclusions: Directional evidence links interictal EEG severity to neurodevelopmental outcomes in early-onset epilepsy, but the evidence base is, however, too sparse, insufficiently standardised, and of too low methodological quality to support definitive prognostic inference. Standardised, state-resolved IED metrics and harmonised outcome batteries are needed to clarify the prognostic role of interictal activity in early-onset epilepsy.
37	Nina Diviza	Prof Saturnino Luz, Dr Angela Roberts, Dr David Breen	Precision Medicine	Conversational Interaction as a System: A basis for Personalised Intervention in Parkinson’s Disease	PD affects everyday communication. Conversational difficulties reflect interactions between motor, cognitive, emotional, and contextual factors. When evaluating conversational interactions, studies often draw on frameworks developed in studies of dementia or aphasia. However, the manifestation of communicative symptoms in PD differs substantially, making it essential to disentangle disorder-specific impairments and to examine how targeted improvements in these domains may enhance conversational performance. Conversely, qualitative approaches provide an in-depth understanding of conversational barriers, facilitators, and interactional strategies. However, these methods do not typically exploit objectively observable signals. In this research we explore a system-level representation of conversational interaction that constrains data collection, annotation, and feature-extraction choices to align with measures of conversational outcome.
38	Dr Eleni Papachristoforou	Prof Karen Horsburgh	INCR	Microglia-Endothelial Cell Axis in Relation to White Matter Disease Progression in VCID	Background: White matter abnormalities driven by vascular dysfunction are a major determinant of vascular cognitive impairment and dementia (VCID). Substantial evidence implicates disruption of the microglia-microvascular endothelial cell axis in the development of white matter injury and cognitive decline but as yet the mechanistic links remain to be defined. To address this, we are investigating microglia-microvascular endothelial cell heterogeneity and alterations in intercellular communication in relation to white matter (WM) abnormalities in VCID using single-nucleus RNA sequencing approaches. Methods: We performed snRNA-seq using the 10x Genomics platform to human frontal cortical white matter tissue obtained from a clinically characterised post-mortem cohort (Cognitive Function After STroke of aged individuals with (n=10) and without (n=8) VCID, alongside age- and sex-matched controls (n=8). Results: Our data revealed cellular heterogeneity within vascular/vessel-related cells and microglia across clinical groups in CogFAST. Distinct transcriptional differences were observed between control, with and without VCID, supporting disease-associated alterations particularly within microglial populations. To provide further mechanistic insight ligand-receptor interactions between microglia and endothelial cells within the WM will be investigated and how these may be altered in VCID. Conclusions: This human transcriptomic dataset has enabled us to resolve, at the single cell level, phenotypic heterogeneity of microglia and endothelial cells. The goal is to define their crosstalk within WM and how these may change with WM abnormalities. Our approach provides a platform to identify conserved microglial-vascular pathways that may drive cerebrovascular-mediated white matter disease and cognitive decline in VCID.
39	Juraj Koudelka	Prof. Karen Horsburgh, Prof. Giles Hardingham	INCR; UKDRI	Investigation of microglia dynamics and state in white matter in a mouse model of VCID	Background: Chronic cerebral hypoperfusion contributes to white matter dysfunction, driving vascular cognitive impairment and dementia (VCID). Altered microglia homeostasis and chronic microvascular inflammation are emerging as key instigators of white matter damage. To investigate microglial responses to reduced cerebral blood flow we combined 2-photon imaging and single-cell RNA sequencing (scRNAseq) in a mouse model relevant to VCID. Methods: A mouse model of VCID was studied in which bilateral carotid artery stenosis (BCAS) causes cerebral hypoperfusion leading to white matter damage and cognitive impairment. Using in vivo 2-photon microscopy in awake CSF1R-eGFP mice, we repeatedly measured microglia dynamics and vascular haemodynamics within white matter over time. In parallel studies we performed scRNA-seq in isolated white matter to assess microglial state. Results: BCAS reduced RBC velocity, which was accompanied by a modest increase in microglia expansion. Ongoing analysis is determining functional changes in microglia. scRNA-seq identified a proliferating population of microglia expressing disease-associated genes. Notably, these changes occur prior to the onset of white matter pathology. Conclusions: This study suggests that microglia state may have important functional consequences on white matter integrity and that regulators of microglia abundance and function may be key targets to modify white matter pathomechanisms relevant to VCID.
40	Katy Reid	William Whiteley, David Hunter	INCR, UK DRI	Ultra-sensitive digital ELISA reveals ischaemic stroke risk associated with circulating interferon-⍺ levels in Generation Scotland.	Type I interferons are essential for innate immune defence against viral infection. Interferon-alpha (IFNα) is a group of potent cytokines that have direct antiviral and immunomodulatory activities. Chronically elevated blood IFNα is associated with cardiovascular disease in patients with interferonopathies, and IFNα may also mediate inflammation in atherosclerosis. A novel ultra-sensitive digital ELISA assay, which combines Simoa technology with unique high-affinity autoantibodies against multiple IFNα subtypes (IFNα-MS), was used to measure circulating IFNα levels in Generation Scotland. The aims of the study were to i) confirm that this ultra-sensitive digital ELISA assay could capture circulating interferon-⍺ at normative (fg/mL) concentrations and ii) determine whether higher IFN⍺ are associated with incident ischaemic stroke (IS). Associations between log-transformed IFNα concentrations and IS risk were examined using conditional logistic regressions. The study included 353 case-control pairs (n=706; mean age=62.0 years [SD=11.8], 50.4% males) with serum samples collected a median of 8.1 years (IQR: 4.4-11.2) before stroke. The median serum IFNα concentration was 32.3 fg/mL (Q1-Q3: 21.3-53.5; range: 9.2-8,089.2 fg/mL). Higher log-IFNα levels were associated with increased IS risk after adjustment for cardiovascular risk factors (per SD increment: OR=1.23; 95% CI: 1.03, 1.48; p=0.025). These findings suggest IFNα may play a role in stroke pathogenesis and demonstrate the value of ultra-sensitive proteomic platforms for stroke biomarker discovery. A “Blood IFNα Reference” App is now in development using a reference distribution of people with normative levels of circulating IFNα. This tool will generate age-adjusted z-scores and percentiles for IFNα.
