BNA Members Meeting Abstracts

Below you can find the abstracts for the talks during our BNA Members Meeting.  Click here for more information about the programme, registration, and other details about the Members Meeting.

Session Abstracts

Neural circuits for learning and representing concepts and categories: the roles of mPFC, MTL, and ATL

Levan Bokeria (chair); University of Cambridge
Beth JefferiesUniversity of York (speaker); 'Context-dependent representation of word meaning'
Timothy BehrensUniversity of Oxford (speaker); Talk title TBC
Bradley Love, University College London (speaker); “Medial prefrontal cortex and the hippocampus support a domain-general learning mechanism”

Decades of neuropsychological and imaging work have uncovered the anterior temporal lobe as the hub for processing of conceptual and semantic information in humans. However, recent neuroimaging studies have found involvement of medial temporal and medial prefrontal regions in acquisition and organization of abstract knowledge structures including concepts. These results suggest that the neural mechanisms underlying physical navigation, such as place and grid cells found in the hippocampal formation and the mPFC, have been repurposed through evolution for “navigation” of higher-dimensional conceptual spaces. An alternative view posits these processes as domain-general learning mechanisms implemented in these brain regions, which can be adapted to specific purposes such as navigation in physical space or organization of conceptual knowledge.

This symposium will present different perspectives on the neuro-computational mechanisms underlying concept learning and representation as implemented in the mPFC, MTL, and ATL. The discussion will focus on the relative contribution of these brain regions to multiple stages of conceptual processing, from their acquisition to long-term representation and context-specific retrieval.

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The interplay between metabolic disorders and Alzheimer’s disease

Prof. Mirela Delibegovic, University of Aberdeen (speaker)
Interventions aimed at improving metabolic health and cognitive dysfunction
Dr. Zara Franklin, University of Aberdeen (speaker)
Molecular mechanisms associated with Alzheimer’s disease and impaired metabolic function
Inga SchmidtUniversity of Aberdeen (chair)
Marina Souza Matos, University of Aberdeen (chair)

Alzheimer’s disease (AD) is a multi-factorial disorder and its causes mostly unknown. Metabolic impairments have been widely associated with AD development, especially with the onset of the sporadic form of the disease. Indeed, disturbances in insulin signalling were found in the brain of AD patients. Furthermore, mice with diabetic phenotypes have increased levels of Aß oligomers and tau phosphorylation in the brain, suggesting a connection between type 2 diabetes and dementia. With the life expectancy of population increasing over the years, the prevalence of age-related diseases, like type 2 diabetes, cardiovascular diseases, and dementia have been increasing. For this reason, finding interventions that could delay the onset of chronic disorders remains essential and have been topic of research in several studies.

We are suggesting a session with experts in the fields of metabolic diseases and AD to raise awareness about factors and pathways that are affected in AD but are often overlooked. By inviting Prof. Delibegovic and Dr. Franklin, we hope to illustrate ways to check for metabolic changes and interventions that can be performed by other members of the British neuroscience community.

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Women in Neuroscience

Lizzie EnglishUniversity of Cambridge (chair)
Tomi AkingbadeUniversity of Cambridge (panellist).
Professor Selina Wray, University College London (panellist).
Professor Gina Rippon, Professor Emeritus of Cognitive NeuroImaging at Aston University, Birmingham (panellist).
Dr Emma YhnellEqual Opportunities and Diversity Representative of the BNA, (panellist)

With science still seen as a male-dominated profession, are we doing enough to help others to pursue neuroscience careers, and to be satisfied and successful in their work?

The session’s panellists include inspiring women in neuroscience from a variety of backgrounds, topics and career stages. Each panellist will introduce themselves, briefly discuss their career progression and current work, before we join together in a panel discussion including delegates questions. Inspired by the ‘Picture a Scientist’ documentary and the ‘leaky pipeline’ theory, we will discuss the challenges that face women in neuroscience and how these could be tackled.

As well as a source of inspiration and advice, this session will promote opportunities to network, including through a new network specific to women in neuroscience: with aims to enable fellow female neuroscientists to form mentorship bonds, strike up collaborations, and share information about relevant scientific training and/or funding opportunities.

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Talk Abstracts

Climate crisis and ecological emergency: why they concern neuroscientists, and what we can do

Charlotte Rae, University of Sussex

The climate crisis and ecological emergency are threatening the future of humanity, including our ability to conduct research unhindered by extreme weather and societal breakdown. Importantly, neuroscience research is also contributing to these environmental catastrophes, from our wet lab practices to big data computing and conference travel. However, there are solutions to these issues, and changes that we can – and should – make to our research endeavours, to ensure our neuroscience is sustainable. In this talk, I will outline what the key environmental issues for neuroscience are, and what we can do about them, inspired by our forthcoming Brain and Neuroscience Advances article on this theme. We also encourage discussion of potential solutions and collective problem-solving in the Q&A.

