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Microscope

Nottingham Neuroscience Day 
9th January 2025
9.00-18.00

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Venue:

The Exchange Building (free car parking voucher:         )

Jubilee Campus

Wollaton Road

Lenton

Nottingham

NG8 1BB

Registration
The Symposium, lunch and coffee breaks are free. However, registration is mandatory. All staff, including students (undergraduate and doctoral) and researchers (at all levels) are encouraged to participate.
Please complete this registration form
Registration deadline: 15th Dec 2024

Abstract submission via Registration page.

Lecture theatre 2 and Poster arrangements in room C3 and C33

 

The Neuroscience@Nottingham conference is an annual event which has been held consecutively since 2011. This will be the second year in which we include members of the Nottingham Trent University Neuroscience team, both as delegates and in the organising committee. The critical mass of diverse and complementary neuroscience research across the two academic institutes will create an outstanding opportunity to build networks, encourage collaborations and knowledge exchange between neuroscientists across Nottingham.

For the 2025 N@N day, we have so far over 170 registered attendees with more than 30 poster presentations - all supported by our numerous sponsors.

Key Note Speakers

  • ​Prof. Tom Wishart (Professor of Molecular Anatomy, Nottingham Trent University & The Roslin Institute, University of Edinburgh)​

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  • Dr. Krista Rantanen (visiting Scientist at Francis Crick [Peter Ratcliffe] and lead of HypoxEU and HypoxAmericas and Director of Scientific Applications at Baker Ruskinn)

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  • Prof. Nikita Gamper (Professor in Neuroscience, University of Leeds)​

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Neuroscience from Synapse to Disease

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Nitric Oxide volume diffusion reaches pre- and post-synaptic targets

Neurons are stained for tyrosine hydroxylase and redox stress (4-HNE)

Mass Spectrometry allows detection of modified proteins

fMRI imaging assesses morphological and functional changes in the brain  

Sponsors

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NTU 

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Baker Ruskinn

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School of Psychology and

Mathematical Sciences

UoN

WPI

Thistle Scientific

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Scientifica

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Friedheim Scientific

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Nanion Technologies

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10x Genomics

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PHC Europe

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PROGRAM
9th January 2025

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8.30-9.00
Registration open (Poster arrangements) 

9.00-9.10

Welcome and introduction to the symposium (Joern)

Introduction to the Symposium, house keeping and Acknowledgement of Sponsors

9.10 - 9.25

Presentation by Sponsors of the Symposium

9.10-9.15 10xgenomics

9.15-9.20 10xgenomics 

9.20-9.25 Novogen Europe

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9.30-10.15 Invited Speaker (Chair: Kamal)

Prof. Tom Wishart (Nottingham Trent University & The Roslin Institute, University of Edinburgh)

Title: Modelling neurological disorders to scale up therapeutic development

10.15-10.45

Coffee

10.45-11.30 Invited Speaker (Chair: Joern)

Dr. Krista Rantanen (Lead of HypoxEU and HypoxAmericas and Director of Scientific Applications at Baker Ruskinn)

Title: The paradigm shift - from normoxia to physoxia in biomedical research

11.30-12.15

Session 1, Chair: Nikita and Asli

11.30-11.45 Elisabetta Verderio Edwards - Mesenchymal /Stromal Stem Cells Extracellular vesicles: tracking the neuroprotective  

11.45-12.00 Wayne Carter - Neuroprotective effects of certain phytochemicals  

12.00-12.15 Philip Bath - The management of post-stroke dysphagia 

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12.15-13.30

Lunch

13.30-15.00

Session 2, Chair: Tom and Kamal

13.30-13.45 Harry Porter - Modelling interactions between astrocytes and childhood brain tumours

13.45-14.00 Mairi Houlgreave - Investigating the neural correlates and oscillatory dynamics of tics in Tourette Syndrome  

14.00-14.15 Karim Kreft - Genetic subtypes of multiple sclerosis predict response to treatment and risk of sustained disability  

14.15-14.30 Mark Humphries - Neural embedding controls locomotion transitions in Aplysia 

14.30-14.45 Michael Okun - Psychedelic drugs' impact on the space of neuronal population activity

14.45-15.00 Lesley Hoyles - Microbiome-associated metabolites influence integrity of the mammalian blood–brain barrier   

15.00 - 15.30

Coffee + Posters

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15.30-15.40​

Presentation by Sponsors of the Symposium

15.30-15.35 Nanion

15.35-15.40 Labtech

15.40-16.10

Session 3, Chair: Krista and Asli

​​​​15.40-15.55 Sebastien Serres - Defining the role of STAT3 in astrocyte reactivity to disease: from brain tumours to neurodegeneration.  

15.55-16.10 Carlo Breda - Investigating the association of RAB39B and Parkinson's Disease 

Prof. Nikita Gamper (University of Leeds)

Title: Dorsal root ganglion as an intrinsic filtering device

16.10-16.55 Invited Speaker (Chair: Joern)

16.55-17.00

Closing Session

Refreshments + Posters 

17.00 - 18.00

Contact us

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Abstracts

Prof Tom Wishart

Title: Modelling neurological disorders to scale up therapeutic development

There is currently a disappointingly high failure to translate for therapies which are effective in rodent models of neurodegenerative disease through to something which is effective in the clinic. 

This is a complex field with multiple potential considerations and confounding factors, but here we will discuss some of the potential issues which may underpin this failure to translate. In the neurological space these include but are not limited to model relevance, lifespan, size and complexity of the nervous system.

We will explore in more detail how we are using livestock as biomedical models to bridge this translational gap. In the context of therapy development how should we treat neurological disorders, how do we scale up from rodents,  how do we assess route of administration, biodistribution and what does success look like? This is particularly important in the context of setting outcome measures and the identification of novel biomarkers for use in IND-enabling research.

Here we will use the childhood dementia - CLN1 - as an example disease where we have learned specific lessons from attempts at enzyme replacement and viral therapy scale up, as well as imaging and molecular biomarker investigation in sheep.

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Dr Krista Rantanen

Title: The paradigm shift - from normoxia to physoxia in biomedical research

Dr Ratanen is the lead of HypoxEU and HypoxAmericas, and a founder of HypoxAsia and HypoxJP - a global network of scientists that share the interest in the effects of oxygen in biomedical research.

In the lecture Dr Rantanen will highlight and discuss the importance of oxygen in general and its impact on biomolecules in particular. She will give an overview of the effect of varying oxygen levels has for example in stem cell research and drug development success of biopharma companies.

In addition she will discuss why paradigm shifts understanding the importance of normoxia and physioxia are so difficult in science and how to make the change possible.

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Prof Nikita Gamper

Title: Dorsal root ganglion as an intrinsic filtering device

Healthy peripheral somatosensory nerves detect and transmit to CNS stimuli that brain interprets as touch, pressure, vibration, temperature, body part movements, as well as pain. These nerves conduct action potentials, triggered by painful and non-painful stimulation, from their peripheral endings to the dorsal spinal cord, from where projection neurons take the information further up, to the thalamus, cortex and other relevant brain centers which generate appropriate sensations. It is often assumed that the first site where peripheral somatosensory signals are integrated and analyzed is in the dorsal horn, yet, current research suggest that such processing can start earlier. The focus of this talk is at one such potential early site, the dorsal root ganglion (DRG). DRG harbors cell bodies of the pseudo-unipolar peripheral sensory neurons and resides outside of the main nerve conduction pathway. Because of the pseudounipolar morphology of the DRG neurons, the action potentials traveling from the peripheral nerve terminals to the spinal cord need to pass through the axonal bifurcations (T-junctions) at the DRG, where a propagating spike could fail. Accumulating evidence suggests that such failure does occur physiologically; moreover, it can be dynamically regulated, manifesting as filtering of the throughput firing frequency. Ultimately, such filtering determines how much of the somatosensory input (e.g. nociceptive) is delivered to the brain. The fundamentals of such filtering are only beginning to emerge, with one revealed mechanism being the ganglion’s intrinsic inhibitory GABAergic system. I will focus on current understanding of biophysical principles of ganglionic filtering, main ion channels and neuromodulatory mechanisms identified thus far, as well as on the therapeutic applications and future perspectives of the research in this exciting area.

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Posters:

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Poster Communication (PC)

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PC1: Evaluation of modified synthetic scaffolds for corneal epithelial and stromal regeneration

 

Prity Sahay1, Perla Filippini1, Mehri Behbehani2, Melissa Townsend2, Harminder Singh Dua1

 

1, Academic Ophthalmology, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, United Kingdom

2, The Electrospinning Company Ltd. Oxfordshire, United Kingdom

 

Introduction: The cornea serves as a transparent barrier to protect the eye against environmental stresses. The optical properties of the tissue require high transparency mediated by intricate organization of the stromal extracellular matrix (ECM). Prolonged or irregular wound healing may promote opacification of the cornea leading to fibrotic ECM deposition and ultimately vision loss. Over six million people are visually impaired dur to corneal scarring, primarily a result of trachoma infections. Cornea transplantation remains the only therapeutic option to recover vision loss due to corneal scarring. The Electrospinning Company (Oxford, UK) have generated an electrospun poly (lactic-co-glycolic acid) (PLGA) ‘synthetic amnion’ impregnated with sodium hyaluronic acid (HA), termed Symatix® and demonstrated its favourable surgical handling properties and biocompatibility with human limbal epithelial cells in terms of cell polarisation, migration, proliferation, stratification, expression of cytokeratins, zonula occludens-1 and epithelial stem cell markers (Sahay P et al., TVST, 2024).

During corneal wound repair, the corneal epithelium can presumably stimulate fibroblast fibrosis or scarless regeneration. The healing process is thought to be partly regulated by the epithelium-stromal interactions. In this study, we applied an in-vitro approach to examine the interaction between epithelium and self-secreted fibroblast matrix. The goal of the study was to develop an in-vitro co-culture model to examine epithelium-stromal interaction mimicking the wound healing process.

Methods: Different modified scaffolds such as poly (lactic-co-glycolic acid) (PLGA) alone, PLGA+HA, PLGA+ low collagen (LC), PLGA+ high collagen (HC), PLGA+ low gelatin (LG) and PLGA+ high gelatin (HG) of varying architecture including pore size and thickness have been tested for determining the ideal characteristics for human corneal epithelial cells (hCEC) and human corneal stromal keratocyte cells (CSKC) infiltration. The wound healing process have also been studied by developing an in-vitro co-culture model of primary hCEC layer and self-assembled construct generated by human corneal stromal fibroblast layer (hCSF) as the stromal layer. The fibrotic, corneal wound healing marker, and formation of basement membrane have been tested in the individual cells, and the epithelial-stromal interface by confocal assay.

Results: In the different scaffolds, the scanning electron microscope (SEM) showed the surface of human epithelium have a mosaic like appearance, intermediate in brightness, with polygonal outlines of various size and shape. The cells showed a microprojections with long axis perpendicular to the surface like microvilli. The different scaffolds showed positive expression of the properties of corneal epithelial cells such as cytokeratin-19 (CK-19), collagen-I (Col-1), fibronectin (FN); and CSKC markers such as aldehyde dehydrogenase 3 (ALDH3A1), keratocan (KTN), CD-34, lumican by immunofluorescence (IF) assay. The scaffolds such as LC, LG and HG showed maximum infiltration than PLGA alone, HA and HC membranes. The In-vitro construct of co-culture hCEC and hCSF cells in LC, LG and HG showed the expression of collagen-III, thromboplastin-1 in the epithelial-stromal interface.

Conclusion: The results suggest that the scaffolds such as LC, LG and HG is a better substrate for corneal epithelial cells and stromal cells that influence cell migration and proliferation in the context of treating deep corneal wounds and the repair mechanism of corneal defects. The scaffolds thus generated can provide a consistent matrix for reconstruction of the corneal epithelium and stroma regeneration.

