A receptor-based analysis of local ecosystems in the human brain

Abstract

Background: As a complex system, the brain is a self-organizing entity that depends on local interactions among cells. Its regions (anatomically defined nuclei and areas) can be conceptualized as cellular ecosystems, but the similarity of their functional profiles is poorly understood. The study used the Allen Human Brain Atlas to classify 169 brain regions into hierarchically-organized environments based on their expression of 100 G protein-coupled neurotransmitter receptors, with no a priori reference to the regions' positions in the brain's anatomy or function. The analysis was based on hierarchical clustering, and multiscale bootstrap resampling was used to estimate the reliability of detected clusters.

Results: The study presents the first unbiased, hierarchical tree of functional environments in the human brain. The similarity of brain regions was strongly influenced by their anatomical proximity, even when they belonged to different functional systems. Generally, spatial vicinity trumped long-range projections or network connectivity. The main cluster of brain regions excluded the dentate gyrus of the hippocampus. The nuclei of the amygdala formed a cluster irrespective of their striatal or pallial origin. In its receptor profile, the hypothalamus was more closely associated with the midbrain than with the thalamus. The cerebellar cortical areas formed a tight and exclusive cluster. Most of the neocortical areas (with the exception of some occipital areas) clustered in a large, statistically well supported group that included no other brain regions.

Conclusions: This study adds a new dimension to the established classifications of brain divisions. In a single framework, they are reconsidered at multiple scales-from individual nuclei and areas to their groups to the entire brain. The analysis provides support for predictive models of brain self-organization and adaptation.

Keywords: Cerebral cortex; Ecosystems; Forebrain; Hierarchical clustering; Hindbrain; Midbrain; Multiscale bootstrap resampling; Neural networks; Neurotransmitter receptors; Pallium.

Fig. 1

The estimated standard errors of the approximately unbiased p values (AU)

Fig. 2

The hierarchical clustering of brain structures (Group 1). At each cluster, the top two numbers represent the estimated approximately unbiased p value (AU, left, red, %) and bootstrap probability value (BP, right, blue,  %), and the cluster identification number is indicated below (gray). The right branch of cluster #165 (Group 2) is expanded in Fig. 3. For compactness, the length of the branches does not represent distances. The “lobules” refer to the hemispheric parts of the cerebellar lobules

Fig. 3

The hierarchical clustering of Group 2. At each cluster, the top two numbers represent the estimated approximately unbiased p value (AU, left, red, %) and bootstrap probability value (BP, right, blue, %), and the cluster identification number is indicated below (gray). The right branches of cluster #131 (Group 3) and cluster #157 (Group 4) are expanded in Figs. 4 and 5, respectively. For compactness, the length of the branches does not represent distances. The term “basal nuclei” is replacing the traditional but anatomically inaccurate term “basal ganglia” [30]

Fig. 4

The hierarchical clustering of Group 3 (from Fig. 3). At each cluster, the top two numbers represent the estimated approximately unbiased p value (AU, left, red, %) and bootstrap probability value (BP, right, blue, %), and the cluster identification number is indicated below (gray). For compactness, the length of the branches does not represent distances. FL frontal lobe, OL occipital lobe, PL parietal lobe, TL temporal lobe

Fig. 5

The hierarchical clustering of Group 4 (from Fig. 3). At each cluster, the top two numbers represent the estimated approximately unbiased p value (AU, left, red, %) and bootstrap probability value (BP, right, blue, %), and the cluster identification number is indicated below (gray). The right branch of cluster #145 (Group 5) is expanded in Fig. 6. For compactness, the length of the branches does not represent distances

Fig. 6

The hierarchical clustering of Group 5 (from Fig. 5). At each cluster, the top two numbers represent the estimated approximately unbiased p value (AU, left, red, %) and bootstrap probability value (BP, right, blue, %), and the cluster identification number is indicated below (gray). For compactness, the length of the branches does not represent distances