41	Amina McDiarmid	Neil Carragher	IGC, ERI UK DTC Programme	Identifying MELK as a Therapeutic Target in Alzheimer’s Disease Through Kinase Screening in SORL1-Deficient Human Neuronal Models	Alzheimer’s disease (AD) is characterised by progressive accumulation of amyloid-β plaques and intraneuronal tau fibrils, with dementia emerging after a prodromal phase of mild cognitive impairment. Although anti-amyloid immunotherapies can reduce plaque burden, their impact on meaningful cognitive outcomes remains uncertain, and their clinical use is limited by safety concerns and a narrow therapeutic window. Consequently, there is an ongoing need to identify novel therapeutic targets to sustain the AD drug discovery pipeline. Genetic risk factors play a major role in sporadic AD, with SORL1 emerging as a key susceptibility gene; loss-of-function variants are strongly associated with disease, particularly alongside APOE risk alleles. Human induced pluripotent stem cell (iPSC)-derived neuronal models lacking SORL1 recapitulate AD-relevant phenotypes and provide a tractable platform for phenotypic screening. Here, we apply a cell painting-based approach to screen a kinase inhibitor library in SORL1-deficient neurons. Kinases are implicated in tau phosphorylation, cellular stress responses and neurodegeneration. Our analyses identify maternal embryonic leucine zipper kinase (MELK) as a putative therapeutic target. Functional assays, gene expression profiling and in silico modelling support a role for MELK in modulating AD-relevant pathways, with favourable druggability and pharmacokinetic properties predicted. These findings highlight MELK as a promising candidate and demonstrate the utility of human genetic models for early-stage AD drug discovery.
42	Rosie Jones	Dr Rebecca Jordan	SIDB; INCR	Elevated locus coeruleus output during unexpected events in a mouse model of Fragile X syndrome	The hyperarousal hypothesis of Fragile X syndrome (FXS) posits that excessive arousal contributes to symptoms such as hypersensitivity and hyperactivity. The locus coeruleus (LC) is a central noradrenergic system implicated in arousal control, but evidence that LC activity differs in FXS is limited. Using pupillometry and fibre photometry of a noradrenaline sensor (GRABNE2m), we aimed to understand how LC output differs between Fmr1-knockout (KO) mice and wildtype littermates. Significantly elevated LC output was indicated in Fmr1-KO mice during unexpected stimuli: pupil dilation responses to visuomotor mismatches and cortical GRABNE2m responses to unpredictable auditory stimuli were larger in Fmr1-KO relative to wildtype mice. Similar responses to running onsets indicated elevated LC output is stimulus specific. LC axon density measured histologically was comparable between genotypes, demonstrating that anatomical differences cannot explain the elevated response. We next investigated activity differences upstream of the LC, in the neocortex, using in vivo electrophysiology. We found a greater proportion of neurons in V1 respond to visuomotor mismatch in Fmr1-KO compared to wildtypes, consistent with elevated pupil dilation responses. We conclude that LC output is elevated during unexpected events in Fmr1-KO compared to wildtype mice – an effect which could arise from increased cortical drive of the LC.
43	Isaac Chau	Suvankar Pal	PhD Clinical Brain Sciences, INCR	Attitudes and experiences of participants in the Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART)	Objective: This sub-study of the UK-wide platform trial MND-SMART evaluated factors influencing clinical trial participation among people with motor neuron disease (MND), including decisions to participate, discontinue study medication, or withdraw from the trial. The influence of caregiver feedback and attitudes on these decisions was also examined. Materials and Method: A convergent mixed-methods design was used, combining structured longitudinal questionnaires with optional exit interviews at withdrawal. Results: 297 MND-SMART participants (52.1%) (180 males [61%]; 117 females [39%]) and 251 associated caregivers (97%) were included. Sub-study participants had a median age at baseline of 63 years and a median disease duration from baseline of 11.8 months. Amyotrophic lateral sclerosis (246, 83%) was the most common MND subtype. 108 participants were allocated to memantine (36%), 97 to trazodone (33%), and 92 to Placebo (31%). Exit interviews were completed by 14% of withdrawn participants. Regression analysis showed that older baseline age (adjusted OR per year 1.11, 95% CI 1.02-1.23; p= 0.03) and participant-caregiver disagreement at screening (adjusted OR per year 2.05, 95% CI 1.23-3.43; p= 0.006) were significantly associated with treatment discontinuation. Qualitative analysis identified protective factors including hope, altruistic motivation, supportive caregiving, positive trial experiences, and accessible trial design. Risk factors included side effects, disease progression, caregiver burden, and participant-caregiver discordance. Conclusions Treatment discontinuation was associated with older baseline age and early participant-caregiver disagreement. Findings highlight the importance of expectation alignment at trial enrolment and sustained caregiver engagement. These results provide an evidence-based framework to inform recruitment, communication strategies, and participant support in MND-SMART and future clinical trials.
