Identifying age-specific gene signatures of the human cerebral cortex with joint analysis of transcriptomes and functional connectomes

Abstract The human cerebral cortex undergoes profound structural and functional dynamic variations across the lifespan, whereas the underlying molecular mechanisms remain unclear. Here, with a novel method transcriptome-connectome correlation analysis (TCA), which integrates the brain functional magnetic resonance images and region-specific transcriptomes, we identify age-specific cortex (ASC) gene signatures for adolescence, early adulthood and late adulthood. The ASC gene signatures are significantly correlated with the cortical thickness (P-value <2.00e-3) and myelination (P-value <1.00e-3), two key brain structural features that vary in accordance with brain development. In addition to the molecular underpinning of age-related brain functions, the ASC gene signatures allow delineation of the molecular mechanisms of neuropsychiatric disorders, such as the regulation between ARNT2 and its target gene ETF1 involved in Schizophrenia. We further validate the ASC gene signatures with published gene sets associated with the adult cortex, and confirm the robustness of TCA on other brain image datasets. Availability: All scripts are written in R. Scripts for the TCA method and related statistics result can be freely accessed at https://github.com/Soulnature/TCA. Additional data related to this paper may be requested from the authors.

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Age-specific gene signatures underlying the transcriptomes and functional connectomes of human cerebral cortex

10.1101/2020.09.15.297754 ◽

2020 ◽

Author(s):

Xingzhong Zhao ◽

Jingqi Chen ◽

Peipei Xiao ◽

Jianfeng Feng ◽

Ning Qing ◽

...

Keyword(s):

Cerebral Cortex ◽

Molecular Mechanisms ◽

Early Adulthood ◽

Structural Features ◽

Magnetic Resonance Images ◽

Specific Gene ◽

Human Cerebral Cortex ◽

Gene Signatures ◽

Brain Functions ◽

Age Related

AbstractThe human cerebral cortex undergoes profound structural and functional dynamic variations across the lifespan, whereas the underlying molecular mechanisms remain unclear. Here, with a novel method TCA (Transcriptome-connectome Correlation Analysis), which integrates the brain functional MR magnetic resonance images and region-specific transcriptomes, we identify age-specific cortex (ASC) gene signatures for adolescence, early adulthood, and late adulthood. The ASC gene signatures are significantly correlated with the cortical thickness (P-value <2.00e-3) and myelination (P-value <1.00e-3), two key brain structural features that vary in accordance with brain development. In addition to the molecular underpinning of age-related brain functions, the ASC gene signatures allow delineation of the molecular mechanisms of neuropsychiatric disorders, such as the regulation between ARNT2 and its target gene ETF1 involved in Schizophrenia. We further validate the ASC gene signatures with published gene sets associated with the adult cortex, and confirm the robustness of TCA on other brain image datasets.

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Maturation of the Human Cerebral Cortex During Adolescence: Myelin or Dendritic Arbor?

Cerebral Cortex ◽

10.1093/cercor/bhy204 ◽

2018 ◽

Vol 29 (8) ◽

pp. 3351-3362 ◽

Cited By ~ 12

Author(s):

Y Patel ◽

J Shin ◽

P A Gowland ◽

Z Pausova ◽

T Paus ◽

...

Keyword(s):

Cerebral Cortex ◽

Pyramidal Cells ◽

In Vivo Studies ◽

Ependymal Cells ◽

Specific Gene ◽

Magnetization Transfer Ratio ◽

Dendritic Arbor ◽

Human Cerebral Cortex ◽

Regional Variations ◽

Age Related

Abstract Previous in vivo studies revealed robust age-related variations in structural properties of the human cerebral cortex during adolescence. Neurobiology underlying these maturational phenomena is largely unknown. Here we employ a virtual-histology approach to gain insights into processes associated with inter-regional variations in cortical microstructure and its maturation, as indexed by magnetization transfer ratio (MTR). Inter-regional variations in MTR correlate with inter-regional variations in expression of genes specific to pyramidal cells (CA1) and ependymal cells; enrichment analyses indicate involvement of these genes in dendritic growth. On the other hand, inter-regional variations in the change of MTR during adolescence correlate with inter-regional profiles of oligodendrocyte-specific gene expression. Complemented by a quantitative hypothetical model of the contribution of surfaces associated with dendritic arbor (1631 m2) and myelin (48 m2), these findings suggest that MTR signals are driven mainly by macromolecules associated with dendritic arbor while maturational changes in the MTR signal are associated with myelination.

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A Network Analysis of Multiple Myeloma Related Gene Signatures

Cancers ◽

10.3390/cancers11101452 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1452 ◽

Cited By ~ 4

Author(s):

Yu Liu ◽

Haocheng Yu ◽

Seungyeul Yoo ◽

Eunjee Lee ◽

Alessandro Laganà ◽

...

