Neuroscience breakthrough: Connecting microscope, molecules and brain imaging

Understanding how molecules, genes, proteins, and structures in the brain cell communicate across the brain's vast network is one of neuroscience's greatest ambitions - and difficulties.

While significant advances have been made in cataloging the brain’s molecular components and mapping its connections through imaging, a critical gap remains: linking these two parts of investigation.

In this pioneering study, researchers bridged this gap by combining molecular data from postmortem brain tissue with neuroimaging data from the same individuals collected before death.

The study
The study included 98 older adults participating in a long-term aging research project. The average age of participants at the time of MRI scan was 88 years and the average time of death 91 years. In total, 77% of the participants were female, and the participants had 15 ± 3 years of education.

Researchers concentrated on two brain regions: the superior frontal gyrus, associated with higher-order intellectual tasks, and the inferior temporal gyrus, a key area to memory and recognition.

Data collection spanned multiple biological scales, including gene expression, protein abundance, and post-mortem studies of the structure of dendrites on the brain cells.

Dendrites are like branches that grow on nerve cells. Tiny but essential structures for synaptic communication, they receive messages from other cells and send them to the main part of the nerve cell to be processed. Think of them as the "receivers" that gather information for the brain cells they branch from.

Between 8 and 12 neurons were sampled per individual. A single dendrite was then imaged per neuron and described in detail regarding the structure of the tiny spines on that dendrite.

The measurements categorized the spines on the dendrite into thin, stubby, mushroom, and filopodia classes, as these shapes indicate their function. Spine density and morphology were linked to connectivity patterns observed in neuroimaging.

A total of 10,426 master proteins were identified across the brains. Proteins that were found in more than 50% of the samples were included in subsequent analyses.

All the above data were then linked to the pre-mortem neuroimaging findings, including structural and functional MRI brain scans.

Thereby, they combined structural data (scan) with microscopic brain cell morphology (dendrite spine type) and molecule data (proteins).

Integrating big data
The researchers identified hundreds of proteins linked to specific functional connections on the MRI scan.

In addition to identifying connectivity-related molecules, the study provides a blueprint for integrating data across biological scales. The researchers used state-of-the-art techniques to ensure the robustness of their findings.

This rigorous approach confirmed that synaptic proteins and the genes (that are the blueprints for the specific proteins) consistently explain variability in connectivity between individuals.

This research represents a significant step toward a unified, integrated understanding of brain function, from the microscopic to the macroscopic. By connecting molecular data to brain imaging, the study addresses fundamental questions about the mechanisms underlying how the human brain works.

IRL
The findings also have practical implications, particularly for drug discovery.

Many drugs fail because molecular findings in cell cultures or animal models do not translate to human brain function. This integrative approach offers a pathway to overcome this challenge by identifying molecules that resonate across biological scales.

Future research could also examine whether specific types of synapses or cell populations are more relevant to brain connectivity, adding another layer of precision.

A central goal of neuroscience is to develop an understanding of the brain that ultimately describes the basis of human cognition and behavior on "all" levels.

This work lays the foundation for bridging the microscopic and macroscopic realms of brain science.

About the scientific paper:

First author: Bernard Ng, USA
Published: Nature Neuroscience, October 2024.
Link to paper: https://www.nature.com/articles/s41593-024-01788-z