44	Takeshi Kaizuka	Seth Grant	INCR	A Brainwide Atlas of Synaptic Nanoarchitecture Across the Mouse Lifespan	How biological complexity emerges from the ordered assembly of molecular building blocks into supramolecular systems remains a central question, particularly in the mammalian brain with its vast synaptic diversity. We introduce NanoSYNMAP, a genetic, optical, and computational platform that integrates FRET with synaptome mapping to quantify nanoscale proximity of proteins in individual synapses brain-wide. We generate the first brain atlas of synaptic nanoarchitecture, based on the proximity of postsynaptic MAGUK supercomplexes. This reveals a molecular logic in which spacing of supramolecular assemblies specifies nanoscale architecture that organizes the global synaptome architecture. Nanoarchitecture varies across brain regions, differentiates during postnatal development, and remodels with aging. Supercomplex proximity reflects scaffold abundance, nanodomain organization, and competitive interactions among MAGUK assemblies. Deletion of a neuropsychiatric risk gene triggers widespread reorganization of nanoscale architecture. These findings establish molecular proximity as a fundamental scalable dimension of synapse diversity in health and disease.
45	Rebecca Robertson	Anna Williams, Joanna Wardlaw, Lorraine Work	Centre of Regenerative Medicine, IRR, Precision Medicine PhD Programme	Aberrant extracellular vesicle signalling by endothelial cells – a potential mechanism in cerebral small vessel disease?	Cerebral small vessel disease (SVD) is common and increases the risk of cognitive impairment and stroke, but the pathological mechanisms involved are not well understood. In SVD, endothelial cells lining the vessels of the brain are initially dysfunctional, and impact surrounding but non-adjacent oligodendrocytes, contributing to the white matter change seen on MR scans in humans. This implies that impaired endothelial cells secrete substances through altered extracellular vesicle (EV) release to communicate with oligodendrocytes. One preclinical model of SVD is the Atp11bKO rat which reproduces the pathological phenotype of dysfunctional endothelial cells and white matter vulnerability. Project aim - to use the Atp11bKO rat model to determine the communication of endothelial cell EVs with oligodendrocytes in SVD. Isolated EVs from the medium of cultured primary brain endothelial cells were applied to primary cultured oligodendrocytes to determine effects on proliferation and maturation. I found that EVs alone are not responsible for the reduction in branching morphology in Atp11bKO rats compared to wildtype (WT). This implies that soluble factors released from endothelial cells could be responsible. Endothelial EVs are altered in a preclinical SVD model, and this may help us understand their effect in humans, as well as providing a potential disease biomarker.
46	Alyssa Khoo	Dr Carole Torsney	SIDB; INCR	Characterising tactile reactivity during postnatal development in a rat model of SYNGAP1 haploinsufficiency	Mutations in the SYNGAP1 gene are a leading monogenetic cause of neurodevelopmental disorders (NDDs) linked to intellectual disability, epilepsy and autism spectrum disorder (Satterstrom et al., 2020). SYNGAP1 haploinsufficiency has been associated with altered somatosensory processing, and caregivers report tactile-seeking and tactile-aversive behaviours (Michaelson et al., 2018). Tactile function during development is associated with later social and cognitive behaviours in mouse models of NDDs (Tasnim et al., 2025). Adult Syngap heterozygous knockout (Syngap1+/-) rats display a tactile hypo-reactivity phenotype (Torsney lab, unpublished). Aim: Investigate tactile behavioural phenotype during postnatal development (P10/11) in a rat model of SYNGAP1 haploinsufficiency (Mastro et al., 2020). Syngap1+/- and wild-type (WT) rats underwent two behavioural tests at postnatal day 10/11 (P10/11). 1) Masking tape (2cmx1cm) was placed on the nape and both grooming behaviour and pup ultrasonic vocalisations (USVs) were recorded before, during, and after tape application. Syngap1+/- pups displayed reduced grooming behaviour and fewer USVs compared to WT when the tape is applied. 2) Startle reflex response to air puff (50ms, 5psi) was assessed using the SR-LABS system. Syngap1+/- pups show a dampened startle response to the air puff. These behavioural tests indicate a tactile hypo-reactivity phenotype in Syngap1+/- rats during postnatal development.
47	Steaphan Connell	Barry McColl	UK DRI	Understanding chronicity-plasticity relations of reactive microglia in brain injury and disease	Microglia adopt ‘reactive’ phenotypes responding to acute injury and during chronic neurodegeneration. Such microglial states are recognised as key modulators of disease progression, with both protective and detrimental effects. However, it remains unclear (i) if/how phenotypes/function change within the same microglial population over time/disease phases, (ii) the extent to which these phenotypes are governed by cell-autonomous or environmental cues, (iii) which underlying regulators can affect this. We established a novel model system combining isolation and ex vivo transfer of mouse microglia from injury/ageing/disease to assess their functional/phenotypic plasticity. Whilst naive microglia lose key homeostatic features, partly due to loss of environmentally active TGF-β, initial findings suggest that post-stroke microglia show altered dependence on environmental cues. Using fate-mapped microglia born early after stroke, which persist long-term and resemble chronic disease reactive states, we are probing their adaptability to environmental change across acute and chronic phases. Epigenomic profiling and functional assays will link regulatory features with functional plasticity. Reactive microglia are major therapeutic targets in dementia-causing disease. Our work is addressing key knowledge gaps on the plasticity and functional trajectory of these reactive microglia, which is essential to guide optimal manipulation of reactive phenotypes applied at the most appropriate phase in disease.