Keyword(s):

Multiple Myeloma ◽

Drug Response ◽

Molecular Mechanisms ◽

Proteasome Inhibitors ◽

Risk Groups ◽

Rank Test ◽

P Value ◽

Causal Network ◽

Gene Signatures ◽

Network Analyses

Multiple myeloma (MM) is the second most prevalent hematological cancer. MM is a complex and heterogeneous disease, and thus, it is essential to leverage omics data from large MM cohorts to understand the molecular mechanisms underlying MM tumorigenesis, progression, and drug responses, which may aid in the development of better treatments. In this study, we analyzed gene expression, copy number variation, and clinical data from the Multiple Myeloma Research Consortium (MMRC) dataset and constructed a multiple myeloma molecular causal network (M3CN). The M3CN was used to unify eight prognostic gene signatures in the literature that shared very few genes between them, resulting in a prognostic subnetwork of the M3CN, consisting of 178 genes that were enriched for genes involved in cell cycle (fold enrichment = 8.4, p value = 6.1 × 10−26). The M3CN was further used to characterize immunomodulators and proteasome inhibitors for MM, demonstrating the pleiotropic effects of these drugs, with drug-response signature genes enriched across multiple M3CN subnetworks. Network analyses indicated potential links between these drug-response subnetworks and the prognostic subnetwork. To elucidate the structure of these important MM subnetworks, we identified putative key regulators predicted to modulate the state of these subnetworks. Finally, to assess the predictive power of our network-based models, we stratified MM patients in an independent cohort, the MMRF-CoMMpass study, based on the prognostic subnetwork, and compared the performance of this subnetwork against other signatures in the literature. We show that the M3CN-derived prognostic subnetwork achieved the best separation between different risk groups in terms of log-rank test p-values and hazard ratios. In summary, this work demonstrates the power of a probabilistic causal network approach to understanding molecular mechanisms underlying the different MM signatures.

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Age-related changes in the synaptic density of amyloid-b protein precursor and secretases in the human cerebral cortex

European Neuropsychopharmacology ◽

10.1016/s0924-977x(16)31773-4 ◽

2016 ◽

Vol 26 ◽

pp. S662-S663

Author(s):

A. Pliássova ◽

P. Canas ◽

A. Xavier ◽

B. Da Silva ◽

R. Cunha ◽

...

Keyword(s):

Cerebral Cortex ◽

Human Cerebral Cortex ◽

Synaptic Density ◽

Protein Precursor ◽

Age Related ◽

Age Related Changes

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Human cerebral cortex networks use expanding and contracting state dynamic to shape cortical functions

10.1101/2020.09.24.309468 ◽

2020 ◽

Author(s):

Alex Willumsen ◽

Jens Midtgaard ◽

Bo Jespersen ◽

Christoffer K.K. Hansen ◽

Salina N. Lam ◽

...

Keyword(s):

Cerebral Cortex ◽

Cognitive Functions ◽

List Type ◽

Field Potentials ◽

Human Cerebral Cortex ◽

Local Networks ◽

Cortical Dynamics ◽

Brain Functions ◽

Sensory Motor ◽

Attractor Dynamic

SummaryWe lack viable explanations of how collective activities of neurons in networks produce brain functions. We recorded field potentials from many local networks in the human cerebral cortex during a wide variety of brain functions. The network dynamics showed that each local cortical network produced fluctuating attractor states. The state trajectories continuously stretched and contracted during all brain functions, leaving no stable patterns. Different local networks all produced this dynamic, despite different architectures. Single trial stimuli and tasks modified the stretching and contractions. These modified fluctuations cross-correlated among particular networks during specific brain functions. Spontaneous activity, rest, sensory, motor and cognitive functions all emerged from this dynamic. Its mathematical structure provides a general theoretical model of cortical dynamics that can be tested experimentally. This universal dynamic is a simple functional organizing principle for brain functions at the mm3 scale that is distinct from existing frameworks.Graphical abstractIn briefWillumsen et al. developed a method to show that local cortical networks contribute to sensory, motor and cognitive functions by stretching and contracting the trajectory of the multidimensional field potential. In single trials the networks communicate by cross-correlating the stretching and contracting. This ubiquitous attractor dynamic forms a departure from existing models of how postsynaptic dynamics contribute to sensory, motor and cognitive brain functions.HighlightsCortical fluctuating expanding and contacting attractor dynamics (FECAT) drive collective postsynaptic operations at the mm3 scaleFECAT dynamic accounted for all behavioral conditions and all tested cortical areasCortical states show no stationary patterns, but continuously expand and contract with a stable attractor dynamicOur method reveals multi-dimensional cortical dynamics in field potentials, also useful for EEG and MEG

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Measuring the thickness of the human cerebral cortex from magnetic resonance images

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.200033797 ◽

2000 ◽

Vol 97 (20) ◽

pp. 11050-11055 ◽

Cited By ~ 3261

Author(s):

B. Fischl ◽

A. M. Dale

Keyword(s):

Cerebral Cortex ◽

Magnetic Resonance ◽

Magnetic Resonance Images ◽

Human Cerebral Cortex

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Brainprints: Computer-Generated Two-Dimensional Maps of the Human Cerebral Cortex in vivo

Journal of Cognitive Neuroscience ◽

10.1162/jocn.1989.1.1.88 ◽

1989 ◽

Vol 1 (1) ◽

pp. 88-117 ◽

Cited By ~ 48

Author(s):

Marc L. Jouandet ◽

Mark Jude Tramo ◽

Daniel M. Herron ◽

Allison Hermann ◽

William C. Loftus ◽

...

