Cerebral cortex

Summary

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 77% (n=15445) 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.

Anatomical divisions



The cerebral cortex is divided into its cingulate, frontal, insular, limbic, occipital, parietal and temporal parts. 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. FInally, 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.


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 (https://dev.www.proteinatlas.org/humanproteome/single+cell+type/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.

Regionally elevated protein expression in human

The transcriptome analysis shows that 77% (n=15445) of all human proteins (n=20090) are expressed in the cerebral cortex and 202 genes show an elevated expression in cerebral cortex compared to other regions of the brain.

  • 45 regionally enriched genes
  • 202 regionally elevated genes in total
  • 121 of the cerebral cortex elevated genes are elevated in other tissues than the brain.
  • 81 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

Specificity Number of Human elevated genes
Region enriched 45
Group enriched 45
Region enhanced 112
Elevated 202

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 1. Very few genes are classified as regionally enriched in cerebral cortex, examples of interesting genes are DUSP2, FMN1, HECW1 and KCNS2. Proteins with elevated expression in cerebral cortex compared to all the other brain regions were often group enriched due to the similarity to other forebrain regions. Examples of group enriched expression in cerebral cortex are NPTXR, CDH9 and NRGN.


NPTXR

CDH9

NRGN

Regionally elevated protein expression in mouse

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

Specificity Number of Mouse elevated genes
Region enriched 1
Group enriched 35
Region enhanced 19
Elevated 55

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.


RAP1GAP

LRPAP1

LHX2

Regionally elevated protein expression in pig

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

Specificity Number of Pig elevated genes
Region enriched 0
Group enriched 75
Region enhanced 21
Elevated 96




Figure 5. Schematic drawing of the pig brain, indicating the location of cerebral cortex from a sagittal view.

Extended information

Extended human cerebral cortex tissue section

The standard setup in the Tissue Atlas, which profiles human tissues, is based on Tissue Micro array technique, saving valuable tissue material as well as reagents and provide a good tissue representation for protein profiling. However, due to the complex nature of the brain, with different cell types and subfeilds, larger tissue sample is occationally used to better understand the protein location. In Table 4, the selected targets used for protein profiling on extended tissue material are listed.

Table 4. The following 71 genes have been analyzed using extended cerebral cortex samples.

Gene Gene description Staining pattern
ABCG4 ATP binding cassette subfamily G member 4 Positive in neuronal projections.
AC024598.1 Novel protein Distinct cytoplasmic positivity in a subset of glial cells.
ANKS1B Ankyrin repeat and sterile alpha motif domain containing 1B Stains a subset of glial cells.
BCL11A BAF chromatin remodeling complex subunit BCL11A Nuclear positivity in a subset of neuronal cells.
CACNG3 Calcium voltage-gated channel auxiliary subunit gamma 3 Projection and synaptic staining.
CALB1 Calbindin 1 Moderate cytoplasmic positivity in a subset of neuronal cells.
CALHM1 Calcium homeostasis modulator 1 Strong in a subset of neurons.
CALY Calcyon neuron specific vesicular protein Strong staining in neurons, neuronal projections and a subset of glial cells.
CAMK2N1 Calcium/calmodulin dependent protein kinase II inhibitor 1 Neuronal projections and synaptic staining.
CAMK2N2 Calcium/calmodulin dependent protein kinase II inhibitor 2 Neuronal projections and synaptic staining.
CDH9 Cadherin 9 Membranous and cytoplasmic staining in neurons.
CHI3L2 Chitinase 3 like 2 Strong cytoplasmic positivity in neurons and projections.
CHRNA5 Cholinergic receptor nicotinic alpha 5 subunit Strong staining in astrocytes.
CLVS1 Clavesin 1 Stains mainly in a subset of pyramidal neurons.
DCX Doublecortin Stains in a subset of cortical neurons.
DDX25 DEAD-box helicase 25 Strong cytoplasmic staining in subsets of astrocyte-like cells and neuronal cells.
DNER Delta/notch like EGF repeat containing Strong staining in a few neurons.
DOCK3 Dedicator of cytokinesis 3 Stains neurons with varying intensities.
EGR4 Early growth response 4 Strong cytoplasmic and nuclear positivity in subsets of neuronal cells with moderate positivity in a rare number of glial cells.
FGF2 Fibroblast growth factor 2 Nuclear in glia.
GALNTL5 Polypeptide N-acetylgalactosaminyltransferase like 5 Moderate cytoplasmic positivity in a subcet of neurons.
GPR26 G protein-coupled receptor 26 Strong cytoplasmic staining in a subset of glial cells.
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