Daniele Bertoglio tenure track asst. professor

Research Daniele Bertoglio

Research team

Expertise

My research is aimed at the application of state-of-the-art small animal translational neuroimaging tools to quantify structural, functional, and molecular changes in preclinical models of neurological diseases to accelerate the development of therapies. The main effort is dedicated to the identification, validation, and assessment of innovative imaging biomarkers for the central nervous system (CNS) in neurodegenerative disorders, with a specific focus on both movement and traumatic disorders, including Huntington's disease (HD) and spinal cord injury (SCI), respectively. This is achieved thanks to the state-of-the-art preclinical magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging equipment available. In addition to imaging modalities, my expertise includes in vivo and in vitro techniques to support imaging findings. By performing longitudinal multimodal studies, we can assess the prognostic and/or predictive value imaging biomarkers hold in relation to disease progression or the efficacy of a therapeutic intervention. I have also extensive expertise in behavioural studies, histology, autoradiography, and brain surgeries. The final goal is to identify candidate clinically relevant markers for the monitoring of disease progression as well as the assessment of the therapeutic effect of novel treatments during the early stages of neurological disorders.

Alliance for multidimensional and multidisciplinary neuroscience (µNEURO). 01/01/2026 - 31/12/2031

Abstract

Owing to their high spatiotemporal resolution and non-invasive nature, (bio)medical imaging technologies have become key to understanding the complex structure and function of the nervous system in health and disease. Recognizing this unique potential, μNEURO has assembled the expertise of eight complementary research teams from three different faculties, capitalizing on advanced neuro-imaging tools across scales and model systems to accelerate high-impact fundamental and clinical neuro-research. Building on the multidisciplinary collaboration that has been successfully established since its inception (2020-2025), μNEURO (2026-2031) now intends to integrate and consolidate the synergy between its members to become an international focal point for true multidimensional neuroscience. Technologically, we envision enriching spatiotemporally resolved multimodal imaging datasets (advanced microscopy, MRI, PET, SPECT, CT) with functional read-outs (fMRI, EEG, MEG, electrophysiology, behaviour and clinical evaluation) and a molecular context (e.g., fluid biomarkers, genetic models, spatial omics) to achieve unprecedented insight into the nervous system and mechanisms of disease. Biologically, μNEURO spans a variety of neurological disorders including neurodegeneration, movement disorders, spinal cord and traumatic brain injury, glioblastoma and peripheral neuropathies, which are investigated in a variety of complementary model systems ranging from healthy control and patient-derived organoids and assembloids to fruit flies, rodents, and humans. With close collaboration between fundamental and preclinical research teams, method developers, and clinical departments at the University Hospital Antwerp (UZA), μNEURO effectively encompasses a fully translational platform for bench-to-bedside research. Now that we have intensified the interaction, in the next phase, μNEURO intends to formalize the integration by securing additional large-scale international research projects, by promoting the interaction between its members and core facilities and by fuelling high-risk-high-gain research within the hub and beyond. This way, μNEURO will foster breakthroughs for the neuroscience community. In addition, by focusing on technological and biological innovations that will streamline the translational pipeline for discovery and validation of novel biomarkers and therapeutic compounds, μNEURO aims to generate a long-term societal impact on the growing burden of rare and common diseases of the nervous system, connecting to key research priorities of the University of Antwerp, Belgium, and Europe.