 

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PC2: Title: 'Flying high': A Model for Studying the Neurobiological Mechanisms of Psilocybin as a Treatment for Affective Disorders in Drosophila Melanogaster 

 

Alice Stringer1,2, Rachel Hunt1, Joern R Steinert1 & Claire Gibson2

 

1, School of Life Sciences,

2, School of Psychology, The University of Nottingham

 

Text body: Numerous mental health conditions are associated with abnormal regulation of signalling of neurotransmitters, in particular, serotonin and dopamine. Psilocybin, a psychoactive compound, binds to serotonergic 5-HT2A receptors with an agonist effect (Ling et al, 2022; Mann, 2023). The aim of this study is to demonstrate its possible effectiveness as a treatment for affective disorders such as depression through modulation of serotonergic systems (Doss et al, 2021). Through expression of green fluorescent protein (GFP) in serotonergic neurons using a TPH-GAL4 line which induces the expression of GFP within serotonergic systems in Drosophila (Huser et al 2012; Hingham et al, 2019), we are able to visualise the how long-term psilocybin exposure acts on the serotonergic systems of Drosophila. Furthermore, through exploring calcium signalling in GCaMP6s expressing serotonergic neurons we study the acute effects of psilocybin on serotonergic activity. In combination with this, we have optimised local field potential recordings (LFP) within the Drosophila central nervous system in order to record from the mushroom body structures of Drosophila, which is the region of the Drosophila brain that expresses serotonergic neurons (Huser et al, 2012). This provides data how psilocybin influences the electrical activity of the serotonergic system. Through this model, we aim to be able to uncover how psilocybin can modulate serotonergic systems and how this may be successful in treating affective disorders that are associated with abnormal functioning of such systems.

 

References:

Doss, M.K., Považan, M., Rosenberg, M.D., Sepeda, N.D., Davis, A.K., Finan, P.H., Smith, G.S., Pekar, J.J., Barker, P.B., Griffiths, R.R., Barrett, F.S. (2021). Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder. Translational Psychiatry, 11, 574.

Higham, J.P. et al. (2019) ‘Restoration of olfactory memory in drosophila overexpressing human Alzheimer's disease associated Tau by manipulation of L-type Ca2+ channels’, Frontiers in Cellular Neuroscience, 13.

Huser, A. et al. (2012) ‘The serotonergic central nervous system of the drosophila larva: Anatomy and behavioralfunction’, PLoS ONE, 7(10).

Ling, S., Ceban, F., Lui, L.M.W., Lee, Y., Teopiz, K.M., Rodrigues, N.B., Lipsitz., O., Gill,H., Subramaniapillai, M., Mansur, R.B., Lin, K., Ho, R., Rosenblat, J.R., Castle, D., & McIntyre, R.S. (2022) Molecular mechanisms of psilocybin and implications for the treatment of depression. CNS Drugs, 36, 17-30. 

Mann, J.J. (2023). Is psilocybin an effective antidepressant and what is its mechanism of action? Cell Reports, 4 (1), 100906. 

 

PC3: Triose-phosphate isomerase (TPI) dysfunction alters synaptic vesicle release mechanisms and reduces life span

 

Ælfwin Stone & Joern R. Steinert

 

School of Life Sciences, The University of Nottingham

 

Neurodegeneration has been extensively linked to aberrant production of redox active molecules, e.g. nitric oxide (NO). One target of NO-mediated post-translational modifications is the glycolytic enzyme triose-phosphate isomerase (TPI) which catalyses the conversion of dihydroxyacetone phosphate and glyceraldehyde-3-phosphate. In parallel, reported mutations within the TPI protein render it inactive and are linked to neurodegenerative human disease, named TPI Deficiency, which is caused by a point mutation in the TPI gene.

In this work Drosophila melanogaster expressing mutant TPI (wstd1, M80T, and I170V point mutations) were used as disease models to identify impacts of aberrant TPI function on neuronal physiology at excitatory glutamatergic neuromuscular junctions (NMJ) (w1118 and Canton.S served as controls).

Two-electrode voltage-clamp recordings were taken from third instar larvae fillets. Confocal images of larval NMJs and adult brains, labelled with HRP/BRP, and caspase/anti-AGE, were taken on a Zeiss LSM 880 confocal microscope to characterise active zones (BRP), bouton morphology (HRP), apoptosis (caspase), and advanced glycation end-products (AGE). Western blots were run as standard, longevity assays assessed daily survival.

Data is expressed as mean±SEM (n=no. of muscles/flies). Student’s t-test and Log-rank (Mantel-Cox test) were used for comparisons with p<0.05 being significant.

Longevity was seen to be reduced in TPI mutants, median lifespans of 40 and 42 days in wstd1 and M80T vs 60 and 68 days in w1118 and Canton.S respectively (p<0.005, N>139).

M80T showed slightly increased evoked amplitudes and Wstd1 showed significantly increased evoked amplitudes compared to Canton.S. I170V showed significantly reduced amplitudes compared to w1118. None of the TPI mutants showed altered amplitudes of spontaneous events.

Synaptic depletion and recovery following 50Hz train stimulations differed between lines, amplitudes showed suppression to 67±4%, 47±6%, 52±8%, and 54±9% for w1118, wstd1, M80T, and I170V respectively (n=11-4 N=≥3 p<0.0001). Wsdt1 and M80T lines show significantly reduced expression of TPI protein, however the I170V line does not show this reduction in comparison to controls.

The data suggests that the TPI-mutant phenotype is in part due to altered synaptic vesicle dynamics, possibly associated with vesicle pool organisation or endo/exocytosis. Suppressed TPI activity also enhances protein glycation and redox stress, possibly contributing to the observed phenotypes. Both possibilities offer potential therapeutic routes to manage or treat disease.

 

PC4; The contribution of a high-fat diet to neurodegeneration and oxidative stress in a Drosophila melanogaster model of Alzheimer’s disease

 

Megan de Lange & Joern R Steinert

 

School of Life Sciences, The University of Nottingham

 

Alzheimer’s disease (AD) poses a growing global health challenge due to its increasing prevalence. AD is a complex neurodegenerative disease characterised by abnormal accumulation of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) consisting of hyperphosphorylated Tau, leading to brain changes and cognitive decline. Predisposing genetic mutations, such as those affecting Aβ accumulation and aggregation or apolipoprotein signalling, enhance the risk of developing AD which may be further accelerated by environmental factors such as diet.

To investigate the effect of a high-fat (HF) diet on AD pathology a Drosophila melanogaster model was used, including flies overexpressing Aβarc mutations, resembling familial AD, and hApoE4 expressing flies modelling sporadic AD.

The flies were divided into normal food (NF) and high-fat (HF) groups with further grouping by age, 10 and 45 days old, and sex. Multiple assays were conducted, characterising oxidative stress markers, cleaved Caspase-3 expression, lifespan and climbing ability. This is the first study to characterise combinatorial effects of diet and genetics on pathological phenotypes in AD in both genders in a Drosophila model. 

The findings suggest a HF diet, age, and genotype are all factors that can influence oxidative stress, the response to oxidative stress, and AD pathogenesis. Notably, the use of coconut oil in the HF diet hinted at potential neuroprotective effects, challenging expectations that this diet would exacerbate AD pathogenesis.

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PC5: Zinc Finger Homeobox-3 Alters Arcuate Nucleus Growth Hormone Axis Components and Whole Body Metabolism in Mice

 

Marwa Al-Khalidi1, Bharat Muthukumar1, Joshua Brunt1, Athira S. N. Jayalekshmy1, Stephanie Mitchell1, Louisa Zolkiewski2, Gisela Helfer3, Ashleigh G Wilcox2, Gareth Banks1,2, Lee Moir2, Liz Bentley2, Dana Wilson4, Perry Barrett4, Patrick M Nolan2 and Rebecca Dumbell1,2

 

1. School of Science and Technology, Nottingham Trent University, Nottingham, UK. 2. Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell, Oxford, UK. 3. School of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford, UK. 4. The Rowett Institute, University of Aberdeen, Aberdeen, UK. 

 

Text body: Zinc finger homeobox-3 (ZFHX3) is a transcriptional regulator of behavioural circadian rhythms, and has role in neuronal development and peripheral signal pathway modulation. Our recent work identified a role for ZFHX3 in metabolism for the first time, in a mouse harbouring a missense mutation in ZFHX3 called Short Circuit (Sci). This mutation is similar to a human mutation in a highly conserved protein coding region of ZFHX3. Sci mice have shorter body length and lower body weight, circulating metabolic hormones and food intake. To demonstrate that this mouse models the lower BMI found in people with the similar mutation, we calculated that Sci mice also have a lower index measurement (“mouse BMI”). We demonstrated that expression of growth axis components Ghrh, Sst, Ghr and Npy and Pomc were altered in the arcuate nucleus (ARC), but not in other brain regions. In these mice, lean mass was significantly lower from an early age, while fat mass differences were only apparent at one year old. Here we show the expression of ZFHX3 protein through the hypothalamus is limited to regions we found altered transcripts in our previous study, further implicating the functional role of ZFHX3 to drive these changes. While our hypothesis has been that ZFHX3 drives altered metabolism through hypothalamic processes, it is also highly expressed in adipose tissues. Therefore, we tested whether ZFHX3 may have additional roles in peripheral metabolism. We demonstrate differential expression of Zfhx3 in multiple white and brown adipose tissues from wildtype mice, although consistent across a diurnal 24 h timecourse (qPCR). We found that ZFXH3 protein levels are higher in undifferentiated vs differentiated 3t3l1 (pre)-adipocytes (western blot), implying a role in adipocyte development. This suggests that ZFHX3 may have a pleiotropic effect to drive metabolic changes both centrally and peripherally. 

 

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PC6: The role of monoamine oxidase A in controlling protein degradation and neuronal cell death

 

Narinder Gill, Luigi De Girolamo and Aslihan Ugun-Klusek

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Nottingham Trent University

 

Parkinson’s disease (PD) is a neurodegenerative condition that affects around 1% of the population above the age of 60. Disease involves the progressive loss of dopaminergic neurons (dopamine producing neurons) in the mid-brain. There are no disease modifying drugs for PD and current pharmacological treatments for PD focus on the alleviation of the symptoms. Around 70% of dopaminergic neurons are lost before the symptoms of PD begin. Exact molecular mechanisms involved in PD pathology are still unknown, however, several studies suggest that abnormal protein clearance, mitochondrial dysfunction, and oxidative stress play a crucial role.

Monoamine oxidases (MAOs) are mitochondrial enzymes that play a central role in the homeostasis of neurotransmitters such as serotonin and dopamine in the brain. Oxidation of monoamines by MAOs generate hydrogen peroxide (reactive oxygen species, ROS) and aldehydes as by-products. Oxidative stress is known to damage proteins as oxidized proteins become aberrantly folded. The proteasome degrades aberrant proteins and therefore plays an important role in protein clearance and homeostasis. The proteasome is a large protease complex, has a barrel shaped structure that is composed of two subcomplexes: a catalytic core particle (CP; also known as the 20S proteasome) and one or two terminal 19S regulatory particles. The 26S proteasome consists of a 20S core with additional 19S regulatory units. The 26S proteasome requires ATP to degrade proteins on the other hand the 20S proteasome can cleave proteins in an ATP independent manner. Oxidative stress suggested to cause the disassembly of the 26S proteasome into the constituent 19S and 20S subunits, which may be an adaptive mechanism.

