Amy Arnsten
American neuroscientist
- 3 min read
- 4 chapters
Related on Lably
Through Schizophrenia, Alzheimer's disease and Stress (mechanics)
Arnsten’s research identified the molecular mechanisms by which the prefrontal cortex regulates higher cognition and how these mechanisms are disrupted by stress and inflammation, which is relevant to cognitive disorders such as schizophrenia and Alzheimer’s disease. She coined the term Dynamic Network Connectivity to describe the rapid,reversible modulation of synaptic strength in prefrontal cortical networks by ion-channel signaling. Her discovery that alpha-2A -adrenoceptor stimulation strengthens prefrontal cortical network connections led to the development of guanfacine (marketed as Intuniv) for the treatment of attention deficit hyperactivity disorder (ADHD), which received FDA approval in 2009.
Early life and education
Arnsten grew up in Maplewood, New Jersey, and graduated from Columbia High School in 1972. She received a bachelor’s degree in neuroscience from Brown University in 1976, where she created the Neuroscience undergraduate major, the first of its kind at Brown.She earned a Ph.D. in neuroscience from the University of California, San Diego in 1981. She performed a brief postdoctoral fellowship with Dr. Susan Iversen at the University of Cambridge in 1982, and then came to Yale University as a postdoctoral fellow with Patricia Goldman-Rakic, where she was appointed Assistant Professor in 1986.
Sign in to keep reading
3 more chapters are free with a Lably account.
Career
Arnsten is the Albert E. Kent Professor of Neuroscience and Psychology at Yale University. She was appointed to the Kent Professorship in 2019.Her research group at Yale studies the molecular signaling pathways that govern prefrontal cortical circuits, with a focus on how these circuits are strengthened or weakened by neuromodulators and stress.
Arnsten was elected to the National Academy of Medicine in 2017, recognized for her discovery of guanfacine for the treatment of prefrontal cortical disorders. The National Academy of Medicine is one of the highest honors in American medicine and biomedical science.
Research
Arnsten’s research has shown that the prefrontal cortex, the brain region that mediates higher cognitive functions such as working memory and executive control, is regulated by molecular signaling pathways that differ from those in more primitive brain circuits. She and her colleagues identified a constellation of signaling pathways in prefrontal cortical dendritic spines that control the opening and closing of potassium channels, rapidly weakening or strengthening synaptic connections. She termed this mechanism Dynamic Network Connectivity.
Arnsten demonstrated that acute, uncontrollable stress impairs prefrontal cortical function by triggering high levels of catecholamine release, which activate alpha-1- and beta-1-adrenoceptors and drive the opening of potassium channels, rapidly weakening synaptic connections and switching behavioral control to more primitive brain circuits. With chronic stress exposure, this sustained weakening leads to loss of dendritic spines. She showed that inhibiting these molecular events can protect dendrites and cognitive function.
More recently, Arnsten’s group has found that inflammation also takes the prefrontal cortex “off-line,” contributing to the cognitive impairment often described as “brain fog,” and that inflammation and aging dysregulate the stress response in ways that may contribute to the etiology of Alzheimer’s disease.
Guanfacine and clinical translation
Arnsten discovered and developed the alpha-2A-adrenoceptor agonist guanfacine for the treatment of prefrontal cortical disorders. Extended-release guanfacine, marketed as Intuniv, was approved by the U.S. Food and Drug Administration on 2 September 2009 for the treatment of ADHD in children and adolescents aged 6 to 17. It was subsequently approved in Japan for the treatment of ADHD in children and adults.
Arnsten’s lab established the neurobiological basis for guanfacine’s therapeutic effects. They showed that alpha-2A-adrenoceptors are localised on prefrontal cortical dendritic spines, where they close potassium channels and strengthen network connections, enhancing prefrontal neuronal firing and cognitive function. The group also showed that guanfacine can protect prefrontal dendritic spines and cognitive abilities from the effects of chronic stress.
Based on this research, guanfacine has been investigated or used for a range of prefrontal cortical disorders beyond ADHD, including post-traumatic stress disorder in children, disinhibited behaviors in autism spectrum disorder, cognitive impairment associated with long COVID and traumatic brain injury, delirium, the cognitive biotype of depression, and genetic disorders that weaken synaptic function.