Data-driven integrative analysis of neuropeptide systems in human prefrontal cortex

An international team of scientists from Karolinska Institutet, SciLifeLab, KTH, Linköping University, the Human Brain Tissue Bank (Hungary) and McGill University (Canada), has created a detailed molecular map of the neuropeptide systems in 17 micro-dissected human prefrontal cortex subregions and three reference cortical regions (frontal, parietal and temporal cortex). Their results have been published in the Proceedings of the National Academy of Sciences (PNAS).

The prefrontal cortex (PFC) is highly developed in the human brain and is involved in multiple complex functions, including cognitive processes, e.g. working memory and decision making as well as generation and regulation of emotions. It is also thought to be of significance in pathological processes of many psychiatric disorders.

In a recent study, researchers from Sweden, Canada and Hungary, used RNA-seq gene expression profiling to analyze 165 micro-dissected samples from 17 hPFC subregions and three reference cortices (frontal, parietal and temporal cortex), obtained from both male and female donors, including both left and right hemispheres.

Using advanced data-driven strategies, these analyses have been complemented with both RNAscope (RNA in situ hybridization allowing visualization of single RNA molecules in individual cells) and published single-cell transcriptomics data for cellular localization, to identify possible micro-circuitries of neuropeptidergic systems in PFC.

“Neuropeptides represent the most diverse group on neurotransmitters (>100) with a corresponding number of receptors. They always co-exist with one or more classic transmitters, like GABA or noradrenaline. Some may also be important for neuronal development, but their exact functional role, especially in the human brain, is still not well understood. The present study high-lights this family of molecules and presents new and sometimes surprising information on their expression and localization in one of the critical regions, the PFC, in the human brain”, says last author Tomas Hökfelt (Karolinska Institutet).

The study provides profound insights into the chemical anatomy of the PFC and suggests, in particular, that a wide spectrum of peptidergic systems may fine-tune/modulate functions that are executed in the PFC during health and disease.

“Detailed analysis of gene expression in the human prefrontal cortex allowed us to identify distinct molecular differences between closely related regions. The next step is to further explore these differences link these to cell types and prefrontal cortex physiology in health and disease”, says co-author Jan Mulder (Karolinska Institutet).

“The integration of bulk RNA-seq, single-cell sequencing and RNAscope data allows us to explore the peptidergic micro-circuitries in the PFC of humans, which provides new insights to neuroscience and medical research to understand possible roles of neuropeptides in different subregions of the PFC”, says first author Wen Zhong (DDLS Fellow at LiU and researcher at Karolinska Institutet/KTH/SciLifeLab).

The new open-access PFC resource will provide neuroscience and medical research with a tool to explore proteins in different subregions of the cortex, which controls many cognitive functions that evolved in humans. All data are released in the Human Protein Atlas (HPA) Brain section and can be explored and downloaded for further analysis.

“The work is so far the broadest and deepest dive into the molecular architecture of the different regions of human prefrontal cortex. This part of the brain is vital for cognitive processes in the brain, and it is involved in many psychiatric disorders and thus, this makes the open access resource an important encyclopedia for molecular neuroscientists”, says SciLifeLab researcher and Program Director of the HPA, Mathias Uhlén (KTH).

The project was supported by the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Hungarian Brain Research Program and the SciLifeLab & Wallenberg Data Driven Life Science Program.

About

Human Protein Atlas

The Human Protein Atlas (HPA) is a program based at the Science for Life Laboratory (Stockholm) and started in 2003 with the aim to map all of the human proteins in cells, tissues and organs using integration of various omics technologies, including antibody-based imaging, mass spectrometry based proteomics, transcriptomics and systems biology. All the data in the knowledge resource is open access to allow scientists both in academia and industry to freely use the data for exploration of the human proteome. Version 21.1 consists of 10 separate sections, each focusing on a particular aspect of analysis of the human proteins, including one section on brain. The Human Protein Atlas program has already contributed to several thousands of publications in the field of human biology and disease and it has been selected by the organization ELIXIR (www.elixireurope.org) as a European core resource due to its fundamental importance for a wider life science community. The HPA consortium is funded by the Knut and Alice Wallenberg Foundation.

For more information, see: www.proteinatlas.org

Semmelweis Human Brain Tissue Bank

The Human Brain Tissue Bank, Semmelweis University, Budapest (HBTB) is unique for two reasons: 1) It collects only microdissected human brain samples individually removed by the “micropunch technique” from 274 different brain areas or nuclei, and store them at -70oC. The Database of the HBTB contains medical, pathological and neuro-pathological reports on each of the diseased persons. 2) Samples are taken only from brains with short, 2-10 hours, post-mortem delay. The microdissected brain samples are available strictly for research studies in scientific collaborations.