The overall aim of this study is to elucidate the role of MAO-A in controlling the protein degradation pathways with a focus on proteasome. Proteasome activity assays were conducted to determine potential alteration in proteasome activity with increased expression of MAO-A and addition of exogenous substrate. Data obtained so far suggest increased MAO-A activity results in increased proteasomal activity at all three proteasome catalytic sites. The increase in proteasome activity correlates with an increase in ROS; neurons overexpressing MAO-A and treated with exogenous substrate (100µM tyramine) show a higher level of ROS than control and untreated cells. Current experiments are focusing on unravelling the mechanism and increased proteasome activity appears to be linked to proteasomal dissociation (increased free 20S, ATP independent degradation). This is the first study demonstrating increased MAO-A activity can modify proteasome function.

 

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PC7: Investigating the mechanical signals that regulate hippocampal neurogenesis

 

 Irem Akyel, Graham Sheridan 

 

 The University of Nottingham

 

Alzheimer's disease (AD) is a neurodegenerative disorder that dysregulates learning and memory and disrupts daily activities. A hallmark of AD is a marked reduction in hippocampal neurogenesis, a process that also naturally declines with age. This raises a compelling therapeutic question: Could enhancing neurogenesis help mitigate AD-associated cognitive deficits? Recent studies indicate that altered mechanical properties of AD brain tissue, e.g. decreased stiffness, may impair neurogenesis by disrupting mechanotransduction signalling pathways via Piezo1 channels. We aim to investigate if modulating Piezo1 activity promotes hippocampal neurogenesis and the intracellular pathways involved, thus providing new insights into mechanisms of cognitive decline in AD.

 

Using organotypic hippocampal slice cultures from the brains of wild-type CD1 mice, we investigated the role of Piezo1-mediated mechanotransduction in neurogenesis in the dentate gyrus. Hippocampal slices were treated with either GsMTx-4, an inhibitor of mechanosensitive channels, or Yoda1, a selective agonist of Piezo1. Slices were then fixed and immunofluorescently-labelled with the stem cell markers Ki67 or EdU and with NeuN and glial fibrillary acidic protein (GFAP). Preliminary results of image analysis using R Studio illustrated a significant reduction in the number of EdU+ cells in GsMTx4-treated slices, while Yoda1 treatment resulted in a non-significant increase in EdU+ cells. Further experiments with different doses of Yoda1 (1, 3, and 10 µM) demonstrated that there is an increase in the number of neurons co-stained with NeuN and EdU with increasing dosage suggesting a role of Piezo1 in regulating neurogenesis. 

  

These findings highlight the critical role of mechanotransduction in regulating the neurogenic niche of the dentate gyrus within the hippocampus, emphasising the potential of Piezo1 as a therapeutic target. By advancing our understanding of molecular regulators of neurogenesis, this work may contribute to the development of targeted interventions aimed at alleviating cognitive symptoms associated with AD. 

 

PC8: Towards an astrocyte miRNA-targeted ALS treatment

 

Hannah Bailey1, Katherine White1, David Boocock2, Claire Coveney2, Federico Dajas-Bailador1, Dan Scott1, Sébastien Serres1, Rob Layfield1.

 

  1. School of Life Sciences, University of Nottingham

  2. John van Geest Cancer Research Centre, Nottingham Trent University

 

Introduction: Astrocyte reactivity and neurotoxicity is a known contributor to the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease. There are currently few approved drugs to treat ALS, with average life expectancy remaining at 2-5 years after diagnosis.

The aim of this research was to use a multi-omics approach to identify cellular pathways altered upon chronic astrocyte reactivity. Manipulation of these pathways in reactive astrocytes using miRNA inhibitors as RNA therapeutics is now being investigated, with the aim of promoting neuroprotection. 

Methods: Human primary astrocytes were cultured in a serum-free model of ‘quiescent’ astrocytes and a serum-cultured model of ‘reactive’ astrocytes. RNA and protein were extracted from 3 replicates of quiescent and reactive astrocytes. Small RNAseq was performed to profile miRNA, while a label-free semi-quantitative mass spectrometry approach called SWATH-MS was used for proteomics.

Results: Proteomics and RT-qPCR reveals downregulation of the antioxidant defence Nrf2 pathway, a known ALS pathomechanism, upon chronic astrocyte reactivity. Integration with miRNAseq data showed this is unlikely to be due to miRNA targeting of Nrf2. Additionally, integration of miRNAseq with RT-qPCR data suggests a possible reactivity-induced pathway, where upregulation of the ALS-associated miR-206 may result in reduced expression of the anti-inflammatory transcription factor NURR1. In current work, lentivirus-mediated inhibition of Nrf2 and NURR1-targeting miRNAs in reactive astrocytes is being investigated, with the aim of reducing oxidative stress and neuroinflammation. We predict this will improve astrocyte-mediated neuroprotection, thus working towards a future astrocyte-targeted ALS therapeutic strategy.

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PC9: Hypoxia induced HIF1α activity and it’s potential connections to diabetic chronic pain

 

 Jack Corbett, Richard Hulse

 

Nottingham Trent University

 

Abstract: In the UK, approximately 4.3 million people are diagnosed with Diabetes as of 2023. Of those afflicted, diabetic neuropathy has been found to effect up to 60% of diabetic patients at some point during their life. This neuropathic pain often manifests as chronic hypersensitivity in the periphery. Unlike normal pains however, painkillers are mostly ineffective and so finding the root cause of this chronic pain is important for improving the living quality of those afflicted. The main aim of my project is to study how hypoxia effects the development of chronic pain in the spinal cord. To investigate this, we have currently been primarily researching HIF1α which has been previously linked to pain formation during hypoxia. Previous experiments alluded to HIF1α being involved in pain processing however the exact mechanism is not yet fully understood. Our experimental plans involved exploring how microenvironmental disturbances in the dorsal horn influences nociceptive processing. Initial studies involved using a rodent model of hypoxia induced pain. Here we instigated hypoxia induced pain through intrathecal injections of either a PBS vehicle control or 1mM DMOG. Immunohistochemistry was performed to identify hypoxia induced alterations in synaptic architecture, primarily focussing on excitatory (PSD95) and inhibitory (Gephyrin) synaptic markers (Figure 1).

 

Figure 1: (A) x20 immunofluorescent image of a DMOG treated spinal cord stained with Gephyrin (Red), NeuN (Green) and DAPI (Blue). (B, C) Red Gephyrin channel split and thresholded to measure integrated density. (D) Integrated density analysis of spinal cords stained with PSD95 and Gephyrin post 4-hour 1mM DMOG treatment. (E) Integrated density analysis of spinal cords stained with PSD95 and Gephyrin post 24-hour 1mM DMOG treatment. (* P=<0.05)

 

Figure 2: Non-linear curve showing the changes in mechanical withdrawal threshold of mice intrathecally treated with PBS vehicle, DMOG and DMOG with WNT5a.

Further to this, we performed behavioural Von Frey studies on mice to explore the development of mechanical hyperalgesia and to determine the mechanistic dependence upon WNT5a signalling. WNT5a is a glycoprotein mediator of cell-cell interactions and has been implicated in the development of the nervous system and synaptic physiology. As seen in Figure 2, we demonstrated that intrathecal delivery of WNT5a prevented DMOG induced pain. The DMOG treatment in Figure 2 sees the mechanical withdrawal threshold curve move to the left which is indicative of the formation of hyperalgesia. Further to this we can see that compared to the vehicle line, the DMOG with WNT5a line shifts slightly to the right which could be indicative of a reduction in mechanical sensitivity. This, paired with the results seen in Figure 1 has brought about a new theory into GABA Disinhibition and how this may impact our system. GABA Disinhibition is the theory by which typically inhibitory GABA synapses flip and become effectively excitatory. From these conclusions so far, the changes to GABA functioning may help explain why traditional painkillers lose their effectiveness during chronic pain and so we hope to look into how this disinhibition occurs and how it can potentially be reversed.

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PC10: The effect of medulloblastoma-derived extracellular vesicles on the development of mouse primary cortical neurones in vitro

 

Sophie McCann, Hannah Jackson, Gareth Hathway, Beth Coyle and Federico-Dajas Bailador

 

 University of Nottingham 

 

Text body: Medulloblastoma is the most common malignant paediatric brain tumour and has a relatively high overall five-year survival rate of approximately 65%. Although paediatric brain tumour survivors are more likely to experience major psychiatric disorders, neurodevelopmental disorders and chronic pain than their healthy peers, little research has been done on the neurobiological consequences of experiencing a brain tumour during such a key developmental window. One unexplored avenue is the ability of medulloblastoma cells to affect the development and connectivity of cortical neurones within the brain via the release of extracellular vesicles (EVs). We added EVs from several medulloblastoma cell lines to mouse primary cortical neurones in culture. After 24 hours, we observed a significant increase in axon length exerted by the recurrent tumour EVs but not the primary tumour EVs. Small RNA sequencing of the cargo of these EVs revealed high expression of several microRNAs (miRNAs) that are known to control axon growth. Ongoing work to investigate whether these miRNAs are responsible for the observed increase in axon length will help us to unravel the ability of medulloblastoma cells to communicate with neurones in the brain.  

 

PC11: Investigating the role of the ubiquitously expressed thioesterase Ppt1- a proposed multi organ morphological and molecular study to inform therapeutic targeting

 

Zak Vincent, Samantha L. Eaton, LARIF research team, Mark Gray, Fraser Murdoch, Simon G Lillico, Stefano Guido, Bruce A. Whitelaw, Jonathon D. Cooper, Dominic Kurian, Gerard Thompson & Thomas M. Wishart.

 

Affiliation: Nottingham Trent University

 

Text body: Neuronal ceroid lipofuscinoses (NCL)/Batten disease are often used interchangeably as an umbrella term to describe a group of lysosomal storage disorders characterised by a build-up of autofluorescent storage material within cells. This group of autosomal recessive neurodegenerative diseases collectively represent the most common form of ‘childhood dementia’. There are 13 distinct types of Batten disease caused by different mutations which all affect the form and/or function of the lysosome, with typical symptoms include blindness, psychological and motor deficits and seizures. A key difference is the onset and duration of symptoms. This study focuses on CLN1 which is an infantile and aggressive form of the disease caused by a PPT1 deficiency. In the absence of a functional PPT1 gene, lipofuscin granules accumulate within lysosomes. with an average life expectancy of 9 years old.

 

PPT1 is a ubiquitously expressed protein responsible for the removal of palmitate groups from proteins. There is no cure due to several issues predicated by a relatively poor understanding of the regional nature of the disease: 1. Why is the nervous system preferentially affected at early stages of the disorder? 2. What (if any) impact is there on other organ systems? and 3. How can (and should) we predict disease staging and track progression?

 

We have generated a unique resource address this– a CLN1 ovine model. Here we will outline our plans to use this as a tool to carry out a comprehensive morphological analysis through high resolution MRI of the nervous system and fully body CT scans to characterise regional morphometrics from early to end stage disease. We will also carry out a proteomic analysis of multiple brain regions, organ systems and body fluids to further our understanding of the molecular consequences of altered PPT1 throughout the body.

 

We believe this study will play a significant role in informing preclinical therapeutic trials on regional targeting and timing of intervention.

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PC12: Connexin 43 mediated monocyte mitochondrial transfer prevents cisplatin induced sensory neurodegenerationJessica Bates, Beccy Owen, Jack Corbett, Mark Paul-Clark, Richard Philip Hulse*.

​

Centre for Systems Health and integrated Metabolic Research, Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, NG11 8NS.

 

Platinum based chemotherapeutics cisplatin are front-line treatments for pediatric and adult cancer. Despite advancements in medical interventions, chemotherapy-induced peripheral sensory neuropathy is a common adverse health related complication that can persist for the long-term and impacts upon individual’s quality of life. Recently, the causes of chemotherapy induced sensory neurodegeneration has been linked to sensory neuronal mitochondrial dysfunction.