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  • Research Project

Multimodal super-resolution tomography of the neurodegenerative mouse brain. 01/01/2025 - 31/12/2028

Abstract

Neurodegenerative diseases are rapidly emerging as an insidious epidemic, presenting a significant challenge due to their limited therapeutic options. While Magnetic Resonance Imaging (MRI) has become indispensable for monitoring disease progression in both clinical and preclinical settings, its capacity to capture the underlying pathophysiological mechanisms remains constrained. Our preliminary work has demonstrated that sophisticated contrasts obtained from diffusion weighted MRI (DWI) or arterial spin labeling (ASL) hold promise in detecting subtle microstructural and perfusion alterations, respectively. However, their sensitivity and resolution are hindered by imaging time limitations. Light sheet microscopy (LSM) can complement these in vivo imaging modalities with molecular information, but equally suffers from suboptimal image quality. Recognizing the complementary potential of these modalities and acknowledging their existing limitations, our intent is to propel multimodal brain imaging forward by enhancing MRI and LSM images through model-based superresolution reconstruction. Our proposed framework is built on the premise that isotropic high-resolution images can be estimated from a collection of oblique lower resolution images. We plan to accomplish this by employing iterative algorithms and leveraging deep learning techniques, rendering the calculations more efficient. Specifically, we seek to develop superresolution reconstruction frameworks that will enable precise estimation of neuronal density from DWI, reproducible estimation of cerebral blood flow from ASL, and comprehensive quantification of sub-cellular structures from LSM. Upon successful development, we will validate these enhanced imaging techniques using a well-characterized mouse model for Huntington's Disease, a condition that necessitates a comprehensive high-resolution approach. By correlating the different imaging modalities at high resolution, we intend to enable ultra-high-content imaging of the brain, ultimately revealing intricate relationships between measured parameters and pathological defects at an individual level. Our team comprises experts from diverse disciplines, including image processing and modeling (VLAB), neuro-oriented MRI (BIL), and advanced cell biology coupled with microscopy (CBH). This multidisciplinary collaboration positions us ideally to accomplish our ambitious objectives. Moreover, as members of the µNEURO research excellence consortium, along with our roles as representatives of core facilities and coordinators of two valorization platforms, we have established a robust platform for amplifying the impact of our project. This strategic positioning ensures that the outcomes of our research will have a far-reaching effect in advancing our understanding of neurodegenerative diseases through cutting-edge imaging technologies.

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  • Research Project

Improving QMRI By Realizing trustworthy integration of AI in Neuro-imaging (IQ-BRAIN). 01/12/2024 - 30/11/2028

Abstract

MRI is a key methodology in modern neuroimaging, but conventional MRI relies on visual interpretation of intensity differences in the images, which is heavily dependent on scanner settings. Quantitative MRI (qMRI) is an attractive alternative MRI method that allows quantitative measurement of physical tissue parameters, enabling objective comparison between patients and across time. Moreover, qMRI facilitates early detection of pathological changes in the brain resulting from neurological disorders such as multiple sclerosis. Unfortunately, and despite the demonstrated potential in research settings, the implementation of qMRI in routine clinical practice remains limited due to long scan and post-processing times. While recent developments in artificial intelligence have the potential to accelerate and improve medical imaging pipelines, reduced transparency about the underlying processes, the lack of training data sets and limited information about the accuracy of the results has limited its use for clinical qMRI applications so far. In IQ-BRAIN, we propose a unique research and training programme that tackles this urgent need for improved and accelerated qMRI methodology for neuroimaging applications. By integrating both physics-based models and trustworthy artificial intelligence methods along the qMRI pipeline, our innovative approach combines the best of both worlds. IQ-BRAIN will prepare the next generation of qMRI specialists trained in the different aspects of the qMRI-neuroimaging pipeline, that can bridge the gap between qMRI method development and clinical need. Through a training programme of network-wide events, international secondments, and strong interaction between partners from academia, industry and hospitals, IQ-BRAIN offers early-stage researchers a rich combination of knowledge, expertise and essential transferable skills that prepares them for a thriving career as R&D professionals in the qMRI field.

