Understanding the brain’s resilience

As a teenager, Amy Arnsten, PhD, the Albert E. Kent Professor of Neuroscience and professor of psychology, watched her father slowly recover from a massive heart attack. She noticed how attentive and knowledgeable the doctors were, and that friends and neighbors were very sympathetic. Soon after, Arnsten’s paternal aunt also suffered a debilitating health scare: severe clinical depression. Unlike those who had treated her father, however, these doctors had a harder time helping Arnsten’s aunt. “Having no idea of what was actually going on in her brain, her doctors were handicapped in what they could do,” Arnsten said. “And she didn’t receive the same kind of compassion as my father did.”

With that experience seared in her memory, Arnsten dedicated herself to understanding how parts of the brain’s circuitry malfunction in mental illnesses—just as coronary arteries narrow and cut off life-giving blood to the heart during a heart attack.

After studying neuroscience at Brown University (and creating the neuroscience major there), Arnsten earned her PhD in neuroscience from the University of California at San Diego. She then pursued postdoctoral research at the University of Cambridge under the tutelage of Susan Iversen, PhD, a ground-breaking experimental psychologist. Arnsten then joined the Yale lab of the late pioneering neuroscientist Patricia Goldman-Rakic, PhD. Goldman-Rakic changed the field’s understanding of the prefrontal cortex (PFC), the highly developed part of the frontal lobe in human brains. She discovered the cellular basis of working memory, our so-called mental sketch pad, the foundation of abstract thought. Goldman-Rakic also learned how reliant the PFC is on the neurotransmitter dopamine to perform its memory functions. Arnsten came to Goldman-Rakic’s lab at Yale in 1982 as a postdoctoral fellow to study dopamine’s actions in aging brains, and became an assistant professor in the then-named Neurobiology Section just four years later.

Throughout her nearly four-decades-long career, Arnsten has fulfilled a teenage promise to herself by uncovering findings on how higher cortical circuits are regulated at the molecular level, and how their dysregulation can contribute to illnesses like Alzheimer’s disease, schizophrenia, attention deficit and hyperactivity disorder (ADHD), and depression. She discovered that the prefrontal cortex has unique molecular needs compared to classic neural circuits, including built-in mechanisms to take the prefrontal cortex “off-line” during stressful events. Her research has led to treatments for cognitive disorders in humans—a rare instance of successful translation from basic neuroscience into the clinic.

Among her many awards, Arnsten received the National Institutes of Health Director’s Pioneer Award, and in 2017 was elected to the National Academy of Medicine. Yale Medicine Magazine sat down with Arnsten in her office—the very same one she worked in as a fellow with Goldman-Rakic—to discuss how stress affects the brain; why physicians can benefit by understanding the physiology underlying burnout; and a meaningful discovery.

What is the prefrontal cortex? The prefrontal cortex (PFC) is a newly evolved brain region directly under our forehead, which governs higher cognition. The PFC is needed for working memory, abstract reasoning, and flexible decision-making; for planning, organizing, and regulating our attention; and for insight and judgment about ourselves and others. It provides thoughtful “top-down” regulation of our thoughts, actions, and emotions. The PFC is able to represent information in working memory without any sensory input by having neurons excite each other to keep information “in mind.”

Stress acts as a sort of toxin to the prefrontal cortex. How is that so? When we are stressed and feel out of control, there is a flood of catecholamines released in the brain, similar to epinephrine being released from our adrenal gland. The high levels of catecholamines rapidly weaken the connections between PFC neurons by opening potassium channels near the synapses, thus rapidly taking the PFC “off-line.” At the same time, the high levels of catecholamines strengthen more primitive brain circuits that generate emotional responses and habitual reactions. This can be important for survival. If a lion appears in your path, you don’t want to rely on your thoughtful PFC to philosophize about the situation. In modern day [life], if a car cuts you off on the highway, it’s not helpful to think, ‘I’ve just been cut off by a 2020 model Toyota.’ You want to stop thinking and slam on the brakes. However, weakening PFC function during stress is not helpful when dealing with a more complex stressor such as an invisible COVID-19 virus, which requires thoughtful evaluation and planning for survival. Importantly, with chronic stress the changes in [the] brain become even more pronounced as PFC connections are lost, while the neuronal connections in primitive brain circuits actually grow stronger. Thus we can be more reactive than reflective at a time when we need thoughtful responses to survive.

Physician burnout has reached record-setting levels in the United States, especially under the conditions of COVID-19. What do you want physicians and other health care workers to keep in mind on this topic? The stress of modern medical practice was growing even before COVID-19; for example, the burden of electronic health records, or limited control over reducing scheduling time needed to spend with patients. But with COVID-19, the uncontrollable stressors are even worse: not having the appropriate PPE to stay safe; not having the supplies, equipment, or information needed to assess and save patients. A sense of lack of control can lead to cognitive errors and impaired regulation of emotion, which can become even worse if one blames oneself for mental shortcomings. Understanding that this is a natural neurobiological response can help to break that vicious cycle, and can help motivate actions to “treat” the situation and strengthen [the] PFC. For example, deep breathing can help to normalize the brain’s stress response through mechanisms in the brainstem, and things like mindfulness meditation, exercise, and administrative and peer support can help protect PFC function. If you are interested in this topic, we have a video on how stress alters brain function at the Yale School of Medicine YouTube channel.

Which of your discoveries has been most meaningful to you? Early on, we discovered that the proper functioning of the PFC relies on having the correct neurochemical state. This optimal state includes having just the right amount of the catecholamine norepinephrine to stimulate alpha-2A adrenergic receptors that are localized on prefrontal cortical neurons. We learned that alpha-2A adrenergic receptors inhibit the opening of nearby potassium channels (the ones opened by stress), and that this serves to strengthen PFC connections. We found that a compound that is very selective for alpha-2A adrenergic receptors called guanfacine could strengthen PFC connections and function; and [we] wondered if it could help patients with PFC deficits. For example, ADHD (attention deficit hyperactivity disorder) is caused by weaker PFC regulation of behavior and attention. The FDA approved extended-release guanfacine under the brand name Intuniv for the treatment of ADHD in 2009 based on our research—one of the few examples where basic neuroscience research has successfully translated to the clinic. Guanfacine has allowed kids and young adults with ADHD to better regulate their own behavior. It is also being used off-label in children who have been traumatized or abused, including [in] ongoing research at the Yale Child Study Center. It’s been deeply moving for me to hear stories about how guanfacine has made such a difference in people’s lives.

Your lab has also been investigating how Alzheimer’s disease might develop. Yes, we’ve been studying how aging affects the newly evolved circuits in the PFC and another cortical region called the entorhinal cortex that is the most vulnerable to Alzheimer’s degeneration. We are finding that stress-signaling pathways inside of neurons become unregulated with advancing age, and that this causes loss of neuronal firing, and also the increased phosphorylation of tau, the forerunner to the neurofibrillary tangles that kill neurons in Alzheimer’s disease. We are hoping that learning how brain circuits become vulnerable with age will provide clues for a “baby aspirin” approach for reducing risk of Alzheimer’s disease.

What have you gained from your research personally? The PFC is important for metacognition—or thinking about thinking. I do this all the time. You rely on the PFC to think about who you will be in the future and what your weaknesses will be, and how to shore up for them. I know I must remember to remember. But there’s someone I talk to every night who remembers a lot—she’s still firing on all cylinders—and that’s my 98-year-old mother. We need to learn how we can be more like her!