Microscopic features (i.e., microstructure) of axons affect neural circuit activity through characteristics such as conduction speed. To what extent axonal microstructure in white matter relates to functional connectivity (synchrony) between brain regions is largely unknown. Using magnetic resonance imaging data in 11,354 subjects, we constructed multi-variate models that predict functional connectivity of pairs of brain regions from the microstructural signature of white matter pathways that connect them. Microstructure-derived models provide predictions of functional connectivity that explained 3.5% of cross-subject variance on average (ranging from 1-13%, or r=0.1-0.36) and reached statistical significance in 90% of the brain regions considered. The microstructure-function relationships were associated to genetic variants, co-located with genes DAAM1 and LPAR1, that have previously been linked to neural development. Our results Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Susceptibility to stress-related psychopathology is associated with reduced expression of the serotonin transporter (5-HTT), particularly in combination with stress exposure. Aberrant physiological and neuronal responses to threat may underlie this increased vulnerability. Here, implementing a cross-species approach, we investigated the association between 5-HTT expression and the neural correlates of fear bradycardia, a defensive response linked to vigilance and action preparation. We tested this during threat anticipation induced by a well-established fear conditioning paradigm applied in both humans and rodents. In humans, we studied the effect of the common 5-HTT-linked polymorphic region (5-HTTLPR) on bradycardia and neural responses to anticipatory threat during functional magnetic resonance imaging scanning in healthy volunteers (n= 104). Compared with homozygous long-allele carriers, the 5-HTTLPR short-allele carriers displayed an exaggerated bradycardic response to threat, overall reduced activation of the medial prefrontal cortex (mPFC), and increased threat-induced connectivity between the amygdala and periaqueductal gray (PAG), which statistically mediated the effect of the 5-HTTLPR genotype on bradycardia. In parallel, 5-HTT knockout (KO) rats also showed exaggerated threat-related bradycardia and behavioral freezing. Immunohistochemistry indicated overall reduced activity of glutamatergic neurons in the mPFC of KO rats and increased activity of central amygdala somatostatin-positive neurons, putatively projecting to the PAG, which—similarly to the human population—mediated the 5-HTT genotype’s effect on freezing. Moreover, the ventrolateral PAG of KO rats displayed elevated overall activity and increased relative activation of CaMKII-expressing projection neurons. Our results provide a mechanistic explanation for previously reported associations between 5-HTT gene variance and a stress-sensitive phenotype.

Highlights 29 30• TIRL: new framework for prototyping bespoke image registration pipelines 31• Pipeline for automated registration of small-slide histology to whole-brain MRI 32• Slice-to-volume registration accounting for through-plane deformations 33• No need for serial histological sampling 34 35Abstract 36 37 There is a need to understand the histopathological basis of MRI signal characteristics in 38 complex biological matter. Microstructural imaging holds promise for sensitive and specific 39 indicators of the early stages of human neurodegeneration but requires validation against 40 traditional histological markers before it can be reliably applied in the clinical setting. 41Validation relies on a precise and preferably automatic method to align MRI and histological 42 images of the same tissue, which poses unique challenges compared to more conventional 43 MRI-to-MRI registration. 44 45A customisable open-source platform, Tensor Image Registration Library (TIRL) is presented. 46Based on TIRL, a fully automated pipeline was implemented to align small stained histological 47

Objective The aim of this study was to test the hypothesis that white matter degeneration of the perforant path – as part of the Papez circuit – is a key feature of amyotrophic lateral sclerosis (ALS), even in the absence of frontotemporal dementia (FTD) or deposition of pTDP‐43 inclusions in hippocampal granule cells. Methods We used diffusion Magnetic Resonance Imaging (dMRI), polarized light imaging (PLI) and immunohistochemical analysis of post mortem hippocampus specimens from controls (n = 5) and ALS patients (n = 14) to study white matter degeneration in the perforant path. Results diffusion Magnetic Resonance Imaging demonstrated a decrease in fractional anisotropy (P = 0.01) and an increase in mean diffusivity (P = 0.01) in the perforant path in ALS compared to controls. PLI‐myelin density was lower in ALS (P = 0.05) and correlated with fractional anisotropy (r = 0.52, P = 0.03). These results were confirmed by immunohistochemistry; both myelin (proteolipid protein, P = 0.03) and neurofilaments (SMI‐312, P = 0.02) were lower in ALS. Two out of the fourteen ALS cases showed pTDP‐43 pathology in the dentate gyrus, but with comparable myelination levels in the perforant path to other ALS cases. Conclusion We conclude that degeneration of the perforant path occurs in ALS patients and that this may occur before, or independent of, pTDP‐43 aggregation in the dentate gyrus of the hippocampus. Future research should focus on correlating the degree of cognitive decline to the amount of white matter atrophy in the perforant path.

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