Keynote Series: Dr. Nicola Palomero-Gallager and the interplay between receptors, connectivity, and cognitive networks

By Alejandra Lopez-Castro

One of the most significant challenges in neuroscience is understanding how the brain, with its relatively static anatomy, can adapt to the ever-changing world around us. The brain's connectivity, or the way different brain regions communicate with each other, is a crucial component in this process. Mapping the brain's connectivity, known as the connectome, is a major ongoing effort in the field. However, connectivity alone is not enough to explain the neural circuit dynamics that underlie brain functions. The functional impact of synaptic connections depends on the types of receptors present in neurons, which are crucial for processing information. Receptors are specialized proteins on the surface of neurons that allow them to respond to chemical signals, such as neurotransmitters. Different types of receptors are responsible for various functions, such as transmitting sensory information, regulating mood, and facilitating learning and memory. In this matter, Dr. Nicola Palomero-Gallagher and her work group have given science a unique perspective and innovative research that harmonizes the neurochemical, neurophysiology, and neuroanatomy research.

Mapping receptors across the cortex 

Dr. Palomero-Gallagher’s team—led by first author Seán Froudist-Walsh— focused on the distribution of 14 types of neurotransmitter receptors across the macaque cortex. With this, they established a crucial link between the molecular and systems organizations of the brain. How do they do it? Firstly, the researchers used a technique called in vitro receptor autoradiography to analyze the expression of these receptors in the macaque brain. This method involves radioactive ligands that enable quantification of the endogenous receptors in the cell membrane. Long story short, after the neuroanatomists Painstakingly analyzed glutamate, GABA, acetylcholine, serotonin, noradrenaline, and dopamine receptor distributions to identify neurochemically distinct cortical areas, a small cortical hierarchy emerged, described by some gradients in the cortex. The cortical hierarchy is dominated by the principal receptor gradient. It spreads from early sensory areas to higher cognitive regions, indicating that neurons near the top of the hierarchy, which contribute to more complex functions, express more receptors. Surely now, you see why it is a gradient, remembering for example, when we set the background of an image to go in a gradient of blue tones. Then on one side we see more blue contrast and on the other side there is a tendency towards white, which ultimately is the absence of color. Now imagine that the units of the colors were the receptors, where the blue looks darker there would tend to be more receptors, and the score of the gradient will be positive. Towards the opposite direction, the gradient will tend to negative gradient scores, then fewer receptors.

Going back to the principal gradient, it is robust to the removal of any individual receptor type, suggesting that it captures strong underlying trends across receptors. So, to translate these findings to humans, they explored the relationship between receptor gradients and cognitive networks and found that the principal receptor gradient separates sensory networks from higher cognitive networks. Visual and somatosensory, which are sensory networks, tend to have negative gradient scores, and higher cognitive networks have a range of positive and negative scores.

What about the microstructural itself?

If you are wondering if they saw results on the anatomy or structural level in addition to the receptor level, the answer is Yes! Dr. Palomo-Gallagher’s research group investigated the relationship between dendritic tree size and receptor density. They found that the principal receptor gradient is positively correlated with dendritic tree size, which likely provides the neural real estate required to house a greater number of synaptic connections and receptors. This is important because pyramidal cells, the main type of neuron in the cortex, receive the vast majority of their synaptic inputs on their dendrites. In addition, they found that there is a strong negative correlation between the principal receptor gradient and the ratio of T1-weighted to T2-weighted MRI signal, which is a proposed marker of myelination in the cortical gray matter (myelin is a fatty substance that insulates nerve fibers and plays a crucial role in the brain's functioning). This suggests that receptor expression may be constrained by myelination across cortical regions and layers.

This study provides a fascinating glimpse into the complex relationships between cell receptors and brain anatomy, function, and cognition. The findings highlight the importance of receptors in understanding the neural circuit dynamics that underlie brain functions and the role of myelination in constraining receptor expression. The study also demonstrates the potential for integrating in vitro neuroanatomy with in vivo neuroimaging to accelerate translation across species and levels of neuroscience. 

We invite you not to miss the opportunity to attend Dr. Palomo-Gallagher's keynote presentation at OHBM 2024.

Source

Froudist-Walsh, S., Xu, T., Niu, M. et al. Gradients of neurotransmitter receptor expression in the macaque cortex. Nat Neurosci 26, 1281–1294 (2023). https://doi.org/10.1038/s41593-023-01351-2

If you’d like to hear more about Dr. Palomero-Gallager’s research, check out our interview with her here.