Nicola Palomero-Gallagher, PhD - Neurotransmitter Receptors Link Structural and Functional Segregation Patterns in the Brain

COEX 

The interaction between neurotransmitters and their receptors plays a pivotal role in mediating signal transduction within the nervous system and ultimately enables brain function. Receptors can be visualized with various methods at granularity levels ranging from the molecular to the whole-brain perspective. Immunohistochemistry and in situ hybridization enable visualization of receptor subunit proteins and of their encoding genes, respectively, at the highest spatial resolution, whereas that of in vitro receptor autoradiography is at the microcircuit level. However, this latter method has the enormous advantage of revealing receptors in their native configuration (i.e., as functional protein complexes embedded in the cellular membrane). Despite its relatively low spatial resolution and limited number of suitable radiotracers, PET enables dynamic imaging and is thus crucial for the analysis of receptor changes associated with the progression and pharmacological treatment of neurological and neuropsychiatric disorders. Of interest for translational neuroscience, radioligands which can be applied both in vivo and in vitro have demonstrated a good correspondence between the receptor distribution patterns revealed by in vitro autoradiography and PET imaging. Thus, post mortem data serves as a valuable source of data to create biologically informed computational models aimed at simulating in vivo receptor densities even for receptor types for which no PET radioligand is available.

The term "receptor fingerprint" was coined to describe the unique co-distribution pattern of multiple receptor types within a given brain region. Importantly for the analysis of structure-function relationships in the brain, the heterogeneous distribution patterns of neurotransmitter receptors have been shown not only to reveal borders between cortical areas or subcortical nuclei, but also to highlight organizational principles in the brain. Differences in the size and/or shape of receptor fingerprints segregate phylogenetically older from more recently developed areas, unimodal from multimodal and association areas. Analysis of receptor fingerprints in combination with data from functional imaging studies confirms the hypothesis that receptor fingerprints constitute the molecular underpinning of functional networks and reflect hierarchical processing levels within a given functional system. Thus, the heterogeneous distribution of receptors throughout the brain should not be interpreted as merely reflecting differences in cell packing densities. Rather, receptors play a crucial role in integrating the structural architecture of the brain (i.e., its cyto- and myeloarchitecture) with its dynamic and functional capabilities.