The hypothalamus proteomeThe hypothalamus is a part of the diencephalon, together with the thalamus, epithalamus, subthalamus and metathalamus. The hypothalamus develops from the embryonic diencephalon and is located at the bottom of the dienchepalon. In humans, it is an almond-like small structure. The hypothalamus is the center of the vegetative nervous system as well as a key regulator of the endocrine system. The transcriptome analysis shows that 82% (n=16165) of all human protein-coding genes (n=19670) are expressed in the human hypothalamus. Human one-to-one orthologues were investigated in pig and mouse brain, suggesting that 11844 of all mouse one-to-one orthologues (n=15160) are expressed in the mouse hypothalamus and that 12670 of all pig orthologues (n=14656) are expressed in the pig hypothalamus. Gene classification based on regional RNA expression in human, pig and mouse hypothalamus defines 36 genes as hypothalamus enriched in either of the three species, and 18 out of those genes show highest expression levels in hypothalamus in all three species.
Figure 1. Schematic drawing of the human brain, indicating the location of hypothalamus below the thalamus, at the bottom of diencephalon from a sagittal view. Anatomically, the hypothalamus can be divided to anterior, tuberal and posterior parts. The anterior part involves the preoptic nucleus (thermoregulation), the medial preoptic nucleus (releases GnRH hormone), supraoptic nucleus (releases oxytocin - OXT and vasopressin - AVP), the paraventricular nucleus (releases the thyrotropin releasing hormone - TRH, corticotropin releasing factor - CRH, oxytocin, vasopressin and somatostatin hormones), the anterior hypothalamic nucleus (involved in thermoregulation) and the suprachismatic nucleus (involved in the regulation of the circadian rhythms). The tuberal hypothalamus consists of a medial and a lateral part. The medial part involves the dorsomedial- (regulation of blood pressure and heart rate), ventromedial- (regulation of satiety) and arcuate nucleus (regulation of food intake, among others). The lateral part of the tuberal hypothalamus is a complex hub of neuronal networks; it contains, among others, the orexin and MCH neurons that regulate food intake and the sleep/wake cycle. The lateral hypothalamus partially extends also to the anterior and posterior hypothalamus. The posterior hypothalamus consists of the mammillary nuclei, the lateral nucleus (that involved in the regulation of blood pressure) and the tuberomamillary nucleus (that involved in the regulation of arousal, energy balance, learning-memory processes and sleep). MicroanatomyHistologically, the hypothalamus could be divided to magnocellular and microcellular neurosecretory neurons and to non-secretory neurons. The magnocellular neurons releases oxytocin and vasopressin in the neurohypophysis. The axons of these magnocellular neurons form the suproopticohyphophyseal tract. The microcellular neurons secretes the ‘releasing’ and ‘release inhibiting’ hormones to the portal veins that will transport these hormones to the adenohyphophysis. The axons of the microcellular neurons form the tuberoinfundibular tract. The non-secretory neurons are involved in the regulation of multiple and complex vegetative functions. The tuberomamillary and mammillary nuclei are important parts of the limbic-system. The hypothalamus neurons express several neuropeptides and several hypothalamic neuronal populations and sub-populations can be identified by their neuropeptide markers. (e.g. orexin- and MCH-expressing neurons in the lateral hypothalamus; NPY- and POMC-expressing neurons in the arcuate nucleus etc.) Galanin (GAL) is a physiologically active neuropeptide that is implicated in nociception, feeding and energy homeostasis, osmotic regulation and water balance. Galanin immunoreactivity can be observed in the tuberal hypothalamus. Nucleobindin 2 (NUCB2) is a calcium-binding protein and has a role in eating regulation in the hypothalamus NUCB2 immunoreactivity is observed in the hypothalamic paraventricular nucleus. Regionally elevated expression in human hypothalamusThe transcriptome analysis shows that 82% (n=16165) of all human proteins (n=19670) are expressed in the hypothalamus. 80 genes show an elevated expression level in hypothalamus compared to other regions of the brain.
Elevated expression in hypothalamus compared to other brain regions is divided into three different categories; regionally enriched (at least four-fold higher mRNA levels in hypothalamus compared to all other regions), group enriched (at least four-fold higher mRNA levels in a group of 2-5 regions) and regionally enhanced (at least four-fold higher mRNA levels in hypothalamus compared to the average of all regions), The number of genes in the individual category is shown in Table 1. In Table 2, the 12 genes with the highest level of regional specificity among the 19 enriched genes are listed. Table 2. The 12 genes with the highest level of enriched expression in human hypothalamus. "Predicted localization" shows the classification of each gene into three main classes: Secreted, Membrane, and Intracellular, where the latter consists of genes without any predicted membrane and secreted features. RS-score (Regional Specificity score) corresponds to the score calculated as the fold change to the second highest region.