48	Charlotte Wu	Mosi Li, Giles Hardingham, Szu-Han Wang	INCR	Microglia absence on behavioural phenotypes and cognitive functions in a genetic model of Alzheimer’s disease	The brain's resident immune cells, microglia, have been closely linked with neuropathology in Alzheimer's disease (AD). However, their role in cognitive functions in prodromal AD is not fully elucidated. We ask whether, and which types of cognitive functions, are dependent on microglia during the early phase of beta-amyloid deposition. We crossed mice lacking microglia (Csf1r∆FIRE/∆FIRE) with mice carrying AD risk genes. Offspring from the selected strain are healthy and fertile. We find that adult mice lacking microglia show normal movement, working memory, object- or location-recognition memory, and spatial or reversal-learning rates. Impairment in contextual fear memory is observed in AD mice, but not in AD mice without microglia. Collectively, the absence of microglia does not affect a wide range of behavioural and cognitive functions and can prevent specific memory impairment in AD.
49	Arlo Simmerman	Anna Williams, Barry McColl	IRR, Wellcome Trust Translational Neuroscience PhD Programme	Modelling microglial lipid processing to identify new therapies for multiple sclerosis	Microglia are the resident macrophages of the central nervous system (CNS) and respond to acute and chronic injury within the brain parenchyma. In demyelinating lesions characteristic of multiple sclerosis (MS), microglia become reactive, ingesting lipid-rich myelin debris to be recycled by remyelinating oligodendrocytes and other cells. In MS brain lesions, lipid-laden microglia (LLM) exhibit impaired processing of excess lipids and potentially other important functions, worsening disease severity. Microglial lipid processing pathways represent potent targets for therapeutic intervention. Here, we aim to model microglial lipid metabolism in vitro with the eventual goal of developing a platform for high-throughput phenotype-based drug screening to improve LLM phenotypes. P2Y12+ microglia were isolated and cultured from three-month-old wild-type mouse brains via magnetic-activated cell sorting. Cells were treated with mouse myelin homogenate and various purified lipids to induce intracellular lipid droplet formation. We observed differences in lipid droplet accumulation and activated lipid processing pathways between the lipid species and myelin homogenate. This project provides an insight into the relevant lipid processing pathways that could be therapeutically targeted to improve MS patient outcomes.
50	Alexander Edwards	Jelena Baranovic	Institute of Quantitative Biology, Biochemistry and Biotechnology (IQB3); EastBio	AMPA-type glutamate receptor positional pairs exhibit non-equivalent conductances	AMPA receptors are tetrameric glutamate-gated ion channels composed of GluA1–4 subunits and mediate the majority of excitatory neurotransmission. Within the tetramer, two subunits occupy positions proximal to the two-fold axis (A/C) and two occupy distal positions (B/D) at the ligand-binding domains (LBD). Structures indicate asymmetry between the A/C and B/D positional pairs at the transmembrane (TM) and LBD-TM linker regions, with the B/D linkers undergoing greater conformational rearrangements upon activation. This has led to the assumption that the B/D pair dominates activation; however, direct functional evidence remains absent. We recorded from outside-out patches containing single GluA1/A2(R) receptors and used the desensitisation-blocking Lurcher mutation to resolve subunit-specific contributions. As AMPARs assemble with GluA2 subunits occupying the B/D positions (and GluA1 the A/C positions), the Lurcher mutant provides a functional readout from the positional pairs in which the subunits reside. We found heterotetramers with Lurcher-mutated GluA2(R) produced larger currents than those with mutated GluA1, despite similar homomeric conductance. Recordings from GluA2(Q) Lurcher homotetramers also revealed open levels best described by multiple components, consistent with differential contributions of positional pairs. Together, these results provide functional evidence that AMPAR subunits contribute unequally to activation, supporting a dominant role for B/D-positioned subunits in gating.
51	Hilde van den Brink	Susanne van Veluw	INCR	Spatial proteomic evidence for complement activation in CAA-affected cerebral vessels in post-mortem human brain tissue	Immune activation is hypothesised to play a role in vascular remodelling and subsequent haemorrhages in cerebral amyloid angiopathy (CAA). This study used digital spatial proteomics to characterise the inflammatory profile in and around arterioles with increasing CAA severity. Post-mortem parietal brain tissue from nine definite-CAA and three non-CAA cases underwent digital spatial profiling (GeoMx, NanoString) using 76 antibodies. Circular ROIs (150µm) were placed around arterioles across the Vonsattel scale, with vessel wall and perivascular tissue analysed separately. In CAA cases, n=53 arterioles per grade 0, 1, and 2, and n=49 grade 3 arterioles were selected. In controls, n=72 grade 0 arterioles were selected. Profiling indicated a more immune-protective state in and around grade 0 arterioles from CAA versus control cases. Within CAA tissue, complement components were higher in vessel walls of grade 1 (C4B) and grade 2–3 arterioles (C3, C4B) compared to grade 0. CD11b was higher in grade 2 versus grade 0 vessel walls, suggesting possible microglial recruitment. Perivascular C4B per-cell counts were also higher around CAA-affected versus normal-appearing arterioles. Together, these findings support a role for complement activation in CAA-affected arterioles with increasing severity, warranting further investigation into complement's role in vessel remodelling and rupture in CAA.
