MidbrainMidbrain is located between forebrain and hindbrain and is commonly segmented into tectum, aqueduct, tegmentum, basis pedunculi. The major part of tectum constitutes superior and interior colliculi (processing visual and auditory information, respectively). The cerebral aqueduct, which is the smallest ventricle in the brain linking 3rd and 4th ventricle, accommodates periaqueductal grey, dorsal raphe nucleus and several nuclei related to visual system. Tegmentum facilitates homeostasis and reflexes. The crucial tegmental nuclei include median raphe-, red nuclei (involved in motor coordination) and ventral tegmental area, the biggest dopamine production site. The basis pedunculi provides path to major nerve tracts, eg. corticospinal tract, internal capsule. It also contains affected in Parkinson disease substantia nigra, the dopamine production center. Developmentally, midbrain emerges from the second vesicle of neural tube and does not sub-divide further, in comparison to other brain regions. The transcriptome analysis shows that 83% (n=16240) of all human protein-coding genes (n=19670) are expressed in the human midbrain (represented by RNA expression in substantia nigra). Human one-to-one orthologues were investigated in pig and mouse brain, suggesting that 11762 of all mouse one-to-one orthologues (n=15160) are expressed in the mouse midbrain and that 12635 of all pig orthologues (n=14656) are expressed in the pig midbrain.
Figure 1. Schematic drawing of the human brain, indicating the location of midbrain from a sagittal view. The transcriptome analysis shows that 83% (n=16240) of all human protein-coding genes (n=19670) are expressed in the human midbrain (represented by RNA expression in substantia nigra). Human one-to-one orthologues were investigated in pig and mouse brain, suggesting that 11762 of all mouse one-to-one orthologues (n=15160) are expressed in the mouse midbrain and that 12635 of all pig orthologues (n=14656) are expressed in the pig midbrain. Gene classification based on regional RNA expression in human, pig and mouse midbrain defines 31 genes as midbrain enriched in either of the three species, and 8 out of those genes show highest expression levels in midbrain in all three species. Sub regions of the midbrainRaphe nucleus Raphe nuclei are clusters of nuclei in the brain stem, containing
Ventral tegmental area Ventral tegmental area (VTA) is the largest center for production of dopamine, and together with Substantia Nigra, origin of the major dopamine pathways: 1) mesolimbic (projecting to nucleus accumbens and olfactory tubercle); 2) mesocortical (delivering dopamine to the prefrontal cortex). VTA outputs are also targeting Hippocampal formation, Amygdala and Olfactory bulb. Most of the neuronal connections are reciprocal. The VTA is implicated in the reward system (addiction), cognition and psychiatric disorders.
Substantia Nigra Substantia Nigra is divided into two parts: 1) pars compacta (SNc) projects to the caudate and putamen (dopaminergic niagrostratal pathway); 2) pars reticulata (SNpr) receives inputs from basal ganglia (direct and indirect pathway) and conveys to other brain areas, including thalamus and superior colliculus. SN is involved in the reward system and motor control. The name substantia nigra (latin for black substance) comes from the darker color of the residing dopaminergic cells, containing pigment neuromelanin. Loss of dopaminergic neurons is implicated in Parkinson's Disease.
Regionally elevated expression in human (Substantia Nigra)The transcriptome analysis shows that 83% (n=16240) of all human proteins (n=19670) are expressed in the midbrain. 56 genes show an elevated expression level in midbrain compared to other regions of the brain.
Elevated expression in midbrain compared to other brain regions is divided into three different categories; regionally enriched (at least four-fold higher mRNA levels in midbrain 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 midbrain 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 14 enriched genes are listed. Table 2. The 12 genes with the highest level of enriched expression in human midbrain. "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.
Regionally elevated expression in mouse midbrainThe whole of mouse midbrain was dissected and used for this analysis, mean value of the 2 male and 2 female mice is used as representative of the midbrain. The transcriptome analysis shows that 60% (n=11762) of all mouse one-to-one human orthologue genes (n=15160) are expressed in the midbrain and 44 genes show an elevated expression in midbrain compared to other regions of the brain. Table 3: Number of genes within the different categories of regionally elevated expression, in mouse midbrain
Figure 2. Schematic drawing of the mouse brain, indicating the location of midbrain from a sagittal view. Table 4: The 8 genes with the highest level of enriched expression in mouse midbrain. "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.
Regionally elevated expression in pig midbrain
Figure 3. Schematic drawing of the pig brain, indicating the location of midbrain from a sagittal view. Elevated expression in midbrain compared to other brain regions is divided into three different categories; regionally enriched (at least four-fold higher mRNA levels in midbrain 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 midbrain compared to the average of all regions). The substantia nigra, superior colliculus and periaqueductal gray were dissected out as separate areas of the midbrain and analyzed separated from the remaining midbrain area. The highest expression value of the 4 midbrain samples were used as representative as midbrain in the regional expression comparison.
The transcriptome analysis shows that 64% (n=12635) of all pig one-to-one human orthologue genes (n=14656) are expressed in the midbrain. 93 genes show an elevated expression in midbrain compared to other regions of the brain. Table 5: Number of genes within the different categories of regionally elevated expression, in pig midbrain
Table 6: The 12 genes with the highest level of enriched expression in pig midbrain. "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.
Extended human midbrain tissue sectionThe standard setup in the Tissue Atlas, that profiles the human tissues, is based on Tissue Micro array technique, saving valuable tissue material as well as reagents but still provide a good tissue representation for protein profiling. Cerebral cortex, caudate nucleus, hippocampus and cerebellum are the four brain regions in the standard human brain profiling. However, when literature suggests a function related to either Substantia nigra or Dorsal raphe, or when RNA expression data suggests selective expression in those two regions, special tissue material have been added to the protein profiling. So far, only 4 different genes have been analyzed on the extended material. Table 7. The following 5 genes have been analyzed using extended midbrain samples. |