Weighting the structural connectome: Exploring its impact on network properties and predicting cognitive performance in the human brain.

Brain function does not emerge from isolated activity, but rather from the interactions and exchanges between neural elements that form a network known as the connectome. The human connectome consists of structural and functional aspects. The structural connectome (SC) represents the anatomical connections, and the functional connectome represents the resulting dynamics that emerge from this arrangement of structures. As there are different ways of weighting these connections, it is important to consider how such different approaches impact study conclusions. Here, we propose that different weighted connectomes result in varied network properties, and while neither superior the other, selection might affect interpretation and conclusions in different study cases. We present three different weighting models, namely, number of streamlines (NOS), fractional anisotropy (FA), and axon diameter distribution (ADD), to demonstrate these differences. The later, is extracted using recently published AxSI method and is first compared to commonly used weighting methods. Moreover, we explore the functional relevance of each weighted SC, using the Human Connectome Project (HCP) database. By analyzing intelligence-related data, we develop a predictive model for cognitive performance based on graph properties and the National Institutes of Health (NIH) toolbox. Results demonstrate that the ADD SC, combined with a functional subnetwork model, outperforms other models in estimating cognitive performance.

A Method for In-Vivo Mapping of Axonal Diameter Distributions in the Human Brain Using Diffusion-Based Axonal Spectrum Imaging (AxSI).

In this paper we demonstrate a generalized and simplified pipeline called axonal spectrum imaging (AxSI) for in-vivo estimation of axonal characteristics in the human brain. Whole-brain estimation of the axon diameter, in-vivo and non-invasively, across all fiber systems will allow exploring uncharted aspects of brain structure and function relations with emphasis on connectivity and connectome analysis. While axon diameter mapping is important in and of itself, its correlation with conduction velocity will allow, for the first time, the explorations of information transfer mechanisms within the brain. We demonstrate various well-known aspects of axonal morphometry (e.g., the corpus callosum axon diameter variation) as well as other aspects that are less explored (e.g., axon diameter-based separation of the superior longitudinal fasciculus into segments). Moreover, we have created an MNI based mean axon diameter map over the entire brain for a large cohort of subjects providing the reference basis for future studies exploring relation between axon properties, its connectome representation, and other functional and behavioral aspects of the brain.

Elongator promotes neuritogenesis via regulation of tau stability through acly activity.

The six subunits (Elp1 to Elp6) Elongator complex promotes specific uridine modifications in tRNA's wobble site. Moreover, this complex has been indirectly involved in the regulation of α-tubulin acetylation in microtubules (MTs) via the stabilization of ATP-Citrate Lyase (Acly), the main cytosolic source of acetyl-CoA production in cells, a key substrate used for global protein acetylation. Here, we report additional evidence that Elongator activity is important for proper cytoskeleton remodeling as cells lacking expression of Elp1 show morphology impairment; including distinct neurite process formation and disorganization and instability of MTs. Here, we show that loss of Elongator results in a reduction of expression of the microtubule associated protein Tau (MAPT). Tau, is a well-known key MT regulator in neurons whose lysines can be competitively acetylated or ubiquitylated. Therefore, we tested whether Tau is an indirect acetylation target of Elongator. We found that a reduction of Elongator activity leads to a decrease of lysine acetylation on Tau that favors its proteasomal degradation. This phenotype was prevented by using selective deacetylase or proteasomal inhibitors. Moreover, our data demonstrate that Acly's activity regulates the mechanism underlying Tau mediated neurite morphology defects found in Elp1 KD since both Tau levels and neurites morphology are restored due to Acly overexpression. This suggests a possible involvement of both Tau and Acly dysfunction in Familial Dysautonomia (FD), which is an autosomal recessive peripheral neuropathy caused by mutation in the ELP1 gene that severely affects Elp1 expression levels in the nervous system in FD patients in a similar way as found previously in Elp1 KD neuroblastoma cells.