Keyword(s):

Cerebral Cortex ◽

Monozygotic Twins ◽

Magnetic Resonance Images ◽

Two Dimensional ◽

Post Mortem ◽

Human Cerebral Cortex ◽

Brain Organization ◽

Potential Applications ◽

Perceptual Performance

We describe an in vivo method for the quantitative analysis of human necrotical anatomy. The technique allows unfolded regions of functional and morphological interest to be measured planimetrically. Two-dimensional cortical maps and surface area determinations derived from magnetic resonance images of monozygotic twins are presented. In addition, reconstructions and measurements of published post-mortem human and rhesus monkey hemispheres are reported. Potential applications for the study of brain organization in relation to cognitive, motor, and perceptual performance in normal and neurological populations are considered.

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Dietary Polyphenols as Modulators of Brain Functions: Biological Actions and Molecular Mechanisms Underpinning Their Beneficial Effects

Oxidative Medicine and Cellular Longevity ◽

10.1155/2012/914273 ◽

2012 ◽

Vol 2012 ◽

pp. 1-16 ◽

Cited By ~ 169

Author(s):

David Vauzour

Keyword(s):

Cognitive Function ◽

Molecular Mechanisms ◽

Inflammatory Stress ◽

Dietary Polyphenols ◽

Beneficial Effects ◽

Brain Functions ◽

Expression Of Genes ◽

Age Related ◽

Neuroprotective Actions ◽

Protective Signaling

Accumulating evidence suggests that diet and lifestyle can play an important role in delaying the onset or halting the progression of age-related health disorders and to improve cognitive function. In particular, polyphenols have been reported to exert their neuroprotective actions through the potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation, and the potential to promote memory, learning, and cognitive function. Despite significant advances in our understanding of the biology of polyphenols, they are still mistakenly regarded as simply acting as antioxidants. However, recent evidence suggests that their beneficial effects involve decreases in oxidative/inflammatory stress signaling, increases in protective signaling and neurohormetic effects leading to the expression of genes that encode antioxidant enzymes, phase-2 enzymes, neurotrophic factors, and cytoprotective proteins. Specific examples of such pathways include the sirtuin-FoxO pathway, the NF-κB pathway, and the Nrf-2/ARE pathway. Together, these processes act to maintain brain homeostasis and play important roles in neuronal stress adaptation and thus polyphenols have the potential to prevent the progression of neurodegenerative pathologies.

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Corticosteroids and Regional Variations in Thickness of the Human Cerebral Cortex across the Lifespan

Cerebral Cortex ◽

10.1093/cercor/bhz108 ◽

2019 ◽

Vol 30 (2) ◽

pp. 575-586 ◽

Cited By ~ 3

Author(s):

Nadine Parker ◽

Didac Vidal-Pineiro ◽

Leon French ◽

Jean Shin ◽

Hieab H H Adams ◽

...

Keyword(s):

Cerebral Cortex ◽

Cortical Thickness ◽

Brain Structure ◽

Pyramidal Cells ◽

Brain Atlas ◽

Variable Degree ◽

Human Cerebral Cortex ◽

Age Related ◽

The Relationship ◽

Age Related Changes

Abstract Exposures to life stressors accumulate across the lifespan, with possible impact on brain health. Little is known, however, about the mechanisms mediating age-related changes in brain structure. We use a lifespan sample of participants (n = 21 251; 4–97 years) to investigate the relationship between the thickness of cerebral cortex and the expression of the glucocorticoid- and the mineralocorticoid-receptor genes (NR3C1 and NR3C2, respectively), obtained from the Allen Human Brain Atlas. In all participants, cortical thickness correlated negatively with the expression of both NR3C1 and NR3C2 across 34 cortical regions. The magnitude of this correlation varied across the lifespan. From childhood through early adulthood, the profile similarity (between NR3C1/NR3C2 expression and thickness) increased with age. Conversely, both profile similarities decreased with age in late life. These variations do not reflect age-related changes in NR3C1 and NR3C2 expression, as observed in 5 databases of gene expression in the human cerebral cortex (502 donors). Based on the co-expression of NR3C1 (and NR3C2) with genes specific to neural cell types, we determine the potential involvement of microglia, astrocytes, and CA1 pyramidal cells in mediating the relationship between corticosteroid exposure and cortical thickness. Therefore, corticosteroids may influence brain structure to a variable degree throughout life.

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