Temporal Alterations in White Matter in An App Knock-In Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia and results in neurodegeneration and cognitive impairment. White matter (WM) is affected in AD and has implications for neural circuitry and cognitive function. The trajectory of these changes across age, however, is still not well understood, especially at earlier stages in life. To address this, we used the AppNL-G-F/NL-G-F knock-in (APPKI) mouse model that harbors a single copy knock-in of the human amyloid precursor protein (APP) gene with three familial AD mutations. We performed in vivo diffusion tensor imaging (DTI) to study how the structural properties of the brain change across age in the context of AD. In late age APPKI mice, we observed reduced fractional anisotropy (FA), a proxy of WM integrity, in multiple brain regions, including the hippocampus, anterior commissure (AC), neocortex, and hypothalamus. At the cellular level, we observed greater numbers of oligodendrocytes in middle age (prior to observations in DTI) in both the AC, a major interhemispheric WM tract, and the hippocampus, which is involved in memory and heavily affected in AD, prior to observations in DTI. Proteomics analysis of the hippocampus also revealed altered expression of oligodendrocyte-related proteins with age and in APPKI mice. Together, these results help to improve our understanding of the development of AD pathology with age, and imply that middle age may be an important temporal window for potential therapeutic intervention.

Hippocampal functional connectivity across age in an App knock-in mouse model of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disease. The early processes of AD, however, are not fully understood and likely begin years before symptoms manifest. Importantly, disruption of the default mode network, including the hippocampus, has been implicated in AD. Methods: To examine the role of functional network connectivity changes in the early stages of AD, we performed resting-state functional magnetic resonance imaging (rs-fMRI) using a mouse model harboring three familial AD mutations (App NL-G-F/NL-G-F knock-in, APPKI) in female mice in early, middle, and late age groups. The interhemispheric and intrahemispheric functional connectivity (FC) of the hippocampus was modeled across age. Results: We observed higher interhemispheric functional connectivity (FC) in the hippocampus across age. This was reduced, however, in APPKI mice in later age. Further, we observed loss of hemispheric asymmetry in FC in APPKI mice. Discussion: Together, this suggests that there are early changes in hippocampal FC prior to heavy onset of amyloid ß plaques, and which may be clinically relevant as an early biomarker of AD.

rest2vec: Vectorizing the resting-state functional connectome using graph embedding.

Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used in connectomics for studying the functional relationships between regions of the human brain. rs-fMRI connectomics, however, has inherent analytical challenges, such as how to properly model negative correlations between BOLD time series. In addition, functional relationships between brain regions do not necessarily correspond to their anatomical distance, making the functional topology of the brain less well understood. Recent machine learning techniques, such as word2vec, have used embedding methods to map high-dimensional data into vector spaces, where words with more similar meanings are mapped closer to one another. Inspired by this approach, we have developed the graph embedding pipeline rest2vec for studying the vector space of functional connectomes. We demonstrate how rest2vec uses the phase angle spatial embedding (PhASE) method with dimensionality reduction to embed the connectome into lower dimensions, where the functional definition of a brain region is represented continuously in an intrinsic "functional space." Furthermore, we show how the "functional distance" between brain regions in this space can be applied to discover biologically-relevant connectivity gradients. Interestingly, rest2vec can be conceptualized in the context of the recently proposed maximum mean discrepancy (MMD) metric, followed by a double-centering approach seen in kernel PCA. In sum, rest2vec creates a low-dimensional representation of the rs-fMRI connectome where brain regions are mapped according to their functional relationships, giving a more informed understanding of the functional organization of the brain.

From Default Mode Network to the Basal Configuration: Sex Differences in the Resting-State Brain Connectivity as a Function of Age and Their Clinical Correlates.

