Huda Akil began her research career as a Ph.D. student in neuroscience at the University of California Los Angeles, where her dissertation research was directed by John Liebeskind. During her graduate studies, her research focused on understanding the role the brain plays in perceiving pain. “Our original interest was in certain mechanisms of central pain that is mediated by the brain,” Akil said. An example of central pain is phantom limb pain, where people feel pain in the missing limb, which suggested there was a circuit in the brain that was replaying the pain and projecting it to the missing organ as though it were real.
To understand the mechanism of central pain, the Liebeskind lab focused on mapping the regions of the brain involved in sensing pain using electrical stimulation. Much to their surprise, they discovered that there were regions of the brain that, if stimulated, could stop the sensation of pain, a phenomenon called stimulation-produced analgesia. The idea that the brain could actively fight pain was new at the time. “We primarily thought of the body as being able to feel pain, maybe filter it at the sensory level, but we never discussed the possibility that the brain had an entire system that could block pain,” Akil said.
Akil’s dissertation work focused on trying to understand the molecular players involved in the pain blockade. This included experiments showing that stimulation-produced analgesia was turning on an active system in the brain that could block pain. As Akil and her collaborators showed, the regions of the brain that could block the sensation of pain were similar to the regions of the brain that responded to opiates. “A focus of my dissertation was to compare opiates side by side with this brain stimulation, and we found many parallels,” Akil said. Stimulation-produced analgesia could also be blocked, in part, by naloxone, which is an opiate-specific antagonist. This suggested that the brain was producing an opiate-like molecule that was responsible for blocking pain. “That was the first physiological evidence that the brain has a pain inhibitory system, and an opiate-like mechanism is central to it,” Akil said. This turned out to be the first evidence for endorphins, which are molecules that bind to opiate receptors in the brain and have since been shown to play many important roles.
After completing her Ph.D., Akil joined the laboratory of Dr. Jack Barchas at Stanford University, where she continued her research on endorphins, and the mechanism by which the brain modulates feelings of pain. This included showing that the brain can block feelings of pain while under stress, which is a phenomenon called stress-induced analgesia. “By then, we knew enough about endorphins to show that stress releases endorphins,” Akil said. “When you are under stress, you need to run, you need to fight, you need to survive. It is not the time to feel the pain.” She showed that this analgesia was dependent on the type of stressor. “Pain is important to feel, because it tells us that something is wrong,” Akil said. “Not feeling pain is also important, because it is terribly distracting when survival is at stake.”
This early work on pain perception turned into a lifetime of researching the brain circuits underlying emotion, such as stress, depression, anxiety or chronic pain. More broadly, Akil’s career has been centered on understanding negative emotions, be it physical or psychological pain, stress, anxiety and depression, and understanding the mechanisms in the brain that counter them, whether it is the role of endorphins in modulating the perception of pain, or the molecular pathways that induce resilience and counter anxiety and depression.
As Akil’s research has shown, opiates play a complex role in the brain, affecting pain pathways in a way that leads to dependence. “Opiates can minimize psychological pain,” Akil said. “The worse you feel beforehand, the greater the impact of opioids, which means that people who are in either physical or emotional pain are highly sensitive to them.” However, chronic exposure leads to tolerance and dependence, which affects the normal functioning of the brain. “Brain circuits that produce opioids come to rely on external opiates instead,” Akil said. “This leads to the painful physical and psychological symptoms of withdrawal and the need to continue to use drugs”.
Akil’s interest in brain biology of stress and emotion has led her to an interest in the genetic and brain mechanisms that lead to depression. She was one of the founding members of the Pritzker Consortium which used postmortem human brains to discover molecular changes associated with severe depression. They discovered the Fibroblast Growth Factor family (FGF) was altered in the brains of individuals who had been depressed relative to people with no psychiatric history. In particular, FGF2 was reduced in depressed brains. “FGF2 is our own natural antidepressant,” Akil said. Indeed, her laboratory showed in follow-up animal studies that FGF2 can block anxiety and depression-like behaviors, that natural levels of FGF2 in brain inhibit anxiety. Moreover, an enriched environment induces higher levels of FGF2 and enhances the ability of the brain to remodel itself (neuroplasticity). This discovery that offered context on the ways in which early environmental conditions can offer a protective benefit against depression later in life. They also discovered the role of FGF9, which has an opposite effect. “FGF2 has an evil twin, which is FGF9,” Akil said. FGF9 levels were higher in depressed individuals and follow-up studies showed that it functions to increase anxiety.
More broadly, Akil is interested in the factors that render different individuals more or less vulnerable to stress, depression and addiction. These are challenging topics, and she strongly believes in team science and collaborates with other major groups in the field of affective neuroscience, including the laboratory of Dr. Stanley Watson and colleagues at the Hope for Depression Research Foundation and the Pritzker Neuropsychiatric Research Consortium. She is currently focusing on understanding the factors that shape different types of temperament that predispose to distinct psychiatric and addictive disorders. “Stress biology is the biology of how you react to the environment”. Some individuals can be highly sensitive to their environment, and this can be both a source of vulnerability, but also a source of resilience. Much of her current research aims to understand the genetic and environmental factors that shape psychological resilience, and to define ways to enhance it, especially in genetically vulnerable individuals.