52	Danilo Negro	Claire Durrant and Patricio Opazo	Wellcome Trust Translational Neuroscience PhD programme	The role of tau in mechanisms of synaptic loss and compensation	Clinical symptoms in Alzheimer's disease (AD) emerge decades after the onset of neuropathology. This may be due to early compensatory mechanisms counteracting synaptic loss, such as synaptic enlargement and/or synaptogenesis. While tau-lowering therapies are under development for AD, tau also plays important physiological roles in synaptic homeostasis. We hypothesize that tau might physiologically support synaptic compensation, but that its aggregation or depletion might impair these protective mechanisms. Using two-photon live microscopy and biolistic transfection, we tracked dendritic spine dynamics in mouse hippocampal organotypic slices under different conditions of tau concentration and aggregation. Exploiting an inducible tool for the artificial ablation of dendritic spines to trigger synaptic compensatory responses, we also investigated the effect that tau depletion might have on synaptic compensation. Tau aggregation-induced spine loss led to the enlargement of surviving dendritic spines, although no compensatory spinogenesis was observed. In contrast, tau depletion prevented the emergence of dendritic spine enlargement and spinogenesis in response to artificially induced synaptic loss, suggesting that tau might be physiologically necessary for synaptic compensation. This work suggests that compensatory synaptic remodelling is maximised within an optimal window of tau concentration, with implications for designing tau-targeting therapies that preserve endogenous synaptic resilience in AD.
53	Nika Balkic	Cathy Abbott, Alfredo Gonzalez-Sulser	IGC, ERI UK DTC Programme	Novel Therapeutic Candidates and Behavioural Signatures in a Mouse Model of EEF1A2-Related Neurodevelopmental Disorder	Background: Epilepsy affects 50 million people, with one-third remaining drug-resistant despite over 25 anti-seizure medications. Induced mouse models fail to replicate human epilepsy, while genetic models often lack spontaneous seizures. The EEF1A2-Related Neurodevelopmental Disorder, most commonly linked to the E122K mutation, shows EEG abnormalities but no behavioural seizures with traditional, behavioural testing methods. Therefore, seizure phenotype is typically measured by electroencephalogram (EEG), which requires invasive electrode implantation in mice. Methods: We used DeepLabCut for pose estimation and Keypoint-MoSeq for behavioural classification to detect phenotypes in open field recordings. Connectivity Map analysis of E122K/+ translatome and proteome data identified drugs with potential to reverse mutation effects. These drugs were tested in Eef1a2^E122K/+ mice through simultaneous EEG and video recordings. Results: Keypoint-MoSeq identified behavioural changes in Eef1a2^E122K/+ mice for the first time, revealing an increased frequency and duration of pausing movements. Connectivity Map highlighted Entinostat and Dactolisib as potential treatments, supported by literature as possible anti-seizure medications. The drugs reversed the pausing phenotype, and ongoing analysis aims to confirm if these pauses coincide with any EEG abnormalities. Conclusion: Genetic models with no apparent behavioural phenotype may indeed possess subtle differences undetected by traditional methods. Keypoint-MoSeq offers significant potential as a drug screening tool. While it cannot replace EEGs, it serves as a rapid preliminary step to identify promising candidates for further EEG analysis, enhancing the drug discovery process.
54	Lydia Lorenzo Cisneros	Aida Rodrigo Albors (primary) and Steven Pollard (Secondary)	IRR, Martin Lee PhD programme	Investigating the role of ependymal cell maturation in spinal cord regeneration	Ependymal cells are the neural stem cells of the adult spinal cord. Upon injury, they differentiate into astrocytes and oligodendrocytes but not neurons. What limits their neurogenic capacity is unknown. Mouse ependymal cells co-exist in mature and immature cell states. Mature ependymal cells express secreted factors associated with quiescence (e.g. Dkk3). Moreover, the fraction of mature cells increases with age, which correlates with a decay in ependymal stem cell potential. We hypothesise that mature cell-secreted factors (Dkk3) induce ependymal maturation and quiescence, limiting the regenerative capacity of mouse spinal cord ependymal cells. We are using AAVs to specifically overexpress Dkk3 in ependymal cells and assess the impact of these manipulations on ependymal maturation and ependymal behaviour upon injury. Our preliminary results suggest that Dkk3 is not the sole factor regulating ependymal maturation. To assess the translation of these findings, we are developing protocols to generate human ependymal cells in vitro from foetal spinal cord stem cells. We have found that removal of mitogens from the medium and inhibition of BMP signalling induce the expression of the pan-ependymal marker FOXJ1. This work will provide a better understanding of ependymal biology, uncovering new ways to unlock spinal cord regeneration in non-regenerative species.
55	Nagore Elu	Susana Louros	INCR	Deciphering cell-type specific proteome dysfunction in neurodevelopmental disorders through spatial proteomics	One of the most extensively studied models of intellectual disability (ID) is Angelman syndrome (AS), caused by mutations in a ubiquitin ligase resulting in the lack of UBE3A protein in the brain (Kishino et al., 1997). 85% of AS patients experience seizures, a symptom that significantly affects their quality of life (Xia et al., 2023). A hallmark of these seizures is neuronal hyperexcitability, arising from an imbalance between neuronal excitation and inhibition (Wallace et al., 2012; Rotaru et al., 2018). Importantly, different neuronal populations contribute distinctly to AS phenotypes, with GABAergic-specific loss of Ube3a increasing seizure susceptibility in mice (Judson et al., 2016). However, the molecular pathways driving hyperexcitability in AS remain poorly understood. Here, we aim to explore spatial and cell-type specific proteomic changes in cortical neurons of Ube3am-/p+ mice. We performed spatial proteomics in Ube3am-/p+ mice crossed with the VGAT-YFP reporter line. Using laser microdissection, we isolated excitatory and inhibitory neurons from cortical layers II/III and V/VI, where hyperexcitability is observed in both cell types. Our study will reveal how UBE3A differentially modulates the proteome across inhibitory and excitatory neuronal populations, improving understanding of the mechanisms underlying seizure development in AS.