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Graph Theory in Analysis of EEGs in Epilepsy

Aneirin (Nye) Rhys Potter, King's College London

The nervous system has increasingly been described using the language of network analysis. For example, that the brain can be modelled as a set of nodes connected by edges, to which multiple measurement tools can be applied. However, there are no widely agreed definitions for nodes or edges or what underlying physiology the measures correspond to. Network modelling is particularly useful for spreading phenomenon such as epidemics, but this could also apply to seizure propagation in the brain. The standard measurement tool for seizures is electroencephalography (EEG). Modelling this as a network each node is an electrode corresponding to summed activity from an area of underlying cortex. Edge definitions are less consistent but can represent white matter tracts between areas of cortex. So far, I have constructed network diagrams from subdural recordings in six patients with temporal lobe epilepsy by ascribing a higher weight to edges between nodes that showed consistently similar seizure activity. I want to investigate if these edges have a physiological basis. For example, are those nodes connected by high weight edges more likely to be adjacent or known to have specific white matter tracts between them and can these networks predict seizure types in epileptogenic brains.

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Posterior parietal cortex and precision encoding: a neurocomputational pattern relevant for subclinical psychosis?

Francesco Scaramozzino, Royal Holloway, University of London

The aim of our study is to identify neurocomputational patterns of evidence-accumulation possibly involved in the emergence of hallucinations- and delusion-like experiences. According to predictive coding, imbalances in the precision of prior or sensory signals might bias inferential processes and lead to reality-testing alterations. Neural activity in the posterior parietal cortex (PPC) seems to encode the precision of accumulated evidence in perceptual and cognitive inferences. Altered synaptic gain in PPC could translate into precision imbalances and represent a key[1]neurocomputational mechanism contributing to psychotic and psychotic-like symptoms. We will compare performances of the random dot motion task (RDM) and the beads task between participants undergoing a session of low-frequency (1Hz) repetitive transcranial magnetic stimulation (rTMS) over P4 (10-20 system) or a sham-rTMS session. By fitting RDM data into hierarchical drift-diffusion models, we will phenotype participants in terms of drift[1]rate (taken as a proxy of precision of sensory evidence) and evaluate between-groups differences in parameters estimates and test for interactions with measures of subclinical psychosis. Results may reveal a causal role of PPC neural activity in the encoding of evidence precision and suggest a new neurocomputational mechanism in this area involved in subclinical psychosis.

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A multi-level model of hippocampal function from behaviour to neurons

Robert Mok, University of Cambridge

Ideally, computational neuroscience would have multi-level explanations in which a component of a mechanistic account could be further decomposed into its own lower-level mechanism (Craver, 2001). Unfortunately, we don't have cognitive models of behaviour whose components can be decomposed into the neural dynamics that give rise to behaviour, leaving an explanatory gap. For example, how can constructs in SUSTAIN, an established cognitive model of concept learning that captures behaviour (Love et al., 2004) and brain-activity patterns in hippocampus (Davis et al., 2012; Mack et al., 2016), be decomposed into lower-level mechanisms while retaining the higher-level theory? We address this gap by decomposing SUSTAIN's clusters, which are groupings of stimuli (a concept) to the neuron level. One major challenge we surmounted was how to coordinate activity of neural populations to represent clusters (concepts). Inspired by algorithms that capture flocking behaviour in birds, we introduce a novel learning rule with a “recurrence" mechanism and propose that the hippocampus exhibits “neural flocking", where coordinated activity arises from local rules. Our model captures concept learning behaviour, spatial neural representations, and the learning rule naturally leads to similarly-tuned neural assemblies (“virtual clusters"), demonstrating how clusters, concept cells, and neural assemblies (e.g., place-cell assemblies) form.

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Zooming In and Out: assessing three different network-level relationships of brain and behaviour

Danielle Kurtin, University of Surrey

As an orchestra conductor guides coalitions of musicians to produce a symphony, so too does the brain organize regions to work together synchronously to complete cognitive functions. Imaging and modelling studies have developed understanding of how networks of regions come together to meet cognitive demands, yet the relationship between network dynamics and behaviour is unclear. I will introduce a series of experiments with diverse methodology that probe the brain-behaviour relationship. I begin with a study that investigates the role of the default mode network in task switching, and whether its prevalence during task influences switch costs (the deficit in performance in switch trials as opposed to stay). Then, I zoom in to a finer-grained topological level, identifying recurrent phase-based connectivity states during cognitive tasks and rest, and investigating whether these states' dynamics relate to behaviour. My last experiments zoom out and evaluate the relationship between task performance and complexity of state dynamics in both task and rest. I will end by highlighting the comparative strengths and weaknesses of each method and introduce future avenues of research on the relationship brain state dynamics and behaviour.

