By integrating different data sources, researchers are revealing how cellular mechanisms influence individual brain connectivity patterns, bridging molecular detail with large-scale brain function.
Study: Integration at biophysical scales identifies molecular and cellular correlates of interindividual variability in human brain connectivity. Image credit: Shutterstock AI / Shutterstock.com
In a recent study published in the journal Nature Neuroscience, Researchers are investigating correlations between biochemical switches and functional connectivity between brain regions.
New approaches in neuroscience research
One of the primary goals of neuroscience is to elucidate the role of microscale components, including protein molecules and cellular structures, in communication between distinct brain regions. To date, the molecular mechanisms involved in functional connectivity within the brain remain unclear despite molecular and neuroimaging research independently revealing that cognitive and brain function are correlated.
To date, ante-mortem neuroimaging data and post-mortem molecular ohmic data have been collected separately and, rarely, from the same individual, which has prevented the analysis of patient-specific comparisons of ante-mortem and post-mortem data.
A possible solution to this data gap is to obtain multiple lines of ante-mortem and post-mortem data from a consistent group of human samples. However, the complexity of this approach has prevented validation of this hypothesis.
About the study
The present study used six unique data sources, including pre- and postmortems from elderly volunteers, to identify molecular mechanisms involved in brain connectivity. The study cohort included 98 adults, 77% of whom were women, from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP).
While alive, patients underwent magnetic resonance imaging (MRI) and provided samples for genetic sequencing. Protein abundance, gene expression, and dendritic spine morphometry were determined postmortem. Data collection included annual clinical assessments, alongside the collection of ante-mortem data and brain donations of participants for post-mortem data.
Given that the high number of identified proteins may differ in relative abundance and expression levels between participants and across brain region connectivity, the researchers focused on connectivity between the superior frontal gyrus (SFG) and the inferior temporal gyrus ( ITG).
Experimental procedures included structural and functional magnetic resonance imaging (fMRI) scans to acquire neuroimaging data, multiplexed mass spectrometry (TMT-MS) and liquid chromatography coupled to tandem mass spectrometry (LS-MS/MS) for proteomic analysis, dicinchonate assay acid to estimate protein concentration and the Illumina TruSeq platform for transcriptome data. For dendritic spine morphometry assessments, excised SFG and ITG samples were subjected to Golgi-Cox staining followed by bright-field microscopy imaging.
Resting-state fMRI data from the Schaefer2018 functional atlas were used to segment the brain into functionally homogeneous regions, thereby allowing estimation of functional connectivity between SFG and ITG. The Desikan-Killiany-Tourville (DKT) atlas, in conjunction with the Freesurfer cortical surface platform, was used to extract structural covariance from the participants’ brain morphological data.
Molecular model estimation using SpeakEasy, proteomic characterization from the GSEA database, and unit and molecular level correlation analyzes were also performed.
Study findings
The mean age of participants at the time of MRI imaging and mortality was 88 and 91 years, respectively. Structural features extracted from Schaefer2018 functional atlas were combined with DKT atlas datasets to segment the brain into 62 unique anatomical regions. Proteomic investigations of SFG and ITG molecular systems revealed significant gene/protein overlap between these regions.
Characterization of dendritic spine morphology combined with GSEA analysis revealed protein-associated enrichment in spine density, synapses, and actin cytoskeletons. Functional correlates, including neurotransmitter release and synaptic signaling, were also enriched. Specifically, SFG and ITG differed statistically in spine density, filopodia density, and mushroom spine head diameter.
The current study validated the relevance of using antemortem and postmortem data together, highlighting the molecular abundance and connectivity patterns of the brain. These patterns demonstrate significant regional specificity, necessitating future research on connectivity between other brain regions. Molecular and neuroimaging data showed strong agreement with the results, confirming the robustness of this approach.
Our study has broader implications in that it demonstrates the feasibility of detecting synchrony between systems of different scales in humans, which is a step toward a more coherent understanding of brain function.”
conclusions
The current study is the first to combine ante-mortem and post-mortem data from the same subjects. These findings reveal hundreds of unique proteins associated with brain region connectivity, 12 of which showed causal associations, while others showed structural contribution.
These results provide a better understanding of the various molecular correlates involved in brain region connectivity. The researchers also successfully characterized a robust set of molecular signatures that can be used for future connectivity and drug discovery research in the brain.
Obtaining data from the main perspectives of human neuroscience from the same set of brains is fundamental to understanding how human brain function is supported at multiple biophysical scales.”
Journal Reference:
- Ng, B., Tasaki, S., Greathouse, KM et al. (2024). Integration at biophysical scales identifies molecular and cellular correlates of interindividual variability in human brain connectivity. Nature Neuroscience. doi:10.1038/s41593-024-01788-z
