The hypothalamus is a structure in the brain that links our nervous system to our hormonal system. The team of Prof. Frédéric Clotman traced the development of the neurons which compose it and discovered a reserve of cells available for producing neurons according to the needs of the hypothalamus throughout a lifetime. The discovery could ultimately help treat diseases associated with lesions of the hypothalamus, such as anorexia/bulimia, depression and schizophrenia.
Between neurons and hormones
The nervous system and the hormonal (or endocrine) system are like two small factories in our body, allowing us to interact with our environment and maintain our internal functions. Between these two factories is the hypothalamus, a small region at the base of the brain (just above the back of the mouth). It allows the two systems to communicate with each other. The hypothalamus receives a great amount of information from the entire nervous system and from the bloodstream, then acts in two ways. In the posterior pituitary gland, , projections of neurons from the hypothalamus produce hormones (oxytocin, for example, which is important for childbirth and breastfeeding) and release them into the bloodstream. In the anterior pituitary gland, other neurons make other hormones (such as growth hormone) whose release is regulated by the hypothalamus. It is by controlling pituitary gland activity that the hypothalamus links the nervous system to the hormonal/endocrine system. The hypothalamus thus controls the hormones which regulate, for example, appetite, growth, fear, the reproductive cycle, breastfeeding, etc.
Complex groups of neurons
As the hypothalamus is part of the nervous system, it’s made up of a multitude of neurons, grouped into neuronal populations whose organisation is extremely complex and difficult to study with traditional morphological tools. The scientific community already knows how hypothalamus activity is regulated, what the structure is used for, and the hormones whose release into the bloodstream it controls. However, until recently, no one knew what types of neurons were in the hypothalamus. Using innovative molecular biology and data analysis approaches, collaborators at the University of Vienna identified the molecular characteristics of many hypothalamus populations and learned how they develop. Prof. Clotman, a researcher at the UCLouvain Institute of Neuroscience, and his team contributed to this research, which resulted in an article[1] published early June in the scientific journal Nature.
Early nervous system development
So until recently, no diagram of the development of hypothalamus neuronal populations existed. The UCLouvain Institute of Neuroscience contributes to the study of the early development of another region of the nervous system, the spinal cord. In humans, the development of the spinal cord begins during the second month of gestation, between the fourth and eighth week of pregnancy. To explore this question further, Prof. Clotman and his laboratory examined two mechanisms of early development:
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Neuronal differentiation : Each neuron in the nervous system acquires its own characteristics. To become independent, they differentiate themselves from others, just like the cells of other organs that differentiate and specialise during development.
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Neuronal migration : Each neuron in our nervous system is produced in a place different from where the neuron will be in adulthood. Neurons must therefore move during development to reach the right place, at the right time, and establish connections with other cells to form functional and efficient circuits.
Mechanisms that reactivate
In addition to contributing early development expertise, the UCLouvain team provided expertise in reactivating the differentiation and migration mechanisms after the nervous system is damaged. For 20 years now, we’ve known that after an injury (car accident, stroke) mechanisms that are normally active during development but silent in adulthood are reactivated, whether in the cortex or in the spinal cord. So even in adulthood neurons differentiate again and migrate to the damaged part of the nervous system, forming, as much as they can, new connections to repair damaged circuits.
An identity and function specific to each population
UCLouvain’s knowledge and skills were recently added to a major research effort by the University of Vienna. ‘In 2016,’ Prof. Clotman explains, ‘with a University of Vienna team, we managed to identify 62 different neuronal populations in the hypothalamus. Each had its own characteristics or identity and therefore had different functions in the hypothalamus.’ For example, one of these neuronal populations is responsible for controlling the release by pituitary gland cells of two hormones, follicle stimulating hormone (FSH) and luteinising hormone (LH), which regulate the female menstrual cycle.
