Integrative analysis of the connectivity and gene expression atlases in the mouse brain

Ji, Shuiwang; Fakhry, Ahmed; Deng, Houtao

doi:10.1016/j.neuroimage.2013.08.049

Cited by 45 publications

(54 citation statements)

References 46 publications

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“…For both reciprocal and unidirectional connections, correlated gene expression is driven by the same types of functional gene groups, pointing to a uniform transcriptional profile of connectivity that increases with connection reciprocity. Similar functional categories of genes related to the development of neurons, neurites, and synapses, as well as the regulation of neuronal activity and synaptic plasticity, contribute to predicting the presence of a connection between neurons in Caenorhabditis elegans (15,16) and larger-scale neuronal populations of the rat (17) and mouse brains (18,19). The consistency of these findings across species, datasets, and analysis methods points to a robust transcriptional signature of neuronal connectivity characterized by the coordinated expression of genes involved in the development and ongoing function of neuronal networks.…”

Section: Discussionmentioning

confidence: 99%

“…This conservation suggests that hub connectivity may be under tight genetic control. Growing evidence indicates that gene expression affects neuronal connectivity, with studies of worm, rat, and mouse nervous systems showing that the transcriptional profile of an individual neuron or neuronal population can predict its connectivity to other areas with greater than chance accuracy (15)(16)(17)(18)(19). Brain regions with similar transcriptional profiles display similar connectivity profiles (20,21), and gene expression profiles are more correlated between pairs of structurally connected brain regions in the mouse/rat (20) and within functionally coupled networks of the human cortex (22).…”

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confidence: 99%

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A transcriptional signature of hub connectivity in the mouse connectome

Fulcher

Fornito

2016

Proc. Natl. Acad. Sci. U.S.A.

223

310

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Connectivity is not distributed evenly throughout the brain. Instead, it is concentrated on a small number of highly connected neural elements that act as network hubs. Across different species and measurement scales, these hubs show dense interconnectivity, forming a core or "rich club" that integrates information across anatomically distributed neural systems. Here, we show that projections between connectivity hubs of the mouse brain are both central (i.e., they play an important role in neural communication) and costly (i.e., they extend over long anatomical distances) aspects of network organization that carry a distinctive genetic signature. Analyzing the neuronal connectivity of 213 brain regions and the transcriptional coupling, across 17,642 genes, between each pair of regions, we find that coupling is highest for pairs of connected hubs, intermediate for links between hubs and nonhubs, and lowest for connected pairs of nonhubs. The high transcriptional coupling associated with hub connectivity is driven by genes regulating the oxidative synthesis and metabolism of ATP-the primary energetic currency of neuronal communication. This genetic signature contrasts that identified for neuronal connectivity in general, which is driven by genes regulating neuronal, synaptic, and axonal structure and function. Our findings establish a direct link between molecular function and the large-scale topology of neuronal connectivity, showing that brain hubs display a tight coordination of gene expression, often over long anatomical distances, that is intimately related to the metabolic requirements of these highly active network elements.connectome | complex networks | hub | rich club | metabolism C ertain neural elements possess an unusually high degree of connectivity, designating them as putative network hubs (1). Analyses of microscale, mesoscale, and macroscale connectomes of multiple species, constructed using a variety of methods, indicate that these hubs are strongly interconnected with each other, forming a so-called "rich club" of connectivity that mediates a large fraction of communication traffic in the brain and supports the efficient integration of otherwise segregated neural systems (2-8).Hub connectivity is functionally advantageous, but it is also costly. Hub regions make more connections with other areas, and these connections often extend over long anatomical distances, thus requiring greater physical space, cellular material, and metabolic resources (3, 9). Accordingly, human neuroimaging studies have indicated that topologically central hub regions have a higher energetic demand than other brain areas (9-12), which may render them particularly vulnerable to the effects of damage or disease (10, 13). This hypothesis is supported by evidence that pathology in a broad range of disorders preferentially accumulates within highly connected brain regions (14).Hub connectivity is thus a topologically central and costly aspect of brain network organization that is conserved across species and spatial scales....

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A transcriptional signature of hub connectivity in the mouse connectome

Fulcher

Fornito

2016

Proc. Natl. Acad. Sci. U.S.A.

