Scientists finally solved the mystery of 'hair-like' structures found on almost all human cells

Synapses are the junctions between neurons (nerve cells) where signals cross, often involving chemicals called neurotransmitters, allowing neurons to communicate. Such communication is fundamental in linking the sensory organs of the nervous system to the brain, which regulates everything from your mind to your muscles as well as organ functions. In other words, communication between your nerve cells plays a role in everything you think, feel, and do.

On average, there are around 86 billion neurons in the human brain. With this figure in mind and knowing that each of these neurons may connect to thousands of other neurons, the number of synaptic junctions in the brain could easily fall into the trillions.

And that's only considering one "widely -acknowledged" pathway of how synapses work. That is, between one neuron's axon and the dendrites of other neurons. But what if there's another, previously unknown, signaling pathway?

Scientists at HHMI's Janelia Research Campus have discovered just that — a new kind of synapse in the tiny hairs (cilia) on the surface of neurons. Interesting Engineering (IE) interviewed Dr. Shu-Hsien Sheu, the senior researcher behind the discovery, to explore how this came to be and how it could boost understanding of cell-cell communication.

The discovery of a new synapse is exciting, but there's more to it than that, says Dr. Sheu

"It appears that many people are excited about the new synapse," said Dr. Sheu. The senior scientist admitted that it is indeed exciting, given that few new structures have been identified since the golden age of electron microscopy in the last century.

"However, we think that the connection to the nucleus, and the fact that ciliary signaling can directly impact neuronal chromatin and thus drive gene expression changes- is just as exciting."

To put it another way, the study team identified a novel type of synapse and realized that this type allows neurotransmitters (like serotonin) to modify the chromatin directly. Chromatin is the mixture of DNA and proteins that form chromosomes.

Cilia, which have signal-detecting receptors, are crucial for cell division during the development

Almost every cell in the human body contains these bacteria-sized, hair-like structures, possibly a relic from our unicellular ancestors. Non-motile cilia, which have signal-detecting receptors, are crucial for cell division during development. Later, some cilia, like those in our lungs, olfactory receptors, and the tail of a sperm, have vital roles.

However, the reason why neurons and many other cells in our body continued to possess this hair-like structure remained poorly understood.

Scientists have typically disregarded these cilia because they were difficult to observe using standard imaging techniques. Recently, the interest in these tiny structures has increased thanks to developments in imaging technology- with this study serving as a prime example.

Seeing cilia: Tapping into the power of ion beam–scanning electron microscopy (FIB-SEM)

The study focused on the visualization of the hair-like projections, or cilia, of neurons in the hippocampus (an area of the brain that is important for learning and memory) using focused ion beam–scanning electron microscopy (FIB-SEM).

FIB-SEM produces 'volume' or '3D' electron microscopy datasets. So, unlike traditional transmission electron microscopy methods, which rely on sectioning and constructing single images, FIB-SEM enables 3D reconstruction of cells and tissues at the nanometer scale. To put it simply, scientists could view the whole structure instead of using imaging that only looked at individual slices.

A breakthrough discovery of a previously unknown "axo-ciliary" synapse

Thanks to the powerful microscope, the team observed a synapse between the neuron's axon and the cilium that protruded from the cell body. They refer to these connections as "axon-cilium" or "axo-ciliary" synapses because of their structural similarities to those of known synapses.

"In addition, we used FIB-SEM directly in hippocampal tissues, which in contrast to cultured cells in a dish, provides a reconstruction of cilia in their native environment," revealed Sheu. This way, the team was able to detect the connections between cilia and their 'natural' neighbors.

Fluorescent lifetime imaging uncovered a surprising link between serotonin and the cell's nucleus

Sheu explained that the second part of the project studied the functional properties of these novel synapses and relied heavily on fluorescent lifetime imaging. "This is an emerging technology that can be used to measure the changing concentrations of molecules in small compartments much more robustly than other techniques."

FIB-SEM and fluorescent lifetime imaging together allowed the team to show in great detail how the neurotransmitter serotonin is transported from the axon onto receptors on the cilia. They discovered that this triggers a signaling cascade that unlocks the chromatin structure and permits alterations to the genetic material in the cell's nucleus.

Focusing on the serotonin receptor (5-HTR6)- which is crucial for memory, fear, and attentiveness

From a previous IE story on the study, we know that the researchers believe these 'axo-ciliary' synapses are likely responsible for longer-term changes in neurons. That is, when compared to signals passed from axons to dendrites. Such changes could persist anywhere from a few hours to several years, depending on the proteins that the chromatin encodes.

This study focused on serotonin receptors- a neurotransmitter widely distributed in the brain and crucial for memory, fear, attentiveness, and mood (with particular ties to depression). Of all neurotransmitters found in the human body, we asked, why this one?

"Among all the receptors people have found to be on neuronal cilia, the data supporting 5-HTR6 (receptor for serotonin) is the most robust," explained Dr. Sheu. "In addition, serotonin is also known to modulate hippocampal function."

'The fact that 5-HTR6 primarily causes changes in the nucleus was surprising to us'

Sheu disclosed that the 5-HTR6 receptor's ability to convert signals and regulate multiple cellular processes is a pathway that really surprised him. "I wasn't aware of this non-canonical pathway at all before I started to study 5-HTR6 signaling more deeply. I got stuck for a while," said Sheu.

The scientist admitted he didn't know where to look after characterizing the 5-HTR6 signaling pathway. "The fact that it primarily causes changes in the nucleus was surprising to us," Sheu added before saying that it all made sense in the end, even though it was 'totally' unexpected.

Future studies may reveal 'the molecular underpinnings' of psychiatric disorders

The cilia-restricted receptor 5-HTR6 is thought to be associated with bipolar disorders. Therefore, the senior researcher claims that further studies on the axo-ciliary synapses may provide novel insights into neuropsychiatric disorders or other mental illnesses.

The novel synapses can also inspire future studies on how serotonin modulates brain function at the molecular level. "Maybe in a not-too-distant future, the molecular underpinnings or "neuropathology of psychiatric disorders" can be elucidated," revealed Dr. Sheu.

Considering that the pattern of synaptic activity is thought by some to be the closest correlation or representation of our consciousness, mood, and, consequently, psychiatric disorders such as depression, you can start to grasp why understanding this interrelatedness is important.

A step toward creating previously unimagined treatments for conditions like depression

While the study is undoubtedly a step forward in understanding the role of cilia, Sheu explained the brightness of the serotonin sensor could be improved so that changes in these structures in slices or even in vivo brain imaging can be more easily measured.

"We also don't know all the steps between ciliary Rho-A activation and nuclear actin changes," said Sheu. [Rho-A is a protein associated with cytoskeleton regulation, and nuclear actin is found throughout the cell nucleus, where it participates in essential steps of gene expression.]

The team reveals that it is now necessary to look into the additional cilia-based neurotransmitter receptors. As the latest study looked at cilia on brain cells (of mice), the next steps will include looking at cilia on other types of cells, such as those in the liver and kidney, which also merit more study.

In the future, it may be possible to create more precise drugs thanks to a greater knowledge of the function of these ciliary synapses and receptors.

For example, drugs targeting serotonin transporters are currently used to treat some types of depression. By factoring in "axo-ciliary synapses," scientists could now look into these transporters' novel pathways and develop previously unimagined therapies.