An international team of Human Brain Project (HBP) researchers has mapped out neurotransmitter receptors across the macaque brain, defining key organizational principles in the brain, and revealing a potential role in distinguishing internal thoughts and emotions from those generated by external influences.

The resulting data have been made freely available to the neuroscientific community via the HBP’s EBRAINS infrastructure, serving as a bridge linking different scales of neuroscience—from the microscopic to the whole brain. Sean Froudist-Walsh, PhD, at the University of Bristol’s Department of Computer Science explained, “Imagine the brain as a city. In recent years, brain research has been focused on been studying its roads, but in this research, we’ve made the most detailed map yet of the traffic lights—the neurotransmitter receptors—that control information flow … Our study aimed to create the most detailed map yet of these ‘traffic lights’” … “We’ve discovered patterns in how these ‘traffic lights’ are arranged that help us understand their function in perception, memory, and emotion. It’s like finding the key to a city’s traffic flow, and it opens up exciting possibilities for understanding how the normal brain works. Potentially in the future, other researchers may use these maps to target particular brain networks and functions with new medicines.”

Froudist-Walsh is lead author of the team’s published paper in Nature Neuroscience, which is titled “Gradients of neurotransmitter receptor expression in the macaque cortex.” The collaboration included researchers at the Forschungszentrum Jülich, Heinrich-Heine-University Düsseldorf, the University of Bristol, New York University, Child Mind Institute, and University of Paris Cité.

One of the key challenges in neuroscience is understanding how the brain can adapt to a changing world, even with a relatively static anatomy, the authors wrote. And the way that the brain’s areas are structurally and functionally related to each other—its connectivity—is a key component. However, the team continued, connectivity alone isn’t sufficient to explain neural circuit dynamics underlying brain functions. The functional impact of synaptic connections depends on receptors, they pointed out. “To complement ongoing efforts to map the connectome, a systematic map of receptor densities across cortex is needed. This would provide a crucial link between the molecular and systems organization of the cortex.”

Receptors are key molecules in signal transmission in the brain. Within a neuron, information transmission occurs via electric signals along the axon. But transfer of information between neurons usually requires the release of molecules called neurotransmitters into the extracellular space and their binding to receptors on the target neuron.

For their reported study the HBP team used in-vitro receptor autoradiography to map the density of receptors to analyze the density of receptors for neurotransmitters on very thin sections of the macaque brain. They measured the density of 14 neurotransmitter receptor types in 109 areas of the macaque cortex and then integrated their data with multiple structural parameters into neuroimaging templates.

To find the patterns in this vast data, they applied statistical techniques and used modern neuroimaging techniques, combined with expert anatomical knowledge. This allowed them to uncover the relationships between receptor patterns, brain connectivity, and anatomy. The researchers uncovered a primary and a secondary gradient of receptor expression per neuron. In other words, by mapping receptor densities across the cortex they identified two main arrangements, shedding light on the links between molecular and neuron organization of the cortex. “We discovered a principal gradient of increasing receptor expression along the cortical hierarchy. This receptor gradient separates sensory and cognitive networks,” they noted. “The secondary gradient segregates the dorsal attention from the default mode network and salience network. The second receptor gradient also separates activity from socio-emotional and numerical-spatial functions.”

Senior author Nicola Palomero-Gallagher, PhD, a researcher at the Forschungszentrum Jülich, further explained. “These two major axes of receptor organization in the macaque cortex align with two different functional systems, namely the sensory-cognitive and the external-internal cognition networks. “This is the first time that such an association has been described.”

The researchers integrated the new neurotransmitter receptor data with multiple layers of anatomical and functional data onto a common cortical space within the cortical surface of Yerkes19, a frequently used non-human primate template. Few studies so far had integrated in vitro anatomy and in vivo imaging of the macaque brain. “We mapped these data and multiple types of anatomical and functional data onto a common cortical space,” they wrote. These other data types included neuron density, dendritic tree size, spines, tract-tracing connectivity, gene expression and structural and functional magnetic resonance imaging (MRI).”  The receptor gradients also segregated functional networks, the investigators noted. “This suggests a potential role for neuromodulators in propagating activity along cortical hierarchies and between higher cognitive networks.”

By understanding the receptor organization across the brain, it is hoped new studies can better link brain activity, behavior, and the action of drugs. And  because receptors are the targets of medicines, the research could, in the future, guide the development of new treatments targeting specific brain functions. Froudist-Walsh addedm “Next, we aim to use this dataset to develop computational models of the brain … These brain-inspired neural network models will help us understand normal perception and memory, as well as differences in people with conditions like schizophrenia or under the influence of substances like ‘magic mushrooms’. “We also plan to better integrate findings across species—linking detailed circuit-level neuroscience often conducted in rodents, to large-scale brain activity seen in humans.”

Creating openly-accessible maps of receptor expression across the cortex that integrate neuroimaging data, such as what was done by the HBP team, could speed up translation across species. “It is being made freely available to the neuroscientific community so that they can be used by other computational neuroscientists aiming to create other biologically informed models,” Palomero-Gallagher said. Part of the data generated for this study has already been implemented in a computational model of how dopamine gates information into the frontoparietal working-memory network.

As the authors concluded, “The receptor data presented here, along with connectivity data, can provide an anatomical basis for large-scale models and theories of brain function. Future large-scale theories of brain function may reveal how flexible higher cognition emerges along the principal receptor gradient.”

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