Directionality bias underpins divergent spatiotemporal progression of Alzheimer-related tauopathy in mouse models.

Mounting evidence implicates trans-synaptic connectome-based spread as a shared mechanism behind different tauopathic conditions, yet also suggests there is divergent spatiotemporal progression between them. A potential parsimonious explanation for this apparent contradiction could be that different conditions incur differential rates and directional biases in tau transmission along fiber tracts. In this meta-analysis we closely examined this hypothesis and quantitatively tested it using spatiotemporal tau pathology patterns from 11 distinct models across 4 experimental studies.

Establishing neuroanatomical correspondences across mouse and marmoset brain structures.

Interest in the common marmoset is growing due to evolutionarily proximity to humans compared to laboratory mice, necessitating a comparison of mouse and marmoset brain architectures, including connectivity and cell type distributions. Creating an actionable comparative platform is challenging since these brains have distinct spatial organizations and expert neuroanatomists disagree. We propose a general theoretical framework to relate named atlas compartments across taxa and use it to establish a detailed correspondence between marmoset and mice brains.

Spatial cell-type enrichment predicts mouse brain connectivity.

A fundamental neuroscience topic is the link between the brain's molecular, cellular, and cytoarchitectonic properties and structural connectivity. Recent studies relate inter-regional connectivity to gene expression, but the relationship to regional cell-type distributions remains understudied. Here, we utilize whole-brain mapping of neuronal and non-neuronal subtypes via the matrix inversion and subset selection algorithm to model inter-regional connectivity as a function of regional cell-type composition with machine learning.

The effects of microglia on tauopathy progression can be quantified using Nexopathy in silico (Nexis) models.

The prion-like transsynaptic propagation of misfolded tau along the brain's connectome has previously been modeled using connectome-based network diffusion models. In addition to the connectome, interactions between the general neurological "milieu" in the neurodegenerative brain and proteinopathic species can also contribute to pathology propagation. Such a molecular nexopathy framework posits that the distinct characteristics of neurodegenerative disorders stem from interactions between the network and surrounding molecular players.

Matrix Inversion and Subset Selection (MISS): A pipeline for mapping of diverse cell types across the murine brain.

The advent of increasingly sophisticated imaging platforms has allowed for the visualization of the murine nervous system at single-cell resolution. However, current experimental approaches have not yet produced whole-brain maps of a comprehensive set of neuronal and nonneuronal types that approaches the cellular diversity of the mammalian cortex. Here, we aim to fill in this gap in knowledge with an open-source computational pipeline, Matrix Inversion and Subset Selection (MISS), that can infer quantitatively validated distributions of diverse collections of neural cell types at 200-μm resolution using a combination of single-cell RNA sequencing (RNAseq) and in situ hybridization datasets.

Emergence of directional bias in tau deposition from axonal transport dynamics.

Defects in axonal transport may partly underpin the differences between the observed pathophysiology of Alzheimer's disease (AD) and that of other non-amyloidogenic tauopathies. Particularly, pathological tau variants may have molecular properties that dysregulate motor proteins responsible for the anterograde-directed transport of tau in a disease-specific fashion. Here we develop the first computational model of tau-modified axonal transport that produces directional biases in the spread of tau pathology.

Neural connectivity predicts spreading of alpha-synuclein pathology in fibril-injected mouse models: Involvement of retrograde and anterograde axonal propagation.

In Parkinson's disease, some of the first alpha-synuclein aggregates appear in the olfactory system and the dorsal motor nucleus of the vagus nerve before spreading to connected brain regions. We previously demonstrated that injection of alpha-synuclein fibrils unilaterally into the olfactory bulb of wild type mice leads to widespread synucleinopathy in brain regions directly and indirectly connected to the injection site, consistently, over the course of periods longer than 6 months. Our previously reported observations support the idea that alpha-synuclein inclusions propagates between brain region through neuronal networks.