56	Rana Fetit	Anna Williams	IRR, Wellcome Trust Translational Neuroscience PhD Programme	MODELLING HUMAN OLIGODENDROCYTE (OL) HETEROGENEITY USING STEM CELLS, MOUSE CHIMERAS AND ORGANOIDS TO STUDY MYELINATION AND METABOLISM	Human oligodendrocytes (OLs) can be classified into three subtypes defined by SPARC, OPALIN, or RBFOX1 expression. SPARC+OLs are spinal cord (SC)-specific and uniquely human, but whether these subtypes differ in myelination or metabolism remains unclear. Computational analyses indicate SPARC+OLs are transcriptionally distinct, with signatures of elevated metabolic activity, signalling roles, and unique regulatory networks. To investigate functional differences, GFP-tagged human ESCs were differentiated into OLs and patterned toward SC or forebrain (FB) identities. SC- and FB-like progenitors were transplanted into organoids and myelin-deficient mice, where enhanced OL maturation was previously observed. In monoculture, MBP+OLs co-expressed all subtype markers. Similarly, most MBP+OLs in-vivo and in organoids expressed all three markers, unlike adult human tissue. To overcome this, stable hESC lines expressing inducible CRISPRa/i tools at the AAVS1 site were generated to enable high numbers of single OL subtypes for myelination and metabolic assays.
57	Isaac Chau, Eleanor Carter, Maryam Tintila	Prof Suvankar Pal	INCR, PhD in Clinical Brain Sciences	Equity of access to research amongst people living with MND in Scotland	Objective Understanding barriers to participation can inform strategies to reduce health inequalities. This project aimed to identify patient-reported barriers to research participation in MND research and explore strategies to improve future inclusion. Methods A cross-sectional survey was distributed to pwMND who consented to be contacted about research through the Scottish MND Register (CARE-MND; Scotland A REC 15/SS/0216). Structured questionnaires were sent to 257 individuals (115 paper, 142 online). A mixed-methods approach was used to triangulate quantitative and qualitative data Results Seventy-seven questionnaire responses were received. Barriers to participation included logistical challenges and disease-related functional limitations. Logistical barriers included travel distance, financial costs, and time commitment, with approximately one-third of respondents reporting that travel to research centres limited participation. Disease-related barriers included disability associated with disease progression, fatigue (reported by 19.7% of participants), and reliance on caregiver support to attend visits. Suggested solutions clustered into two themes: flexible and localised research delivery, including home visits and remote participation, and improved communication and engagement through trusted healthcare professionals, clear study information, and feedback on study outcomes. Despite these barriers, many respondents expressed strong motivation to contribute to research. Conclusion PwMND remain highly motivated to participate in research but face barriers related to logistical demands and disease-related limitations.
58	Isaac Chau, Dominic Ng	Prof Suvankar Pal	INCR, PhD in Clinical Brain Sciences	Clinicopathological correlation of Motor Neuron Disease: A 10-year retrospective case series	Objectives: Amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) is a clinically and biologically heterogeneous neurodegenerative disorder. As understanding neuropathological substrates may help explain clinical heterogeneity and inform diagnosis and prognosis, we examined co-pathology prevalence and clinical associations in a large post-mortem MND cohort. Methods We assessed 163 neuropathologically confirmed MND cases from the Edinburgh Brain Bank. Six co-pathologies (beta-amyloid, tau, cerebral amyloid angiopathy, cerebrovascular disease, p62 inclusions, alpha-synuclein) were systematically evaluated. Cox proportional hazards models assessed survival associations, while linear and logistic regression evaluated functional and clinical correlates. All models were adjusted for age at diagnosis and sex. Results The cohort was 56% male with a median age at diagnosis of 67 years and median disease duration of 17 months. Co-pathology was highly prevalent: 92.2% had at least one additional finding, with a median of two per case and 25.9% carrying four or more. Tau (69.9%), cerebrovascular disease (63.3%), and beta-amyloid (53.6%) were the most common. Greater TDP-43 regional spread was associated with shorter survival (p < 0.001), lower ECAS scores (p ≤ 0.003), and increased odds of bulbar and cognitive/behavioural onset. Conclusion: Non-MND neuropathology is highly prevalent in this cohort. These clinicopathological correlations provide greater insight into clinical heterogeneity that may inform clinical practice and stratification for research studies.
59	Elena Hein	Susana R. Louros (primary supervisor), Kathryn R. Bowles (secondary supervisor)	SIDB; INCR	Cell type-specific protein turnover regulation in human neurons	Correct proteasome-mediated protein degradation at the synapses is vital in regulating neurotransmission and ensuring balanced excitatory and inhibitory synaptic inputs (E/I balance) across the brain. Both excessive and impaired protein turnover have been implicated in the pathology of neurodevelopmental disorders (NDDs) and seizures, with disruption of the regulatory 19S proteasome subunit genes being particularly detrimental in the context of NDDs. However, while most research has been done in rodent models or primary cultured cells of mixed neuronal subtypes, little is known about cell-type specific protein turnover regulation in human neurons and its impact on overall neuronal network excitability and synaptic proteome composition. In this project we aim to understand how dysfunctional proteasome function contributes to changes in excitability in human neurons and identify the differentially degraded proteome in excitatory vs inhibitory human neurons. To achieve this, we are establishing an hiPSC-derived neuronal co-culture system using defined ratios of pure glutamatergic and GABAergic neurons. This model will be used to modulate proteasome function and assess neuronal subtype excitability, as well as protein turnover by proteomics using proximity ligation. In summary, this project will interrogate the contribution of proteasomal function in different human neuronal subtypes, paving the way for the development of more effective therapeutic strategies to ameliorate the impact of NDDs.