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Oxytocin Neuropeptide Neuromodulatory Action in Dopaminergic and Serotoninergic Neurotransmission in Central Nervous System

Pratibha Thakur, Barkatullah University, Bhopal, India

Background:- The neuropeptide oxytocin has been implicated in social behavior and being evaluated as a possible treatment for neurodegenerative disorders i.e. schizophrenia, autism spectrum disorders, anxiety, and depression etc., but the neural mechanisms how oxytocin modulates social behavior is unknown. Dopamine and serotonin are important neurotransmitter in central nervous system and disruption in dopaminergic and serotoninergic neurotransmission have been found in the patients of neuropsychiatric disorder i.e. autism, depression etc. Here, we have explored the influence of exogenous oxytocin in the neurotransmission of dopamine and serotonin level in various regions of the brain. Material & Methods:- Experimental animal, were exposed intraperitoneally (i.p.) to oxytocin 0.0116mg/kg for 30, 60, and 90 days while control animals were treated with normal saline. After the completion of different duration, all the animals of different groups were sacrificed by cervical dislocation; the brains were carefully removed, washed in normal saline, and frozen tissue was divided into seven regions, the medulla oblongata, midbrain, cerebellum, cerebral cortex, striatum, hippocampus, and hypothalamus, adopting the methodology of (Glowinski & Iversen, 1966) for the estimation of dopamine and serotonin in different region of the brain. Results:- In the present study we found that, there is significant increase (p<0.001, one way analysis of variance [ANOVA]) in dopamine level in hypothalamus, cerebral cortex, and midbrain of the brain region of the animals treated upto 90 days, which indicates the stimulation of dopamine mesocorticolimbic pathway. Furthermore, dopamine level significantly decreased in cerebellum of 30 days oxytocin treated group, while the level of dopamine increased after 60 and 90 days of treatment with oxytocin, which may be due to dose and duration dependent factor of oxytocin. However, oxytocin treatment upto 90 days results significantly increase in the level of serotonin in selected seven region of the brain. Conclusion:- This finding is consistent with the effect of exogenous oxytocin on neuromodulation of serotonergic system in different region of the brain and regulates appetite social cognition, homeostasis, and energy metabolism and further paves the way for the identification of novel neurodegenerative drug target. ><0.001, one way analysis of variance [ANOVA]) in dopamine level in hypothalamus, cerebral cortex, and midbrain of the brain region of the animals treated upto 90 days, which indicates the stimulation of dopamine mesocorticolimbic pathway. Furthermore, dopamine level significantly decreased in cerebellum of 30 days oxytocin treated group, while the level of dopamine increased after 60 and 90 days of treatment with oxytocin, which may be due to dose and duration dependent factor of oxytocin. However, oxytocin treatment upto 90 days results significantly increase in the level of serotonin in selected seven region of the brain. Conclusion:- This finding is consistent with the effect of exogenous oxytocin on neuromodulation of serotonergic system in different region of the brain and regulates appetite social cognition, homeostasis, and energy metabolism and further paves the way for the identification of novel neurodegenerative drug target.

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Differential effects of sucrose exposure during the adolescent period on operant novelty seeking in male and female rats

America Bustos Segura, California State University, Bakersfield

The US Department of Agricultural Research Service (2020) indicates adolescents exceed Dietary Guidelines for added sugar consumption. Previous work from our lab indicates that exposure to sucrose in adolescence increases vulnerability to drugs of abuse in adult rats. The purpose of this study was to investigate if the effects of adolescence sucrose exposure generalize to sensation seeking (SS). SS is a personality trait that is described as preference for novel sensations and experiences. In rodents, operant novelty seeking (ONS), an animal model of SS, has been shown to predict drug self-administration (Gancarz et al., 2013). Here, we hypothesize that sucrose exposure will enhance levels of ONS compared to controls. In order to test this, adolescent rats were exposed to either 10% sucrose or water. In adulthood, rats were then tested for ONS, during which active responses resulted in the presentation of varied, novel sensory (visual and auditory) stimuli. This project is currently ongoing, however preliminary data suggests that female rats exposed to sucrose during the adolescent period emitted significantly more active responses and earned more sensory rewards compared to males. Furthermore, there is a non[1]significant trend that adolescent sucrose exposure increased ONS performance to compared to water controls.