 

Here this study investigated how monocytic mitochondria donation to recipient cisplatin damaged dorsal root ganglia (DRG) sensory neurons prevented platinum-based chemotherapy-induced sensory neurotoxicity. Neuronal cell line, SH-SY5Y, or mouse DRG sensory neurons were treated with either vehicle or cisplatin, and co-cultured with mitotracker-labelled THP1 monocytes. This study is complemented by in vivo study using a single 0.1 mg/kg injection of cisplatin into P14 C57BL/6 mice.

 

Cisplatin induced dysmorphic mitochondria in and diminished oxidative phosphorylation dependent energy production in cisplatin treated dorsal root ganglia sensory neurons. DRG sensory neurons exposed to cisplatin were recipients of monocyte mitochondria indicated by increased intracellular mitotracker fluorescent labelling. Mitochondrial transfer to sensory neurons was neuroprotective, preventing neurite loss and sensory neuronal apoptosis. Vehicle treated DRG sensory neurons did not demonstrate significant mitochondrial uptake. Furthermore, cisplatin induced mitochondrial transfer was prevented by pharmacological inhibition of gap junction protein, connexin 43. Connexin 43 inhibition led to reduced neuroprotective capacity via mitochondrial transfer.

 

These findings demonstrate that monocytic mitochondria transfer to DRG sensory neurons damaged by cisplatin, is dependent upon gap junction intercellular communication to promote sensory neuronal survival. This novel process in sensory neuronal protection is a potential novel therapeutic intervention for alleviating neuropathic pain in individuals treated for cancer.

 

PC13: Investigating sensory phenomena and neurometabolites in Tourette Syndrome

 

Caitlin M. Smith1,2, Adam Berrington2,3, Susan T. Francis2,3, Stephen R. Jackson1,2,4

 

1 School of Psychology, University of Nottingham

2 Precision Imaging Beacon of Excellence, School of Medicine, University of Nottingham

3 Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham

4 Institute of Mental Health, School of Medicine, University of Nottingham

 

Tourette Syndrome (TS) is a neurodevelopmental disorder characterised by involuntary movements and vocalisations. Sensory processing abnormalities are a commonly reported source of discomfort in TS, and while underexplored, are proposed to stem from inhibitory dysfunction in TS. However, the precise relationship between any disruptions in sensorimotor cortical inhibition and sensory processing is unclear. To investigate this, we measured self-reported external sensitivity and quantitative sensory thresholds in 19 typically developing controls and 16 participants with TS. In vivo 1H 7T MRS was also used to quantify concentrations of the inhibitory neurometabolite, GABA, in the left sensorimotor cortex. Results revealed no significant group differences in self-reported external sensitivity but displayed evidence of poorer quantitative sensory thresholds and lower MRS-GABA concentrations in the TS group. Moreover, while sensory thresholds and MRS-GABA were not correlated in either group, self-reported external sensitivity positively correlated with MRS-GABA in TS. These findings provide preliminary support that while disruptions in sensory processing and inhibition are evident in TS, there may only be a link between perceived external sensitivity and inhibitory functioning.

 

 

PC14: Unhealthy Ageing and Memory Loss Associated with Vascular Insufficiency 

 

Jennifer Cale, Sébastien Serres, Tracy D. Farr, Joern R. Steinert

 

School of Life Sciences, University of Nottingham, UK, NG7 2UH

 

Vascular risk factors like high blood pressure and cholesterol are well-known risk factors for heart diseases but they also increase the risk of developing dementia. Vascular dementia is the second most common type of dementia after Alzheimer’s disease, but many people living with Alzheimer’s disease also features blood vessels that don’t work properly. This could mean there is compromised blood flow to the brain. If new treatments are to be developed that could help tackle this, we must understand what is happening in the blood vessels as well as the brain.  

 

Perivascular astrocytes are abundant in the brain and form a physical bridge between neurons and blood vessels. In addition to providing neurons with nutrients and oxygen, astrocytes control neurovascular coupling that serves to match local cerebral blood flow to regional neuronal energy use and ensures normal functioning of the brain. Vascular insufficiency takes place over several years without any obvious clinical symptoms and could be exacerbated by environmental stress or lifestyle choices. Astrocytes in particular respond to endothelial cell activation that arises from vascular insufficiency, and collectively these processes have a huge impact on brain function as we age. Recently, we have shown that astrocytes react to pathological changes with dysregulated oxidative and nitric oxide signalling which prevents astrocytes from regulating neurovascular coupling. Therefore, we aim to investigate the link between compromised energy resources and oxygen supply and perivascular cells to better understand how neurovascular coupling may be affected and predispose the brain to damage during unhealthy ageing.  

 

This will be accomplished via an in vitro characterisation of astrocyte and neuronal response to vascular insufficiency-like conditions as well as an in vivo mouse model, particularly in differing oxygen concentrations in cell culture. We hypothesis that the same damage to astrocyte-blood vessels communication may result in cognitive changes observed in these mice. 

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PC15: Understanding the Role of Maxi Potassium Channels in Glioblastoma multiforme

 

Authors: Kirree Tannahill

 

School of Life Science, The University of Nottingham

 

Text body: Glioblastoma multiforme (GBM) is a highly aggressive and invasive grade 4 tumour, which is the most common primary brain tumour in adult. GBM biology is regulated through a variety of Ion channel, maxi potassium channels (BK) have been shown to be over expressed in GBM cell lines. These high conductance voltage gated potassium channels have been related to many physiological events involved in GBM, these include proliferation of the tumour, invasion and migration all enhancing the aggressive nature suggested by these tumours.

This study has confirmed the biophysical character of BK within SF188 cells lines throughout the use of cell attached patch clamping configuration. Through this study aims to explore the mechanosensitive expression of these channels, further aiming to explore an association BK channels an ion channel, PIEZO1 and TRPC, shown to be expressed in GBM in order of better understanding the effects these channels may have of BK channel kinetics and expression of these channels.

BK channels were confirmed in patches, a mechanosensitive impact was seen by these channels increasing expression in the presence of an increased negative pressure being applied to the patch. In presence of Ruthenium red a block of this mechanosensitive effect has been observed.

Increased activation of BK by mechanical strain through increasing a negative pressure indicates a sensitivity to cellular biomechanics of these channels. Further the loss of mechanosensitive effect in the presence of ruthenium red indicates an indirect modulation of these channels by other channel types within these cells which are also involved in calcium signalling these cells thus suggesting an involvement of TRPC and PIEZO1. This highlights the need for isolation of these channels to gain further insights into the kinetics of these smaller channels.

 

PC16: Investigating the impact of Alzheimer’s Disease on mitochondria

 

Rachel Cruickshank, Lisa Chakrabarti, Kevin Gough.

 

School of veterinary medicine and science, University of Nottingham

​

Alzheimer’s Disease (AD) is a neurodegenerative disease characterised by gradual onset cognitive decline. One theorised causative agent in AD is Amyloid-beta (Aβ). Aβ is a protein expressed in healthy individuals, but during AD Aβ has been shown to aggregate into fibrils and accumulate in the brain. It is not entirely clear whether Aβ is a cause or result of AD. Mitochondrial dysfunction is an early hallmark of AD. This project aims to explore the impact of Aβ on mitochondrial function.

This project uses MTT assays and high resolution respirometry (HRR) on SH-SY5Y cells to assess mitochondrial function.

Aβ was shown to reduce mitochondrial function. Incubating Aβ to induce aggregation state of the Aβ did not change the effect on mitochondria. Removing Aβ reversed the effect.

The next steps are to further explore the impact of Aβ on mitochondrial function using HRR. This will allow us to develop a robust mitochondrial phenotype for AD which we can use to test the efficacy of antibodies for potential immunotherapy use.

 

PC17: An investigation of the effects of α and β-frequency neural entrainment using tACS on phase-aligned TMS-evoked corticospinal excitability”

 

Aikaterini Gialopsou1*, Stephen R. Jackson1,2,3

1School of Psychology, University of Nottingham, University Park, Nottingham, NG7 2RD, UK

2Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, NG7 2RD, UK

3Institute of Mental Health, School of Medicine, University of Nottingham, University Park, Nottingham, NG7 2RD, UK

 

In this study we investigate the effects of phase-aligned tACS-TMS stimulation for α and β-frequency tACS on entrainment. Although deep brain stimulation (DBS) is an effective neurostimulation method for many brain disorders, DBS is inaccessible for most individuals, expensive or unsuitable for children and adolescents. Other non-invasive neurostimulation approaches, like TMS and tACS, unfortunately exhibit large intra- and inter-subject variability in their efficacy, which limits their use clinically. Here, we propose that synchronizing TMS with ongoing brain oscillations (α-and β-tACS) could enhance its efficacy and reduce variability, addressing a critical limitation in current clinical use. The variability was assessed based on changes of the inter-trail coefficient of variation (CV).

 Indeed, our findings confirm that during both α- and β-tACS, the corticospinal excitability and inter-trial variability varied as a function of tACS phase. Maximum excitability during α-tACS was observed at the negative peak (trough), while during β-tACS the maximum coincided with the positive peak (peak). However, the minimum inter-trial variability was observed at the falling edge during α-tACS and at the trough during β-tACS. The findings indicate that the optimal tACS phase to deliver TMS may vary based on the study's objective: maximizing TMS efficacy (i.e., increasing MEP amplitude) or minimizing stimulation variability.

 

PC18: Mitochondrial free radical detection via modulation of photoluminescence from nitrogen vacancies in diamond-based quantum sensors

 

Jacob Reed¹, Brad Ebanks¹, Shalini Menon², Nicoletta Moisoi³, Melissa Mather², Lisa Chakrabarti¹

 

1 School of Veterinary Medicine and Science, Sutton Bonnington, University of Nottingham, Loughborough, England 

2 Optics and Photonics Research Group, Faculty of Engineering, University of Nottingham, Nottingham, England

3 Leicester School of Pharmacy, De Montfort University, Leicester, England

 

Mitochondria, essential for cellular viability, are the primary source of free radicals, crucial molecules with high reactivity and dynamic nature, making their detection challenging. This work presents a robust and straightforward quantum sensing method for selective free radical detection throughout biological processes. We employ negative charge state of Nitrogen-Vacancy (NV) colour centres in diamond exploiting their spin-dependent photoluminescence. We employ a low optical power method to harness the NV ground state spin triplet's sensitivity to paramagnetic species, like free radicals, that preserves the NV charge state. Using simple modifications to an inverted fluorescent microscope we perform Optically Detected Magnetic Resonance (ODMR) and Microwave Modulation (MM) of the NV photoluminescence and evaluate changes ODMR and MM contrast, as surrogate measures of the NV optical polarizability and hence paramagnetic species. We introduce a methodology using the spin probe 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) for selective free radical identification. TEMPOL, a cell-permeable probe, scavenges free radicals, as a Superoxide dismutase 2 (SOD2) mimic, quenching the contrast in both ODMR and MM. Restoration of contrast is observed upon free radical species that preferentially react with TEMPOL (hydroxyl radical, superoxide radicals). Validation experiments with irradiation of H2O2 corroborated the findings.

The aforementioned methodology was employed in biological studies encompassing neuroblastoma cells, and wildtype versus PINK1 (PINK189/Y) whole Drosophila Melanogaster. PINK1 mutations exhibit a set of relevant phenotypes of Parkinson’s Disease such as impaired locomotor activity, dopaminergic neuron degradation and mitochondrial abnormalities. High-resolution respirometry alongside specific substrate-uncoupler-inhibitor titrations with TEMPOL was performed to monitor mitochondrial function. This approach effectively detected free radicals across the electron transport system (ETS). Furthermore, the method distinguished enhanced free radical expression in PINK1 flies across the ETS compared to wildtype flies. This simple protocol offers significant advantages for cell biologists and medical discovery, lowering the barrier to entry for quantum sensing applications. This approach allows for studying the entire oxidative phosphorylation process and spin-active intermediates within biological systems. The proposed technology has the potential to help elucidate the biophysical parameters underlying mitochondrial function and dysfunction.

