Understanding how molecules, genes, proteins, and cellular structures drive communication across the brain's vast network is one of neuroscience's greatest ambitions.

While significant advances have been made in cataloging the brain’s molecular components and mapping its functional connectivity through imaging, a critical gap remains: linking these two scales 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 and death is 88 and 91 years. In total, 77% of the participants are female, and the participants have 15 ± 3 years of education.

Data collection spanned multiple biological scales, including gene expression, protein abundance, and post-mortem morphological studies of the structure of dendritic spines. Researchers concentrated on two brain regions: the superior frontal gyrus, associated with higher-order cognitive tasks, and the inferior temporal gyrus, key to memory and recognition.

A total of 10,426 master proteins were identified across batches. Proteins quantified in >50% of samples were included in subsequent analyses.

One of the study's highlights is the role of dendritic spines, tiny but essential structures for synaptic communication. Between 8 and 12 neurons were sampled per individual.

A single dendritic segment was then imaged per neuron and described in detail in regard to the structure of the spines. Reconstructions of dendrites and dendritic spines were conducted by blinded experimenters. Morphometric analysis was conducted for each spine. The measurements categorized spines into thin, stubby, mushroom, and filopodia classes, as these shapes affect their function.

Spine density and morphology were linked to connectivity patterns observed in neuroimaging, suggesting that structural features at the cellular level influence how brain regions communicate. This finding aligns with known neurobiology: spines are critical for synaptic signaling, and their dynamic changes mirror the plasticity underlying learning and memory.

Molecular analyses further integrated proteins and RNA/genetic data that influence connectivity. These molecules are enriched in synaptic processes, such as neurotransmitter release and energy metabolism.

These data were tied to the pre-mortem neuroimaging findings, including structural and functional MRI brain scans. Thereby, they combined structural data with microscopic brain cell morphology and molecular data.

The researchers identified hundreds of proteins linked to functional MRI connectivity. Additionally, they discovered that the genetic basis of about a dozen of these genes is connected to brain connectivity, indicating potential causal roles for these genes.

Integrating big data
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, including replication with alternative data types like structural MRI and gene expression.

This rigorous approach confirmed that synaptic proteins and genes consistently explain variability in connectivity between individuals. The study also revealed that some molecules influencing connectivity may do so through their genetic components, pointing to potential causal roles.

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 human cognition and behavior.

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 mechanistic basis of human cognition and behavior. This progress not only deepens our understanding of how the brain works but also 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