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Mice can extract information from temporally-complex odour plumes to learn about odour source location

Alina Cristina Marin, Francis Crick Institute / University College London

Natural odour plumes are shaped by airflow turbulence, resulting in high frequency odour intensity fluctuations that may contain information about odour source location. We aimed to investigate whether mice can extract and use this information in a distance discrimination task. We built an odour delivery system that reliably generates and records odour plumes. In addition, we created an “olfactory virtual reality” by replicating the recorded odour plumes with a high-temporal-bandwidth odour delivery device. Using odour sources placed at different distances in a wind tunnel, we found trained mice can respond differently to odour sources based on their distance. In a separate set of mice, we performed calcium imaging of neurons in the mouse Olfactory Bulb while presenting distant odour plumes in olfactory virtual reality, and found a subset of Mitral and Tufted Cells that responded differently to different distances. As total odour concentration was kept constant, we suggest these neurons respond to features of the temporal structures of odour plumes, which are informative of source distance. We conclude that the mouse Olfactory Bulb can extract information from temporally-complex olfactory stimuli, and this information could be relevant to performing a distance discrimination task based on olfactory information.

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Role of C-Tactile Afferent Nerve Fibres for Infant Development

Laura Mulligan, Liverpool John Moores University

The aim of our research is to investigate the role of nurturing touch during infant development. This type of touch stimulates a distinct population of mechanosensitive c-fibres, called C-tactile afferents (CTs), in the skin that respond optimally to a low force/velocity ‘caressing’ touch, delivered at skin temperature. CTs are associated with the affective component of touch, thus, we hypothesise that CTs play a vital developmental impact in social and emotional brain development. To investigate this hypothesis, focus will be placed on preterm infant populations, who do not experience typical environmental stimuli during a critical developmental period, as the environment in a Neonatal Intensive Care Unit (NICU) differs greatly to that in utero. Unexpected stimuli, such as pain from clinically relevant procedures and sensory overload (bright light, loud noises, etc.), are stressors which result in physiological and biochemical implications (e.g., increased heart rate, reduced blood oxygenation levels and inflated levels of cortisol). Neural development is partially dependent on physiological and biochemical response to external stimuli; therefore, typical synaptic connections are not made in the developing brain. Comparison of preterm and healthy term infants physiological and biochemical responses to touch, will attempt to establish a link between CT stimulation and physiological regulation

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Lack of glutamate co-release from 5-HT neurons is associated with putative anhedonia in mice

Luisa Sophie Gullino, University of Oxford

A recent breakthrough in the 5-hydroxytryptamine (5-HT) field is the discovery that 5-HT neurons release not only 5- HT but also glutamate. Thus, the majority of midbrain 5-HT neurons express the vesicular glutamate transporter 3 (vGLUT3), which stores glutamate in presynaptic vesicles prior to release. The role of co-released glutamate is still poorly understood, hence, it was investigated using a novel conditional knockout mouse model in which 5-HT neurons lack vGLUT3 expression (vGLUT3cKO-5HT). Using a battery of anxiety, reward-sensitivity, and learning behavioural paradigms it was found that vGLUT3cKO-5HT mice present an anhedonic-like phenotype, as measured in novelty suppressed feeding and sucrose preference tests. The putative anhedonia observed could be underpinned by a decrease in reward sensitivity, as suggested by a reduction in overall performance of vGLUT3cKO-5HT mice in a reward-based learning paradigm. Altogether these findings suggest a role of co-released glutamate from 5-HT neurons in anhedonia and sensitivity to reward. The vGLUT3cKO-5HT line will be employed for further behavioural experiments investigating both reward sensitivity and vulnerability to stress, with the aim of advancing the understanding of the role of glutamate/5-HT co-release in the pathophysiology of mood disorders.

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Investigating the behavioural and neurochemical effects of SSRI discontinuation in mice

Helen Collins, University of Oxford

The abrupt cessation and even tapering of selective serotonin reuptake inhibitor (SSRI) antidepressants can produce a debilitating discontinuation syndrome, affecting up to half of patients stopping treatment. Typical symptoms include anxiety, nausea, and dizziness, which appear within 1-7 days of stopping treatment. However, there are vanishingly few preclinical studies on the condition, thus the cause of the symptoms is unknown. Nonetheless, previous reports have speculated that a decrease in extracellular serotonin immediately following SSRI discontinuation may be responsible. My project aims to establish a mouse model of SSRI discontinuation to investigate its neurological and neurochemical mechanisms. This talk will discuss my data showing that 48 h after discontinuation from chronic paroxetine treatment, mice exhibit increased anxiety-like behaviours on the elevated plus maze (EPM) compared to continued treatment controls, mirroring a core symptom in patients. I have also identified increased activity in serotoninergic brain circuitry using c-Fos immunohistochemistry that may be contributing to the behavioural effects observed. Finally, experiments using anaesthetised in vivo microdialysis in the ventral hippocampus have demonstrated an acute decrease in extracellular serotonin 48 h after discontinuation, as previously hypothesised. Investigations of the causal link between these behavioural and neurochemical changes are ongoing.

