Multi-omics data integration methods and their applications in psychiatric disorders.

To study mental illness and health, in the past researchers have often broken down their complexity into individual subsystems (e.g., genomics, transcriptomics, proteomics, clinical data) and explored the components independently. Technological advancements and decreasing costs of high throughput sequencing has led to an unprecedented increase in data generation. Furthermore, over the years it has become increasingly clear that these subsystems do not act in isolation but instead interact with each other to drive mental illness and health. Consequently, individual subsystems are now analysed jointly to promote a holistic understanding of the underlying biological complexity of health and disease. Complementing the increasing data availability, current research is geared towards developing novel methods that can efficiently combine the information rich multi-omics data to discover biologically meaningful biomarkers for diagnosis, treatment, and prognosis. However, clinical translation of the research is still challenging. In this review, we summarise conventional and state-of-the-art statistical and machine learning approaches for discovery of biomarker, diagnosis, as well as outcome and treatment response prediction through integrating multi-omics and clinical data. In addition, we describe the role of biological model systems and in silico multi-omics model designs in clinical translation of psychiatric research from bench to bedside. Finally, we discuss the current challenges and explore the application of multi-omics integration in future psychiatric research. The review provides a structured overview and latest updates in the field of multi-omics in psychiatry.

RORα Coordinates Thalamic and Cortical Maturation to Instruct Barrel Cortex Development.

The retinoic acid-related orphan receptor alpha (RORα) is well-known for its role in cerebellar development and maturation as revealed in staggerer mice. However, its potential involvement in the development of other brain regions has hardly been assessed. Here, we describe a new role of RORα in the development of primary somatosensory maps. Staggerer mice showed a complete disruption of barrels in the somatosensory cortex and of barreloids in the thalamus. This phenotype results from a severe reduction of thalamocortical axon (TCA) branching and a defective maturation of layer IV cortical neurons during postnatal development. Conditional deletion of RORα was conducted in the thalamus or the cortex to determine the specific contribution of RORα in each of these structures to these phenotypes. This showed that RORα is cell-autonomously required in the thalamus for the organization of TCAs into periphery-related clusters and in the somatosensory cortex for the dendritic maturation of layer IV neurons. Microarray analyses revealed that Sema7a, Neph, and Adcy8 are RORα regulated genes that could be implicated in TCA and cortical maturation. Overall, our study outlines a new role of RORα for the coordinated maturation of the somatosensory thalamus and cortex during the assembly of columnar barrel structures.

Seeding and propagation of lesions in neurodegenerative diseases: a new paradigm.

Specific extracellular deposits, glial or neuronal inclusions help defining an ever increasing number of neurodegenerative diseases. Deposits or inclusions are aggregates of proteins: Aß peptide and tau proteins in Alzheimer disease, a-synuclein in Parkinson disease, for instance. The protein that specifically accumulates in a given disease may be modified by a mutation that can increase its aggregability. Most often the sequence of the protein is normal. Misfolding, despite the protein normal sequence, is then considered the cause of the aggregation. The ubiquitin-proteasome system detects and eliminates misfolded proteins from the cell. Almost all the inclusions are indeed labeled by anti-ubiquitin antibodies, but, in neurodegenerative diseases, the system is unable to get rid of them. The large protein aggregates constituting the inclusions are poorly reactive. Their formation has been consi- dered a defense mechanism, protecting the cell against the toxic action of soluble oligomers that are, in that hypothesis, the real toxic agent, neutralized through aggregation. Soluble oligomers of Aß peptide, tau or a-synuclein,for instance, have indeed been isolated and were shown to be toxic. In the prion hypothesis, the misfolded configuration may be passed from the misfolded to the normal protein by simple contact. There are indeed experimental evidences suggesting that this prion-like mechanism does occur in transgenic rodent models of Aß, tau or a-synuclein pathology. This might be the explanation of thepropagation of the pathology through connections, observed in many neurodegenerative diseases. There is currently no epidemiological data suggesting a transmission of neurodegenerative diseases, comparable to the transmission of Creutzfeldt-Jakob or other prion diseases. The prion-like mechanisms of protein aggregation observed in the experimental animals or suspected through human neuropathology make that possibility not as remote as previously thought.

In vivo 1H MRS study in microlitre voxels in the hippocampus of a mouse model of Down syndrome at 11.7 T.

