Understanding the complexity of the brain

The complexity of the brain and the unpredictable nature of behavior is one of the most intriguing areas of science and one of the most significant1. Many questions are still on the bench today: How have brains evolved? What can the brain compute? What are the neuronal correlates of consciousness? How do neurons interact? Well, have we answered any of these questions? Some problems in neuroscience are nearly solved. For others, solutions are decades away. Consciousness remains the ultimate.

Identifying the molecular organization and signature of the brain, at the regional, cellular, and subcellular levels advances our understanding of brain physiology and disease. Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture.

Previous studies have gained insight into the molecular landscape of the brain by measuring gene expression in different brain regions2,3. Today the Brain Atlas helps us to understand the difficulty of the topic in an accessible manner.

The Brain Atlas

The Human Protein Atlas (HPA) is a public online database that provides an integrated overview of protein expression and location in all major human organ and tissue types. Within this portal, you can now access the Brain Atlas where a similar approach (the combination of transcriptomic data and antibody-based protein profiling) is used to provide a comprehensive overview of protein expression in the main anatomical structures of the mammalian brains.

The information in the Brain Atlas database read well, is well-illustrated, and has useful reference sections. Neurons can be categorized according to a variety of features, such as their size, shape, or location in the brain. Serial sections of the mouse brain provide a full overview for a selection of over 250 targets, available as an online virtual microscope of high-resolution images. You can also see which commercial antibodies have been used to produce the staining.

An innovative way to look at the brain

The human, mouse, and pig protein-coding genes are grouped into 10 color-coded anatomical regions (Fig.1), and classified based on RNA expression in the brain from two different perspectives:

• A brain-centric perspective comparing the brain regions to each other. Here you can explore which proteins are expressed in a particular part of the brain or where in the brain your protein of interest is expressed. Even if your favorite brain region is not covered, you will find plenty to interest you (Fig.2).

• A whole-body tissue type perspective that considers the brain as a whole tissue. Here you can explore which proteins are expressed in the brain compared to other tissues type in the human body (Figure.3).

1. The brain-centric perspective: exploring the mammalian brains

The samples in the Brain Atlas database provide the regional classification of >16,000 genes based on RNA expression, indicating which proteins are elevated in one region compared to the other. The transcriptomics analysis of the basic brain structures reveals the fundamental molecular organization of the mammalian brain, but also some unique features not shared by all 3 species. The consensus normalized expression (NX) levels were created for the 10 brain regions by combining the data from two transcriptomics datasets (GTEx and FANTOM5). 

2. The brain-tissue type perspective: comparing the brain to other tissues

In-depth analysis, using antibody-based protein profiling, allowed the understanding of the distribution of the brain-specific genes and their protein location in the brain as well as in all other human tissues and organs. 

The brain-specific genes can be grouped into different categories based on transcript abundance (the number of genes with elevated or non-elevated expression in the brain compared to other tissues) or transcript detection (how many genes have, or do not have detectable levels - above the cut-off - of transcribed mRNA molecules in the brain compared to other tissues,).

With this classification, only 33 genes were found to be selectively detected in the brain compared to all other tissues.

Next step: human neurodegenerative disorders

Approximately one billion people in the world suffer from a neurological condition, defined as progressive loss of neurological functions, including dementia, stroke, multiple sclerosis, epilepsy, migraines, brain injuries, cancer, and neuro infections. At the moment all data in the Brain Atlas is based on healthy tissue and no human disease or animal model data is included.

Understanding how the brain is built is the first necessary step for knowing how to prevent and treat brain disorders. In the future, the ability to compare gene expression in the brains of different mammalian species will help to understand some human-specific pathomechanisms and could be used to validate or select a model system for human disease.

Facts from the Brain Atlas

• The regional classification of the human brain is based on available FANTOM5 and GTEx expression data and includes the classification of more than 17,000 protein-coding genes. Expression data from pig and mouse brains are also used for the regional classification, of human one-to-one orthologous genes.
• More than 15,000 genes are detected in the brain and classified on the regional expression, limited by the gene mapping used in external datasets.
• The transcriptome analysis shows that 82% (>16,000) of all human proteins expressed in various tissue types are also expressed in the brain.
• Almost 2600 genes show an elevated expression in the brain compared to other tissue types.
• Out of the genes with regional expression classification, > 1000 are categorized as regionally elevated.
• Almost 500 regionally elevated genes are elevated in other tissues than the brain.
• The cerebellum has the most regionally enriched genes (>200).
• 33 genes are only detected in the brain compared to other tissues in the human body.

Do you love the brain? Stay tuned!

With this amazing tool so rich in information, you and other researchers all around the world can now gain in-depth insights into the inner structure of the brain.

It is hoped that these insights will provide you a foundation upon which to build a more complete understanding of normal brain function as well as give researchers a means to investigate the etiology and pathology of neurodegenerative and other brain diseases.

In our next blog Jan Mulder, one of the scientists behind the project will share his thoughts about the Brain Atlas.