A long-standing goal of neuroscience is to understand how molecules and cellular structures on a microscale give rise to communication between brain regions at the macroscale.
Now, a study “Integration across biophysical scales identifies molecular and cellular correlates of person-to-person variability in human brain connectivity” in Nature Neuroscience identifies, for the first time, hundreds of brain proteins that explain inter-individual differences in functional connectivity and structural covariation in the human brain.
“A central goal of neuroscience is to develop an understanding of the brain that ultimately describes the mechanistic basis of human cognition and behavior,” said Jeremy Herskowitz, PhD, associate professor, department of neurology, University of Alabama at Birmingham, and co-corresponding author of the study with Chris Gaiteri, PhD, SUNY Upstate Medical University, Syracuse. “This study demonstrates the feasibility of integrating data from vastly different biophysical scales to provide a molecular understanding of human brain connectivity.”
Bridging the gap
Bridging the gap from the molecular scale of proteins and mRNA to the brain-wide neuroimaging scale of functional and structural magnetic resonance imaging (a span of about seven orders of magnitude) was made possible by the Religious Orders Study and Rush Memory and Aging Project, or ROSMAP, at Rush University in Chicago. ROSMAP enrolls Catholic nuns, priests, and brothers age 65 or older, who are without known dementia at time of enrollment. Participants receive medical and psychological evaluations each year and agree to donate their brains after death.
Herskowitz, Gaiteri and colleagues studied postmortem brain samples and data from a unique cohort of 98 ROSMAP participants. Their data types included resting state fMRI, structural MRI, genetics, dendritic spine morphometry, proteomics and gene expression measurements from the superior frontal gyrus and inferior temporal gyrus of the brain.
“Through the integration of the molecular and dendritic spine morphology data, we identified hundreds of proteins that explain interindividual differences in functional connectivity and structural covariation. These proteins are enriched for synaptic structures and functions, energy metabolism and RNA processing,” write the investigators.
“By integrating data at the genetic, molecular, subcellular and tissue levels, we link specific biochemical changes at synapses to connectivity between brain regions. These results demonstrate the feasibility of integrating data from vastly different biophysical scales to provide a more comprehensive understanding of brain connectivity.”
Based on the stability of functional connectivity patterns within individuals, “we hypothesized that it is possible to combine postmortem molecular and subcellular data with antemortem neuroimaging data from the same individuals to prioritize molecular mechanisms underlying brain connectivity,” Herskowitz said.
The scientists noted that the key to the research was using an intermediate scale measurement—dendritic spine morphometry, the shapes, sizes, and densities of the spines—to link the molecular scale with the brain-wide neuroimaging scale. The integration of dendritic spine morphometry to contextualize the proteomic and transcriptomic signals was critical for detecting protein association with functional connectivity.
“Initially, the protein and RNA measures could not explain the person-to-person variability in functional connectivity; however, it all clicked once we integrated the dendritic spine morphology to bridge the gap from molecules to inter-brain region communication,” explained Herskowitz.
Dendritic spines can rapidly change shape or volume while forming new synapses, part of the process called brain plasticity, and the head of the spine structurally supports postsynaptic density. Spines can be divided into shape subclasses based on their three-dimensional structure as thin, mushroom, stubby or filopodia. This summer, in a different study, Herskowitz and colleagues used ROSMAP samples to show that preservation of memory in the old was maintained by the quality, as measured by dendritic spine head diameter, not the quantity of synapses in the brain.
In this latest study, the hundreds of proteins the researchers identified that explain inter-individual differences in functional connectivity and structural covariation were enriched for proteins involved in synapses, energy metabolism, and RNA processing.
“By integrating data at the genetic, molecular, subcellular and tissue levels, we linked specific biochemical changes at synapses to connectivity between brain regions. Overall, 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,” continued Herskowitz.
“While future research is necessary for fully determining the scope and components of multi-scale brain synchrony, we have established a robustly defined initial set of molecules whose effects likely resonate across biophysical scales.”
