The human circuit

In order to understand how our brains work, scientists have often made use of the fact that other animals share brains that seem similar to ours. We learned how neurons work by studying the squid, how vision and locomotion work by studying cats, and now look to mice and rats to gain insight into how computations are performed in groups of neurons. However, the danger of such an approach is that it may leave out some of the qualities of the brain and its organization that make us uniquely human. With rapid technological advances in neuroscience tools, studying human brains has become possible in new ways.

This year, a group from Hungary used an impressive combination of techniques in conjunction with novel human datasets to discover a completely new type of neuron that appears to be unique to humans, and that may allow certain neurons to compute things in a uniquely human way. Neurons are very genetically diverse, making up a small fraction of the total number of cells in the body. However, they require ~90% of the different genes in the genome to develop and function, while the rest of the cells use only 10%. Even neurons that seem to be of the same type and perform the same function in different circuits have slight genetic differences from one another! This all makes classifying individual neurons into groups difficult, but recently, improvement in mass sequencing of expressed genes through single cell sequencing has allowed scientists to develop a non-trivial classification of various brain regions and layers. The authors of this study used RNA-seq, which involves making a soup out of brain tissue and sequencing nuclei, on Layer I in the human temporal lobe (specifically middle temporal gyrus), thought to mostly contain apical dendrites of cortical pyramidal cells (the major player in the cortex) to discover 11 new types of inhibitory cell types in this layer. Inhibitory cells are usually thought to serve as interneurons--cells that regulate the activity of other neurons. This is interesting because number of interneurons in a neuronal system is usually related to its complexity. Previous studies in other mammals had found at most this number throughout all six layers of the cortex, so this is quite a surprising result.

Figure: Rosehip cell synapsing on pyramidal cell apical dendrite in Layer I

Discovery of relevant cell types includes understanding their role in the brain circuitry as well as their genetics. Using their findings from the  “transcriptomic” approach to identify their new cell types, the authors looked at the same layer of cortex in intact brain slices and stained cells based on the unique clusters of genes they found. They found that one of eleven new cell types in particular, what they termed the “rosehip” cell, , seemed to be communicating with the apical dendrites in Layer I. The authors thoroughly characterized the identifying cell-surface markers on this new cell type, which they determined was inhibitory based on its genetic signature.

Next, in an exciting series of experiments, the authors studied the function of these new rosehip cells. They catalogued basic properties of the neuron such as response to externally-delivered electrical pulses, spiking patterns, and cell shape. The authors then investigated the interaction of rosehip neurons with other well-known neuron types, such as pyramidal cells . They found that a variety of other interneurons, also mostly inhibitory, synapse onto rosehip cells. As for the output of rosehip cells, intriguingly, the authors found that most synapse onto the apical dendrites of the pyramidal neurons, and that stimulating the rosehip cells caused extremely local changes in membrane potential. This, the authors hypothesize, creates “micro-computation domains” in the dendrites that can affect other inputs onto these important pyramidal neurons in very specific locations. Such a mechanism has never been found in the cortex of other animals, in which the entire dendrite is modulated at once in a non-specific way, and perhaps may account for some of the added complexity required for human thought and consciousness. In addition to adding an intriguing piece to the puzzle of how the human mind might work, the study is notable for making excellent and new use of state-of-the-art tools in neuroscience to further our understanding of brain.

Edited by Kristin Muench

References:

Boldog, Eszter, et al. "Transcriptomic and morphophysiological evidence for a specialized human cortical GABAergic cell type." Nature neuroscience 21.9 (2018): 1185.