In this article, we report in vivo (1)H MRS performed in 1.8-µL voxels in a mouse model of Down syndrome (DS). To characterise the excitation-inhibition imbalance observed in DS, metabolite concentrations in the hippocampi of adult Ts65Dn mice, which recapitulate features of DS, were compared with those of their euploid littermates at a voxel 42-fold smaller than in a previously published study. Quantification of the metabolites was performed using a linear combination model. We detected 16 metabolites in the right and left hippocampi. Principal component analysis revealed that the absolute concentrations of the 16 detected metabolites could differentiate between Ts65Dn and euploid hippocampi. Although measurements in the left and right hippocampi were highly correlated, the concentration of individual metabolites was sometimes significantly different in the left and right structures. Thus, bilateral values from Ts65Dn and euploid mice were further compared with Hotelling's test. The level of glutamine was found to be significantly lower, whereas myo-inositol was significantly higher, in the hippocampi of Ts65Dn relative to euploid mice. However, γ-aminobutyric acid (GABA) and glutamate levels remained similar between the groups. Thus, the excitation-inhibition imbalance described in DS does not appear to be related to a radical change in the levels of either GABA or glutamate in the hippocampus. In conclusion, microliter MRS appears to be a valuable tool to detect changes associated with DS, which may be useful in investigating whether differences can be rescued after pharmacological treatments or supplementation with glutamine.

Vaccination with Sarkosyl insoluble PHF-tau decrease neurofibrillary tangles formation in aged tau transgenic mouse model: a pilot study.

Active immunization using tau phospho-peptides in tauopathy mouse models has been observed to reduce tau pathology, especially when given prior to the onset of pathology. Since tau aggregates in these models and in human tauopathies are composed of full-length tau with many post-translational modifications, and are composed of several tau isoforms in many of them, pathological tau proteins bearing all these post-translational modifications might prove to be optimal tau conformers to use as immunogens, especially in models with advanced tau pathology. To this aim, we immunized aged wild-type and mutant tau mice with preparations containing human paired helical filaments (PHF) emulsified in Alum-adjuvant. This immunization protocol with fibrillar PHF-tau was well tolerated and did not induce an inflammatory reaction in the brain or adverse effect in these aged mice. Mice immunized with four repeated injections developed anti-PHF-tau antibodies with rising titers that labeled human neurofibrillary tangles in situ. Immunized mutant tau mice had a lower density of hippocampal Gallyas-positive neurons. Brain levels of Sarkosyl-insoluble tau were also reduced in immunized mice. These results indicate that an immunization protocol using fibrillar PHF-tau proteins is an efficient and tolerated approach to reduce tau pathology in an aged tauopathy animal model.

[The lesions of Alzheimer's disease: which therapeutic perspectives?]. / "La maladie d'Alzheimer, Les lésions de la maladie d'Alzheimer. Perspectives thérapeutiques?

The brain lesions associated with Alzheimer's disease are caused by extracellular accumulation of Abeta peptide and intracellular accumulation of tau protein. Abeta peptide makes the core of the senile plaque (the "focal deposit"); it is also present in the extracellular "diffuse deposits" and in the vessel walls. Neurofibrillary tangles, and neuropil threads are composed of hyperphosphorylated tau that also accumulates in the processes of the corona of the senile plaque. The Abeta deposits first involve the neocortex, while the tau pathology is initially found in the hippocampal region. Abeta deposits first occur in the neocortex, while intracellular tau accumulation mainly affect the hippocampal region. Abeta peptide deposits are initially found in all the neocortical areas, then involve the hippocampus and the subcortical nuclei. Tau lesions successively involve the hippocampal regions, multi- and uni-modal areas and finally the primary cortices in stereotyped stages. Mutations of APP, the precursor of Abeta peptide, cause autosomal dominant familial Alzheimer disease, suggesting that a cascade of reactions link Abeta overproduction, tau pathology and the clinical phenotype. Transgenic mice bearing the mutated human APP gene (APP mice) develop A deposits. Systemic injection of Abeta peptide prevents the deposition of Abeta peptide. However, a clinical trial had to be interrupted when meningoencephalitis occurred in a significant proportion of treated patients. Post mortem studies showed a relative scarcity of Abeta deposits. Forthcoming immunotherapy studies should soon show whether the prevention of Abeta deposition interrupts disease progression.