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Does a sub-anesthetic dose of ketamine influence the negative emotional biases associated with autobiographical memories in treatment resistant depression?

Sara Costi, University of Oxford

Major depressive disorder is among the most disabling illnesses worldwide and the efficacy of current treatments is limited. About one third of patients do not experience an antidepressant response despite multiple treatment attempts, so called treatment-resistant depression (TRD). Recent evidence suggests that a sub-anesthetic dose of the NMDA antagonist ketamine can be effective in TRD with a fast onset of action. However, the neurobehavioral mechanisms underlying ketamine antidepressant effects are still largely unknown. Behavioural models of emotional memory suggest that while conventional antidepressants affect how new information is processed, ketamine reduces the retrieval of established negative memories. However, to date, no study has been conducted exploring the potential of ketamine in memory reconsolidation within TRD. In this talk I am going to discuss the development of a psychological task to test the emotional biases associated with autobiographical memories and its application in an experimental medicine design study aiming to test if a single sub-anesthetic dose of ketamine, compared to placebo, can attenuate negative emotional biases associated with autobiographical memories in TRD subjects 24-hours and one week post drug administration.

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Using organotypic brain slice cultures to model the interferon response in the brain

Paige Mumford, University College London, UK Dementia Research Institute

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21). Neuroinflammation is different in people with DS, including altered microglial morphology. The peripheral immune system is also different, including an over[1]activated interferon response likely due to four genes encoding interferon receptors being located on Hsa21, but how this affects neuroinflammation is unknown. Organotypic brain slice cultures (OBSCs) can be used to model neuroinflammation. We treated OBSCs from wild-type mice with interferon-β to establish if this “ex vivo” system can model the interferon response in the brain. Cortico-hippocampal OBSCs were prepared from C57BL6/J mice and treated with varying concentrations of interferon-β for 3- or 24-hours. Slices were used for western blotting or qPCR, and conditioned media used for ELISAs. OBSCs treated with IFN-β exhibited phenotypes of an interferon response, with elevated expression of interferon-stimulated genes and elevated levels of transcription factors. 24- hour-treated OBSCs also had elevated levels of CXCL10 in the conditioned media. Thus, this “ex vivo” system can model the interferon response in the brain. Next, we will use this paradigm on a DS mouse model with three copies of the Hsa21 interferon receptor genes, to investigate the effect of interferon hyper-sensitivity on neuroinflammation in DS.

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Investigating the Effects of 16p11.2 Microdeletion on Progenitors and Interneuron Development Using Region-Specific Brain Organoids 

Rana Fetit, University of Edinburgh

Copy number variations of chromosomal region 16p11.2 are genetically linked to 1% of Autism Spectrum Disorder (ASD) cases. This 600kbp region contains 29 genes, but the functions of many genes in this CNV remain poorly defined and the underlying mechanisms linking it to ASD pathophysiology remain largely unknown. We generated ventral organoids from 16p11.2deletion-CRISPR/Cas9-iPSC lines and isogenic controls to mimic early-to-mid-foetal ventral-telencephalic development. Organoids were analysed by flow cytometry, immunohistochemistry and RT[1]qPCR. Both deletion and control organoids expressed forebrain, ventral telencephalic and GABAergic markers. Compared to controls, deletion organoids were significantly larger in size in some lines. Significantly larger neural rosettes (circular arrangements of neural progenitor cells) and more differentiating TUJ1+ neurons were found in the deletion. This was in line with increased SOX2 (progenitor marker) and NEUN (neuronal marker) mRNA expression initially found in deletion organoids. Furthermore, we found no difference in the proportion of cells in different cell cycle phases. Similarly, no differences in total cell cycle length or the duration of the individual phases were found, although the deletion lines showed trends towards longer S-phase. Our results suggest that regardless of the organoid size, deletion organoids show a tendency towards increased progenitor proliferation and differentiation into interneurons. This could be due to a shift towards asymmetric, neurogenic divisions. Whether the increased interneuron progeny is immature, dysfunctional, or favours a certain interneuron subtype over another is yet to be investigated.

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Meta-analysis of preclinical studies as a tool to improve study design in anti-migraine drug discovery research.

Antonina Dolgorukova, Pavlov First Saint Petersburg State Medical University

Currently, the problem of low reliability and reproducibility of preclinical studies is attracting more attention. The possible sources include poor experimental design, the lack of sample size calculations, and measures to reduce the risk of bias. We will report on our ongoing work - a systematic review with meta-analysis of the effects of clinically established anti-migraine medications in the rodent model of migraine pain (study protocol at PROSPERO: CRD42021276448). We will discuss the use of meta-analysis as a tool for 1) establishing effect size of interest, which can be used to determine the sample size for future experiments, 2) revealing factors, including methodological features and measures to reduce bias, which can influence the outcome. We are now at the end of the data extraction phase and we would like to share our experiences of the difficulties and obstacles we have encountered on the way with the hope to contribute to improving the robustness and reproducibility of preclinical research.

