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Final Report Summary - R'BIRTH (Brain Imaging Return to Health)

Brain Imaging Return to Health
The rBIRTH consortium set out to gain improved molecular understanding of mood disorders, especially anxiety and depression, while advancing biomarker diagnostics through non-invasive high-resolution imaging and spectroscopy. We achieved these goals by exploiting the network’s multidisciplinary training platform established by 9 partners in 6 European countries encompassing expertise in molecular and cellular neuroscience, clinical neuroscience and neuroimaging, chemistry and mass spectrometry and pharmacological science. In addition, the consortium partnered with several private enterprises focusing on diagnostic assay development, medical device development and sequencing services. The project has yielded 23 peer reviewed publications to date, including those from the Nature Publishing Group, namely Neuropsychopharmacology, Nature Communications and Molecular Psychiatry. At least 10 additional manuscripts are under preparation with anticipated publication during 2018-2019, many of which involve network collaborations. The scientific results have attracted considerable public attention, and were profiled on national evening news (MTV in Finland), local TV channel in Germany and national daily and evening newspapers, while at the same time generating considerable media buzz. In addition, the consortium published three reviews on molecular mechanisms of depression and psychiatric disorders and a book entitled “Systems Neuroscience in Depression” was compiled by consortium PI Prof Frodl with Harkin and Coffey as contributing authors. Two additional reviews describing results from the consortium are in preparation for publication during 2018.

A novel mechanism underlying anxiety and depressive-like behaviour identified -
A major aim of the consortium was to evaluate the role of c-Jun N-terminal kinases (JNK) in anxiety and depression. Results from mouse models showed that either genetic deletion of Jnk1 or inhibition of JNK by chronic infusion of a specific inhibitor, lowers anxiety and depressive behaviour in mice, whilst improving cognitive function. The locus of anxiolytic and anti-depressant action was traced to the hippocampal neurogenic niche, as inhibition of JNK solely in adult born granule cells of the dentate gyrus using retroviruses, was sufficient to alleviate mood. This work was published in Molecular Psychiatry. In addition to the cell autonomous effect of JNK in dentate gyrus granule cells, JNK inhibition increased the number of adult born granule cells. The molecular mechanism whereby JNK inhibition promotes neurogenesis was examined in detail and is in preparation for publication.

Phosphoproteomic signatures of depression, a new frontier in molecular understanding -
A phospho-signature of JNK-regulated protein phosphorylation changes that correlate with anxious and depressive behaviour was obtained from the hippocampus and nucleus accumbens. This has uncovered region-specific molecular insight on pathway regulation contributing to affective behaviour in rodent models. The resulting SRM assays provide a sensitive screen that can be applied to studies of human biopsies of clinical relevance. This data, not yet published, offers proteomic insight on molecular drivers of behaviour.
Imaging tools developed -
Novel imaging tools were developed by the rBIRTH consortium. Among these, new plasma membrane markers of neurogenic cells were identified and scFv antibodies targeting them were generated. Significantly, the scFvs encode “brain-tags” that will help them to penetrate the blood brain barrier. In addition to antibody imaging tools, novel optogenetic tools were developed by groups in the network. These include a photo-switchable inhibitor of JNK, developed by partners 1 and 3, and published in Nature Communications. It comprises the JBD peptide inhibitor of JNK tethered to the light-sensitive LOV2 domain from Avena Sativa to generate a light-activatable inhibitor of JNK. This tool is being applied to the study of synaptic plasticity regulation in depression. It allows tight spatio-temporal control of JNK activity within the dendritic spine-head and assists precise study of this kinase during spine elimination, as occurs in major depression.
Thirdly, a novel set of retroviral GCaMP6s reporter-inhibitors were engineered within the network by partner 1. These report calcium activity from individual neurons in vivo in awake behaving mice, providing a correlate of neurotransmission. The project continues, using these reporters to delineate connections from the dentate neurogenic niche to the prefrontal cortex and amygdala using fiber-photometry.

Signalling mechanisms regulating dendritic spines and depression –
Several fellows (TCD, AAU) examined the role of the signalling mechanisms that lead to dendritic spine elimination in vivo, in rat and mouse models of depression. They identified new information on signals that control dendritic spine stability and molecules that prevents spine elimination while alleviating depressive behaviour. These mechanisms, either as single or separable pathways, contribute to spine elimination, a structural hallmark of depression that contributes to maladaptive endocrine loop control.

