Survival. In an animal kingdom enriched by a diversity of species, it is the one trait shared by organisms as simple as worms and as complex as humans. And the proof is in a protein with the hopelessly complex name of pituitary adenylate cyclase-activating polypeptide.
Commonly referred to by scientists as PACAP, this neuropeptide—and its interactions with the corticotropin-releasing factor (CRF) that regulates the stress hormone cortisol—are at the center of a 5-year, $13.5 million research effort at McLean Hospital, where the Silvio O. Conte Center for Basic Neuroscience was recently established. The Conte Center, funded via a massive new grant from the National Institute of Mental Health, will aim to better understand the biological roots of post-traumatic stress disorder (PTSD) and other trauma- and stress-related disorders, including depression.
What makes this project unique is that it will look at stress and PTSD through the interaction of these compounds—at the molecular and brain circuit level—via animal studies focusing on fear responses; by examining the relationship to sleep and circadian rhythms; and via a human clinical study involving patients with PTSD. It will also bring in young researchers, from local colleges with strong neuroscience programs, to educate the public.
According to the Substance Abuse and Mental Health Services Administration, in the United States, 61% of men and 51% of women report exposure to at least one traumatic event in their lifetime. Violence and abuse—whether via war, traffic accidents, physical attacks, child abuse, or sexual abuse—are the primary triggers of significant stress. For 5 to 10% of the population, key symptoms can persist after a month, a sign of PTSD.
Nightmares and flashbacks are widely recognized symptoms of a person re-experiencing trauma. It also presents itself as other problems, such as being constantly on edge or having trouble sleeping. Finally, a person with PTSD exhibits thought or mood problems, having trouble focusing and experiencing feelings of low self-esteem.
A foundation of the project is recognition that all animals exhibit what is commonly known as the fight-or-flight response, expressed in specific regions of the brain and triggered by chemical responses involving neuropeptides, small protein-like molecules used by neurons to communicate with each other. Different neuropeptides are involved in a wide range of brain functions, including pain, reward, food intake, metabolism, reproduction, social behaviors, learning, and memory.
PACAP is “involved in the important function of species survival,” said Edward G. Meloni, PhD, one of the principal investigators of the Conte Center. Meloni started PACAP research at McLean over a decade ago, providing a foundation for what is now one of the world’s premier research centers focusing on this peptide.
“If you administer CRF or PACAP to animals, they show the hallmark signs of stress, including fear, anxiety, and aggression,” explained Bill Carlezon, PhD, chief of the Jerry and Phyllis Rappaport Center of Excellence in Basic Neuroscience Research and director of the Behavioral Genetics Laboratory at McLean. “Our basic hypothesis is that these peptides work together and can substitute for one another. It’s not an especially complicated idea, but very few research teams prioritize studying peptides in tandem in this way.”
This work has the potential to revolutionize the way in which clinicians deliver care to their patients.
But while most animals recover the next day after receiving CRF, it can take 3-4 weeks to recover after administration of PACAP, he explained. “The consequences of PACAP are persistent and enduring—just like conditions such as PTSD,” he said. “That’s what makes us interested in comparing and contrasting how these peptides work in the brain.”
McLean’s position as a freestanding psychiatric academic medical center makes it particularly suited to this research that encompasses five interrelated projects, said Chief Scientific Officer Kerry J. Ressler, MD, PhD. There are only a handful of Conte Centers across the U.S., named for a longtime Massachusetts congressman who was a strong advocate for federally funded research.
“The ability to have all aspects of psychiatry, including very basic science research, clinical research, and clinical treatment, provided in one place, focused on a targeted question, makes McLean uniquely positioned to address translational questions and to understand mechanisms, and then to apply those novel findings toward improved diagnosis, treatment, and prevention,” said Ressler.
Ressler noted that identifying the biological roots of PTSD and other related disorders, and applying the science to the care that individuals receive, will have enormous implications across the psychiatric field in delivering trauma-informed care across a person’s life span and within all diagnostic categories.
“This work has the potential to revolutionize the way in which clinicians deliver care to their patients,” said Ressler.