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Further characterisation of the rat model of Tourette-related striatal disinhibition: in vivo electrophysiological, behavioural, and translational imaging studies 

Joanna Loayza, University of Nottingham

Tourette’s syndrome is characterised by loss of GABAergic inhibition, so called neural disinhibition, in the striatum. Dorsal-striatal microinjection of a GABA-A antagonist like picrotoxin produces tic-like movements in rodents and primates that resemble motor tics in Tourette’s. I will present studies aimed at further characterisation of the rats’ striatal disinhibition model. Electrophysiological recordings in the striatum of anaesthetised rats, showed that picrotoxin disinhibition enhanced burst firing and evoked large local field potential spike-wave discharges, consisting of a single negative spike followed by a positive wave, with sharp multi-unit bursts during the negative spike. Behavioural studies confirmed that striatal picrotoxin induced tic-like movements. Automated photobeam measurements revealed increased locomotor activity and fine-motor-counts. The temporal pattern of the latter matched that of tic-like movements, suggesting a simple automated way to measure tics. There was a trend for startle amplitude to be reduced and prepulse inhibition to be increased with picrotoxin, the latter contrasting findings of Tourette’s patients, possibly reflecting differences between acute and chronic disinhibition. Future studies will use translational imaging, including SPECT and MRS, to map brain-wide activity changes caused by striatal disinhibition, both within the striatum and in projection sites, and to compare the changes to imaging findings in Tourette’s.

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Gambling addiction and the Brain 

Rayyan Zafar, Imperial College London

Gambling disorder has recently been categorised in the DSM-5 as an addiction. A recent yougov poll estimates that 1.4million individuals in the UK are problem gamblers and in recent years a dedicated NHS clinical service has been set up to address the mounting burden of this condition. Neuroscience has been able to elucidate disturbances within reward and salience processing in addiction although little research has been conducted in individuals with a gambling disorder. This talk will explain an ongoing research study at Imperial college to understand the neurobiology of this condition and how this research can inform the development of novel treatments.

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Hypoxia Signaling in Parkinson’s Disease: There Is Use in Asking “What HIF?”

Laura Leston Pinilla, Nottingham Trent University

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the selective degeneration of a specific subset of dopamine-producing neurons. To date, treatments have focused on compensating dopamine deficiency without addressing the progressive neuronal cell damage. PD related dopaminergic cell death has been associated to environmental factors, genetic predisposition and disruptions to vital molecular pathways such as mitochondrial function, reactive oxygen species production and protein degradation systems. Recent evidence suggests that events causing reductions in oxygen supply (hypoxia) to these neurons might also be related to PD development. HIF-1α, the master transcriptional regulator of the cellular response to hypoxia, can target several pathways specifically disrupted in PD by activating a wide and diverse transcription programme, encompassing genes involved in mitochondrial fitness, oxidative stress, autophagy and dopamine production, potentially alleviating neuronal damage. Interestingly, HIF-1α stabilization seems to be impaired in PD patients. Therefore, novel drugs that stabilize HIF-1α may constitute a promising therapeutic strategy for PD. Our results show how PD-related stress can block HIF-1α stabilization in neural cells and highlight the therapeutic potential of novel HIF-1α stabilizing compounds, such as ML228, in reducing PD-related neuronal damage. Future studies will explore the specific link between hypoxia and Parkinson’s disease.

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Virally mediated synaptic dysfunction in ALS

Nick Pasternack, University of Cambridge

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disorder affecting the body’s motor system. At present the cause of sporadic ALS remains unknown, and existing treatments only minimally modify the rapidly progressive course of the disease. The goal of this project is to identify novel druggable targets to ameliorate the neurotoxicity of a transposable element gene human endogenous retrovirus-K (HERV-K). Autopsy studies show that nearly half of sporadic ALS patients have activation of a HERV-K, subtype HML-2, in the brain and spinal cord. Additionally, transgenic mice in which the HML-2 envelope (env) protein is expressed in neurons develop an ALS-like phenotype with degeneration of motor neurons. A dataset of over 2,000 ALS and control bulk RNA sequencing (RNA-seq) samples was utilized to determine expression patterns of genes and genetic pathways of interest. A cluster of ALS patients with elevated expression of HERV-K env mRNA transcripts was identified and synaptogenesis and synaptic plasticity-related pathways were found to be both upregulated in specific patient clusters as well as HML-2 env transgenic mice. Future studies will aim to clarify the pathological role of synaptogenesis in HERVK-mediated disease and whether it could lead to novel druggable targets to treat ALS.

