Human Imaging of Neuroplastic Changes in Depression

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Human Imaging of Plastic Changes in Depression
ESR3: Experimental Neuroimaging in animal models: NMDA modifiers and their effect on brain structure function in animal models

This position has been filled

Summary: There is growing evidence that glutamate is involved in the pathophysiology of depression. Inhibition of nNOS downstream of NMDA has been investigated as an experimental approach to produce antidepressant effects, lacking the side effects associated with direct receptor inhibition. By targeting the PDZnNOS-PDZ2PSD95 interaction, we propose an alternative approach to regulate NMDA-R-nNOS signalling by specifically uncoupling nNOS from NMDA-R. Two compounds (IC87201 and ZL006), small molecule inhibitors that disrupt the PSD-95/nNOS interaction have been identified.  We adopt this selective approach to test our hypothesis for the development of a novel glutamatergic based treatment for depression. We propose to examine concurrently the relationship between anatomical changes determined with MRI in vivo and transfocal imaging of neurogenesis and neuronal and glial integrity determined ex vivo in brain tissue together with the antidepressant potential of the experimental glutamate compounds (IC87201 and ZL006)  in the animal model of cortical glial ablation described.

Role: The early stage researcher (ESR) will work within the stimulating environment of Trinity College Institute of Neuroscience (TCIN). He/She will learn the behavioural tests open field, novelty suppressed feeding, forced swimming test and novel object recognition (NOR) in order to test the efficacy of novel compounds using a rat animal model of glial ablation at Trinity College and during placements with Itä-Suomen Yliopisto (UEF). Together with Michael Courtney from Itä-Suomen Yliopisto (UEF), he/she will test the most promising inhibitors of NMDA signalling identified in the rat model. Moreover, The ESR will perform 7 Tesla neuroimaging including volumetric morphometry, relaxometry, magnetic resonance spectroscopy for determination of glutamate concentrations and arterial spin labelling in order to determine neuroimaging markers for glial ablation and for neurogenesis and neuroplasticity. For this purpose the ESR will use immunohistochemistry to determine neurogenesis by visualisation of BrdU incorporated into cells. The ESR will learn using confocal laser scanning microscope to determine the phenotypes of BrdU-labelled cells tissue sections with double labelling for NeuN and GFAP with assistance of Magdeburg Brain Bank (MW).  Deliverables/Research Training: 1) To learn how to develop an animal model of depression. 2) To carry out specific neuroimaging methods and analysis using 7 Tesla rat imaging. 3) To learn histochemical and transfocal microscopy of neurogenesis markers. 4) To gain experience in statistical analysis for associations between neuroimaging and microscopy.

Supervisor:   Professor Dr. Andrew Harkin
Host institution:   Neuroscience Institute, Trinity College Dublin
Duration:  36 months. Contact person: Thomas Frodl.

ESR4: Human imaging of neuroplastic changes in depression

This position has been filled

Summary: Despite the experimental findings involving neuroplasticity in the pathophysiology of MDD, to date this work has not been translated into the clinical setting in terms of elucidating a causal role for stress, epigenetic regulation and inflammatory neurotcytotoxic processes in mediating functional neurochemical and structural brain changes. In the clinic it is well established that depressed patients hypersecrete cortisol, have impaired glucocorticoid receptor (GR) functioning, have increased circulating concentrations of inflammatory cytokines and C-Reactive Protein (CRP) and have reduced hippocampal volumes. It has been shown that hippocampal volume reduction is associated with exposure to stress and that it is influenced by genetic variation.

However, it still is unclear how inflammatory and stress related blood markers might be associated with in-vivo Brain Imaging changes and thus might include relevant information on brain function. Aim of the project is to determine how neuroplasticity-related brain changes are associated with peripheral inflammatory, stress and neurogenesis biomarkers and to explore how these are related to epigenetics. We will apply sophisticated neuroimaging techniques – high resolution hippocampal structural MRI, blood flow (arterial spin labelling) MRI, resting state functional MRI and MR Spectroscopy of the cingulate cortex- and will obtain blood for protein and mRNA analyses in a sample a 100 patients with MDD and 100 healthy controls.