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  • Research Project

Temporal profiling of neuroplasticity in the brain following spinal cord injury towards improved functional recovery. 01/11/2024 - 31/10/2026

Abstract

Traumatic spinal cord injury (SCI) is characterized by sensory, motor and autonomic deficits. Following a SCI, neuroplasticity levels are increased in the entire central nervous system, which is associated with functional recovery in people with SCI. Several neuro-imaging techniques are used to visualize this neuroplasticity. However, in the studies conducted in humans to evaluate brain plasticity following SCI, the results are often contradictory. Therefore, our understanding of brain plasticity following SCI is still limited. Additionally, different types of therapy are being developed, including neuromodulation of specific spared pathways to improve functional recovery of patients. However, the location of brain stimulation is often hypothesis based. So, in this project I will develop in-vivo brain imaging methods to visualize functional and structural brain plasticity following SCI to identify potential targets for stimulation by using a rat model of SCI. Afterwards, I will also assess if stimulation of these potential targets improves functional recovery in that same rat model. This project will give us essential information about the association between neuroplasticity in the brain and functional recovery. Because our methods are highly translatable to human patients, the identification of unique patterns of neuroplasticity in individual patients by using neuro-imaging methods will pave the way to a more personalized medicine for SCI patients.

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Establishing a multimodal preclinical imaging platform for the in vivo assessment of spinal cord injury outcome and therapeutic response. 01/11/2023 - 31/10/2025

Abstract

Spinal cord injury (SCI) is a devastating condition characterized by long-term motor and sensory neurological deficits, severely affecting the life of patients and their families. Although emerging therapeutic strategies focused on functional recovery are being explored, their development and translation to clinical use are severely limited by the lack of functional, objective, and non-invasive imaging biomarkers. Without quantifiable prognostic biomarkers, the clinical heterogeneity between SCI patients limits healthcare workers' qualitative measure of the potential future functional recovery. Using clinically relevant rat models, we propose a multimodal neuroimaging approach focused on synaptic and white matter markers to determine the prognostic and predictive outcome of (non)traumatic SCI. Longitudinal imaging with positron emission tomography (PET, for synaptic marker) and magnetic resonance imaging (MRI, for inflammation and white matter integrity) will be used for the establishment of a multimodal imaging platform to define lesions affecting the spinal cord to ultimately provide meaningful information related to lesion severity, functional outcome, and predictive value in a therapeutic context. Our platform will facilitate the interpretation of therapeutic results in preclinical studies, supporting the identification of most responsive treatment approaches and thus lowering the risks and costs for pharmaceutical companies' interest in the clinical translation of SCI.

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Dissecting the functional integrity of direct and indirect pathways of the dopaminergic system in Huntington's Disease 01/07/2023 - 30/06/2027

Abstract

Huntington's disease (HD) is a rare, autosomal dominant inherited neurodegenerative disorder caused by an expanded polyglutamine sequence in the huntingtin gene (HTT) encoding for mutant huntingtin (mHTT). HD neuropathology is characterized by basal ganglia neurodegeneration, leading to progressive motor, psychiatric, and cognitive impairments, and ultimately death. While the pathogenic mechanisms by which mHTT causes selective dysfunction of the medium-size spiny neurons (MSNs) in the basal ganglia remain uncertain, we have extensive (pre)clinical evidence on the progressive loss of both D1 receptors (D1R) and D2 receptors (D2R), involved in direct and indirect dopaminergic pathways, respectively. Although MSN degeneration occurs roughly in equal proportions for D1R and D2R, the indirect dopaminergic pathway is affected first, resulting in the occurrence of the involuntary movements (hyperkinesia) characteristic of HD. As of today, there is a substantial knowledge gap in understanding the relationship between dopaminergic receptor density and the functional signalling of both direct and indirect dopaminergic pathways. In this project, a multimodal approach will be applied consisting of advanced non-invasive functional magnetic resonance imaging (fMRI), electrophysiology, behaviour, and post-mortem techniques in HD mouse models, with specific modulation of the direct or indirect dopamine pathway. The outcome will increase our understanding of the functional integrity of both dopaminergic pathways of the basal ganglia in HD.

