Reporting Psychiatric Disease Characteristics in Post-Mortem- and Biological Research.

Inflammation is a prominent hypothesis in the neurobiology of depression. In our transcriptomic profiling study of microglia in chronic major depressive disorder (MDD), we revealed a distinct disease-associated microglia (DAM) transcriptomic profile exclusively found in cortical gray matter, that we have designated DepDAM. These DepDAM revealed an immune-suppressed state, with a possible upstream mechanism for microglial suppression, by upregulation of CD200 and CD47 ("don't eat me signals") located on synapses. We extensively report on disease characteristics, such as cause of death, reason for euthanasia, and psychiatric state when deceased. When excluding MDD donors in a euthymic state, the trend of lower CD45 membrane expression on white matter microglia became significant, and the difference in gray matter microglia became larger. For Western blot analysis of CD47 and CD200, both means of the definitely depressed donor groups (MDD-D) increased. This underscores the utmost importance of reporting on patient and episode characteristics, such as severity, episode traits, (type of) suicidality, mode of decease, and state of illness at death in post-mortem- and biological psychiatric research. For psychiatric post-mortem research, we suggest using well-characterized donors (eg, after "psychological autopsy") selected by an experienced clinician.

Identification of clinical disease trajectories in neurodegenerative disorders with natural language processing.

Neurodegenerative disorders exhibit considerable clinical heterogeneity and are frequently misdiagnosed. This heterogeneity is often neglected and difficult to study. Therefore, innovative data-driven approaches utilizing substantial autopsy cohorts are needed to address this complexity and improve diagnosis, prognosis and fundamental research. We present clinical disease trajectories from 3,042 Netherlands Brain Bank donors, encompassing 84 neuropsychiatric signs and symptoms identified through natural language processing. This unique resource provides valuable new insights into neurodegenerative disorder symptomatology. To illustrate, we identified signs and symptoms that differed between frequently misdiagnosed disorders. In addition, we performed predictive modeling and identified clinical subtypes of various brain disorders, indicative of neural substructures being differently affected. Finally, integrating clinical diagnosis information revealed a substantial proportion of inaccurately diagnosed donors that masquerade as another disorder. The unique datasets allow researchers to study the clinical manifestation of signs and symptoms across neurodegenerative disorders, and identify associated molecular and cellular features.

Microglia Transcriptional Profiling in Major Depressive Disorder Shows Inhibition of Cortical Gray Matter Microglia.

BACKGROUND: Microglia have been implicated in the pathophysiology of major depressive disorder (MDD), but information on biological mechanisms is limited. Therefore, we investigated the gene expression profile of microglial cells in relation to neuronal regulators of microglia activity in well-characterized MDD and control autopsy brains. METHODS: Pure, intact microglia were isolated at brain autopsy from occipital cortex gray matter (GM) and corpus callosum white matter of 13 donors with MDD and 10 age-matched control donors for RNA sequencing. Top differentially expressed genes were validated using immunohistochemistry staining. Because gene expression changes were only detected in GM microglia, neuronal regulators of microglia were investigated in cortical tissue and synaptosomes from the cortex by reverse transcriptase-quantitative polymerase chain reaction and Western blot. RESULTS: Transcriptome analysis revealed 92 genes differentially expressed in microglia isolated from GM, but none in microglia from white matter in donors with MDD, compared with control donors. Of these, 81 genes were less abundantly expressed in GM in MDD, including CD163, MKI67, SPP1, CD14, FCGR1A/C, and C1QA/B/C. Accordingly, pathways related to effector mechanisms, such as the complement system and phagocytosis, were differentially regulated in GM microglia in MDD. Immunohistochemistry staining revealed significantly lower expression of CD163 protein in MDD. Whole tissue analysis showed an increase in CD200 (p = .0009) and CD47 (p = .068) messenger RNA, and CD47 protein was significantly elevated (p = .0396) in synaptic fractions of MDD cases. CONCLUSIONS: Transcriptional profiling indicates an immune-suppressed microglial phenotype in MDD that is possibly caused by neuronal regulation.

