Research linking individual differences in brain proteins and functional connectivity

A long-standing goal of neuroscience is to understand how molecules and cellular structures at the microscale give rise to communication between brain regions at the macroscale. Research published in natural neuroscience For the first time, we identify hundreds of brain proteins that explain 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 explains the mechanistic basis of human cognition and behavior,” said Jeremy Herskowitz, associate professor of neurology at the University of Alabama at Birmingham. said the doctor. -Co-author of the study with Dr. Chris Gaiteri of Upstate Medical University of New York in Syracuse, New York. “This study demonstrates the feasibility of integrating data from very different biophysical scales to gain a molecular understanding of human brain connectivity.”

Bridging the gap from the molecular scale of proteins and mRNAs to the whole-brain neuroimaging scale of functional and structural magnetic resonance imaging – a range of approximately 7 orders of magnitude -; Made possible by the Religious Order Research and Rush Memory and Aging Project (ROSMAP).

ROSMAP enrolls Catholic nuns, priests, and brothers aged 65 and older with no known dementia at the time of enrollment. Participants undergo annual medical and psychological evaluations and agree to donate their brains postmortem.

Herskowitz, Gaiteri, and colleagues studied postmortem brain samples and data from a unique cohort of 98 ROSMAP participants. Data types include resting-state fMRI, structural MRI, genetics, dendritic spine morphometry, proteomics, and gene expression measurements from the superior frontal and inferior temporal gyri of the brain.

Based on the stability of within-individual functional connectivity patterns, we combine postmortem molecular and intracellular data with antemortem neuroimaging data from the same individuals to prioritize molecular mechanisms underlying brain connectivity. We hypothesized that it would be possible to rank them. ”

Dr. Jeremy Herskowitz, Associate Professor of Neurology, University of Alabama at Birmingham

The mean age at the time of MRI scan and death for ROSMAP participants was 88 +/- 6 years and 91 +/- 6 years, respectively, and the mean time interval between MRI scan and age at death was 3 +/- did. 2 years. The mean interval between postmortem brain sampling was 8.5 +/- 4.6 hours. In this study, the researchers performed detailed characterization of omics, cellular, and neuroimaging data types and used computational clustering algorithms to integrate the different data types.

Key to the study was the use of intermediate scale measurements. Dendritic spine morphometry, spine shape, size, and density – linking the molecular scale with the whole-brain neuroimaging scale. Integration of dendritic spine morphometry to contextualize proteomic and transcriptomic signals was important to detect protein-functional connectivity associations. “Initially, protein and RNA measurements failed to explain interindividual variation in functional connectivity, but integrating dendritic spine morphology to bridge the gap from molecules to communication between brain regions shows that all It worked,” Herskowitz said. .

Dendrites are branched extensions from the neuron's body that receive impulses from other neurons. Each dendrite can have thousands of tiny projections called spines. The head of each vertebra can form contact points called synapses to receive impulses sent from the axons of other neurons. Dendritic spines can rapidly change shape and volume when forming new synapses. This is part of a process called. brain plasticityand the head of the spine structurally supports the postsynaptic density. Based on their three-dimensional structure, vertebrae can be divided into subclasses of shapes such as slender, mushroom-like, stubby, or filopodial. This summer, Herskovitz and colleagues used ROSMAP samples in another study to show that memory storage in very old people is of quality, measured not by the quantity of synapses in the brain, but by the diameter of dendritic spine heads. It was shown that it is maintained by

In this latest study, proteins involved in synapses, energy metabolism, and RNA processing are enriched among the hundreds of proteins the researchers identified to explain interindividual differences in functional connectivity and structural covariation. was included in. “By integrating data at the genetic, molecular, subcellular, and tissue levels, we linked specific biochemical changes at synapses to connections between brain regions,” Herskowitz said.

“Overall, this study shows that obtaining data across key aspects of human neuroscience from the same set of brains will help us understand how human brain function is supported at multiple biophysical scales. “This shows that it is the basis for further research,” Professor Herskowitz said. “Although future research is needed to fully determine the extent and components of multiscale brain synchronization, we believe that the effects resonate across biophysical scales and are robustly defined. We established an initial set of molecules.

In addition to Herskowitz and Gaiteri, co-authors of the study, “Multiscale integration identifies synaptic proteins associated with human brain connectivity,” are Bernard Ng and Shinya Tasaki of Rush University Medical Center in Chicago, Illinois; , David A. Bennett. Kelsey M. Greathouse, Courtney K. Walker, Audrey J. Weber, Ashley B. Adamson, Julia P. Andrade, Emily H. Poovey, Kendall A. Curtis, Hamad M. Muhammad, UAB Department of Neurology and Neurodegeneration Experimental Center Therapeutics Ada Zhang, Upstate Medical University, New York; Sidney Kowitz, Matt Cieslak, Jacob Seidlitz, Ted Satterthwaite, Jacob Vogel, University of Pennsylvania, Philadelphia, Pennsylvania; and Nicholas T. Seyfried of Emory University School of Medicine in Atlanta, Georgia.

National Institutes of Health grants AG061800, AG061798, AG057911, AG067635, AG054719, AG063755, AG068024, NS061788, AG10161, AG72975, AG15819, AG17917, AG46152 and support from AG61356.

At UAB, the Department of Neurology is a division of the Marnix E. Hersink School of Medicine.