Mapping the brain’s control centre

Breaking new ground 26. aug 2020 3 min Professor Tibor Harkany Written by Kristian Sjøgren

Researchers have identified molecular principles that shape the development of the hypothalamus. The research provides new insight into the mechanisms that can go wrong and lead to the development of metabolic diseases, stress, anorexia, obesity and sleep disorders.

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The brain is by far the human body’s most complex and mysterious organ, the source of mind, identity and consciousness.

Weighing just 4 grams in humans (out of more than 1,200 grams), the hypothalamus is a primary metabolic control centre of the brain that secretes hormones and thereby regulates sleep, body temperature, hunger, stress, sex drive and much more. For the first time, researchers have mapped in detail how this extremely complex part of the brain is assembled and how it develops during intrauterine and neonatal development.

The research reveals surprising new things about brain development and describes how myriads of cells collaborate to assemble one of the most complicated neural networks so that it is ready right from birth.

The research also reveals how defects in the development of the hypothalamus can lead to hormonal and metabolic diseases and obesity.

“Being able to map the many types of cells in the hypothalamus is a breakthrough. This creates a much more complete cellular toolbox for studying hormonal functions and even various metabolic diseases that can be linked to the hypothalamus,” explains a researcher behind the new study, Tibor Harkany, Professor, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden and Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Austria.

The research has been published in Nature.

Mapping the function and development of more than 50,000 ectodermal cells

The researchers studied the development of the hypothalamus in mice using single-cell RNA sequencing. This very potent molecular biology tool enabled the researchers to distinguish the cells from each other in the developmental stages by first analysing their RNA make-up at single-cell resolution at different fetal stages and then processing the data with supercomputers.

The researchers then built models of how the individual cells develop at the fetal stages and eventually end up in a very precisely organized network.

For the individual cells, the researchers determined the cells’ origin (from stem and progenitor cells), how they communicate with the environment as they develop and the dynamics of how they start to function in the fully developed hypothalamus.

“We have identified how cells can have the same starting-point and undergo similar developmental stages in time yet eventually diverge and end up with specific functions, such as regulating the secretion of a particular hormone,” explains Tibor Harkany.

The researchers used their method to track more than 50,000 mouse cells from the mid-gestational embryo based on their function, development and origin.

“This provides us with opportunities to identify new hormones, peptides, neurotransmitters and cell types and to link them to the development of diseases in later life,” says Tibor Harkany.

Linking data from mice with human diseases

The researchers mapped the function of the individual hypothalamic neurons in mice, and then they asked the obvious question: is this also relevant to humans?

To answer that question, they made genetic models of mice in which they disabled specific genes in specific cells to determine whether these genes were so important to the cells that disabling them could lead to disease.

They then compared their findings with data from the genome-wide association study by the UK Biobank to determine whether the consequences of altered genetic expression (phenotype) in hypothalamic mouse neurons could cause known diseases in humans.

They found that defects in some of the genes on which they focused were linked to the development of obesity, stress and sleep disorders.

Specifically, the researchers identified that the transcription factors Onecut2 and Onecut3 were associated with the development of obesity, sleep disorders and post-traumatic stress disorder by dysregulating some of the communication pathways that lead to normal and healthy cell function in the hypothalamus.

Surprising new knowledge on dopamine regulation

The researchers also identified as many as nine types of dopamine-containing neurons in the hypothalamus that differ vastly in their molecular composition and development.

When dopamine is released into the bloodstream, it controls the availability of the hormone prolactin, which plays a central role in regulating fertility and breast-milk production.

In comparison with known genetic anomalies in humans, the researchers found that mutations in the signalling pathways that ultimately lead to the differentiation of the nine different types of dopamine-containing cells may be related to the development of obesity and an abnormal stress response.

“This suggests that molecular heterogeneity in the hypothalamus is the basis of functional heterogeneity, which enables us to pinpoint critical pathways in how the numerous responses the hypothalamus produces are orchestrated,” says Tibor Harkany.

May lead to new medicine to combat many diseases

Tibor Harkany predicts that the mapping of cell types in the hypothalamus may improve understanding of many diseases and also lead to developing new types of medicine to treat people with metabolic diseases.

Many diseases and conditions are thought to originate in defects in the development of the hypothalamus, such as many metabolic diseases, stress, anorexia, obesity and sleep disorders.

Researchers are often well aware of the network of cells that causes the defects, but they have not previously had the opportunity to go a step further in linking the diseases to specific defects and pinpointing the molecular contacts that have gone wrong during the development of the diseases.

Now, however, the researchers have a catalogue of the specific cells and details of their development and can use this knowledge as a resource to define novel molecular mechanisms that ultimately lead to disease.

“This means that we may be able to target these molecular changes with novel generations of drugs with unprecedented selectivity and efficacy,” says Tibor Harkany.

Molecular design of hypothalamus development” has been published in Nature. In 2017, the Novo Nordisk Foundation awarded a grant to lead authors Tibor Harkany and Tomas Hökfelt for the project Exploiting Cell Fate and State Switches in the Determination of Cellular Heterogeneity in Pancreatic Islets for Therapeutic Benefit, which is a project that shares technical and conceptual principles with the present project but focuses on the neuronal control of beta cells in the pancreas and pathomechanisms of diabetes.

Tibor Harkany is a molecular neurobiologist. He is professor and research group leader at the Department of Medical Biochemistry and Biophysics. Res...

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