Gifts from generous donors have helped researchers who are working to answer basic questions about the human brain—answers that could lead to important discoveries in disease and improve patient outcomes.
Kevin Franks, PhD, and Fan Wang, PhD, are conducting such research. Franks’s work on the relationship between perception and memory can provide fundamental insights into how the brain changes in illnesses such as Alzheimer’s disease. And Wang’s research identifying how different brain areas represent and control pain could help lead to a new line of non-addictive pain therapies that could change the future of pain management.
The underlying shared interest between their work is perception, specifically how the brain forms internal representations of things in the external world.
Franks and his colleagues seek to answer the question, “How are we able to recognize an odor?” They are examining the olfactory system of mice to understand how odors are encoded or represented in the brain. They want to learn how these representations change with experience.
“Memory is what happens when previous experience changes how these representations are formed, or what they represent,” says Franks, an associate professor of neurobiology. “We have a number of approaches to get at this problem, but the main one is to record from populations of neurons in a mouse brain while they’re exposed to different odors, and then to try to make sense of what happens in the olfactory cortex when things change.
“For example, a novel odor may have no particular meaning to a mouse, but if that odor is then paired with an external event, such as a sugar reward or an electric shock, the odor will now acquire salience, or meaning, and the mouse will remember the association; that is, the representation of the odor in the mouse brain will associate the odor with the sugar or shock. We first want to understand how these associations are made, and then understand how this process can go wrong.”
Knowledge of how perception is related to memory could give researchers insight into how memories are formed and what happens in the brain when we lose memories. “We think that the processes that underlie this in the olfactory system are probably the same as those in other forms of memory,” Franks says. “In fact, olfactory complications are early indicators of multiple diseases, including Alzheimer’s and Parkinson’s diseases, and also, interestingly, COVID-19.”
The research of Franks and his colleagues may guide the development of early indicators of these diseases.
Wang, the Morris N. Broad Distinguished Professor of Neuroscience and a professor of neurobiology, has long been interested in learning about pain and finding better ways to treat it. She and her team seek to learn what pain is and where the perception of pain is processed in the brain. They are currently focused on neural circuits underlying active touch and pain perception. They are also interested in identifying the brain’s endogenous pain-suppressing circuit, with a goal to translate such findings into a new line of pain therapy.
It is known that mental processes can “make pain disappear.” The placebo effect is one such example. When chronic pain patients believed they were given pain-relieving medicine, their pain disappeared, even though they were actually given a placebo drug. Where in the brain such endogenous pain-relieving neurons reside and how they exert analgesic functions remain unknown. Wang hypothesized that general anesthetics block pain perception by activating the endogenous pain-suppressing circuit. With the support of Holland-Trice funds, based on this innovative yet highly risky hypothesis, the Wang lab made a ground-breaking discovery that specific types of neurons located in one of the brain’s emotional centers called the central amygdala are activated by low dose of anesthetics and produce profound pain-suppressing effect.
“These cells have the effect of completely suppressing animals’ pain perception,” Wang says. “When we activate these cells, the animals are essentially pain free.
“Our dream is to find drugs that mimic anesthetics but are not anesthetics and that can activate these cells,” Wang says. “If we can find selective ligand or molecules that don’t have the sedative effect of anesthetics—but more specifically activate these cells—they will be the pain treatment drugs, the future of pain management.”
“Our dream is to find drugs that mimic anesthetics but are not anesthetics and that can activate these cells,” Wang says. “If we can find selective ligand or molecules that don’t have the sedative effect of anesthetics—but more specifically activate these cells—they will be the pain treatment drugs, the future of pain management.”
Both Wang and Franks credit philanthropy with opening the door to substantial federal grants to support their research. Wang initially applied for two grants that were denied because she lacked enough preliminary data. But a two-year Holland-Trice grant allowed her to gather the data she needed. She then was awarded funding from the NIH HEAL initiative, which is a federal initiative aimed at stemming the national opioid public health crisis. She and her team also wrote a paper describing the central pain-suppressing neurons that was recently accepted by Nature Neuroscience.
Franks says the work sponsored by the Holland-Trice Scholars Program and awarded to him and to his student, Shiva Nagappan, supported early efforts to tease apart the specific roles that different types of olfactory cortex neurons play in odor coding, and this work provided a crucial foundation for two different NIH grants, including a $2.3 million grant from the NIH’s BRAIN Initiative. The research team also had a significant paper published in Science in 2018.
Wang says the Holland-Trice funding “is a continued funding mechanism that provides seed or incubator money. When I applied, I knew it was a risky project, but I am determined. I’m extremely grateful the Trices see that in me, and they’re very supportive.”
Franks adds, “They’re the people who tend to the little seedlings and make sure that the roots get big enough to go into the world.”
June 2020