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In vivo imaging of synaptic density and white matter integrity as noninvasive biomarkers for spinal cord injury and repair. 01/07/2023 - 30/06/2025

Abstract

Traumatic spinal cord injury (SCI) is a devastating condition characterized by long-term motor and sensory neurological deficits. The functional loss in patients with SCI is mostly dictated by the precise anatomical location, with injuries to the cervical region accounting for nearly 50% of the patients with SCI, and the extent of damage at the spinal level, with contusion injuries being the most frequent. Although emerging therapeutic strategies focused on functional recovery after SCI are being explored, their development and translation to clinical use are severely limited by the lack of functional, objective, and noninvasive in vivo imaging biomarkers related to pathophysiological processes, thus reflecting the underlying SCI damage, functional outcome, and repair mechanisms. The goal of this project is to establish synaptic and white matter integrity changes, two key pathophysiological hallmarks of SCI, as in vivo biomarkers for monitoring and predicting SCI outcomes. In a clinically relevant cervical contusion rat model of SCI, we will apply state-of-the-art MRI and synaptic PET neuroimaging in a longitudinal multimodal approach to visualize and quantify synaptic and white matter integrity over time. In vivo imaging data will be complemented by behavioural tests and ultrasensitive detection of blood biomarkers to correlate molecular or cellular changes with functional motor deficits. In combination with post-mortem analyses, this provides an extremely powerful paradigm for the interpretation of the biomarker findings in relation to the underlying mechanisms and functional outcomes. The unique position of this multidisciplinary proposal is embraced by the investigation of in vivo noninvasive multimodal imaging biomarkers of key pathophysiological processing occurring during SCI in a clinically ready set-up. Accurate quantitative imaging biomarkers will facilitate the interpretation of therapeutic results in preclinical studies, ensuring a faster translation of promising new treatment strategies to patients with SCI.

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Biomarker and therapy development through in vivo Molecular Imaging of small animals. 01/06/2022 - 31/05/2026

Abstract

During the past decades, many traditional medical imaging techniques have been established for routine use. These imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and radionuclide imaging (PET/SPECT) are widely applicable for both small animal and clinical imaging, diagnosis and treatment. A unique feature of molecular imaging is the use of molecular imaging agents (either endogenous molecules or exogenous tracers) to image particular targets or pathways and to visualize, characterize, and quantify biological processes in vivo. Dedicated high-resolution small animal imaging systems such as microPET/CT scanners have emerged as important new tools for preclinical research. Considerable benefits include the robust and non-invasive nature of these small animal imaging experiments, enabling longitudinal studies with the animal acting as its own control and reducing the number of laboratory animals needed. This approach of "miniaturised" clinical scanners efficiently closes the translational feedback loop to the hospital, ultimately resulting in improved patient care and treatment. By this underlying submission, our consortium aims to renew our 2011 microPET/CT scanners after their ten-year lifetime by a digital up-to-date system in order to continue our preclinical molecular imaging studies in several research fields, including neuroscience, oncology and tracer development.

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Molecular Imaging Center Antwerp - Bio-Imaging Lab (MICA-BIL). 01/01/2022 - 31/12/2026

Abstract

The envisaged core facility brings together key preclinical imaging expertise and facilities within UA located in the Uc building on CDE. This joint venture provides preclinical imaging instruments of the highest performance of all Belgian universities. Concretely, the preclinical imaging infrastructure consists of 4 high‐field MRI systems with dedicated RF coils, 2 microPET/CT systems, 1 microSPECT/PET/CT. Using this equipment, virtual sections can be made through a living laboratory animal (which may or may not be a model for a particular pathology) enabling to quantitatively monitor various anatomical, morphological, physiological and molecular processes over time in the same animal. These techniques play a crucial role in basic and applied biomedical and pharmaceutical research and because the same techniques are used in humans/patients (translationally) they are vital for clinical diagnostics and research into early biomarkers of diseases and therapy follow‐up. In addition to the in‐vivo multi‐modal imaging systems, access to Bioluminescence/Fluorescence camera, animal monitoring (pulse oxygenation, temperature, respiration, ECG and EEG), microsurgery, and a radioprotected laboratory animal animalarium (150 laboratory animals single housed) are available.