Myelination synchronizes cortical oscillations by consolidating parvalbumin-mediated phasic inhibition.

Parvalbumin-positive (PV+) γ-aminobutyric acid (GABA) interneurons are critically involved in producing rapid network oscillations and cortical microcircuit computations, but the significance of PV+ axon myelination to the temporal features of inhibition remains elusive. Here, using toxic and genetic mouse models of demyelination and dysmyelination, respectively, we find that loss of compact myelin reduces PV+ interneuron presynaptic terminals and increases failures, and the weak phasic inhibition of pyramidal neurons abolishes optogenetically driven gamma oscillations in vivo. Strikingly, during behaviors of quiet wakefulness selectively theta rhythms are amplified and accompanied by highly synchronized interictal epileptic discharges. In support of a causal role of impaired PV-mediated inhibition, optogenetic activation of myelin-deficient PV+ interneurons attenuated the power of slow theta rhythms and limited interictal spike occurrence. Thus, myelination of PV axons is required to consolidate fast inhibition of pyramidal neurons and enable behavioral state-dependent modulation of local circuit synchronization.

The brain contains billions of neurons that connect with each other via cable-like structures called axons. Axons transmit electrical impulses and are often wrapped in a fatty substance called myelin. This insulation increases the speed of nerve impulses and reduces the energy lost over long distances. Loss or damage of the myelin layer ­ as is the case for multiple sclerosis, a chronic neuroinflammatory and neurodegenerative disease of the central nervous system ­ can cause serious disability. However, a fast-firing neuron within the brain, called PV⁺ interneuron, has short, sparsely myelinated axons. Even so, PV⁺ interneurons are powerful inhibitors that regulate important cognitive processes in gray matter areas, including the outermost parts, in the cortex. Yet it remains unclear how the unusual, patchy myelination affects their function. To examine these questions, Dubey et al. used genetically engineered mice either lacking or losing myelin and studied the impact on PV⁺ interneurons and slow brain waves. As mice progressively lost myelin, the speed of inhibitory signals from PV⁺ interneurons did not change but their signal strength decreased. As a result, the power of slow brain waves, no longer inhibited by PV⁺ interneurons, increased. These waves also triggered spikes of epileptic-like brain activity when the mice were inactive and quiet. Restoring the activity of myelin-deficient PV⁺ interneurons helped to reverse these deficits. This suggests that myelination, however patchy on PV⁺ interneurons, is required to reach their full inhibitory potential. Moreover, the findings shed light on how myelin loss might underpin aberrant brain activity, which have been observed in people with multiple sclerosis. More research could help determine whether these epilepsy-like spikes could be a biomarker of multiple sclerosis and/or a target for developing new therapeutic strategies to limit cognitive impairments.

Microglial activation arises after aggregation of phosphorylated-tau in a neuron-specific P301S tauopathy mouse model.

Alzheimer's disease, progressive supranuclear palsy and frontotemporal dementia are characterized by neuronal expression of aberrant tau protein, tau hyperphosphorylation (pTAU), tau aggregation and neurofibrillary tangle formation sequentially culminating into neuronal cell death, a process termed tauopathy. Our aim was to address at which tauopathy stage neuroinflammation starts and to study the related microglial phenotype. We used Thy1-hTau.P301S (PS) mice expressing human tau with a P301S mutation specifically in neurons. Significant levels of cortical pTAU were present from 2 months onwards. Dystrophic morphological complexity of cortical microglia arose after pTAU accumulation concomitant with increased microglial lysosomal volumes and a significant loss of homeostatic marker Tmem119. Interestingly, we detected increases in neuronal pTAU and postsynaptic structures in the lysosomes of PS microglia. Moreover, the overall cortical postsynaptic density was decreased in 6-month-old PS mice. Together, our results indicate that microglia adopt a pTAU-associated phenotype, and are morphologically and functionally distinct from wild-type microglia after neuronal pTAU accumulation has initiated.