Construct a three-dimensional map of neurotransmitter receptors in the human brain to map brain structure, dynamics, and cognitive function

Neurotransmitter receptors support the transmission
of signals in the human brain.
How receptor systems exist in macroscopic neuroanatomy, how they form emergent functions, is still poorly understood, and a comprehensive receptor map
does not exist.

Recently, Bratislav Misic's team collated the positron emission tomography data of more than 1200 healthy individuals to construct a whole-brain three-dimensional canonical map of 19 receptors and transporters across 9 different neurotransmitter systems, and their results were published in the journal Nature Neuroscience called "Mapping neurotransmitter systems to the structural and.
" functional organization of the human neocortex”
。 This work demonstrates how chemical structure shapes brain structure and function, providing new directions
for studying multiscale brain tissue.

Neurotransmitter receptors are heterogeneously distributed in the neocortex and respond
to the binding of neurotransmitters.
Neurotransmitter receptors effectively mediate the transmission and propagation
of conductive impulses by regulating cell excitability and firing rates.
Thus, neurotransmitter receptors drive synaptic plasticity, alter neural states, and ultimately form communication
across the network.
How the spatial distribution of different neurotransmitter receptors relates to brain structure and how it shapes brain function at the system level remains unknown
.

A comprehensive cortical profile of neurotransmitter receptor densities, including dopamine, norepinephrine, serotonin, acetylcholine, glutamate, GABA, histamine, cannabinoids, and opioids, was constructed by collating PET images from a total of 19 different neurotransmitter receptors, transporters
, and receptor binding sites from nine different neurotransmitter systems (Figure 1).

Figure 1.
PET images of neurotransmitter receptors and transporters

Receptor distribution reflects structural and functional organization

To quantify the potential for two brain regions to be modulated by endogenous or exogenous input similarity, the authors calculated the correlation of receptor-transporter fingerprints between paired brain regions (Figure 2A), called receptor similarity, similar to other commonly used measures of inter-region attribute similarity, including anatomical similarity, morphological similarity, genetic similarity, temporal profile similarity, and microstructural similarity
.
Receptor similarity is approximately normally distributed (Figure 2b), supporting the concept that proximal neurons share similar microstructures (Figure 2c).

For completeness, the authors stratify receptors by biological mechanism (excitatory inhibition, ionization metabolism, and Gs-/Gi-/Gq-couple metabolic pathway) and neurotransmitter protein structure (monoamil-monoamine group) to provide additional information on potential biological pathways (Figure 2g).

Figure 2.
Construction of cortical neurotransmitter receptor and transporter maps

The authors found that neurotransmitter receptor organization reflects structural and functional connectivity
.
There is greater similarity of receptors between pairs of brain regions that are structurally connected, suggesting that anatomically connected regions may be co-modulated (Figure 3A).

The authors observed that brain regions with similar receptor and transporter compositions exhibited stronger functional co-activation
.

These results suggest that the receptor map is systematically consistent with the structural and functional connection patterns above and beyond spatial proximity, consistent with the concept that the receptor map guides signaling between regions
.
The authors found that using receptor profiles as input variables to brain structures significantly improved the prediction of functional connectivity in the unimodal and paracentrolobular regions (Figure 3c).

Figure 3.
Receptor distribution reflects structural and functional organization

The receptor profile forms oscillatory neurodynamics

The authors found that overlapping spatial topography of multiple neurotransmitter systems may eventually manifest as coherent oscillation patterns (Figure 4a).

The authors found that the spatial distribution of MOR (opioid), H3 (histamine), and α4β2 contributed significantly to the fit between the receptor and the low-frequency (θ and α) and low-γ power bands compared to other receptors (Figure 4b).

Figure 4.
Receptor contour formation oscillatory neurodynamics

Map receptors to cognitive functions

PLS analysis extracted a significant latent variable that correlated
receptor transporter density with functional activation throughout the brain.
The latent variables represent the main spatial patterns of receptor distribution (receptor weights) and functional activation (cognitive weights), which together capture 54% of the covariance between the two datasets (Figure 5a).

Projecting the receptor density (functional activation) matrix onto the receptor (cognitive) weights reflects the extent to which brain regions display receptor and cognitive weight patterns, which the authors call receptor scores and cognitive scores, respectively (Figure 5b, c).

Receptor and cognitive scoring patterns show a sensory-fugal spatial gradient that separates the limbic, paramarginal, and insular cortex from the visual and somatosensory cortex
.
The correlation between receptor and cognitive score was then cross-validated using a distance correlation method (Figure 5D).

This result demonstrates a link between receptor distribution and cognitive specialization, which may be regulated by layer differentiation and synaptic levels
.
Figure 5.
Map receptors to cognitive functions

Conclusion

The authors constructed a three-dimensional map of neurotransmitter receptors in the human brain, systematically linking
them to connectivity, dynamics, cognitive specialization, and disease susceptibility.
This work reveals a fundamental organizational feature of the brain and provides new directions
for understanding brain structure and function at the multiscale system level.