Cerebral cortex is the largest region of the human brain and its main function is information processing. Subregions of the cerebral corex are important for generating voluntary motor output, processing of sensory information or are involved in cognitive functions. The cerebral cortex is the dorsal part of the forebrain (telencephalon) and mainly consists of excitatory pyramidal projection neurons organized in 6 distinct layers and inhibitory interneurons that form local networks. The cerebral cortex acts as a relay system, information from subcortical regions is filtered and only selected information is projected back to subcortical regions that generate the behavioral output. Many of the human higher cognitive abilities depend on this brain structure and neurodegenerative disease (e.g. Alzheimer's disease) or developmental abnormalities affecting the cerebral cortex often result in cognitive impairments.

Regional expression in the mammalian cerebral cortex

The transcriptome analysis shows that 85% (n=16646) of all human protein-coding genes (n=19670) are expressed in the human cerebral cortex. Human one-to-one orthologues were investigated in pig and mouse brain, suggesting that 11705 of all mouse one-to-one orthologues (n=15160) are expressed in the mouse cerebral cortex and that 12398 of all pig orthologues (n=14656) are expressed in the pig cerebral cortex.

Figure 1. Schematic drawing of the human brain, indicating the location of cerebral cortex from a sagittal view.

Figure 2. Schematic drawing of the lateral, medial and orbital view of the cerebral cortex outlining the regions of the dorsolater (yellow), ventrolateral (blue), dorsomedial (green), ventromedial (purple) and orbitofrontal parts (orange/red) prefrontal cortex. Subregions that are marked grey are currently not included in the prefrontal cortex dataset.

The dorsolateral prefrontal cortex is important for the storage of working memory in the processing and preparation of a forthcoming actions. This subregion includes the lateral aspects of the superior frontal gyrus (SFG) and the dorsal middle frontal gyrus (MFG).

The dorsomedial prefrontal cortex is involved in social cognition and processing of mental states. This prefrontal cortex subregions includes the medial part of the superior frontal gyrus (SFG) and also the upper portions of the dorsal and ventral anterior cingulate cortex (aCGpd & aCGpv).

The ventrolateral prefrontal cortex is involved in decision making by processing the behavioral significance of external events. This part of the prefrontal cortex also contains the Broca areas involved in the production of speech. This prefrontal cortex subregion includes the frontomarginal cortex, the lower part of the medial frontal gyrus (MFG) the orbital part of the inferior frontal gyrus (IFGorb) and the Broca areas, triangular (IFGtr) and opercular (GFGop) parts of the inferior frontal gyrus.

The ventromedial prefrontal cortex is important for empathy, making of value-based decision and regulation of negative emotions. This prefrontal cortex subregions contains frontopolar cortex (FP), the rostral gyrus (ROG), the lower dorsal and ventral pregenual (aCGpd & aCGpv) and subgenual (aCGs) part of the anterior cingulate cortex and the subcallosal gyrus (SCG).

The orbibtofrontal part of the prefrontal cortex is located just above the eye sockets (orbital bone) and is involved in emotional associative learning involving taste, odor and visual objects. This basal part of the prefrontal cortex gyrus rectus (GR), and the medial (OrGm), anterior (OrGa), posterior (OrGp) and lateral (OrGl) areas of the orbitofrontal gyrus.

The transcriptome analysis shows that 85% (n=16646) of all human proteins (n=19670) are expressed in the cerebral cortex and 152 genes show an elevated expression in cerebral cortex compared to other regions of the brain.

• 17 regionally enriched genes
• 152 regionally elevated genes in total
• 67 of the cerebral cortex elevated genes are elevated in other tissues than the brain.
• 85 of the cerebral cortex elevated genes are elevated in the brain.

Table 1: Number of genes within the different categories of regionally elevated expression, in human cerebral cortex

Figure 3. Schematic drawing of the mouse brain, indicating the location of cerebral cortex from a sagittal view and a coronal perspective.

The transcriptome analysis shows that 11709 of all mouse one-to-one orthologues (n=15160) are expressed in the mouse cerebral cortex and 1 genes are classified as regionally enriched genes and in total 114 regionally elevated. Elevated expression in cerebral cortex compared to other brain regions is divided into three different categories; regionally enriched (at least four-fold higher mRNA levels in cerebral cortex 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 cerebral cortex compared to the average of all regions), The number of genes in the individual category is shown in Table 2.

Table 2: Number of genes within the different categories of regionally elevated expression, in mouse cerebral cortex

The expression value representing cerebral cortex in the regional classification is defined as the highest expression (NX) in either of the subregions included. Subregions of the mouse cerebral cortex included in the brain atlas are: frontal cortex (prefrontal and motor cortex sampled together), retrosplenial and cingulate cortex as one sample, somatosensory cortex and visual (occipital) cortex, in total 4 different cortical samples. The entorhinal cortex is also included but grouped together with hippocampus as part of the hippocampal formation.

The transcriptome analysis shows that 12401 of all pig one-to-one orthologues (n=14656) are expressed in the pig cerebral cortex and 1 genes are classified as regionally enriched genes and in total 86 regionally elevated. Elevated expression in cerebral cortex compared to other brain regions is divided into three different categories; regionally enriched (at least four-fold higher mRNA levels in cerebral cortex 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 cerebral cortex compared to the average of all regions), The number of genes in the individual category is shown in Table 3.

Table 3: Number of genes within the different categories of regionally elevated expression, in pig cerebral cortex

Figure 4. Schematic drawing of the pig brain, indicating the location of cerebral cortex from a sagittal view.

Figure 5. Example of tripple labeling of the human cortex indicating cells located in the different layers.Yellow color show staining of TPPP3, green color represent NECAB1, red color is the labeling of PCP4 and blue is DAPI counterstaining.

The main neuronal cell type in the cerebral cortex are glutamatergic pyramidal neurons and inhibitory (mainly GABA-ergic) interneurons. These cells are organized in six cellular layers based on cell densities, morphology electrophysiological properties and connections. The cerebral cortex receives its main excitatory input from the thalamus. The neuronal networks, organized in columns spanning all layers of the cerebral cortex, process this information and output signals are send back to thalamus and other subcortical structures. The white matter, approximately 40% of the cerebral cortex, contains the myelinated input axons originating from subcortical structures and myelinated axons originating from cortical pyramidal neurons projecting to subcortical areas of the brain. In addition the human white matter contains some sparsely distributed neurons including a population of large neurons expressing the calcium binding protein CALHM1.

CALHM1