 

PC19: Identifying translated small open reading frames related to epitranscriptomic processes in the neuron

 

Authors: Joseph Stones1, Nathan Archer2, Rupert Fray3, Helen Miranda Knight1

Affiliations

 

1Division of Cells, Organisms and Molecular Genetics, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK

2School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, Loughborough LE12 5RD, UK

3Division of Plant Science, School of Biosciences, University of Nottingham, Sutton Bonington, Loughborough LE12 5RD, UK

 

Epitranscriptomics, the modification of RNA species, has been shown to have broad regulatory activity on mRNA including splicing, nuclear transport, transcript stability, and translation efficiency. The most common of these modifications in mRNA is the methylation of N6 in adenosine (m6A), which is added, selectively interacted with, and removed by writer, reader, and eraser effector proteins respectively. m6A is especially abundant in the brain, and evidence shows that it plays a role in controlling synaptic translation during plasticity, whereas aberrant levels of m6A has been linked to various neurological disorders.

Recently, there has been a growing number of proteins identified that are translated at under 100 amino acids in length, termed microproteins, which have historically been difficult to identify through mass spectrometry and computational methods. Microproteins have been found within noncoding and coding regions of protein coding mRNA, as well as within what was thought to be noncoding RNA. Some of these proteins have been associated with mRNA metabolism, e.g. NBDY, and Alzheimer’s Disease, e.g. SHMOOSE.

Through the analysis of RNA-sequencing datasets of m6A effector protein knockouts in human cell lines, we identify genes and exons that are differentially expressed and patterns of expression across the different experimental conditions. We compare the differentially expressed regions that are thought to be noncoding to a list of translated open reading frames that we generated from public ribosome profiling data of human cell culture and tissue. From the list of translated open reading frames, we predict their potential functions using existing software and by correlation of expression to known genes. The potential microproteins that we identify may hold important roles in RNA metabolism and synaptic function, and also highlights the vast number of translated open reading frames that exist within cells that have not been studied.

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PC20: Optimizing quantitative approaches to Peri-Neuronal Net quantification in the rat hippocampus: Inter-rater reliability and methodological validation in the CA1 Region

 

Ayesha Mohamed Sherief, Jacob Juty, Tobias Bast

 

The University of Nottingham

 

Peri-neuronal nets (PNNs) are specialized extracellular matrix structures that encapsulate neurons in specific brain regions, particularly within the brain hippocampus, where they play a crucial role in regulating synaptic plasticity, neurogenesis, and memory consolidation. Despite their importance in neuronal function, the lack of standardized, quantitative methods for analyzing PNNs has hindered a comprehensive understanding of their distribution and expression. This study introduces a novel quantitative approach for the identification and enumeration of Wisteria floribunda agglutinin (WFA)-positive PNNs in the CA1 subfield of the adult rat hippocampus. Additionally, the study examines the spatial colocalization of PNNs with parvalbumin (PV)-expressing interneurons in the CA1 region of the hippocampus, to explore their functional significance. The primary objective is to assess the inter-rater reliability of the developed technique, quantifying the consistency and reproducibility of PNN counts across independent raters. The results demonstrate the robustness and reliability of the proposed methodology, offering a high degree of reproducibility in PNN quantification.

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PC21: Gene delivery of nucleic acid therapy targeting MAPT for the treatment of Alzheimer’s disease

 

Xinai Shen

 

The University of Nottingham

 

For Alzheimer's disease (AD) pathology, the abnormal accumulation of phosphorylated tau protein is a key hallmark of AD, which is encoded by the microtubule-associated protein tau (MAPT) gene. Therefore, nucleic acid therapeutics targeting MAPT may provide a promising approach to AD treatment. In this study, a MAPT-targeted antisense oligonucleotide (ASO) was utilized to downregulate the expression of pT181. Glyceraldehyde (GA) was used to induce an AD cell model and a differentiated neuronal cell model, both of which overexpressed total tau and phosphorylated Thr181. These models were then utilized to evaluate the efficacy of ASO. To enhance delivery across the blood-brain barrier (BBB), liposomes modified with transferrin (Tf) was designed and prepared. The penetration of liposomes was then evaluated with a 3D bio printed-on-chip BBB model. Ongoing work focuses on optimizing the ASO delivery system for BBB penetration and evaluating its efficacy using advanced BBB models and analytical methods.

PC22: Investigating the therapeutic potential of Metformin in ameliorating Tau pathology in a cellular model of Alzheimer’s Disease

​

Srinithya Paruchuri1  and Shreyasi Chatterjee

 

Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS

 

Background: Alzheimer’s disease is the leading cause of dementia among aging population. Currently accepted treatments are focused on the symptoms while efforts are made to the develop therapies that target the major pathological hallmarks i.e., β-amyloid (Aβ) plaques and hyperphosphorylated Tau tangles. Evidence from epidemiology and neuroimaging studies suggest that Type 2 Diabetes (T2DM) and Alzheimer's disease (AD) have a shared pathogenesis. Moreover, insulin resistance has been shown to impact hyperphosphorylation and aggregation of Tau making this an important risk factor for the detection of early AD. Therefore, an emerging body of research and clinical trials have focused on evaluating the therapeutic potential of the insulin-sensitizing, anti-diabetic drug Metformin in the treatment of AD. However, the mechanisms by which Metformin might impact Tau pathology and the long-term effect of this drug on cellular environment needs to be investigated thoroughly.

Methodology and Results: For this study we have cultured neuroblastoma cells in high-glucose media and investigated whether Metformin can impact total and phospho-tau levels. We observed that with an increasing dosage of Metformin there was a significant decrease of hyperphosphorylated Tau (Ser199/202 and AT8) compared to untreated controls despite an increase in total Tau levels which is again validates in transiently transfected with Tau-wild-type and E14 (pseudo-hyperphosphorylated) mutants.

Conclusion: Taken together our data implies that Metformin at a high dosage significantly decreases Tau hyperphosphorylation at disease epitopes that might be beneficial to AD. Our preliminary data also suggests that an insulin-responsive cellular environment can decrease Tau expression overall although further research is needed to delineate the underlying mechanistic pathways.

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PC23: Investigate autism and intellectual disabilities in Drosophila melanogaster models

​

:Lauren Amos, Keisha Patel and Carlo Breda

​

 Faculty of Health & Life Sciences, De Montfort University, Leicester, LE1 9BH.

​

Neurodevelopmental disorders (NDDs) include a large number of conditions such as Fragile X syndrome and autism spectrum (ASD), among others. They are characterised by limitations in adaptive and social behaviours, such as difficulties in communication and interaction, presence of repetitive and restrictive comportments, intellectual disability (ID), and are often associated with motor deficits and sleep abnormalities.

 

Our research group focuses on the Ras-like small GTPase RAB39B and Patched Domain Containing 1 (PTCHD1) genes. Mutations in these two genes have been linked to ASD and ID in several patient populations; however, their impacts on the neuronal physiology remain poorly understood.

 

To investigate these genes, we use the fruit fly, Drosophila melanogaster, as a model organism. Specifically, we employ RNA interference combined with the GAL4/UAS system to tissue-specifically downregulate the expression of Drosophila Rab39 and Patched-related (Ptr).

 

This poster presents preliminary findings from value-based feeding decision (VBFD) and free-walking locomotor assays exploited to investigate the cognitive status and locomotor behaviour of Rab39 and Ptr knock-down flies. Future work will aim to explore learning and memory, sleep and social impairments in these flies in order to clarify how RAB39B and PTCHD1 contribute to the mechanisms underpinning ASD and may provide novel insight into potential therapeutic strategies for this syndrome.

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PC24: Intranasal delivery of siRNA targeting ApoE4 as a potential treatment of Alzheimer’s disease

 

Huan Li

 

The University of Nottingham

 

Apolipoprotein E (ApoE) has been identified as a critical genetic target in Alzheimer's disease (AD) with three isoforms, which ApoE4 demonstrating an elevated disease risk while ApoE2 lowers this risk. ApoE4 plays a pivotal role in the pathogenesis of AD through its metabolic associations with Aβ, tau protein, and neuroinflammation. In this study, a gene intranasal delivery strategy was employed to design precise targeting of ApoE4 using siRNA along with intranasal gene delivery formulations involving lipid nanoparticles (LNPs) and polymers, which could help biologics bypass the blood-brain barrier (BBB) and translocate into the brain. siRNA targeting total ApoE formulation was prepared as a model and control, and characterized, including particle size, zeta-potential and TEM imaging, following the permeability assessments of siRNA-loaded formulations on an in vitro nasal mucosa model. Additionally, siRNAs specifically targeting ApoE4 were designed and their ability to target and degrade ApoE4 mRNA was tested using an ApoE4 knock-in cell line. Effective siRNA that downregulates ApoE4 expression was identified. These findings indicate the therapeutic potential of ApoE4-targeting siRNA, and formulations with ApoE4-targeting siRNA will be further evaluated in subsequent experiments by intranasal administration to human ApoE4 knock-in mice to assess its disease-modifying effects in AD animal models, including its interactions with Abeta and Tau proteins.

 

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PC25: Understanding cortical auditory-evoked potentials through EEG-fMRI data fusion – a meta-analysis and forward model based high-resolution fMRI tonotopic mapping

 

Carl Rushworth1,2, Alexander Hardy3, Magdalena Sereda1,2, and Katrin Krumbholz1,2

 

1. Hearing Sciences, Mental Health and Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK

2. NIHR Nottingham Biomedical Research Centre, Ropewalk House, 113 The Ropewalk, Nottingham NG1 5DU, UK.

3. Department of Psychology, Nottingham Trent University, Nottingham, England, UK

 

Background

Cortical auditory-evoked responses (CAERs) are rarely used in clinical practice but could hold crucial information about auditory deficits inaccessible to current diagnostic tests (e.g., hidden hearing loss, tinnitus). However, as CAERs reflect aggregate contributions from multiple sources, which may reinforce or cancel depending on relative orientations, their amplitudes may carry substantial variability unrelated to underlying source strengths. This study presents a first step towards understanding CAER amplitude variability by relating one of its main factors – stimulus frequency – to the topography of the cortical tonotopic map and underlying surface morphology.

 

Methods

We conducted a meta-analysis of studies that recorded auditory-evoked response (AER) amplitudes from all levels of the auditory pathway, including subcortical, as well as early and later cortical levels, for at least two stimulus frequencies. The meta-results were compared with a forward model constructed from an fMRI-based probabilistic tonotopic map and a realistic head model based on the MNI Colin-27 average (2008 Version).

 

Results

The dependence of AER amplitudes on stimulus frequency differed not only between cortical and subcortical responses, as may be expected, but also between earlier and later cortical responses: whilst later CAER amplitudes decreased at higher frequencies, earlier ones showed no such decrease.

 

Discussion

The forward model suggested that the difference in frequency-dependence of earlier versus later CAER amplitudes relates to whether responses activate one or both of two mirror-symmetric primary tonotopic gradients, whose higher-frequency portions are located on opposite banks of Heschl’s gyrus (HG), causing response cancellation when activated simultaneously. This suggest that only one of the two gradients receives direct thalamic input, and is thus homologous to A1, consistent with micro-structural MRI data showing higher intracortical myelination only in the anterior gradient.

 

Conclusion

Cortical morphology represents a major, hitherto unconsidered, factor in CAEP amplitude variability, which can now be addressed through fMRI tonotopic mapping.