Functional imaging in humans -
Magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging (fMRI) were used extensively to elaborate new biomarker diagnostics for major depressive disorder in patients. As one example, molecular and structural correlates obtained from MRS and 7 Tesla MRI were identified in major depressive disorder where cortical thinning and neuronal integrity in hub regions were found to influence functional integration at the whole brain level. New characteristics of the default mode network promoting inter-network communication and elaboration of functional imaging biomarker diagnostics were defined and 7 Tesla multi-voxel STEAM MRS mapped sub-regional diversity in the anterior cingulate cortex and showed it was lower in depressed individuals while MRS signatures identified that ACC glutamine decrease defined a subpopulation of severely depressive patients.
The effect of childhood adversity on structural changes in subcortical structures in depressed patients were studied by rBIRTH investigator Frodl and Tozzi (OVG and TCD) in collaboration with the ENIGMA group. This work identified correlations between subcategories of adversity (emotional, physical neglect and physical abuse) and subcortical volumes, identifying emotional neglect and physical neglect as negatively correlating with subcortical volume in females. This plays an important role in feedback to cortical areas that govern motor, emotional and cognitive processes and controls adaptive responses to adverse environment. Using fMRI, this team showed that major depressive disorder patients that had suffered childhood adversity exhibited differences in activity in regions associated with emotional processing. They also showed that in patients that carry the high-risk variant of FKBP5 (rs1360780), demethylation of the intron sites of the promoter correlated with the amount of early life maltreatment endured. Thus, a combination of genetic and environmental changes can lead to long lasting epigenetic changes in a gene that contributes to glucocorticoid receptor regulation.
Translating from human to rat and back -
As a translational goal, the consortium utilized two rat models of depression. One is based on elimination of glial cells in the prelimbic cortex using a specific toxin (L-AAA) (AAU). This mimics the loss of GFAP glial cell marker, which occurs in post-mortem brain from depressed patients. The second is the Wistar Kyoto inbred strain that exhibits high levels of anxiety, enlarged lateral ventricles and decreased hippocampal volume. These models were imaged using a resting state fMRI protocol developed within the consortium. While challenging, this approach provides potential for translation of human fMRI correlates to animal models and facilitates dissection of cause and effect. Working together, the consortium PIs studied clinical depression and rodent models of depression and co-authored a timely review on the advances in magnetic resonance imaging in animal models of depression.

Training objectives –
The training objectives of the consortium were fulfilled through secondments to partner labs, and private enterprises, but also new secondments arose during the running of the project bringing fellows to labs in Stanford, Florida and Helsinki. 82% of rBIRTH research fellows successfully carried out research ethics training, and the importance this training was emphasized throughout. Advanced training modules and workshops were organised by r’BIRTH covering the following topics: several imaging modalities (fluorescence, immunohistochemistry (human and mouse), PET, fMRI and MRS), proteomics and mass spectrometry, bioinformatics, gene sequencing and animal handling. Fellows travelled extensively to join these and other events and symposia. Attendance at these events was high.

Societal impact –
Research results from the r’BIRTH training program contributes to a continuum of information that reshapes our understanding of molecular mechanisms of anxiety and depression. Consortium results are published in open source journals (e.g. Neuropsychopharmacology, Molecular Psychiatry and Nature Communications), in the Media (TV, Biotech journals, newspapers), in public forums (Twitter, Facebook) and on YouTube videos prepared by the fellows. This maximizes dissemination of results to scientists and to public interest groups. rBIRTH scientific efforts have identified entirely new molecular details on anxiety and depression based on study in animal models. These open up new avenues for translational drug targeting. rBIRTH research has also defined new imaging and proteomics-based biomarker signatures and generated new imaging tools. Some projects extended beyond the original planned work and in so doing, achieved more than expected, while at the same time reaching the planned milestones. While the full extent of rBIRTH findings and the societal impact will take some years to manifest, in the short-term, rBIRTH has produced highly skilled, confident and ambitious young researchers that are equipped to work towards solutions to mental health problems using academic and industrial/pharmaceutical approaches.

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