223

310

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“…Given the results that gyri differ with sulci in terms of neuronal connectivity, we expect that gene expressions in gyri and sulci would have correlation patterns that are consistent with those of neuronal connectivity, since connectivity and gene expressions were found to be correlated (Ji et al 2014). Using the same approach in extracting connectivity data from the ACA, we obtained gene expression data of voxels in gyri and sulci from the ABA.…”

Section: Gyri and Sulci Have Different Gene Expression Patternsmentioning

confidence: 97%

Allen mouse brain atlases reveal different neural connection and gene expression patterns in cerebellum gyri and sulci

et al. 2014

Self Cite

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The recently released Allen Mouse Brain Connectivity Atlas provides a comprehensive mouse brain neuronal connectivity map from brain-wide injection sites via anterograde tracers coupled with serial two-photon tomography. In addition, the Allen Mouse Brain Atlas offers a genome-wide gene expression database built upon a series of in situ hybridization images, covering comprehensive expression energy of over 4,000 genes in coronal sections and over 20,000 genes in sagittal sections across the whole mouse brain. These concurrent and co-registered datasets provide an unparalleled opportunity for systematically analyzing and characterizing spatial neuronal connectivity and gene expression patterns. Inspired by our recent macroscale neuroimaging results showing that there are significantly different structural and functional connectivity patterns on the gyri and sulci of cerebral cortex in primate brains, the present work systematically examines the axonal connectivity and gene expression patterns on gyri and sulci of the cerebellum. Our results demonstrate that the cerebellum gyri and sulci of rodent brains are significantly different in both axonal connectivity and gene expression patterns. This discovery enriches and extends our prior findings in macroscale neuroimaging studies in primates. Additionally, this work offers novel insights on the molecular and structural architectures of the cerebellum in particular and the brain in general.

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“…Thus, the networked brain must somehow be linked to patterns of localized epigenetic changes. Correspondingly, studies in both human and mouse/rat brain demonstrate that the functional connectivity of brain regions can actually be predicted by clustered gene expression data, particularly of synaptic activity-related genes [67, 68]. Data sciences could begin to assist in determining whether this linkage relies on patterns of specific epigenetic changes or corresponding emergent global epigenetic consequences.…”

Section: Introductionmentioning

confidence: 99%

Developmental lead and/or prenatal stress exposures followed by different types of behavioral experience result in the divergence of brain epigenetic profiles in a sex, brain region, and time-dependent manner: Implications for neurotoxicology

Cory‐Slechta

Sobolewski

Varma

et al. 2017

Current Opinion in Toxicology

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Over a lifetime, early developmental exposures to neurocognitive risk factors, such as lead (Pb) exposures and prenatal stress (PS), will be followed by multiple varied behavioral experiences. Pb, PS and behavioral experience can each influence brain epigenetic profiles. Our recent studies show a greater level of complexity, however, as all three factors interact within each sex to generate differential adult variation in global post-translational histone modifications (PTHMs), which may result in fundamentally different consequences for life-long learning and behavioral function. We have reported that PTHM profiles differ by sex, brain region and time point of measurement following developmental exposures to Pb±PS, resulting in different profiles for each unique combination of these parameters. Imposing differing behavioral experience following developmental Pb±PS results in additional divergence of PTHM profiles, again in a sex, brain region and time-dependent manner, further increasing complexity. Such findings underscore the need to link highly localized and variable epigenetic changes along single genes to the highly-integrated brain functional connectome that is ultimately responsible for governing behavioral function. Here we advance the idea that increased understanding may be achieved through iterative reductionist and holistic approaches. Implications for experimental design of animal studies of developmental exposures to neurotoxicants include the necessity of a ‘no behavioral experience’ group, given that epigenetic changes in response to behavioral testing can confound effects of the neurotoxicant itself. They also suggest the potential utility of the inclusion of salient behavioral experiences as a potential effect modifier in epidemiological studies.

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Integrative analysis of the connectivity and gene expression atlases in the mouse brain

Cited by 45 publications

References 46 publications

A transcriptional signature of hub connectivity in the mouse connectome

A transcriptional signature of hub connectivity in the mouse connectome

Allen mouse brain atlases reveal different neural connection and gene expression patterns in cerebellum gyri and sulci

Developmental lead and/or prenatal stress exposures followed by different types of behavioral experience result in the divergence of brain epigenetic profiles in a sex, brain region, and time-dependent manner: Implications for neurotoxicology

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