 

PC26: Low dimensional structure of UPDRS-scored symptoms in Parkinson’s Disease patients

 

Bhadra Santhi Kumar1, Ioana Cociasu2, Fahd Baig2, Lucia Ricciardi2, Francesca Morgante2, Jonathan O’Keeffe3, Mark Humphries1

 

1 School of Psychology, University of Nottingham, Nottingham NG7 2RD, UK

2 St George’s, University of London, Cranmer Terrace, London, SW17 0RE, UK

3 Machine Medicine Technologies Ltd., The Biscuit Factory Unit J112, 100 Drummond Road, London SE16 4DG, UK

 

Patients with Parkinson’s Disease exhibit a wide range of motor and non-motor symptoms commonly evaluated using a set of clinical scores called the UPDRS (Unified Parkinson's Disease Rating Scale). The UPDRS is the only Parkinson’s Disease assessment that is consistent across clinics world-wide, and underpins decisions of pharmacological treatment and surgery, including the implanting of deep brain stimulators.  However, it is unclear what variations in Parkinson’s disease it implicitly captures, and so how these might limit its diagnostic or prognostic capability.

To examine the structure in the UPDRS clinical scores, we analyzed data from 876 PD patients from the Parkinson’s Progression Markers Initiative (PPMI) database, focusing on the 60 features of UPDRS parts I, II, and III. Using Principal Component Analysis (PCA), we found significant redundancy within the UPDRS scores, suggesting it might possess an underlying low-dimensional structure.   To identify a single defined subspace that could represent the patient data with minimal dimensions, we applied our Spectral Estimation approach to find the unique set of data dimensions not predicted by a null model of chance correlations.   

We found that the UPDRS data, originally defined by 60 features, exhibits a six-dimensional structure not captured by the null model. This 6-dimensional structure was robust across subsets of patients. Remarkably, even with this ten-fold reduction in dimensionality, held-out patient data could be accurately represented in the low-dimensional space with minimal reconstruction error. The dimensions of this subspace reflected a meaningful organization of the data, reflecting symptom subtypes such as tremor-dominant and rigidity-dominant PD. Intriguingly, the subspace also differentiated symptoms based on whether they were self-reported or physician-assessed. Together, our results show that the UPDRS instrument contains high redundancy and captures just six dimensions of variation at best.

This robust low-dimensional representation could provide valuable insights into disease heterogeneity and simplify the prediction of distinct PD progression subtypes, which could enhance prognosis and inform tailored treatment strategies, including deep brain stimulation.

 

PC27: The effect of microbiota modulation in a PINK1 mutant Drosophila melanogaster model of Parkinson’s disease

​

 Yulli Passos, Laura Smith and Nicoleta Moisoi

​

 Faculty of Health and Life Sciences, De Montfort University, Leicester

 

Parkinson’s disease (PD) is the second most common neurodegenerative disease. In the last decade, it has been proposed that the gut microbiota is involved in PD etiopathology. Although several studies have determined microbial imbalance and the bacterial species affected, the mechanisms by which this imbalance can lead to neurodegenerative disorders have yet to be unravelled. Therefore, we investigated the effect of modulating the D. melanogaster microbiota by supplementing the food with bacteria strains previously reported as dysregulated in PD patients. We used two fly strains, a wildtype control (w1118) and a PINK1B9 mutant, as a model of PD. We tested the effect of four strains of bacteria: Lactobacillus acidophilus, Enterococcus faecalis, Escherichia coli and Enterobacter cloacae. Lifespan records showed significant alterations between the groups with enhanced viability induced by E. cloacae and E. coli in both w1118 and PINK1B9 mutants. Locomotor ability was assessed using a behavioural climbing test where L. acidophilus and E. faecalis presented impaired motor function that correlated with a viability reduction. As we were investigating the effect of microbiota modulation, we assessed the intestinal parameters of faecal deposition and gut leakage. Moreover, we demonstrated that ageing causes constipation in Drosophila, and the phenomenon is especially pronounced in PINK1B9 flies. Furthermore, the PINK1 genotype flies have increased gut leakage, and E. coli modulation rescues intestinal barrier integrity. Dopaminergic neuron content evaluation showed a reduction in neurons in the PINK1 flies. Ultimately, we have found that modulation of Drosophila microbiota leads to different outcomes depending on the bacteria strain and may distinctly change physiological pathways.

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PC28: Investigating changes in BOLD signal during median nerve stimulation.

 

Isabel Farr

 

University of Nottingham

 

Median nerve stimulation (MNS) at 10Hz has been proposed as a treatment for Tourette syndrome as rhythmic MNS delivered at 100% motor threshold (MT) reduces tic frequency and severity compared to sham (50% MT) MNS. Recent data suggests arrhythmic MNS at 100% MT also reduces tic frequency.

Previous studies have localised BOLD-fMRI activation during rhythmic MNS to sensorimotor regions including the primary somatosensory cortex (S1) and insula cortex. Regional effects of arrhythmic MNS on the BOLD signal have not yet been investigated. This study aimed to replicate identification of regions influenced by rhythmic MNS and contrast effects of arrhythmic MNS.

High-field (7T) fMRI data was collected from 20 healthy participants. Following a baseline period, 3-minute blocks of rhythmic, arrhythmic and sham MNS were delivered in pseudorandom order.

 

Results replicate findings of increased BOLD activation in S1 and insula cortex during MNS. There were no significant differences in activation between rhythmic and arrhythmic conditions. Differences in MNS (rhythmic/arrhythmic) at 100% MT with sham were revealed in S1 and primary motor cortex, suggesting modulation of these regions (associated with tic generation) is important for the observed therapeutic benefit.

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PC 29: Decoding voltage-gated potassium channels in patients derived glioblastoma cell line: a comparative analysis of anatomical regions

 

Jeffy Joseph Vinohar1, Joern R Steinert2, Ruman Rahman1

​

1, BDI, School of Medicine,

2, School of Life Sciences, University of Nottingham

 

Glioblastoma (GBM) is an aggressive malignant tumour that arises in the astrocytic cells of the brain and is characterised by infiltrative growth and resistance to treatment. Whilst surgical resection represents the primary treatment option for GBM, the presence of residual infiltrative GBM cells left behind contributes to post-surgical tumour recurrence. Recent findings have highlighted the ability of GBM cells to form synaptic-like connections with healthy neurons, suggesting functional integration into brain networks. This discovery underscores the importance of understanding the electrical properties of GBM cells, particularly their potential excitability mediated by voltage-gated ion channels. 

In this study, we looked at patient-derived glioblastoma cell lines from two different tumour regions: the core and the infiltrative margin. We performed electrophysiological recordings using Nanion's Port-a-Patch to measure the functional activity of voltage-gated potassium channels (VGKCs). To determine channel selectivity, the study was performed with and without a non-selective VGKC blocker, tetraethylammonium (TEA, 5 mM).

Our results revealed that glioblastoma cells from both anatomical regions exhibit functional voltage-gated potassium channels, with measurable currents modulated by TEA. These findings suggest that VGKCs play an active role in glioblastoma cell physiology and may contribute to the tumour's electrical integration and invasive potential. These preliminary findings provide important insights into the functional behaviour of GBM cells, particularly at the infiltrative margin, and may pave the way for identifying novel therapeutic targets.

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​PC 30: Characterising iPSC models of repeat expansion disorders to study RNA foci pathology 

 

Daisy Stringfellow, Rebecca Trueman, Daniel Scott, Luisa Martinez-Pomares, David Brook 

 

University of Nottingham, School of Life Sciences

 

Repeat expansion disorders are a group of more than 50 genetic conditions caused by excessively long microsatellite repeats occurring within a disease-associated gene. The nervous system is particularly vulnerable to these repeat expansions, with symptoms generally presenting as neuromuscular and neurodegenerative. 

 

Due to the repeat expansion, RNA transcripts of the expanded gene can reach pathological lengths and have toxic effects within cells. One such effect of RNA pathology that remains poorly understood in these diseases is upregulation of innate immune signalling and neuroimmune dysfunction. 

 

Our aim is to study the effects of RNA transcripts in Myotonic Dystrophy type 1 and C9orf72 Amyotrophic Lateral Sclerosis. We are characterising novel iPSC-derived models of motor neurones, microglia and macrophages, expressing disease-relevant repeat expansions, and a novel mouse model of Myotonic Dystrophy type 1.  

 

We aim to investigate RNA pathology, with a focus on neuroimmune function, in our experimental models to further understand the mechanisms driving neurological symptoms in these diseases. 

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PC31: The role of Glial Fibrillary Protein (GFAP) in Astrocyte Function and Neurodegeneration.

 

Renee Lewis, Kim Chisholm

 

University of Nottingham, School of Life Sciences

 

Glial Fibrillary Acidic Protein (GFAP), a Type III intermediate filament protein, is the hallmark cytoskeletal component of astrocytes and plays a critical role in maintaining their structural integrity and mechanical strength. It is known that GFAP expression is upregulated in response to traumatic brain injury and is a characteristic feature of neurodegenerative diseases such as Alzheimer’s, Multiple Sclerosis and Parkinson’s. Notably, mutations in the GFAP gene have been implicated in Alexander disease, a rare and progressive neurodegenerative disease with no known effective treatment options.

Alexander’s disease primarily affects astrocytes in the central nervous system (CNS). The condition is characterized by the formation of Rosenthal fibers—abnormal aggregates of mutant GFAP and small heat shock proteins, which disrupt normal astrocyte function. These aggregates contribute to cellular stress, leading to progressive damage of the CNS, including white matter degeneration. 

Alexander disease presents with a range of symptoms, including motor dysfunction, seizures and difficulty speaking or swallowing. The prevalence of Alexander disease is estimated to affect 1 in 2 million individuals, with onset typically occurring in infancy or early childhood.

Our research aims to explore the effects of GFAP mutations on astrocyte behaviour and better understand the molecular mechanisms underlying Alexander disease, to identify potential therapeutic targets.

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PC32: Investigating Psychedelic-Induced Neural Dynamics Using Local Field Potentials in Drosophila melanogaster

 

Rachel Hunt, Alice Stringer, Joern R. Steinert & Michael Okun

 

University of Nottingham, School of Life Sciences

 

Psychedelics have gained attention for their potential in treating mental health conditions such as depression. While significant progress has been made in understanding their neural mechanisms, key questions remain about their specific effects on neural oscillations and network dynamics. This study uses the advantages of Drosophila melanogaster as a genetically accessible, cost-effective, and high-throughput model to investigate the impact of psychedelics on neural dynamics. Using local field potentials (LFPs), which capture oscillatory brain activity and neural synchrony, we aim to identify dose-dependent and temporal changes induced by psychedelics. This includes examining alterations linked to the 5-HT2A receptor, a key target in psychedelic action. Expected findings include disrupted network synchrony, oscillatory pattern shifts, and insights into the antidepressant mechanisms of psychedelics. This work lays the foundation for understanding psychedelic-induced neural dynamics in Drosophila and supports the development of scalable models for neuropsychiatric research.

