Scientists Sink their Teeth into a Molecular Understanding of Human Personality

There’s plenty of scientific evidence that genes play a key role in defining personality. But how exactly? I mean, how is gene activity in cells ultimately linked to a person’s schmoozing talents at a cocktail party? CIRM-funded research published today in Nature, by collaborative teams at UC San Diego and the Salk Institute identified intriguing connections between brain cells and behavior in Williams Syndrome, a rare genetic disease that has specific effects on personality.

Williams Syndrome 101

Williams Syndrome (WS), occurring in roughly 1 in 10,000 births, is caused by a small deletion in chromosome 7 resulting in the loss of 25 genes. Serious heart disease, distinct facial features, visual-spatial disabilities, developmental delays and hypersensitive hearing are just some of the common WS symptoms. People with WS also share a characteristic pattern of social behaviors: they have extremely out-going, caring personalities and are very good at reading other people’s emotions. By exploring how this chromosome deletion leads to a predictable set of behaviors, the research team sought a better understanding of not only the molecular basis of WS but also of human social interactions in general. UCSD professor and co-senior author, Alysson Muotri, recalled his initial interest in the project in a university press release interview:

“I was fascinated on how a genetic defect, a tiny deletion in one of our chromosomes, could make us friendlier, more empathetic and more able to embrace our differences.”

Making Williams Syndrome in a Dish with Induced Pluripotent Stem Cells
The research team relied on stem cell technology to generate a human model of WS in the lab. With the required permissions, they first obtained dental pulp tissue from the baby teeth of five children with WS as well as from four children with typical development for comparison purposes. Cells from the dental pulp were reprogrammed into induced pluripotent stem (iPS) cells which have the ability to specialize into almost every cell type. Using an established cell culture recipe, the iPS cells were stimulated to become neural progenitor cells (NPCs) which resemble cells of the developing brain that haven’t fully matured into a nerve cell, or neuron.

Initial observations of the NPCs revealed a defect in WS cells: they grew more slowly than the typical cells. Increased cell death in the WS cells was responsible for the slower growth. Based on these results, the team focused on the involvement of FZD9, a gene that is active in NPCs and is known to regulate cell death and cell division. It also is one of the genes deleted in the main form of WS. So the team suppress FZD9 activation in the healthy typical NPCs and, sure enough, the lack of the gene led to an increase in apoptosis just as they saw in WS cells. To confirm this result, they tried the opposite experiment by inserting the FZD9 gene into the WS cells. This genetic manipulation reduced cell death to similar levels seen in the typical NPCs.

muotri_dendrite

Dendrites from one neuron receive incoming nerve signals. Image.

Fully maturing the NPCs into neurons uncovered more differences between the WS and typical cell sets. To receive incoming nerve signals, neurons send out finger like projections called dendrites to make physical connections with other neurons. Several little knob-like structures called dendritic spines grow out of each dendrite to help optimize the nerve signaling. Now, compared to the healthy typical neurons, the WS neurons had more dendrites, more spine structures and a greater dendritic length. These structural differences didn’t just change the appearance of the neurons, they translated into increased activity at the synapses, the spot where an electrical nerve signal travels from one neuron to the next.

Making Connections Between Brain Cells and Behavior
Do these iPS cell-derived results carried out in a lab dish have any relevance to what might be going on in the brain as a whole? Yes. Brain imaging of living study participants with WS shows a reduced surface area in the cortical layer, the same area of the brain implicated in other social function disorders. As Muotri explains, increased cell death – seen in the iPS derived WS cells  – appears to cause the development of abnormally smaller structures in WS brains:

“We discovered that WS neural progenitor cells failed to proliferate due to high levels of cell death. And as a consequence of the lower replication of progenitor cells, WS brains have reduced cortex surface area.”

And a study of brain samples from deceased donors showed increased dendrite length and dendritic spines in neurons of WS brains compared to typical brains, a result also predicted by the iPS experiments. Again, these differences were seen particularly in a layer of the brain cortex thought to be involved in other social function disorders like autism. Putting the results together, Muotri speculates that the out-going personalities seen in people WS may be explained by these structural and functional changes:

“At the functional level, they make more synapses or connections to other neurons than what you would expect. That might underlie the WS super-social aspect and their gregarious human brain, giving insights into autism and other disorders that affect the social brain.”

 

By drawing a direct line from genes to cells to brain structure to human behavior, these scientists are in a great position to chip away at a holistic understanding of how personality is generated and how it can go awry.

 

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