Neuroscientists have been on an inexhaustible quest to find out what really makes the human brain unique. Facts about the composition of the brain can leave many of us bewildered. For instance, the neocortex, which is involved in higher functions such as generating motor commands, conscious thought, spatial reasoning and language, accounts for almost 76% of the brain’s volume. It is divided into six layers, where Layer 1 denotes the outermost layer.
A group of neuroscientists recently made a breakthrough in this quest by discovering a new type of human brain cell in the neocortex that has never been seen in mice and other studied laboratory animals. According to a new study, “Transcriptomic And Morphophysiological Evidence For A Specialized Human Cortical GABAergic Cell Type”, published in the journal Nature Neuroscience on 27 August, these cells have been dubbed “rosehip neurons”. Scientists say the dense bundle each brain cell’s axon—nerve fibre projections that work as the nervous system’s transmission lines—forms around the cell’s centre “looks just like a rose after it has shed its petals”.
The research team was led by Ed Lein, investigator at the Allen Institute for Brain Science in Washington state, US, and Gábor Tamás, a neuroscientist at the University of Szeged in Szeged, Hungary. “We worked in close collaboration with our colleagues (including co-first author Estzer Boldog) in Gábor Tamás’ group in Hungary. They performed all the experiments looking at the 3D shape, connections, and electrical activity of these neurons while in Ed Lein’s group (including co-first author Rebecca Hodge) at the Allen Institute for Brain Science, we measured the gene expression of these neurons,” says Trygve Bakken, a senior scientist at the institute, over email. Bakken is one of the authors on the study.
In an email interview, Bakken explains the challenges involved in studying this part of the human brain and how research could help neuroscientists understand more about cellular diversity across different brains. Edited excerpts:
Why has this brain cell never been seen in mice and other studied laboratory animals? Is it unique to the human brain?
Neurons have been studied well in mice. So if mice have rosehip neurons then they must be exceedingly rare or have very different properties than human rosehip neurons. It is possible that as other laboratory animals are studied in more detail, we will find neurons related to rosehips. There are examples of other cell types that are found in the human but not rodent brain, such as spindle neurons. Spindle neurons are also found in other highly social, large-brained mammals such as monkeys and dolphins, and it may be possible that rosehips are also found in these species. This could be tested by profiling cellular diversity in many species using the same single-nucleus RNA sequencing technique used in this study and seeing if there is evidence for rosehip or rosehip-like interneurons and, if so, how they differ from human.
What methods were used for the discovery of this neuron?
We surveyed neuronal diversity in Layer 1 of human neocortex using two complementary techniques. At the Allen Institute, we used single-nucleus RNA sequencing to profile gene expression from individual cells isolated from post-mortem human brain donors. In the other approach, our collaborators in Gábor Tamás’ group in Hungary used glass pipettes with fine tips to measure the electrical activity of individual neurons in slices of human neurosurgical tissue. After recording, these neurons were filled with a dye and their 3D shape was reconstructed. Combining these approaches, we identified a novel, highly specialized type of inhibitory neuron with distinctive shape, firing properties and gene expression profile.
Considering the specific part of the brain that was examined, how difficult was it to study tissue samples?
The main challenge was in establishing reliable sources of high-quality human brain tissue from post-mortem and neurosurgical sources. A small part of cortex used in this study is removed during routine surgeries for tumour removal and intractable epilepsy. We established collaborations with several local neurosurgeons in Seattle, Washington, and in Hungary and with neuropathologists with access to autopsy tissue. Once we acquired this tissue, we found that it is remarkably robust, and we could measure many properties of neurons in slices of tissue. One additional challenge compared to studying a rodent is that we are still developing tools to label specific populations of neurons to make them easier to identify and record from. That is one reason why we focused on Layer 1 which is highly enriched for the inhibitory neurons that we set out to study.
Your research says the rosehip neurons belong to a class of neurons called inhibitory neurons. Can you tell us more about the functions of inhibitory neurons?
The two main types of neurons in the cortex are inhibitory and excitatory. Inhibitory neurons are an important part of the circuit because they put the brakes on the electrical activity in excitatory neurons. One reason that rosehip interneurons are interesting is because they can put targeted brakes on the circuit as they connect to a specific part of excitatory neurons.
How would learning more about these neurons help neuroscientists improve their understanding of the human brain?
The human cortex is a large circuit composed of 16 billion neurons...If we want to understand how this circuit works, then we need to find out what all the parts are, including all types of inhibitory and excitatory neurons. The properties of rosehip neurons, such as their connections and 3D shape, can give us a hint about their role in the circuit.
Where does your research go from here? What is the next step?
We can design genetic tools to label these neurons in human tissue based on their expression of marker genes. This will help us study their properties in more detail, and we can also look at post-mortem tissue from donors with neuropsychiatric disease to see if these neurons are affected. More generally, we are extending these experimental approaches to understand cellular diversity across human and mouse brains, and how conserved cell types are between species.