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PC33: Impact of ventral hippocampal chondroitinase-ABC infusion on perineuronal nets and diffuse extracellular matrix in male Lister hooded rats

​

J. Juty (1) , R. Grasmeder Allen (1), J. Renstrom (1), J. Fletcher (2), C. Taylor (1), J. Gigg (3), M. Harte (2), T. Bast (1)

 

(1) University of Nottingham, School of Psychology, Nottingham, United Kingdom, 

(2) University of Manchester, Division of Pharmacy and Optometry, Manchester, United Kingdom, 

(3) University of Manchester, Division of Neuroscience, Manchester, United Kingdom

​

Perineuronal nets (PNNs) in the hippocampus primarily surround inhibitory interneurons. PNNs have been suggested to regulate synaptic plasticity and support GABAergic inhibition, and PNN disruption has been implicated in brain disorders, including schizophrenia. Yet, the cognitive and behavioural consequences of hippocampal PNN loss largely remain to be studied.
The enzyme chondroitinase-ABC (chABC) degrades chondroitin-sulfate proteoglycans (CSPGs), a main component of PNNs and the diffuse extracellular matrix (ECM), and has been used to study PNN function in animal models.
Here, we characterised hippocampal PNN expression in male Lister hooded rats and the impact of ventral hippocampal chABC infusion. Control rats were infused with penicillinase, an enzyme with no endogenous substrate. Sensorimotor testing indicated no major impact of ventral hippocampal chABC infusion on locomotor activity, startle reactivity, or prepulse inhibition (PPI), although group sizes were small.
Post-mortem staining of CSPGs by WFA lectin histochemistry revealed that PNNs were mainly expressed in CA2/CA3 of dorsal hippocampus and CA1 of ventral hippocampus. ChABC-treated rats showed profound ablation of WFA-stained PNNs and of diffuse ECM CSPGs in the ventral to intermediate hippocampus. Immunohistochemistry revealed extensive chondroitin-4-sulfate (C4S) “stubs” (products of CSPG degradation by chABC), in the ventral to intermediate hippocampus of chABC-treated rats 1 day post-infusion. 10 days post-infusion, PNN staining had recovered to some extent, whereas the ECM CSPG staining remained attenuated and C4S-stub staining remained marked. Future work will assess the impact of ventral hippocampal PNN removal with chABC on selected cognitive and behavioural functions linked to the hippocampus and regional inhibitory function.

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PC34: Establishing the stability of potential prognostic MEG biomarkers for mTBI: mTBI-predict consortium study

​

Daniel Ford1, Alice E Waitt2,3; Tara Ghafari3; Jessikah Fildes1; Waheeda Hawa 2; Aliza Finch3; Sebastian C Coleman1; Sarah Wolfe1; Sian F Worthen2; Ruwan Wanni Arachchige1; Yidian Gao3; Iman Idrees 2;Lukas Rier1;Qiaoyu Chen3; Hyojin Park3; Lisa J Hill4; Alexandra Sinclair4; Samuel J.E. Lucas4; James Mitchell4; Davinia Fernandez-Espejo3; Ole Jensen3; Matthew J Brookes1; Caroline Witton2; Karen J Mullinger1,3

​

1The Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, The University of Nottingham, Nottingham, UK

2Institute of Health and Neurodevelopment, College of Health and Life Sciences, Aston University, Birmingham, UK

3Centre for Human Brain Health, School of Psychology, The University of Birmingham, Birmingham, UK

4 The University of Birmingham, Birmingham, UK

 

Traumatic brain injury (TBI) is a silent epidemic. TBI leads to 1.4M hospital visits every year in England and Wales, of which 85% are classed as mild (mTBI). ~30% of mTBI patients have disabling long term sequelae impairing their ability to return to work, play or duty. Clinical MRI/CT scans of mTBI patients are mostly negative. MEG measures of Low Frequency Oscillations (LFO) and Functional connectivity (FC) show promise as diagnostic biomarkers. However, their ability to identify those who experience long term symptoms is unknown. These metrics are key prognostic biomarkers which will be explored by mTBI-predict: a harmonised program of detailed clinical phenotyping of acute mTBI patients coupled with state-of-the-art multimodal biomarker evaluation to best predict outcome.

The first MEG-related aim of mTBI-predict is to establish the stability of potential biomarkers across controls and patients in a multi-site, multi-vendor (CTF and MEGIN) comparison. 20 controls complete 6 sessions within 19 days (4 at one site, 1 at the other two) and 20 mTBI patients complete 4 sessions within 12 days (1 site). The MEG session compromises: 2x5-minute resting-state scans and 3 tasks: choice reaction (CRT), spatial attention and implicit face viewing task.

Resting-state LFO and FC will be examined. CRT data will be used to identify changes in beta rebounds and FC. Spatial attention data will be used to assess hemispheric lateralisation. The stability between sessions and sites of each metric will be established with the most stable metrics taken forward to the main patient study.

 
Oral Communications (OC)

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1. Tilting of a neural attractor controls the transitions between movements in Aplysia

 

Andrea Colins Rodriguez(1,2), Evan Hill (3), William Frost (3), Mark Humphries (1)*

 

  1. School of Psychology, University of Nottingham, UK

  2. University of Santiago, Chile

  3. Rosalind Franklin School of Medicine, Chicago, USA

*Presenting author

 

Abstract: While we know much about how neural circuits generate specific movements, little is known about how they transition between distinct movements. Here we show that the transition between classically-defined galloping and crawling in the sea slug Aplysia corresponds to the movement of an attractor in its motor system’s activity. Unsupervised video analysis revealed both forms of rhythmic locomotion are low-dimensional and well-described by three parameters: the animal's length, the period of its cycle of muscle contractions, and the arching of its foot. Changes in these parameters created the transitions between galloping and crawling. Voltage-imaging motor population activity during fictive locomotion revealed a latent low-dimensional limit cycle, whose transitions in amplitude and frequency matched transitions of the animal’s length and muscle cycles. Remarkably, we found that tilting of the entire attractor corresponded to changes in the arching of the animal, and thus drove the transition between galloping and crawling. Our results show that latent neural dynamics can directly control the locomotor parameters of an animal and suggest new mechanisms for controlling the transitions between movements.

 

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2. Microbiota-associated metabolites: methylphenols and the blood–brain barrier

Authors: Lesley Hoyles 1, Simon McArthur 2

 

Affiliation: 1 Nottingham Trent University; 2 Queen Mary University of London

 

p-Cresol is a by-product of microbial fermentation of tyrosine and phenylalanine in the large intestine. Gut-derived p-cresol undergoes extensive conjugation in both enterocytes and the liver, reaching the systemic circulation predominantly as p-cresol sulfate (pCS) with ten-fold lower levels of p-cresol glucuronide (pCG). In metabolically healthy individuals, pCS and pCG are efficiently cleared by the kidneys whereas in patients with renal impairment they accumulate within the blood; pCS is thought to contribute to the impaired cognitive function frequently observed in these patients.

We examined the effects of physiologically relevant concentrations of pCS and pCG on the blood–brain barrier (BBB). In vitro and in mice, pCG prevented the BBB-permeabilising effects of endotoxin, acting by antagonizing the LPS receptor TLR4. In contrast, pCS increased paracellular permeability and disrupted intercellular tight junctions in vitro and in mice. It elicited significant changes in the whole-brain transcriptome, suppressing neuronal activity, transcription and mitochondrial respiration pathways. pCS stimulated the epidermal growth factor receptor (EGFR), leading to mobilisation of matrix metalloproteinase (MMP)-2/9. In vivo, the BBB-damaging effects of pCS could be prevented by the EGFR antagonist erlotinib or the MMP2/9 inhibitor SB-3CT. Human hCMEC/D3 endothelial cells exposed to serum from haemodialysis patients, but not from healthy donors, showed an erlotinib-sensitive increase in paracellular permeability that closely correlated in size to the total serum pCS content.

Our data demonstrate the complexity of microbial metabolite–host communication pathways underlying the gut–brain axis, and identify means by which microbiome-associated metabolites can be targeted to improve brain function.

 

 

3. Genetic subtypes predict multiple sclerosis severity and response to treatment

 

Authors: Karim L Kreft 1,2,8, Nienke J. Mekkes 3,4, Emeka Uzochukwu 2, Sam Loveless 2, Ray Wynford-Thomas 2, Katharine E. Harding 5, Mark Wardle 1, Peter Holmans 2, J William L Brown 6, Michael Lawton 7, Emma C Tallantyre 1,2, Inge R. Holtman 3,4, Neil P Robertson 1,2

 

1 Department of Neurology, University Hospital of Wales, Cardiff, UK.

2 Division of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, UK.

3 Department of Biomedical Sciences, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

4 Machine Learning Lab, Data Science Center in Health, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

5 Department of Neurology, Royal Gwent Hospital, Newport, United Kingdom

6 Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

7 Bristol Population Health Science Institute, Bristol Medical School, University of Bristol, Bristol, United Kingdom

8 School of medicine, University of Nottingham, United Kingdom

 

Background: Predicting response to treatment and risk of long-term disability in multiple sclerosis (MS) is challenging. In other disease areas, combining genetic risk variants enabled detection of relevant clinical endophenotypes associated with important outcomes, but this has never been applied to MS.

Methods: We applied unsupervised hierarchical clustering to genomic risk scores of two cohorts (the prospective cohort study of 1455 Welsh MS patients was used as the discovery cohort and replication was performed in a multi-centre post-mortem Netherlands Brain Bank cohort of 272 MS patients) to predict relevant disease outcomes using survival analysis for time to disability milestones (expanded disability status scale, EDSS), and ANOVA to compare linear clinical outcomes.

Results: Three genomic clusters were identified, in each cluster patients had similar genetic profiles. Baseline demographic characteristics were similar between clusters. Welsh patients in cluster 1 attained key disability milestones later, reaching EDSS6, 6 years later (p=0.003) and EDSS8, 13 years later (p=0.02) than those in clusters 2 and 3. Time to EDSS6 was also significantly longer for patients in cluster 1 versus cluster 2 in the NBB-MS cohort (6 years, p=0.04). Genomic clustering is an independent predictor for disease progression compared with well-validated risk factors (Hazard ratio for time to EDSS6 1.3-2.0, all p<0.05). Welsh patients in cluster 2 and 3 also had a significantly greater annual increase in T2 lesion load on serial MR imaging (p=0.04). In cluster 2, patients who had received MS disease modifying treatments (DMT) had a longer time to EDSS6 (p=0.003) compared to those that had received no DMTs, whereas no differences were observed in either cluster 1 or cluster 3. In the NBB-MS cohort, we also observed differences in symptomatology, including earlier development of swallowing problems (p=0.02) or muscle spasticity (p= 0.0008) in cluster 2 patients.

Conclusion: This study demonstrates that unsupervised genetic clustering has utility to detect clinically relevant endophenotypes of MS, with genetic cluster 2 patients having a more severe phenotype and higher risk of disability. Moreover, genetic stratification is able to predict response to DMTs and could potentially be used for precision medicine in MS management.

 

4. Defining the role of STAT3 in astrocyte adaptation to hypoxia as therapeutic target in glioblastoma

 

Barry S. Shaw1, Hannah Bolland1,4, Philippine Geiszler1,5, David Cohen1, Anton Smith1, Joseph Allen1, Benjamin Moore1, Stuart Smith2, Alan McIntyre3, Sébastien Serres1*

 

1Physiology, Pharmacology and Neuroscience division, School of Life Sciences, University of Nottingham, Nottingham, UK. 

2Children's Brain Tumour Research Centre, School of Medicine, University of Nottingham, Nottingham, UK. 

3Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK. 

4 Sussex University, Brighton, UK.

5 Derby University, Derby, UK.

 

Text body: brain tumours impact on blood vessels not only through mechanical dissociation of astrocyte end-feet from vessels but also through astrocyte reactivity. Here, we investigated brain tumour-astrocyte interaction further by defining the role of STAT3 activation in astrocytes in response to both oxidative stress and inflammation present in tumour environment. Our aim was to identify potential therapeutic targets of STAT3-induced astrocyte reactivity associated with hypoxic brain tumours.

 

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5. Psychedelic drugs' impact on the space of neuronal population activity

 

Dirk Goldschmitt, Bradley Dearnley, Clare Howarth, Jason Berwick, Li Su, Michael Okun

 

Affiliations: U of Sheffield - all the authors, UoN - B.D. and M.O.