The invaluable technique of RNA sequencing
To identify the 62 neuronal populations, the University of Vienna and UCLouvain teams used a technique called single-cell RNA sequencing. A quick review: the deoxyribonucleic acid (DNA) in every one of a human’s cells is identical. Ribonucleic acid (RNA) is a copy of all the active genes in a particular cell. RNA sequencing allows us to know, cell by cell, the repertoire of RNA molecules (genes) active in a particular cell. The researchers carried out this meticulous work on 60,000 cells, organising them into 62 different groups, each with identical gene activity.
Tracing the history of neuronal populations in the hypothalamus
Given this well-established technique and the in-depth knowledge of neuronal differentiation garnered by the Institute of Neuroscience, the two teams decided to use the technique more precisely at different stages of hypothalamus development. ‘We collected the hypothalami of mouse embryos and analysed them at different stages of their development,’ Prof. Clotman says. ‘We were able to trace the history of about 50 neuronal populations, that is, we tracked their development journey.’ What stages of development do these neuronal populations go through before assuming their final character, which allows them to exercise a function in the hypothalamus? Using complex computer algorithms, scientists have been able to answer.
Other hypothalamus secrets revealed
The main result of the research is the precise history of the 50 neuronal populations. The researchers also made other amazing discoveries. ‘We noticed that after birth, in the hypothalamus, there was a reserve neuronal population that wasn’t yet differentiated. These neurons haven’t yet acquired mature characteristics, they’re a stockpile to be developed as needed throughout the lives of new cells in the hypothalamus. This is a great discovery, because we knew that such reserves existed in other parts of the nervous system, but we didn’t know they existed in the hypothalamus.’ Another discovery: the role of the Onecut-3 genetic regulator. This protein, which is used to control genetic programmes and therefore to activate specific genes in certain cells, has proven to be important in the hypothalamus. Several populations of hypothalamus neurons use a neurotransmitter called dopamine as a chemical messenger, and the research has made it possible to show that the differentiation of these neuronal populations is stimulated by the protein Onecut-3, which makes it a key actor in hypothalamus development.
Improve the management of certain diseases
These discoveries not only bring new knowledge to basic research. Using these findings, Prof. Clotman would like ‘to establish the link between developmental disturbances of neuronal populations in the hypothalamus with diseases known to be correlated with abnormalities in the hypothalamus. Lesions of the hypothalamus can, for example, lead to metabolic diseases (anorexia/bulimia) or disturbances in body temperature. A posteriori hypothalamus analysis in individuals with depression or schizophrenia also shows disturbances in this part of the nervous system.’ Driven by these recent discoveries, Prof. Clotman and his team want to understand how such disturbances occur, in order to better diagnose and treat these diseases. This would be a major breakthrough for managing them.
Collaboration and basic research
For Frédéric Clotman, after several years as a researcher, two things are crucial in a research environment: basic research and collaboration. ‘You should never forget the importance of basic research. All the knowledge gathered through it is necessary to move on to more applied research. Generating this knowledge is essential, as the experience of COVID-19 shows us.’ As for collaboration: ‘This research project was possible because researchers from the University of Vienna made a series of observations and came to us knowing that our skills could complement their knowledge. For seven years, we’ve carried out an open, transparent and very constructive collaboration with them. We must preserve and encourage collaboration between universities!’
Lauranne Garitte
A glance at Frédéric Clotman's bio
Frédéric Clotman is an FNRS senior research associate and professor at UCLouvain, where he heads the Neurodifferentiation Laboratory of the Institute of Neuroscience (IoNS). He holds a master’s in biology and a PhD in science obtained respectively in 1991 and 1996 at UCLouvain. His research focuses on the early stages of nervous system development, and on the reactivation of developmental mechanisms after injury to the nervous system in adults.
[1]Romanov, R.A., Tretiakov, E.O., Kastriti, M.E. et al. Molecular design of hypothalamus development. Nature 582, 246–252 (2020). https://doi.org/10.1038/s41586-020-2266-0