The cerebral cortex, located in the dorsal part of the forebrain (telencephalon), is the largest region of the human brain and is greatly involved in information processing. The cortical subregions are important for generating voluntary motor output and processing of sensory information, or are involved in the control of cognitive functions. The cerebral cortex mainly consists of excitatory pyramidal projection neurons, organized in 6 distinct layers, and inhibitory interneurons that form local networks, and acts as a relay system, where information from subcortical regions is filtered and 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.

The transcriptome analysis shows that 76% (n=15332) of all human protein-coding genes (n=20090) are expressed in the human cerebral cortex. Human one-to-one orthologues were investigated in pig and mouse brain, suggesting that 12290 of all mouse one-to-one orthologues (n=16320) are expressed in the mouse cerebral cortex and that 13194 of all pig orthologues (n=15829) 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.

The cerebral cortex is divided into its frontal, cingulate , insular, limbic, occipital, parietal and temporal parts. Each cortical region has a specialized function, for example the parietal cortex with the dorsal, middle and ventral parts of the postcentral gyrus, are important for sensory perception and integration, while the various parts of the temporal cortex (inferior, middle, superior and transverse) are involved in auditory processing, memory acquisition and object and face recognition.

The mammalian frontal lobe contains the motor, pre-motor and prefrontal areas. From all cortical regions, the human prefrontal cortex is special and more developed, compared to other mammalian species. During evolution, its size increased rapidly in primates, especially in great apes and humans. This development has been associated with specialized higher cognitive functions such as language, attention and complex decision-making, involving prediction, imagination and planning. The prefontal cortex is divided in the dorsolateral, dorsomedial, ventrolateral, ventromedial and orbitofrontal regions. These regions can be further subdivided based on gyrification (folding of the brain) or cellular organization of the cortical layers.

The dorsolateral prefrontal cortex is important for the storage of working memory in the processing and preparation of all forthcoming actions and includes the superior frontal (SFG) and the dorsal middle frontal gyrus (MFG). The dorsomedial prefrontal cortex is involved in social cognition and processing of mental states and includes the superior frontal gyrus (SFG) and the dorsal and ventral anterior cingulate parts of cortex (aCGpd & aCGpv). The ventrolateral prefrontal cortex is involved in decision making by processing the behavioral significance of external events and includes the frontomarginal cortex, the medial frontal gyrus (MFG), the inferior frontal gyrus (IFGorb), and the Broca areas that are involved in speech production). The ventromedial prefrontal cortex is important for empathy, making of value-based decision and regulation of negative emotions and contains the frontopolar cortex (FP), the rostral gyrus (ROG), the 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), is involved in emotional associative learning and includes the gyrus rectus (GR), and the medial (OrGm), anterior (OrGa), posterior (OrGp) and lateral (OrGl) areas of the orbitofrontal gyrus. Overall, the cingulate cortex, with its anterior, middle and posterior parts, is involved in the regulation of emotion, while the occipital cortex, with the area parastriata and the lingual gyrus, forms the visual processing center of the brain. A detailed analysis comparing 17 areas of the human prefrontal cortex (Zhong W et al. (2022)) revealed the heterogenic molecular organization of the prefrontal cortex. The results suggest that the well-established anatomical and functional heterogeneity of human PFC is also reflected in the expression pattern of the neuropeptides.

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.

The main neuronal cell types in the cerebral cortex are glutamatergic pyramidal neurons and inhibitory (mainly GABA-ergic) interneurons (neuronal cells). 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

Figure 3. 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 transcriptome analysis shows that 76% (n=15332) of all human proteins (n=20090) are expressed in the cerebral cortex and 409 genes show an elevated expression in cerebral cortex compared to other regions of the brain.

• 71 regionally enriched genes
• 409 regionally elevated genes in total
• 189 of the cerebral cortex elevated genes are elevated in other tissues than the brain.
• 220 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 4. 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 12290 of all mouse one-to-one orthologues (n=16320) are expressed in the mouse cerebral cortex and 1 genes are classified as regionally enriched genes and in total 55 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 (nTPM) 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 13194 of all pig one-to-one orthologues (n=15829) are expressed in the pig cerebral cortex and 0 genes are classified as regionally enriched genes and in total 96 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 5. Schematic drawing of the pig brain, indicating the location of cerebral cortex from a sagittal view.