 

Text body: Psychedelics show great promise in treating mental disorders but their effects on neuronal population activity are not clear. Latent dimensions identified by PCA capture the dynamics of this shared neuronal population activity. We asked whether latent dimensions emerge or disappear as a result of psychedelic administration. Contrastive PCA (cPCA) was applied to Neuropixels recordings of neuronal activity in medial prefrontal cortex of mice, comparing the before vs after drug (or vehicle) conditions. We identified directions that explain considerably more variance in one brain state than in the other state, i.e., dimensions present after drug administration but not before, and vice versa.

Contrastive dimensions are shared dimensions of population activity in both brain states, rather than explaining a large amount of variance in one brain state (e.g. on par with principal component 1) and little variance in the other state (e.g. on par with a random direction). Furthermore, there is preliminary evidence that following psychedelic administration there are more dimensions that are weakened than dimensions that are strengthened.

 

 

6. Investigating the neural correlates and oscillatory dynamics of tics in Tourette Syndrome

 

Mairi Houlgreave1,2, Aikaterini Gialopsou1, Elena Boto2, Matthew Brookes2 & Stephen Jackson1,3

 

1School of Psychology, University of Nottingham, Nottingham, United Kingdom

2Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, United Kingdom

3Academic Unit of Mental Health & Clinical Neurosciences, School of Medicine, Institute of Mental Health, University of Nottingham, Innovation Park, Triumph Road, Nottingham, NG7 2TU, UK

 

In Tourette syndrome (TS), tics are commonly preceded by a premonitory urge which is thought to be a negative reinforcer of tic expression, suggesting that tics may be a voluntary response to these sensations [1]. Here, we explore the oscillatory changes within the primary motor cortex during tics and voluntary movements. We also investigate the oscillatory activity within the right insula prior to tics, which has been shown to be involved in urge [2]. Tic expression during neuroimaging is most often required as an overt marker of increased urge, however this can lead to a loss of large amounts of data due to head movement. Therefore, our data were collected using Optically Pumped Magnetometer (OPM) MEG which uses head-mounted sensors, allowing participant movement throughout the scan.

OPM-MEG data were acquired from 20 participants with TS (11F, mean age (±SD): 32.9 ± 10.6 years) and 20 age- and sex-matched controls (10F, mean age (±SD): 32.2 ± 7.7 years). All participants completed the first paradigm which involved sixty 10 second trials involving a single index finger abduction. Participants with TS also completed a second paradigm involving 4 alternating 5-minute blocks of “Rest” and “Suppress” where participants were instructed to try to suppress their tics.

Analyses of the timecourses of mu-alpha (8-12 Hz) and beta (13-30 Hz) frequencies, from the contralateral motor cortex, demonstrated significant desynchronisation during voluntary movement and no significant differences between participants with TS and controls. In contrast, there was no significant desynchronisation at tic onset across the bilateral motor cortices. In the 1 second prior to tic bouts, different portions of the insula show de-/synchronisation depending on the trial type (suppress vs rest) and the frequency band of interest (mu-alpha/beta/theta).

Our finding of desynchronisation during volitional movements, but not tics, is in-line with previous research which describes desynchronisation of beta oscillations during voluntary movements using EEG, but no movement-related desynchronisation prior to tics [3]. Therefore, our data support the hypothesis that the oscillatory dynamics involved in tic generation differ from that of voluntary movement, suggesting that tics may be involuntary. Regardless, OPM-MEG was shown to be capable of recording participants with TS during their tics where conventional methods such as EEG have previously shown artefacts associated with tic onset [3].

[1] Capriotti, M. R., Brandt, B. C., Turkel, J. E., Lee, H. J., & Woods, D. W. (2014). Negative Reinforcement and Premonitory Urges in Youth With Tourette Syndrome: An Experimental Evaluation. Behavior Modification, 38(2), 276–296.

[2] Jackson, S. R., Parkinson, A., Kim, S. Y., Schüermann, M., & Eickhoff, S. B. (2011). On the functional anatomy of the urge-for-action. In Cognitive Neuroscience (Vol. 2, Issues 3–4, pp. 227–243). 

[3] Morera Maiquez, B., Jackson, G. M., & Jackson, S. R. (2022). Examining the neural antecedents of tics in Tourette syndrome using electroencephalography. Journal of Neuropsychology, 16(1), 1–20. 

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7. Pharyngeal electrical stimulation for acute stroke dysphagia trial (PhEAST)

 

Philip M Bath, Kennedy Cadman, Tim England, Lisa Everton, Marilyn James, Corinne Latulipe, Alan A Montgomery, Cameron Skinner, Patrick Smith, Nikola Sprigg, Lisa Woodhouse; for the PhEAST Investigators

 

Stroke Trials Unit, Mental Health & Clinical Neurosciences, School of Medicine, UoN

 

Background

Dysphagia is common after stroke and an independent predictor of poor outcome. However, there are no definitive treatments. Pharyngeal electrical stimulation (PES) is licensed for use in the UK and Europe but lacks a definitive evidence-base and so is not widely used. 

 

Aim

To assess whether PES is safe and effective at improving post-stroke dysphagia (PSD).

 

Methods

International prospective randomised open-label blinded-endpoint (PROBE) parallel group superiority phase IV effectiveness trial of PES versus control. 800 eligible patients are: Adults with recent (2-31 days) ischaemic or haemorrhagic anterior or posterior circulation stroke and clinical dysphagia defined as a functional oral intake scale (FOIS) =1/2/3. The primary outcome is the dysphagia severity rating scale (DSRS) at 14 days after randomisation. Secondary outcomes include pneumonia, quality of life and cognition.

 

Status

The trial has recruited 301 participants of intended 800. We are hoping to open sites in Austria, Denmark, Germany and Ireland. In blinded analysis, swallowing impairment is improving.

 

8. Cholinesterase inhibitors: friend or foe?

 

Wayne Carter

 

Clinical Toxicology Research Group, School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby DE22 3DT.

​

The number of patients with neurodegenerative diseases (NDDs), particularly Alzheimer’s disease (AD), continues to grow yearly. Cholinesterase inhibitors (ChEIs) represent the first-line symptomatic drug treatment for mild-to-moderate AD; however, there is an unmet need to produce ChEIs with improved efficacy and reduced side effects.  We have studied plant extracts and purified phytochemicals and examined their ChEI activities.  Some display moderate inhibitor potential but also retain beneficial radical scavenging and antioxidant properties able to mitigate oxidative stress; a component of many NDDs including AD. Hence, phytochemical pharmacotherapy and/or dietary intervention have the potential to address multiple elements of AD aetiology.  However, dietary fruit and vegetables are often contaminated with pesticide residues, such as from organophosphate (OP) and carbamate pesticides; the most widely employed insecticides.  OP and carbamate pesticides share a common mechanism of action through the targeted inhibition of acetylcholinesterase (AChE) within synapses, triggering cholinergic toxicity and pest paralysis.  Hence, undesired ChEI activity in humans can result from pesticide exposures and this, in addition to pesticide binding to secondary targets, may be detrimental to health, particularly during neurodevelopment.  The oral presentation will consider our studies of phytochemical ChEIs (as an AD treatment), the activity of OP and carbamate pesticides, and the need to balance useful vs undesired cholinesterase inhibition.

 

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9. Modelling interactions between astrocytes and childhood brain tumours

 

Harry Porter

 

The University of Nottingham

 

Atypical Teratoid/ Rhabdoid Tumours (AT/RTs) are rare but highly aggressive paediatric brain tumours which most often occur in children younger than three years old. Astrocytes, one of the most numerous cell types in healthy brain tissue, have been implicated in therapy resistance and progression of other malignant brain tumours but their role in AT/RT pathophysiology has not been investigated previously. To conduct an unbiased characterisation of AT/RT-astrocyte crosstalk in vitro we co-cultured AT/RT patient derived cell lines with primary astrocytes as 3D spheroids within a human brain specific extracellular matrix hydrogel. RNA sequencing showed that AT/RT cells upregulate genes involved in neurodevelopment, tumour growth, and migration in the presence of astrocytes. Furthermore, several genes which are upregulated in recurrent AT/RT were induced by the presence of astrocytes. These included the gene GAP43 a marker of tumour microtubes (MT), which have been reported to mediate intercellular mitochondria transfer from astrocytes to glioblastoma cells. Using fluorescence microscopy we showed that AT/RT cells form MT-like processes with astrocytes. Furthermore, astrocytes were shown to transfer the mitochondria specific dye MitoTracker™ to AT/RT cells. This suggests that AT/RT cells may interact with astrocytes in a similar manner to canonical mechanisms described in other brain tumours.

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10. Investigate the role of RAB39B in Drosophila melanogaster Parkinson’s disease model

​

Carlo Breda

​

Faculty of Health & Life Sciences, De Montfort University, Leicester, LE1 9BH.

 

The pathogenesis of Parkinson’s Disease (PD) is not fully understood and the treatment options remain limited. Dopaminergic neuron loss and misfolded α-synuclein (aSyn) accumulations are the central hallmarks of PD but emerging evidence associates cellular vesicle trafficking disruption with PD pathogenesis. The most compelling evidence comes from mutations in RAB39B, a Rab GTPase mediating various intracellular membrane trafficking steps that cause early onset X-linked Parkinsonism with intellectual disability, featuring dopaminergic neuron loss and Lewy body pathology. Moreover, RAB39B downregulation enhances aSyn oligomerisation in neuronal models. While the majority of knowledge on RAB39B functions derived from intellectual disability-focused research, in vivo models are still lacking or they have not been exploited in the PD context. My preliminary data show that the downregulation of RAB39B orthologues in Drosophila melanogaster leads to dopaminergic neuron loss and PD-relevant phenotypes which are exacerbated by aSyn overexpression. This project exploiting behavioural, genetic and imaging techniques aims to investigate the effects of RAB39B PD-associated mutations on PD pathogenesis and assess the pathogenic link between RAB39B and familial-associated PD genes (aSyn, LRKK2, PINK1). Finally, to advance the discovery of PD therapeutic candidates, I will assess a panel of known Drosophila RAB39 interactors for their potential to ameliorate RAB39B and PD pathogenesis. Globally, this project will clarify how RAB39B contributes to the mechanisms underpinning PD and may provide novel insight into potential therapeutic strategies for this disorder.

 

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11. Mesenchymal /Stromal Stem Cells Extracellular vesicles: tracking the neuroprotective cargo.

 

Elisabetta Verderio Edwards

 

Nottingham Trent University

 

Mesenchymal Stem Cells (MSC), also referred to as multipotent stromal cells, have the capacity to sustain the growth and viability of certain cell types through secretion of trophic factors and immune modulators.MSC are cytoprotective in brain: in mouse models of Alzheimer disease (AD), MSC-secretome is beneficial in reducing amyloid plaques and modulating inflammation/promoting neurogenesis.Increasing body of evidence have ascribed the therapeutic effect to MSC-secretome and paracrine effects. An important fraction of the MSCs-secretome is carried by extracellular vesicles (EVs), membrane-bound vesicles that operate in cell-to-cell communication.Umbilical cord (UC) MSC-EVs play a therapeutic role in various tissue-injury-related diseases, and there are several clinical studies of EVs in treating diseases. However little is known about the specific mechanism of UC-MSC-EV neuro protection.In this scenario, we have isolated MSC-EVs from 4 different donors (umbilical cord tissue obtained from Antony Nolan) and by comparative proteomics and transcriptomics we have identified the molecular composition of UC-MSC EVs compared to EVs secreted from fibroblast, similar cells but without self-renewal or extended differentiation.By using this original approach we have identified a selection of proteins and miRNAs which are specifically present in MSC-EVs, hence likely to be linked to MSC-secretome regeneration potential.

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