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Light sheet imaging of behaviourally activated neurons in a rodent model of autism spectrum disorders

Cristina Martinez-Gonzalez, University of Edinburgh

Autism spectrum disorders (ASD) are characterized by social impairments and restricted behaviours. To investigate how changes in brain activation mediate behaviour, rodent models of ASD, such as Fragile-X knockout (Fmr1-/y) have provided valuable insights. Nevertheless, studies are generally constrained to a single brain region; hence, whole-brain changes in neuronal activity in ASD are largely unknown. To identify neurons in the rat brain that are activated during behaviour, we used the immediate-early gene cFos as a proxy for neuronal activation and combined this with iDISCO optical clearing and light-sheet microscopy. Given the amygdala-dependent emotional processing altered in individuals with Fragile-X syndrome, we hypothesised that cFos expression in the Fmr1-/y rat brain is altered compared to wild type (WT) in response to fear conditioning. We compared WT and Fmr1-/y animals that received a conditioned (CS:light) paired with an unconditioned-stimulus (US:foot-shock), or a CS only, or remained home-caged (naive). Brains were obtained 90’ after, immunolabeled against cFos, cleared and imaged. Using our pipeline for automatic cell quantification and custom-made atlas of the amygdala (Basolateral complex [BLA]: lateral: LA, basal: BA and basomedial: BM; and Central nucleus [CeA]), we observed an increase in cell density of cFos+ neurons in the BA and BM nuclei of shocked WT and Fmr1-/y rats, compared with naive rats. We also observed this in WT-CS only, but not Fmr1-/y -CS only animals. Finally, no changes were observed in the LA or CeA nuclei of any group (One-way ANOVA, Tukey post-hoc test).

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Continuous neurochemical measurements in traumatically injured brain using a microdialysis coupled mid-infrared sensor

Chisomo Zimphango, University of Cambridge

Abnormal glucose concentrations (low and high) and elevated lactate/pyruvate ratio (LPR>25) that indicate brain metabolic disturbances have been reported in brain microdialysates of severe TBI patients resulting in unfavourable clinical outcomes [1,2]. Cerebral microdialysis (CMD) conventionally allows hourly measurements using a bedside analyser. However, metabolic changes in an injured brain can be more rapid and it is imperative that dynamic changes are continuously monitored, thereby enabling timely clinical interventions to treat adverse brain metabolism, consequently improving patients’ outcomes. Here, our aim is to use CMD connected to a novel mid[1]infrared (mid-IR) sensor, a system developed by our group, to continuously track dynamic changes in an in-vitro model of brain, and in the brains of TBI patients during neuro-critical care.

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Myelin plasticity and sleep-dependent memory consolidation

Yingshi Feng, Wellcome Centre for Integrative Neuroimaging, University of Oxford

Sleep promotes consolidation of various memory tasks. Myelin plasticity might be important in this context, because myelin plasticity is related to learning, myelin dynamics are modulated during sleep, and the timescale of consolidation is well suited to the slow process of oligodendrogenesis. Our project seeks to understand myelin plasticity associated with sleep-dependent memory consolidation. We will use targeted memory reactivation (TMR) to boost consolidation during sleep. TMR involves repeatedly pairing a motor memory with sensory cues during initial learning. Re-presenting the sensory cues during subsequent slow-wave sleep reactivates motor representation, thereby enhancing behavioural consolidation. However, the biological mechanisms underlying TMR are unclear. Therefore, we will first use rodent models to assess myelination directly with histology and indirectly with MRI. We will also use a transgenic mouse model (P-Myrf (−/−)) to determine whether myelin plasticity causes motor consolidation. In this model, tamoxifen-dependent knockout of myelin regulatory factor (MyRF) in oligodendrocyte precursors results in reduced capacity to form new oligodendrocytes following tamoxifen administration, without any loss of existing oligodendrocytes. We will inactivate MyRF at different learning stages and assess its impact on motor memory consolidation. Finally, we will translate these findings to humans and assess myelin plasticity with effective TMR using MRI.

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When are naturalistic events encoded to memory?

Kevin Campion, MRC Cognition and Brain Sciences Unit

Naturalistic stimuli have provided an avenue to address a fundamental question about episodic memory – when are events encoded? Importantly, while viewing film clips, hippocampal activity increases at event boundaries and these increases have been associated with better gist memory for the preceding event. Accordingly, some have argued that event segmentation during perception creates the basic units of episodic memory, and that events are primarily encoded by the hippocampus at event boundaries. It remains unclear, however, if events are only encoded at event boundaries. Previous relevant studies have only tested gist memory for short, temporally uncontrolled events. Therefore, it is unclear if the elements that comprise events are only encoded offline in a gist representation at event boundaries, or if they are also separately encoded when encountered. Further, the event boundaries we perceive in real life form a complex hierarchy, with longer “coarse-grained” events (e.g. “dinner”) typically subsuming clusters of brief “fine-grained” events (e.g. “cooking” & “consuming”). If event elements are encoded at event boundaries, it remains unclear which “level” of boundary triggers encoding. In this talk, I will discuss our ongoing functional magnetic resonance imaging (fMRI) study, which aims to determine when elements of events are encoded by the hippocampus.

