The cryptic gonadotropin-releasing hormone neuronal system of human basal ganglia
- Institute of Experimental Medicine, Hungary
- Semmelweis University, Hungary
- University of Veterinary Medicine, Hungary
- University of Debrecen, Faculty of Medicine, Hungary
- Budapest University of Technology and Economics, Hungary
- Amolyt Pharma, United States
- University of Lille, France
- Univ. Lille, Inserm, France
- Université de Lille, France
Abstract
Human reproduction is controlled by ~2,000 hypothalamic gonadotropin-releasing hormone (GnRH) neurons. Here we report the discovery and characterization of additional ~150,000-200,000 GnRH-synthesizing cells in the human basal ganglia and basal forebrain. Nearly all extrahypothalamic GnRH neurons expressed the cholinergic marker enzyme choline acetyltransferase. Similarly, hypothalamic GnRH neurons were also cholinergic both in embryonic and adult human brains. Whole-transcriptome analysis of cholinergic interneurons and medium spiny projection neurons laser-microdissected from the human putamen showed selective expression of GNRH1 and GNRHR1 autoreceptors in the cholinergic cell population and uncovered the detailed transcriptome profile and molecular connectome of these two cell types. Higher-order non-reproductive functions regulated by GnRH under physiological conditions in the human basal ganglia and basal forebrain require clarification. The role and changes of GnRH/GnRHR1 signaling in neurodegenerative disorders affecting cholinergic neurocircuitries, including Parkinson's and Alzheimer's diseases, need to be explored.
Data availability
RNA sequencing files are available in BioProject with the accession number PRJNA680536.
Article and author information
Author details
Funding
National Science Foundation of Hungary (K128317)
- Erik Hrabovszky
National Science Foundation of Hungary (PD134837)
- Katalin Skrapits
Hungarian Brain Research Program (2017-1.2.1-NKP- 2017-00002)
- Erik Hrabovszky
Institut National de la Santé et de la Recherche Médicale (U1172)
- Vincent Prévot
- Paolo Giacobini
Agence Nationale de la Recherche (ANR-19-CE16-0021-02)
- Paolo Giacobini
Inserm Cross-Cutting Scientific Program (HuDeCa)
- Paolo Giacobini
NRDI Fund, TKP2020 IES (BME-IE-BIO)
- Blanka Tóth
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Experiments involving genetically modified male mice were carried out in accordance with the Institutional Ethical Codex, Hungarian Act of Animal Care and Experimentation (1998, XXVIII, section 243/1998) and the European Union guidelines (directive 2010/63/EU), and with the approval of the Institutional Animal Care and Use Committee of the Institute of Experimental Medicine. All measures were taken to minimize potential stress or suffering during sacrifice and to reduce the number of animals to be used.
Human subjects: Ethic permissions were obtained from the Regional and Institutional Committee of Science and Research Ethics of Semmelweis University (SE-TUKEB 251/2016), in accordance with the Hungarian Law (1997 CLIV and 18/1998/XII.27. EÜM Decree/) and the World Medical Association Declaration of Helsinki. As explicitly declared in the Hungarian Law on Healthcare (1997. CLIV), tissue removal for either donation or research purposes can be done legally in Hungary, unless the deceased person banned the removal in advance. Therefore, collection and use of adult brain samples in this study did not require a priori informed consent of the deceased. The above cited legal article has been extended in 18/1998. (XII. 27. EÜM rendelet) decree of the Hungarian Ministry for Healthcare http://net.jogtar.hu/jr/gen/hjegy_doc.cgi?docid=99800018.EUM. Paragraph 6. speaks about requirements for "Removal of organ or tissue from a cadaver". Paragraph 8. states: Before removal the healthcare professional must check whether the personal documents or health care documentation of deceased person contains a "Declaration of Objection", i.e. explicit statement that he/she does not allow the removal of tissue or organs. In paragraph 8. (3): If such declaration does not exist, then the tissue or organs can be removed. The later Hungarian Law 1999. LXXI. also addresses this issue in the very same spirit: https://mkogy.jogtar.hu/jogszabaly?docid=99900071.TVFetal tissues were made available in accordance with French bylaws (Good Practice Concerning the Conservation, Transformation, and Transportation of Human Tissue to Be Used Therapeutically, published on December 29, 1998). The studies on human fetal tissue were approved by the French agency for biomedical research (Agence de la Biomédecine, Saint-Denis la Plaine, France, protocol n{degree sign}: PFS16-002). Non-pathological human fetuses were obtained at gestational week 11 from pregnancies terminated voluntarily after written informed consent of the parents (Gynaecology Department, Jeanne de Flandre Hospital, Lille, France).
Copyright
© 2021, Skrapits et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The cryptic gonadotropin-releasing hormone neuronal system of human basal ganglia
eLife 10:e67714.
https://doi.org/10.7554/eLife.67714
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