Wei-Dong Yao, PhD, a SUNY Distinguished Professor of Psychiatry and Behavioral Sciences at Upstate Medical University, has been awarded a five-year, $3.2 million grant from the National Institute of Aging (NIA) to explore the neural mechanisms behind the empathy loss observed in dementia patients.

By identifying the specific brain circuits and cellular changes responsible for these symptoms, Yao aims to develop the first effective treatments to restore empathy and improve the quality of life for frontotemporal dementia (FTD) patients and their caregivers. 

This is the second grant from the NIA Yao has been awarded in the last two years for his work on FTD. In 2023, he received $2.3 million to investigate the role of specific gene mutations in FTD.

Frontotemporal Dementia (FTD) is a type of dementia that affects the frontal and/or temporal lobes of the brain, leading to the deterioration of these areas over time. It is the most common cause of dementia for people under 60 and the second most common after Alzheimer's disease. The most common type is the behavioral variant (bvFTD), which makes up about 50% of FTD cases. bvFTD leads to significant changes in personality, poor judgment, inappropriate social behavior, and a lack of emotional responses, including a loss of empathy. 

Yao describes this change as one of the most disturbing symptoms of bvFTD, especially for the patient’s caregivers. “They do not have passion. They do not have an empathetic drive. They lost their capability to love their families. We wanted to see by identifying and targeting the brain mechanisms, can we treat this condition?” 

This project stems from a study done in Yao’s lab looking at a mouse model that mimics the empathy loss seen in humans with bvFTD. They found that the mice that carry the same genetic mutation show similar symptoms, such as reduced emotional responses and a lack of comforting behavior towards other distressed mice. Older mice with this mutation had less activity in a specific part of their brain called the dorsomedial prefrontal cortex (dmPFC). This reduced activity in the dmPFC is linked to their empathy loss. When researchers restored normal activity in the dmPFC, the mice regained their empathetic behavior, even if they were old and had significant brain deterioration. 

Building off these findings, Yao plans to use this grant to achieve three goals: 

1. Identify Brain Circuits: Determine which parts of the brain are responsible for empathy-driven behaviors. 
2. Understand Mechanisms: Investigate how changes at the cellular and circuit levels in the brain lead to empathy loss in mice with the C9orf72 mutation, one of the most common genetic risks for FTD. 
3. Develop Treatments: Explore potential treatments that could prevent or reverse empathy loss in these mice.

While identifying the pathways that lead to empathy loss will require a lot of legwork, Yao knows where to look.  

“The neurons and brain circuits will be activated by a gene called c-Fos,” explains Yao. “So once c-Fos is turned on, we know this cell is activated. The technologies are in place; it's just going to be a little bit labor intensive. But we've got students that are excited to do it.” 

Once Yao and his team have finished mapping and identifying the pathways to target, they have several options to try and reverse the empathy loss. “There are several compounds targeting the ion channels that we can try, we can also use technologies called chemogenetics with which we can selectively target those affected neurons by modulating their membrane excitability.” 

Some of the compounds they want to try are already FDA-approved for other diseases. “Ideally, we wanted to see whether these drugs can be re-purposed to FTD patients knowing that they are not that toxic, and see whether we can show some improvement,” says Yao. “Our goal is to provide a mechanistic clearance; a better understanding of what the drug does and why.” 

Being able to find a way to provide any kind of relief to bvFTD patients is the ultimate goal of Yao’s research. “Right now, there are no therapies, no treatment. They lose their personality, their identity. We should be able to do something.”  

Yao believes that similar approaches can be used to other diseases, where empathy loss is a symptom, such as autism, psychopathy, and Alzheimer’s disease. 

Yao is an Empire Scholar and joined Upstate from Harvard University in 2014 through the SUNY’s Empire Innovation Program.

Read more about Yao’s lab, which researches dopamine; synaptic plasticity and remodeling; prefrontal cortex; neural mechanisms of addiction and FTD here.