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IMARK. Network for image-based biomarker discovery and evaluation 01/01/2021 - 31/12/2026

Abstract

IMARK capitalizes on the deeply rooted expertise in biomedical imaging at the University of Antwerp to push the boundaries of precision medicine. By resolving molecular and structural patterns in space and time, IMARK aims at expediting biomarker discovery and development. To this end, it unites research groups with complementary knowledge and tools that cover all aspects of imaging-centred fundamental research, preclinical validation and clinical evaluation. IMARK harbours high-end infrastructure for electron and light microscopy, mass spectrometry imaging, magnetic resonance imaging, computed tomography, positron emission tomography and single-photon emission computed tomography. Moreover, IMARK members actively develop correlative approaches that involve multiple imaging modalities to enrich information content, and conceive dedicated image analysis pipelines to obtain robust, quantitative readouts. This unique blend of technologies places IMARK in an excellent position as preferential partner for public-private collaborations and offers strategic advantage for expanding the flourishing IP portfolio. The major application fields of the consortium are neuroscience and oncology. With partners from the Antwerp University Hospital and University Psychiatric Centre Duffel, there is direct access to patient data/samples and potential for translational studies.

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  • Research Project

Translational molecular imaging studies 01/01/2017 - 31/12/2024

Abstract

Huntington's disease (HD) is a dominantly inherited disorder characterized by a progressive neurodegeneration of the striatum that also involves other regions, primarily the cerebral cortex. Patients display progressive motor, cognitive, and psychiatric impairment. Symptoms usually start at midlife. The mutation responsible for this fatal disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin. The pathogenic mechanisms by which mutant huntingtin cause neuronal dysfunction and cell death remain uncertain (Menalled, 2005). The mechanism underlying HD-related suppression of inhibition has been shown to include tonic activity of metabotropic glutamate receptor subtype 5 (mGluR5) as a pathophysiological hallmark (Dvorzhak, Semtner, Faber, & Grantyn, 2013) and inhibition of glutamate neurotransmission via specific interaction with mGluRs might be interesting for both inhibition of disease progression as well as early symptomatic treatment (Scheifer et al., 2004). With the objective to elucidate the role of glutamatergic pathways using small animal PET imaging, this study aims to use several PET imaging agents as tracers in a knock-in model of Huntington's disease.

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Award of the Research Board 2021 - Award Vandendriessche: Medicine and Biomedical sciences. 01/12/2021 - 31/12/2022

Abstract

Daniele Bertoglio graduated with the highest honours in Pharmaceutical Biotechnology at the University of Bologna, Italy in November 2014, after performing his master thesis at the Robert Wood Johnson Medical School in New Jersey, USA. Immediately after, he began working as a Ph.D. researcher in Medical Sciences at the University of Antwerp in December 2014 and successfully obtained an FWO Ph.D. fellowship in 2015. His doctoral studies exploited the use of positron emission tomography (PET) imaging as a prime non-invasive in vivo tool for direct assessment of alterations in several molecular targets in preclinical models of Huntington's Disease (HD) to characterize non-invasively dynamic molecular changes occurring at key stages of HD progression. His research pioneers the field of PET imaging of mutant huntingtin (mHTT) aggregates in active preparation for human biomarker studies in longitudinal follow-up of patients and clinical candidate therapies, providing an outstanding contribution to the field of Molecular Imaging for HD. His research included multimodality imaging techniques as well as robust post-mortem assessment to unravel novel candidate markers for HD, which have resulted in excellent contributions in high-impact peer-reviewed international journals and the Ph.D. in Medical Sciences defended at the University of Antwerp in November 2019. His scientific interest and passion for preclinical neuroimaging led him to pursue a second Ph.D. in Biomedical Sciences investigating the process of epileptogenesis in preclinical models of acquired epilepsy using different studies combining magnetic resonance imaging (MRI) and PET imaging which was successfully defended at the University of Antwerp in June 2021. In addition, Daniele obtained an FWO postdoc position, and he is working as a postdoctoral researcher at MICA, University of Antwerp. He uses various translational neuroimaging tools to quantify structural, functional, and molecular changes in preclinical models of neurological diseases, focusing on Huntington's disease, temporal lobe epilepsy, and spinal cord injury. His research applies state-of-the-art small animal neuroimaging techniques, including MRI and PET imaging, to identify novel candidate biomarkers to monitor disease progression, predict disease outcome, and evaluate the efficacy of innovative therapeutic approaches. To date, Daniele has co-authored a total of 23 original peer-reviewed publications in international journals, of which 14 as the first author, and contributed to 2 book chapters.

