A long-standing goal of neuroscience is to understand how molecules and cellular structures on the microscale give rise to communication between brain regions on the macroscale. A study published in Nature Neuroscience now 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, Ph.D., associate professor at the University of Alabama in the Department of Neurology in Birmingham and co. -corresponding author of the study with Chris Gaiteri, Ph.D., SUNY Upstate Medical University, Syracuse, New York. “This study demonstrates the feasibility of integrating data from vastly different biophysical scales to provide a molecular insight into human brain connectivity.”
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, Chicago, Illinois.
ROSMAP enrolls Catholic nuns, priests and brothers aged 65 or over who do not have known dementia at the time of registration. 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 include resting-state fMRI, structural MRI, genetics, dendritic spine morphometry, proteomics, and gene expression measurements of the superior frontal gyrus and inferior temporal gyrus of the brain.
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 the molecular mechanisms underlying brain connectivity.”
Jeremy Herskowitz, Ph.D., associate professor at the University of Alabama, Department of Neurology at Birmingham
The mean age of the ROSMAP participants at the time of the MRI scan and at death was 88 +/- 6 years and 91 +/- 6 years, respectively, with a mean time interval between the MRI scan and the age at death of 3 +/- 2 years. The mean postmortem interval to brain sampling was 8.5 +/- 4.6 hours. In the study, the researchers performed a detailed characterization of each omic, cellular, and neuroimaging data type, and then integrated the different data types using computational clustering algorithms.
The key to the study was the use of a medium scale measurement; dendritic spine morphometry, the shapes, sizes and densities of the spines -; to connect 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 measurements could not explain the person-to-person variability in functional connectivity, but it all clicked when we integrated dendritic spine morphology to bridge the gap between molecules and communication between brain regions,” said Herskowitz . .
A dendrite is a branched extension of a neuron body that receives impulses from other neurons. Each dendrite can have thousands of tiny projections called spines. The head of each spine can form a point of contact, called a synapse, to receive an impulse sent by the axon of another neuron. Dendritic spines can rapidly change shape or volume as they form new synapses, part of the process called brain plasticity, and the spine head structurally supports postsynaptic density. Spines can be divided into shape subclasses based on their three-dimensional structure as thin, mushroom-shaped, blunt, or filopodia. This summer, in another study, Herskowitz and colleagues used ROSMAP samples to show that memory retention in the very old was maintained by quality, as measured by dendritic spine diameter, and not by 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 the connectivity between brain regions,” Herskowitz said.
“Overall, this study indicates that collecting data on key perspectives in human neuroscience from the same set of brains is fundamental to understanding how human brain function is supported at multiple biophysical scales,” Herskowitz said. “While future research is needed to fully determine the scope and components of brain synchronization at multiple scales, we have developed a robustly defined initial set of molecules whose effects likely resonate across biophysical scales.”
In addition to Herskowitz and Gaiteri, co-authors of the study, “Multiscale Integration Identifying Synaptic Proteins Associated with Human Brain Connectivity,” are Bernard Ng, Shinya Tasaki, and David A. Bennett, Rush University Medical Center, Chicago, Illinois; Kelsey M. Greathouse, Courtney K. Walker, Audrey J. Weber, Ashley B. Adamson, Julia P. Andrade, Emily H. Poovey, Kendall A. Curtis and Hamad M. Muhammad, UAB Department of Neurology and Center for Neurodegeneration and Experimental Therapeutics ; Ada Zhang, SUNY Upstate Medical University; Sydney Covitz, Matt Cieslak, Jakob Seidlitz, Ted Satterthwaite, and Jacob Vogel, University of Pennsylvania, Philadelphia, Pennsylvania; and Nicholas T. Seyfried, Emory University School of Medicine, Atlanta, Georgia.
Support came from National Institutes of Health grants AG061800, AG061798, AG057911, AG067635, AG054719, AG063755, AG068024, NS061788, AG10161, AG72975, AG15819, AG17917, AG46152, and AG61356.
At UAB, Neurology is a department of the Marnix E. Heersink School of Medicine.
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Magazine reference:
Ng, B., et al. (2024). Integration at biophysical scales identifies molecular and cellular correlates of person-to-person variability in human brain connectivity. Nature Neuroscience. doi.org/10.1038/s41593-024-01788-z.