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New Study Reveals Brain Proteins Linked to Functional Connectivity
Understanding how molecular and cellular components interact to facilitate communication across various brain regions has been a significant focus in neuroscience. A new study published in Nature Neuroscience successfully identifies an extensive range of brain proteins that contribute to the differences in functional connectivity and structural covariation observed in the human brain.
“A key objective in neuroscience is to elucidate the mechanisms underlying human cognition and behavior,” stated Jeremy Herskowitz, Ph.D., an associate professor at the University of Alabama at Birmingham’s Department of Neurology and co-corresponding author of the study alongside Chris Gaiteri, Ph.D., of SUNY Upstate Medical University. “This research highlights the potential to merge data from distinctly different biophysical scales to achieve a molecular comprehension of human brain connectivity.”
The research connects microscale measurements of proteins and mRNA with macro-level neuroimaging data from functional and structural magnetic resonance imaging (MRI) through the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), based at Rush University in Chicago.
ROSMAP involves participants, primarily Catholic nuns, priests, and brothers aged 65 and older, who were not diagnosed with dementia at the time of their enrollment. Each participant undergoes annual medical and psychological assessments and consents to brain donation posthumously.
Herskowitz, Gaiteri, and their team analyzed brain samples and data from a specialized cohort of 98 ROSMAP participants. This data encompassed various formats including resting state fMRI, structural MRI, genetic assessments, dendritic spine analysis, proteomic metrics, and gene expression profiles from specific brain gyri.
“Given the reliability of functional connectivity patterns within individuals, our hypothesis was that we could amalgamate postmortem molecular and subcellular data with neuroimaging results obtained before death to pinpoint molecular mechanisms that govern brain connectivity,” Herskowitz explained.
The average age of participants during their MRI scans was 88 years, and they were 91 years old at the time of death, with an average interval of three years between the scan and their passing. The study examined a postmortem interval of roughly 8.5 hours before brain sampling. Researchers meticulously characterized each type of omic, cellular, and neuroimaging data before integrating these data sets using computational clustering techniques.
A pivotal approach in the study was employing dendritic spine morphometry—the analysis of the shapes, sizes, and densities of spine-like structures on neurons—to create a connection between the molecular level and neuroimaging data. This integration proved essential for associating proteins with human functional connectivity. “Initially, we found that standalone protein and RNA measures fell short of accounting for the variability between individuals concerning functional connectivity. However, once we incorporated dendritic spine morphology, the pieces began to fall into place, clarifying the relationship from molecular structures to inter-regional brain communication,” Herskowitz remarked.
Dendrites act as neural extensions that receive signals from other neurons, and each can bear thousands of tiny protrusions known as spines, which form synapses that relay impulses from the axon of a neighboring neuron. These dendritic spines play a dynamic role in brain plasticity, adjusting in shape or volume as new synapses form. This past summer, in a separate study, Herskowitz and his team utilized ROSMAP data to reveal that the preservation of memory in elderly subjects was more dependent on the quality of synaptic connections—measured through dendritic spine head diameter—rather than their sheer number.
In this recent investigation, the researchers discovered that the hundreds of identified proteins, which explain variabilities in functional connectivity and structural covariation, were largely concentrated on those associated with synapses, energy metabolism, and RNA processing. “By harmonizing genetic, molecular, subcellular, and tissue-level data, we were able to link particular biochemical alterations at synapses with connectivity across brain regions,” Herskowitz noted.
“This study underscores the necessity of gathering comprehensive data from multiple perspectives in human neuroscience, utilizing the same sets of brains to deepen our understanding of the intricate support for human brain function across varied biophysical scales,” added Herskowitz. “While further research is essential to fully chart the dimensions and elements of multi-scale brain synchrony, we have laid the groundwork by defining an initial set of molecules that likely impact brain function on multiple levels.”
In addition to Herskowitz and Gaiteri, co-authors of the publication titled “Multiscale Integration Identifies Synaptic Proteins Associated with Human Brain Connectivity” include Bernard Ng, Shinya Tasaki, and David A. Bennett from Rush University Medical Center; 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 from the University of Alabama at Birmingham; Ada Zhang from SUNY Upstate Medical University; Sydney Covitz, Matt Cieslak, Jakob Seidlitz, Ted Satterthwaite, and Jacob Vogel from the University of Pennsylvania; as well as Nicholas T. Seyfried from Emory University School of Medicine.
The research received support from various grants provided by the National Institutes of Health.
Within UAB, the Neurology department is part of the Marnix E. Heersink School of Medicine.
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