Connectomics is a framework that models brain structure and function interconnectivity as a network, rather than narrowly focusing on select regions-of-interest. MRI-derived connectomes can be structural, usually based on diffusion-weighted MR imaging, or functional, usually formed by examining fMRI blood-oxygen-level-dependent (BOLD) signal correlations. Recently, we developed a novel method for assessing the hierarchical modularity of functional brain networks-the probability associated community estimation (PACE). PACE uniquely permits a dual formulation, thus yielding equivalent connectome modular structure regardless of whether positive or negative edges are considered. This method was rigorously validated using the 1,000 functional connectomes project data set (F1000, RRID:SCR_005361) (1) and the Human Connectome Project (HCP, RRID:SCR_006942) (2, 3) and we reported novel sex differences in resting-state connectivity not previously reported. (4) This study further examines sex differences in regard to hierarchical modularity as a function of age and clinical correlates, with findings supporting a basal configuration framework as a more nuanced and dynamic way of conceptualizing the resting-state connectome that is modulated by both age and sex. Our results showed that differences in connectivity between men and women in the 22-25 age range were not significantly different. However, these same non-significant differences attained significance in both the 26-30 age group (p = 0.003) and the 31-35 age group (p < 0.001). At the most global level, areas of diverging sex difference include parts of the prefrontal cortex and the temporal lobe, amygdala, hippocampus, inferior parietal lobule, posterior cingulate, and precuneus. Further, we identified statistically different self-reported summary scores of inattention, hyperactivity, and anxiety problems between men and women. These self-reports additionally divergently interact with age and the basal configuration between sexes.

Asymmetric development of the nervous system.

The human nervous system consists of seemingly symmetric left and right halves. However, closer observation of the brain reveals anatomical and functional lateralization. Defects in brain asymmetry correlate with several neurological disorders, yet our understanding of the mechanisms used to establish lateralization in the human central nervous system is extremely limited. Here, we review left-right asymmetries within the nervous system of humans and several model organisms, including rodents, Zebrafish, chickens, Xenopus, Drosophila, and the nematode Caenorhabditis elegans. Comparing and contrasting mechanisms used to develop left-right asymmetry in the nervous system can provide insight into how the human brain is lateralized. Developmental Dynamics 247:124-137, 2018. © 2017 Wiley Periodicals, Inc.

Creating a stem cell niche in the inner ear using self-assembling peptide amphiphiles.

The use of human embryonic stem cells (hESCs) for regeneration of the spiral ganglion will require techniques for promoting otic neuronal progenitor (ONP) differentiation, anchoring of cells to anatomically appropriate and specific niches, and long-term cell survival after transplantation. In this study, we used self-assembling peptide amphiphile (PA) molecules that display an IKVAV epitope (IKVAV-PA) to create a niche for hESC-derived ONPs that supported neuronal differentiation and survival both in vitro and in vivo after transplantation into rodent inner ears. A feature of the IKVAV-PA gel is its ability to form organized nanofibers that promote directed neurite growth. Culture of hESC-derived ONPs in IKVAV-PA gels did not alter cell proliferation or viability. However, the presence of IKVAV-PA gels increased the number of cells expressing the neuronal marker beta-III tubulin and improved neurite extension. The self-assembly properties of the IKVAV-PA gel allowed it to be injected as a liquid into the inner ear to create a biophysical niche for transplanted cells after gelation in vivo. Injection of ONPs combined with IKVAV-PA into the modiolus of X-SCID rats increased survival and localization of the cells around the injection site compared to controls. Human cadaveric temporal bone studies demonstrated the technical feasibility of a transmastoid surgical approach for clinical intracochlear injection of the IKVAV-PA/ONP combination. Combining stem cell transplantation with injection of self-assembling PA gels to create a supportive niche may improve clinical approaches to spiral ganglion regeneration.

Directed Differentiation of Human Embryonic Stem Cells Toward Placode-Derived Spiral Ganglion-Like Sensory Neurons.

The ability to generate spiral ganglion neurons (SGNs) from stem cells is a necessary prerequisite for development of cell-replacement therapies for sensorineural hearing loss. We present a protocol that directs human embryonic stem cells (hESCs) toward a purified population of otic neuronal progenitors (ONPs) and SGN-like cells. Between 82% and 95% of these cells express SGN molecular markers, they preferentially extend neurites to the cochlear nucleus rather than nonauditory nuclei, and they generate action potentials. The protocol follows an in vitro stepwise recapitulation of developmental events inherent to normal differentiation of hESCs into SGNs, resulting in efficient sequential generation of nonneuronal ectoderm, preplacodal ectoderm, early prosensory ONPs, late ONPs, and cells with cellular and molecular characteristics of human SGNs. We thus describe the sequential signaling pathways that generate the early and later lineage species in the human SGN lineage, thereby better describing key developmental processes. The results indicate that our protocol generates cells that closely replicate the phenotypic characteristics of human SGNs, advancing the process of guiding hESCs to states serving inner-ear cell-replacement therapies and possible next-generation hybrid auditory prostheses. © Stem Cells Translational Medicine 2017;6:923-936.