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A link between NMDAR hypofunction and neural disinhibition in the generation of cognitive deficits?

Charlotte Taylor, University of Nottingham

NMDA receptor hypofunction caused by sub-chronic treatment with phencyclidine (scPCP) induces schizophrenia-related cognitive deficits in rodents. The scPCP model shows impairments in hippocampal and prefrontal GABAergic interneurons, and such neural disinhibition has been hypothesised to mediate some of the cognitive deficits (Cadinu et al., 2018, Neuropharmacology). I will present studies addressing this hypothesis. First, we investigated whether neural disinhibition, induced by microinfusion of picrotoxin (GABA-A receptor antagonist), causes novel object recognition (NOR) deficits, a key feature of the scPCP model. Neural disinhibition in the ventral hippocampus (vHip), but not prefrontal cortex, impaired NOR memory. Second, we investigated whether scPCP treatment would impair watermaze delayed-matching-to-place (DMP) performance, similar to vHip neural disinhibition (McGarrity et al., 2017, CerebCortex). scPCP did not impair watermaze DMP task performance. Overall, our findings suggest that vHip, but not prefrontal, disinhibition could contribute to NOR deficits in the scPCP model. The absence of a watermaze DMP impairment in scPCP treated rats is, at first glance, inconsistent with the presence of marked vHip neural disinhibition, but may reflect compensatory mechanisms in the scPCP model. Future studies will directly examine neural disinhibition in the scPCP model by using in-vivo electrophysiology and ex-vivo analyses of GABA markers.

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Prefrontal Disinhibition Disrupts Reversal Learning

Jacco Renstrom, University of Nottingham

A key feature of schizophrenia is a reduction in prefrontal GABAergic inhibition, known as disinhibition. Additionally, schizophrenia is characterised by marked reversal learning deficits (Leeson et al., 2009, BiolPsychiatry). Reversal learning has mainly been found to require orbito-, but not prefrontal, cortex. However, we hypothesised that prefrontal disinhibition may impair reversal learning, because such disinhibition causes aberrant prefrontal neuron firing and may, thus, also disrupt processing in projections sites (Bast et al., 2017, BrJPharmacol), such as the OFC (Sesack at al., 1989, JCompNeurol). In my talk, I will outline our findings in rats that neural disinhibition in the medial prefrontal cortex, by local microinfusion of a GABA receptor antagonist, markedly disrupted performance on an operant repeated reversal paradigm. Beyond classical performance measures (trials-to-criterion, %-correct), I will present Bayesian strategy profiles and discuss how bi-directional agonist/antagonist manipulation of GABAergic inhibition (Pezze et al., 2014, JNeurosci) alters strategy biases and implementation, resulting in disrupted reversal performance. Finally, I will outline ongoing and future work using pharmacogenetic manipulations of GABAergic interneurons, via DREADDs (Roth, 2016, Neuron), to improve on the current pharmacological animal models of prefrontal disinhibition, by producing an impairment in GABAergic interneuron function, which more closely mimics that seen in schizophrenia.

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The Scent of A Worm: Learning and Memory Regulation in Caenorhabditis elegans

Spatika Jayaram, Indian Institute of Science Education and Research, Mohali

This talk is based on my ongoing research on olfactory learning and memory in the nematode, Caenorhabditis elegans. Worms display associative and non-associative forms of memory and in this paradigm, we tested olfactory associative memory using an appetitive stimulus. The Fem-3 mRNA-binding factor 1 (FBF-1) is a part of the PUF protein family. These proteins have been earlier implicated in neurological functions and disorders. KIN-2 is a cAMP[1]dependent protein kinase regulatory subunit involved in the cAMP signaling pathway. In my study, I hypothesize that post-transcriptional regulation of kin-2 by this PUF protein is required for learning and memory. Using behavioral assays and genetic tools, we studied wild-type and mutant strains of C. elegans, as controls to study learning and memory formation. Through positive olfactory assays, we studied learning, short-term and intermediate-term associative memory, and forgetting. We found specific changes in memory formation when worms are mutated in genes involved in Calcium signaling pathways. We are also in the process of confirming our hypothesis through yeast systems where we have tested protein-mRNA interactions, and are designing an experimental mutant through CRISPR-based editing to test our hypothesis on post-transcriptional regulation.

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