Human proteins have been identified that explain inter-

BIRMINGHAM, Ala. – The long-term goal of neuroscience is to understand how microscale molecules and cellular structures cause macroscale communication between brain regions. AND test published in Life neuroscience now identifies for the first time hundreds of brain proteins that explain interindividual differences in functional connectivity and structural covariance in the human brain.

“The primary goal of neuroscience is to understand the brain, which ultimately describes the mechanistic basis of human cognition and behavior,” said Dr. Jeremy Herskowitz, associate professor at the Institute University of Alabama at Birmingham Department of Neurology and co-author of the study by correspondence with Dr. Chris Gaiteri of SUNY Upstate Medical University in Syracuse, New York. “This study demonstrates the feasibility of integrating data from very different biophysical scales to provide a molecular understanding of human brain connectivity.”

Bridging the gap between the molecular scale of proteins and mRNA and the scale of whole-brain neuroimaging with functional and structural magnetic resonance imaging – over approximately seven orders of magnitude – was made possible by the Religious Orders Study and the Rush Memory and Aging Project, or ROSMAP, at Rush University in Chicago , Illinois.

ROSMAP registers Catholic nuns, priests and brothers aged 65 or older who have not been diagnosed with dementia at the time of registration. Participants undergo medical and psychological evaluation every year and agree to donate their brains after death.

Herskowitz, Gaiteri and colleagues examined 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 in the superior frontal gyrus and inferior temporal gyrus of the brain.

“Based on the stability of functional connectivity patterns across individuals, we hypothesized that it may be possible to combine postmortem molecular and subcellular data with antemortem neuroimaging data from the same individuals to prioritize the molecular mechanisms underlying brain connectivity,” Herskowitz said.

The mean age of ROSMAP participants at the time of MRI examination and at death was 88 +/- 6 years and 91 +/- 6 years, respectively, with a mean interval between MRI examination and age at death of 3 +/- 2 years. The mean postmortem time for brain sample collection was 8.5 +/- 4.6 hours. In the study, researchers performed detailed characterization of each type of omics, cellular, and neuroimaging data and then integrated the different types of data using computational clustering algorithms.

The key to the study was to use an intermediate scale measurement – dendritic spine morphometry, spine shapes, sizes and densities – to relate the molecular scale to the scale of whole-brain neuroimaging. Integration of dendritic spine morphometry to contextualize proteomic and transcriptomic signals was crucial to detect protein associations with functional connectivity. “Initially, protein and RNA measurements could not explain individual variability in functional connectivity; however, it all worked out when we integrated dendritic spine morphology to bridge the gap between molecules and communication between brain regions,” Herskowitz said.

A dendrite is a branching extension of a neuron’s body that receives impulses from other neurons. Each dendrite may have thousands of tiny projections called spines. The head of each spine can form a contact point called a synapse that receives an impulse sent from an axon of another neuron. Dendritic spines can rapidly change shape or volume as they form new synapses, part of a process called brain plasticity, and the spine head structurally supports postsynaptic density. Spines can be divided into subclasses of shapes based on their three-dimensional structure, such as thin, mushroom-shaped, stubby, or filopodia. This summer in a different version testHerskowitz and colleagues used ROSMAP samples to show that memory retention in older adults depends on quality, as measured by dendritic spine head diameter, rather than the number of synapses in the brain.

In the latest study, hundreds of proteins identified by scientists that explain inter-individual differences in functional connectivity and structural covariance were enriched for proteins involved in synapses, energy metabolism and RNA processing. “By integrating data at the genetic, molecular, subcellular and tissue levels, we have linked specific biochemical changes at synapses to connectivity between brain regions,” Herskowitz said.

“Overall, this study indicates that obtaining data from mainstream human neuroscience perspectives from the same set of brains is fundamental to understanding how human brain function is supported at multiple biophysical scales,” Herskowitz said. “While future studies are necessary to fully define the scope and components of multiscale brain synchronization, we have established a solidly defined initial set of molecules whose effects are likely to resonate across biophysical scales.”

In addition to Herskowitz and Gaiteri, co-authors test“Multiscale integration identifies synaptic proteins associated with human brain connectivity”: Bernard Ng, Shinya Tasaki and David A. Bennett of 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 Therapy; 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 was provided by 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 in Marnix E. Heersink Medical School.