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Assessment of synaptic density and mHTT aggregates in post-mortem human brain tissue of patients with Huntington's Disease. 01/04/2021 - 31/03/2022

Abstract

Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by mutant huntingtin (mHTT). Patients with HD exhibit progressive motor and cognitive decline, and development of psychiatric symptoms. Pathological features of HD include wide-spread progressive accumulation of mHTT, selective neurodegeneration, and forebrain atrophy. The synaptic vesicle glycoprotein 2A (SV2A) is a vesicle membrane protein expressed ubiquitously in synapses of the brain, involved in neurotransmitter release. SV2A can be used as a proxy to measure synaptic density in vivo using the radioligand [11C]UCB-J and positron emission tomography (PET). Based on our in vivo [11C]UCB-J PET imaging and in vitro [3H]UCB-J autoradiography findings in HD mice, demonstrating SV2A decline, we hypothesize the levels of SV2A to be decreased in patients with HD as a direct effect of mutant huntingtin accumulation as well as by the consequent neurodegeneration occurring with disease progression. Thus, the objective of this project is to provide evidence for the clinical significance of SV2A as a candidate biomarker in patients with HD in comparison to age- and gender-matched healthy non-demented subjects using in vitro autoradiography and immunohistochemistry in post-mortem samples from patients with HD and healthy subjects. The knowledge derived from this project will not only contribute to supporting the preclinical outcomes, filling the gap between preclinical and clinical findings, but it will represent a significant contribution in supporting SV2A as a candidate imaging biomarker for disease progression to be investigated in longitudinal SV2A PET imaging studies in patients with HD.

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Preclinical PET imaging of allele-selective mHTT lowering as candidate treatment for Huntington's Disease. 01/10/2020 - 30/09/2023

Abstract

Huntington's Disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by a genetic mutation in the huntingtin gene (HTT), which encodes for mutant huntingtin (mHTT), the causative agent of the disorder. Since lowering the levels of toxic mHTT is postulated to halt disease progression, the use of engineered zinc finger protein transcription repressors (ZFP-TR) to selectively suppress the mutant HTT allele represents a novel candidate treatment for HD. A major limitation in the assessment of therapeutic efficacy is the lack of objective non-invasive markers. We recently validated the first-ever radioligand to image in vivo mHTT levels using positron emission tomography (PET) imaging in mice. The aim of this project is to assess the preclinical relevance of the use of ZFP-TR at different disease stages as candidate therapeutic intervention. This work will provide proof of efficacy for an mHTT lowering HD therapy in the living (rodent) brain by measuring mHTT in parallel to molecular targets for phenotypic recovery in wellcharacterized mouse models of HD. This multi-modal approach consisting of non-invasive in vivo PET imaging in combination with magnetic resonance imaging (MRI) and post-mortem techniques will represent a strategic multi-disciplinary platform to assess the efficacy of the ZFP-TR therapeutic efficacy providing a key contribution on the timing of intervention, ultimately leading to clinical translation in the future. GENERAL -

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Translocator protein expression in animal models of temporal lobe epilepsy and Huntington's Disease. 01/10/2017 - 30/09/2019