All participants will have MRI imaging at the Neuroimaging Centre at Trinity College Institute of Neuroscience (TCIN) and blood sampling. Response to treatment will be monitored over a period of 1 year. With a secondment of ESR4 in Belgium at the Company Advanced Practical Diagnostics kyrunenine metabolites in the blood will be analysed. PAXgene blood RNA tubes will be used at TCIN for whole blood RNA isolation. Real-time PCR will be used to analyse expression of inflammatory cytokines, GR, glucocorticoid-inducible genes to determine if any of these measures are altered in a static blood sample obtained from depressed patients relative to controls. Moreover, cytokines, CRP and BDNF will be measured using ELISA at TCD. Epigenetic candidate genes like the GR receptor, BDNF, serotonin transporter genes and novel targets like JNK, GILZ, FKBP5 genes as well as those linked to the most relevant targets from the r’BIRTH ITN subproject 1 will be analysed. Following these analyses, the association analysis between stress and neurogenesis related blood markers and epigenetics will be carried out at TCD.

Role: The early stage researcher (ESR) will be placed within the Neuroimaging Research group at Trinity College Institute of Neuroscience (TCIN, http://www.tcd.ie/Neuroscience/). She/he will learn and perform human neuroimaging in patients with MDD and healthy controls. She/he will therefore apply sophisticated neuroimaging techniques such as high-resolution hippocampal structural MRI, resting state and emotion task related functional MRI, MR-Spectroscopy and neuropsychological tests. Moreover, he/she will be trained to analyse the MRI data. In placements in the imaging centre of Magdeburg (Leibniz Institute for Neurobiology) he/she will learn to analyse MR-Spectroscopy data. Moreover, blood will be taken and analysed for inflammation and stress markers in TCD-Immunology lab as well as at  Advanced Practical Diagnostics. To be trained for specific blood analysis ESR4 will go for placements to Advanced Practical Diagnostics (APD). The analysis of bloods for the top candidate markers for neurogenesis will then be carried out by the ESR. In addition the ESR will perform the analyses of associations between peripheral blood markers for inflammation and stress with changes in brain function and structure.

Deliverables/Research Training: 1) To learn and carry out neuroimaging in clinical populations and to learn analyses of neuroimaging data. 2) To learn analysis of neuro-inflammation, stress and neurodegenerative blood markers. 3) To gain experience in statistical analysis for associations between neuroimaging and peripheral blood markers.

Supervisor:   Thomas Frodl
Host institution:   Neuroscience Institute, Trinity College Dublin
Duration:  36 months. Contact person: Thomas Frodl

ER2: Translational Neuroimaging

This position has been filled

Summary: Although neurogenesis and neuroplasticity plays an important role in neuropsychiatric disorders, to date no in-vivo biomarkers had been detected for neurogenesis. Within the project we will apply the top ten candidate markers of neurogenesis identified to brain tissue derived from experiments in WP1 using immunohistochemistry in Turku University. Also most promising inhibitors of NMDA signalling identified will be tested for their potential therapeutic effect in our mice model. In this way we propose to use the animal model to establish neuroimaging markers associated with neuroplasticity and neurogenesis with translation potential for the clinic in relation to depression and antidepressant action and to determine the relationship between these neuroimaging markers and histological changes obtained with transfocal microscopy.

Role:  The early stage researcher (ESR) will be placed within the Neuroimaging Research group at Trinity College Institute of Neuroscience (TCIN, http://www.tcd.ie/Neuroscience/). She/he will use the candidate markers for neurogenesis identified in WP1 in addition standard markers like BrDU, NeuN in the brain tissue derived from rat trials with novel substances and associate these markers to the brain neurochemical and functional imaging findings. Moreover, the ER will test identified neuroimaging markers from the rat model in the clinical population. Deliverables/Research Training: 1) To find novel neurogenesis markers relevant in treatment and diagnosis of depression 2) To analyse neurochemical and functional rat imaging data 3) To translate these markers to human population.

Supervisors:   Thomas Frodl and Andrew Harkin
Host institution:   Neuroscience Institute, Trinity College Dublin
Duration:  24 months. Contact person: Thomas Frodl