60	Sarah Choi	Barry McColl	UK DRI; INCR	Developing microglial replacement therapy for LRRC33 -related encephalopathy	LRRC33-related encephalopathy (LRE) is a rare neurodevelopmental disorder, caused by biallelic mutations in leucine-rich-repeat-containing protein 33 (LRRC33), also called negative regulator of reactive oxygen species (NRROS). Affected children develop normally before onset of seizures and regression of acquired skills from ~1y of age. There are no current treatments, and most children die by 5y of age. LRRC33 is expressed highly in microglia, and we have human and mouse data that suggests the disease is driven by microglial dysfunction. We are developing and testing a microglial replacement therapy approach tailored for the disease, by combining microglial depletion with myeloablation and bone-marrow transplant (BMT). Transplanted bone marrow cells engraft in the brain and serve as precursors for microglial repopulation. We tested this method in Lrrc33-/- (KO) mice which develop human-like neurological decline, and achieved high and consistent brain engraftment. Tests assessing motor function, anxiety-like behaviour and general activity showed that transplanting cells from Lrrc33+/+ (WT) or Lrrc33+/- (Het) donor mice (but not KO donors) into KO recipient mice rescued disease abnormalities. WT/Het BMT also improved survival and attenuated disease-associated astrocytosis. These data provide important insights into microglial replacement strategies for neurological disease, and suggest promise for therapeutic use in LRRC33-related encephalopathy.
61	Ying Sze	Carole Torsney	INCR; SIDB	Exploring affective touch in rat models of Syngap1 haploinsufficiency	Syngap1 haploinsufficiency is associated with alterations in response to touch. Previously, we found that Syngap1+/- and Syngap1+/△-GAP rats both display hypo-reactivity to dynamic tactile stimuli in behavioural assays of discriminative touch. However, the emotional and hedonic value of touch (affective touch) has not been explored. This study aims to investigate affective touch using a place preference assay with stroking. Syngap1+/-, Syngap1+/△-GAP and respective wild-type (WT) littermate rats were habituated to stroking (20cm/s) of the nape/back whilst on the experimenter’s arm (100 strokes/day using a large soft brush for 4 consecutive days). Ultrasonic vocalisations (USVs) were recorded to assess positive affect. In the baseline trial, rats were given 20min to explore a light-dark chamber. During the test trial (20 min), rats were stroked every time they entered the light zone. Videos were recorded and percentage of time spent in light zone, and the behavioural responses towards stroking were coded using BORIS. Unlike WT, Syngap1+/- and Syngap1+/△-GAP rats did not exhibit increased USVs with stroking during habituation sessions. Both rat models also spent less time in the light zone (engaging with stroking stimuli) as compared to WT, suggesting altered responses to affective touch.
62	Jing Huang	Díaz Castro Lab	UK DRI	Characterization of astrocyte and astrocyte-vascular alterations throughout amyloid pathology progression in APP/PS1 mice	Alzheimer’s disease (AD) is characterised by progressive amyloid-β (Aβ) accumulation, blood-brain barrier (BBB) dysfunction and profound cellular alterations. Astrocytes are glial cells that closely interact with the brain vasculature through specialised endfeet and play essential roles in maintaining BBB integrity. Although astrocyte alterations occur during AD progression, the spatial and temporal dynamics of these changes remain incompletely understood. Using the APP/PS1 amyloidopathy mouse model, we characterised astrocyte changes across disease progression in multiple brain regions. We used immunofluorescence to investigate morphological changes in astrocytes with increased amyloidopathy and changes to astrocyte endfeet around the brain vasculature. We measured GFAP expression to assess changes in astrocyte morphology and found an increase in GFAP with increased amyloidopathy, especially around Aβ plaques. We also used the astrocyte endfoot protein aquaporin-4 (AQP4) to measure the distance between astrocyte endfeet and the brain vasculature but found little differences with increased pathology compared to controls. Together, these findings define a stage-dependent astrocyte response during AD progression and establish a morphological framework for investigating astrocyte–vascular interactions in disease.
63	Martina Morchio	Anna WIlliams	IRR	How do cortical neurons respond to white matter demyelination?	Neurodegeneration is a critical feature of progressive MS, for which treatments are lacking. The mechanisms underpinning neuronal degeneration following demyelination remain poorly understood. We do not fully understand which neuronal subtypes are most susceptible to damage in MS, driving progressive symptoms, and which are more resilient, and what the mechanism underpinning these differences are. Here, we investigate the extent to which cortical excitatory neurons are affected by distal demyelination in the white matter and identify the transcriptional changes driving this response. We induced demyelination by LPC injection in the mouse corpus callosum white matter retrogradely labelled cortical neurons projecting to the demyelinated lesion. This allowed us to identify changes in the neuronal cell bodies that have undergone distal demyelination. We investigated transcriptomics and protein changes to identify the early response to demyelination as well as the longer-term response in a model of chronic demyelination. Preliminary evidence suggests that cortical excitatory neurons are more resilient than inhibitory interneurons to the loss of myelin, displaying increased survival, and this may be due to different compensatory metabolic changes. Identifying the transcriptional changes underpinning this increased resilience to demyelination will highlight potential neuroprotective therapies for progressive MS.