The (HCRT) gene produces two neuropeptides, orexin A and orexin B, and are implicated in the regulation of sleep and might also play a role in feeding behavior and homeostasis. Vasopressin (AVP) is synthesized in the supraoptic nucleus and paraventricular nucleus of the hypothalamus and is transported to the nerve endings in the neurohypophysis. When secreted into the bloodstream, vasopressin acts as an antidiuretic hormone in the kidneys. OTP is a transcription factor involved in the development of the hypothalamus. The agouti related neuropeptide (AGRP) has a role in feeding control and weight homeostasis. The HDC protein controls several processes such as gastric acid secretion and smooth muscle contraction. Regionally elevated expression in mouse hypothalamusThe mouse hypothalamus is anatomically similar to the human hypothalamus, with similar topography of nuclei and similar neurochemical character (e.g. neuropeptide-expression) of the homologous nuclei. The transcriptome analysis shows that 60% (n=11844) of all mouse one-to-one human orthologue genes (n=15160) are expressed in the hypothalamus and 99 genes show an elevated expression in hypothalamus compared to other regions of the brain. Table 3: Number of genes within the different categories of regionally elevated expression, in mouse hypothalamus
Figure 2. Schematic drawing of the mouse brain, indicating the location of hypothalamus from a coronal perspective. Elevated expression in hypothalamus compared to other brain regions is divided into three different categories; regionally enriched (at least four-fold higher mRNA levels in hypothalamus compared to all other regions), group enriched (at least four-fold higher mRNA levels in a group of 2-5 regions) and regionally enhanced (at least four-fold higher mRNA levels in hypothalamus compared to the average of all regions). The number of genes in the individual category is shown in Table 3. In Table 4, the 12 genes with the highest level of regional specificity among the 22 enriched genes are listed. Table 4: The 12 genes with the highest level of enriched expression in mouse hypothalamus. "Predicted localization" shows the classification of each gene into three main classes: Secreted, Membrane, and Intracellular, where the latter consists of genes without any predicted membrane and secreted features. RS-score (Regional Specificity score) corresponds to the score calculated as the fold change to the second highest tissue.
Orexin (HCRT) immunostaining in the lateral hypothalamus. Vasopressin (AVP) peptide immunostaining in the paraventricular hypothalamic nucleus. Orthopedia homeobox protein (OTP) localization in the hypothalamic paraventricular nucleus. This video demonstrates the 3D distribution of orexin immunostaining (HCRT) in the mouse lateral hypothalamus (iDISCO volume immunostaining): Regionally elevated expression in pig hypothalamusThe pig hypothalamus is anatomically similar to the human hypothalamus, with similar topography of nuclei and similar neurochemical character (e.g. neuropeptide-expression) of the homologous nuclei. The transcriptome analysis shows that 64% (n=12670) of all pig one-to-one human orthologue genes (n=14656) are expressed in the hypothalamus. 45 genes show an elevated expression in hypothalamus compared to other regions of the brain. Table 5: Number of genes within the different categories of regionally elevated expression, in pig hypothalamus.
Figure 3. Schematic drawing of the pig brain, indicating the location of hypothalamus from a coronal perspective. Elevated expression in hypothalamus compared to other brain regions is divided into three different categories; regionally enriched (at least four-fold higher mRNA levels in hypothalamus compared to all other regions), group enriched (at least four-fold higher mRNA levels in a group of 2-5 regions) and regionally enhanced (at least four-fold higher mRNA levels in hypothalamus compared to the average of all regions), The number of genes in the individual category is shown in Table 5. In Table 6, the 12 genes with the highest level of regional specificity among the 10 enriched genes are listed. Table 6: The 12 genes with the highest level of enriched expression in pig hypothalamus. "Predicted localization" shows the classification of each gene into three main classes: Secreted, Membrane, and Intracellular, where the latter consists of genes without any predicted membrane and secreted features. RS-score (Regional Specificity score) corresponds to the score calculated as the fold change to the second highest region.
List of proteins stained on human hypothalamus tissue sectionThe standard setup in the Tissue Atlas, which profiles the human tissues, is based on Tissue Micro array technique, thus saving valuable tissue material and reagents. The TMA technique provides a wide tissue representation for protein profiling. Cerebral cortex, caudate nucleus, hippocampus and cerebellum are the four brain regions in the standard human brain profiling. In-depth analysis of the elevated genes in hypothalamus and literature search for hypothalamus-associated proteins served as a strategy when selecting which proteins to analyze in human hypothalamus samples. Table 7. The following 41 genes have been analyzed using extended hypothalamus samples.
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The Human Protein Atlas
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