Abstract

Epilepsy is a devastating disorder affecting 65 million people worldwide characterized by recurrent seizures. This research project will investigate a novel hypothesis connecting translocator protein (TSPO) overexpression, a hallmark of brain inflammation, and spontaneous seizure outcome during the development of epilepsy (epileptogenesis). Our hypothesis is supported by the observation that i) TSPO is highly up-regulated in epilepsy and ii) our preliminary data suggest a relationship between TSPO overexpression and spontaneous seizure outcome. Unraveling this relationship will enable us to assess TSPO as a biomarker for maladaptive neuroplasticity during epileptogenesis. Firstly, by means of translational techniques, we will investigate longitudinally the pattern of TSPO expression during epileptogenesis in vivo in the kainic acid-induced status epilepticus (KASE) model. Secondly, the role of TSPO in epileptogenesis will be investigated by the study of the effects of the absence of TSPO in the TSPO knockout mouse, and by pharmacological stimulation of TSPO in the KASE model. This innovative project will increase our understanding of brain excitability during epileptogenesis offering a biomarker to identify patients at risk and moving the field forward giving a contribution to the development of therapies to prevent acquired epilepsy.

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Translocator protein expression in an animal model of temporal lobe epilepsy. 01/10/2015 - 30/09/2017

Abstract

Epilepsy is a devastating disorder affecting 65 million people worldwide characterized by recurrent seizures. This research project will investigate a novel hypothesis connecting translocator protein (TSPO) overexpression, a hallmark of brain inflammation, and spontaneous seizure outcome during the development of epilepsy (epileptogenesis). Our hypothesis is supported by the observation that i) TSPO is highly up-regulated in epilepsy and ii) our preliminary data suggest a relationship between TSPO overexpression and spontaneous seizure outcome. Unraveling this relationship will enable us to assess TSPO as a biomarker for maladaptive neuroplasticity during epileptogenesis. Firstly, by means of translational techniques, we will investigate longitudinally the pattern of TSPO expression during epileptogenesis in vivo in the kainic acid-induced status epilepticus (KASE) model. Secondly, the role of TSPO in epileptogenesis will be investigated by the study of the effects of the absence of TSPO in the TSPO knockout mouse, and by pharmacological stimulation of TSPO in the KASE model. This innovative project will increase our understanding of brain excitability during epileptogenesis offering a biomarker to identify patients at risk and moving the field forward giving a contribution to the development of therapies to prevent acquired epilepsy.

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Translocator protein expression in an animal model of temporal lobe epilepsy: picturing a Janus face? 01/12/2014 - 30/09/2015

Abstract

Epilepsy is a devastating disorder affecting 50 million people worldwide characterised by recurrent seizures and serious psychiatric comorbidities such as anxiety and depression. This research proposal will investigate a novel hypothesis connecting brain inflammation and neurosteriod alterations as protagonists during the development of epilepsy and its comorbidities a process termed epileptogenesis. These former pathways are shown to have bimodal effects on seizure susceptibility, but up till now have only been investigated independently. Our hypothesis of coupling these pathways is supported by the observation that i) the translocator protein (TSPO) a marker of brain inflammation is highly upregulated in epilepsy and ii) the main function of TSPO is cholesterol import, the rate-limiting step in steroidogenesis. Firstly, we will for the first time investigate the brain region and cell specific distribution pattern of TSPO during epileptogenesis and established epilepsy in two rat models of acquired epilepsy. Secondly, pharmacological agents will be used to interfere with TSPO and brain inflammation to investigate a causal relationship between TSPO and epileptogenesis by means of translational techniques namely in vivo TSPO PET imaging, behavioural tests and video-EEG monitoring in a rat model of temporal lobe epilepsy. This innovative project will increase our understanding of the ambiguous complexities related to brain inflammation- and neurosteriod-induced effects on brain excitability potentially revealing an interrelated action. If the proposed hypothesis holds true, this may influence our current thinking regarding the role of brain inflammation in epilepsy and psychiatric conditions.

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