64	Lachin Soufizadeh	Peter Kind, Thomas Watson, Paul Rignanese, Arno Onken	AI4BI CDT- SIDB	Machine Learning-Based Neural Biomarkers of Freezing Behaviour	SYNGAP1 haploinsufficiency is associated with neurodevelopmental disorders including intellectual disability, autism spectrum disorder, epilepsy, and fear-related phenotypes such as anxiety. These phenotypes arise from altered synaptic function and disrupted neural circuit development and include a prominent fear extinction deficit in Syngap+/Δ-GAP heterozygous rats, consistent with persistent fear and anxiety-like responses. Fear regulation depends on coordinated activity across cortical-limbic circuits, particularly interactions among the medial prefrontal cortex (mPFC), amygdala, olfactory bulb (OB), and periaqueductal grey (PAG). Neural activity was recorded from wild-type and Syngap+/Δ-GAP rats using electroencephalography (EEG) and local field potential (LFP) electrodes implanted in the mPFC, amygdala, and OB during a visual fear conditioning paradigm. Data were segmented into 5-second epochs labelled as freezing or non-freezing, and features were extracted from power, complexity, and connectivity domains. Elastic Net classifiers decoded freezing with high holdout accuracy in both genotypes, reaching 0.962 in Syngap+/Δ-GAP and 0.939 in WT. Feature importance analysis revealed genotype-specific neural biomarkers: WT classification relied on a broader combination of power and complexity features, whereas Syngap+/Δ-GAP classification depended mainly on mPFC and OB delta-band spectral entropy. These findings suggest genotype-related differences in the circuit dynamics underlying freezing behaviour in SYNGAP1 haploinsufficiency.
65	Jack Barrington	Barry McColl	UK DRI	Proliferation status impacts a temporally-evolving reactive microglial landscape during disease	Microglia are brain-resident macrophages that proliferate and adopt heterogenous reactive cell states during disease. One such reactive state enriched in phagolysosomal, lipid metabolic and antigen-presentation markers, called disease-associated microglia (DAMs), is thought to influence brain health in Alzheimer’s and other diseases. Although DAMs are being targeted clinically, it is unclear how they emerge and if/how these states evolve during disease. Therefore, addressing this knowledge gap by temporally tracking transcriptional/functional phenotypes of microglia will identify the optimal state(s) to target. Here, we fate-map reactive proliferating microglia in a mouse model of acute ischaemic stroke that synchronises microglia reactivity, thus facilitating study of cell state emergence and transitions over hours/days/weeks. We show microglia mostly proliferate between 2-3d post-injury and daughter cells are stably present up to 28d post-injury. Through scRNAseq, we show cell-cycle majorly contributes to metabolically active DAM-like states over others in the reactive microglial landscape at 5d. By 28d, many of these previously reactive cells return to a homeostatic state, whereas others transition to a chronic DAM-like phenotype marked by increased chemokine and antigen presentation pathways. Our work shows DAMs emerge from proliferating microglia and supports the idea states have plasticity and may functionally (mal)adapt over the course of disease.
66	Maja Skuza	Marino Pagan	SIDB	Individual variability in cognitive flexibility across Scn2a and Syngap1 rats	Cognitive flexibility, the ability to adjust learned behavioural rules as context changes, is a fundamental component of higher cognition, yet its underlying neural computations remain unknown. While it is known that cognitive flexibility can vary greatly across individuals, little is known about the link between this variability and genetic mutations. Autism spectrum disorder (ASD) is often associated with intellectual disability and cognitive inflexibility, thus providing a framework to test how ASD risk genes affect these computations and structure variability in flexible behaviour. Here we trained rats on a rule-switching task that dissociates initial rule acquisition from cognitive flexibility. Animals first learn a spatially cued stimulus–approach ("pro") rule, then learn to alternate this rule with the opposite ("anti") rule. To characterise baseline variability across animals, we first analysed a large cohort (N = 202) of wild-type rats, revealing structured inter-individual differences in rule-switching performance, spanning both successful updating and selective impairment following rule change. We then tested rats carrying heterozygous mutations in two ASD risk genes, Scn2a and Syngap1. Our preliminary data suggest that Syngap1 rats are slower to acquire the initial rule, but are capable of reaching the same final level of performance as control animals. This result indicates a specific impairment in early learning, but it suggests that these rats are capable to eventually learn the task over a longer time span. Meanwhile, Scn2a rats appear to learn the initial rule at the same speed as wild-type rats. However, these rats display a substantially greater cost when required to switch. These animals also showed greater moment-to-moment response time variability when compared to than Syngap1 animals or wild-type animals. Altogether, these findings suggest individual flexibility profiles as a potential phenotypic distinction for different ASD rat models. The Scn2a and Syngap1 mutations might impair distinct components of flexible behaviour with Syngap1 selectively slowing down rule acquisition, while Scn2a haploinsufficiency disrupting the ability to override a learned response.
67	Pierre Mora	Blanca Diaz Castro	UK DRI Edinburgh	Delta like 4 at the GLIA LIMITANS, a key player of neuro-inflammation pathophysiology	Introduction: During neuroinflammation, astrocytes undergo morphological and molecular changes. To characterize the astrocytic transcriptome in this context, we carried out a RNA sequencing on quiescent versus reactive human astrocytes and identified DLL4 as strongly overexpressed. Our aim is to study the contribution of NOTCH signaling to the effects of astrogliosis. Methods: In vitro, we used primary human astrocytes incubated with IL1B to mimic an inflammatory state. In vivo, we developed a mouse model of astrocytic-specific gene inhibition of Dll4. The neuroinflammation model we used experimental autoimmune encephalomyelitis. Results: In vivo, we observed a reduction in the severity of the pathology in Dll4ACKO mice as well as a reduction in astrogliosis, correlated with a decrease in pro-inflammatory factor and of vascular permeability factors. In vitro, we demonstrated that DLL4-NOTCH1 juxtacrine signaling in reactive astrocytes participates in the direct control of the transcriptional levels of those factors. Discussion: Taken together, these data suggest that DLL4 induces some of the deleterious effects of astrogliosis during EAE by promoting inflammation and disrupting the structure of the blood-brain barrier. Thus, we believe that the DLL4-NOTCH1 axis represents an interesting target for the development of new therapeutic strategies for the management of neuroinflammatory pathologies.

This article was published on 2026-06-08