What is it about?

An international team of scientists led by researchers at Karolinska Institutet in Sweden has launched a comprehensive study of all proteins expressed in 17 regions of the hPFC based on RNA-seq gene expression profiling. All together 165 micro-dissected samples from both hPFC and three reference cortices (frontal, parietal and temporal cortex) were obtained from equal numbers of male and female donors, including both left and right hemispheres. Focus of the article is on 60 neuropeptide transmitters and on an equal number of their receptors. The RNA-seq results are complemented with RNAscope in situ hybridization and with published single-cell transcriptomics data, allowing analysis of the cellular localization of transcripts and hypothesizing on putative microcircuits. The hPFC is highly developed and controls many cognitive and other functions and has been associated with several mental and neurological disorders. Thus, the study provides new tools to neuroscience and medical research to help understand possible roles of a large number of proteins, in particular neuropeptides, in different subregions of the hPFC.

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Why is it important?

Understanding the detailed chemical neuroanatomy of the hPFC may shed light on how the many essential functions of this brain region are executed during health and disease. Our study suggests that the well-established anatomical and functional heterogeneity of the human PFC also is reflected in the expression pattern of the neuropeptide systems. The closely located and functionally different hPFC subregions are heterogenous with unique peptide/transmitter-related transcript profiles. We find expression of some peptides in hPFC previously only associated with hypothalamus. Furthermore, based on distribution of the neuropeptides and their receptors we suggest that some peptides from peripheral sources (intestine, fat cells) may directly act on receptors in hPFC. We confirm that also in the hPFC neuropeptides are co-expressed in neurons already working with a classic transmitter like GABA or glutamate. We provide evidence that glutamatergic pyramidal neurons co-express hypocretin/orexin, alternatively galanin. Since inhibitory galanin thus may be co-released with excitatory glutamate, this is an example of co-transmitter antagonism. Co-release of excitatory hypocretin/orexin and glutamate may instead represent co-transmitter agonism. Such information on the cellular expression of neuropeptide transmitters and their receptors, together with results from future studies on diseased brains, may lead to new targets for development of drugs for treatment of, e.g., depression.


Neuropeptides are the most diverse group of neurotransmitters (>100), but their functional significance is in many cases still unclear. Expression of transcripts for neuropeptides and their receptors in the human brain has been demonstrated in many single-cell studies, but this group of molecules has still not been high-lighted. We hope that the results of the present study, thanks to the efforts of our team of authors and thanks to publication in PNAS, will make neuropeptide transmitters better known to a larger audience. There are now three medications acting on peptidergic signaling approved by FDA: antibodies to calcitonin gene-related peptide (CGRP) for treatment of migraine, hypocretin/orexin antagonists for insomnia and neurokinin 1 (substance P) antagonists for the prevention of chemotherapy-induced nausea and vomiting. This progress conveys hope that one day also drugs targeting peptidergic mechanisms in the hPFC can be developed for treatment of mental and neurological disorders.

Professor Tomas Hökfelt

Read the Original

This page is a summary of: The neuropeptide landscape of human prefrontal cortex, Proceedings of the National Academy of Sciences, August 2022, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2123146119.
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