NEW YORK – A team led by investigators at the University of Alabama at Birmingham, Rush University Medical Center, and SUNY Upstate Medical University has teased out protein and gene expression profiles that seem to coincide with variations in the structure and connections of individuals' brains.
The results, published in Nature Neuroscience on Thursday, "demonstrate the feasibility of integrating data from vastly different biophysical scales to provide a more comprehensive understanding of brain connectivity," co-corresponding authors Jeremy Herskowitz, a neurology researcher at the University of Alabama at Birmingham, and Chris Gaiteri, a researcher affiliated with Rush University Medical Center and SUNY Upstate Medical University, and their colleagues reported.
For the study, the researchers used array-based genotyping, RNA sequencing, and multiplex tandem mass tag mass spectrometry (TMT-MS)-based profiling on nearly 7,800 proteins to assess superior frontal gyrus (SFG) and inferior temporal gyrus (ITG) brain regions in post-mortem samples collected through the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) from participants diagnosed with dementia.
"Based on the stability of functional connectivity patterns within individuals, we hypothesized that it is possible to combine post-mortem molecular and subcellular data with antemortem neuroimaging data from the same individuals to prioritize molecular mechanisms underlying brain connectivity," the authors explained.
After combining the molecular data with brain-wide resting-state functional magnetic resonance imaging (MRI) and structural MRI-based neuroimaging data, obtained when individuals were still alive, the team came up with computational models to find protein or gene expression markers for variability of functional connectivity.
From there, the researchers developed models to link measured protein levels with variation in the morphology of dendritic spine branches that extend from neuron bodies to receive messages from other cells. They then validated their findings with models focused on gene expression profiles linked to variations in the structure of the brain regions considered.
"We showed that the same synaptic protein modules can explain between-participant variability in both functional connectivity and structural covariation and replicated this finding with synaptic expression modules," the authors reported. "We also found hundreds of proteins associated with functional connectivity, a subset of which is associated with structural covariation, and again we showed similar trends with gene expression."
In particular, the team's search for contributors to between-individual brain variability pointed to an overrepresentation of proteins and protein modules involved in processes ranging from synaptic function and synapse structures to RNA processing and mitochondria-based energy metabolism.
"The enriched processes are consistent with normal synaptic function, which requires energy and local RNA translation," the authors explained, adding that the current study "established a robustly defined initial set of molecules whose effects likely resonate across biophysical scales."
"Overall," they suggested, "this study indicates that acquiring data across the major perspectives in human neuroscience from the same set of brains is foundational for understanding how human brain function is supported at multiple biophysical scales."
Even so, they cautioned that the current findings may be impacted by the time between the neuroimaging scans from ROSMAP participants and the collection of post-mortem samples from their brains. They also noted that "relationships between molecular abundances and brain connectivity have substantial regional specificity."