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October 25, 2019
Fight or flight. It’s a basic response to a perceived threat in all animals, from the fly to the human.
In complex vertebrates, including mammals, it is controlled by an almond-shaped cluster of neurons in the brain called the amygdala. This cluster regulates both pleasure and fear.
Scientists have long understood that brain chemicals known as neuropeptides are involved in regulation of stress responses, including a specific peptide known as corticotropin-releasing factor (CRF). Scientists at McLean Hospital are now looking at a related neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), and how the two may interact in controlling stress-induced anxiety. The goal of this research is to better understand generalized anxiety and post-traumatic stress disorder (PTSD) in humans.
“PACAP is involved in important behavioral mechanisms essential for species survival,” said Edward G. Meloni, PhD, one of the principal investigators at the Silvio O. Conte Center for Basic Neuroscience at McLean, funded by a grant through the National Institute of Mental Health.
“Animals need the stress- and anxiety- related behavioral responses to survive. These behavioral mechanisms were picked up by evolution and can be seen throughout the animal kingdom, including in humans. For humans, these adaptive mechanisms may become maladaptive, resulting in pathological states such as PTSD.”
According to Vadim Bolshakov, PhD, a Conte Center investigator, elevated CRF levels are frequently found in people with PTSD. While several potential treatments were tested but failed in clinical trials, researchers still believe targeting the CRF system could lead to effective therapeutics for some stress disorders, including generalized anxiety and PTSD.
What’s new about the work of Meloni and Bolshakov is the focus on the interaction between CRF and PACAP.
“The interesting point is that PACAP is the exact same neuropeptide in different animal species,” said Meloni. “In mice, rats, dogs, cows, and humans, evolution has not changed the nucleotide sequence in even one amino acid. This suggests the peptide must be playing a very important role in species survival.”
In humans, he continued, our hypothesis is that this same survival response is triggered when a person is exposed to a trauma-inducing natural disaster, terrorist attack, or school shooting, for example, where one’s life is in danger. But because humans are more evolved cognitively compared to animals, this response has the potential to do more harm than good.
“We believe that when a person is exposed to a life-threatening event, PACAP is released in the brain and may have a role in helping to hard-wire these indelible memories in the brain and/or sustain an anxious state,” said Meloni.
While such a process may have been beneficial for species survival, in humans it may be maladaptive, contributing to nightmares, flashbacks, or waking anxiety triggered by sights, sounds, and smells that remind the individual of the initial traumatic event.
Meloni, an investigator in the Behavioral Genetics Laboratory, and Bolshakov, the director of the Cellular Neurobiology Laboratory, are approaching the research from different angles. While Meloni introduces PACAP directly into animals, Bolshakov induces the release of the neuropeptide in specific brain regions using optogenetics, a relatively new methodology that involves the use of light to control brain cells that have been genetically modified.
In Bolshakov’s experiments, a photosensitive protein called channelrhodopsin, derived from green algae, is delivered to the brain structures, orchestrating emotional and behavioral responses to stress. Brain cells expressing channelrhodopsin are then activated by blue light with unique precision.
Stimulating specific pathways in the brain, the researchers trigger the release of PACAP to see how it affects anxiety levels and how these effects are modulated by chronic stress.
The Bolshakov lab also explores how PACAP and CRF interact in the amygdala and a small region of the brain called the bed nucleus of the stria terminalis (BNST) to control anxiety.
“There is evidence that both neuropeptides contribute to the development of pathological fear,” said Bolshakov. “Thus, their expression is enhanced in the brain when the subjects are experiencing fear-enhancing chronic stress.”
“If you had a treatment that could be given immediately following a trauma... You might protect those people who are most susceptible to developing PTSD.”
This enhanced PACAP- and CRF-mediated signaling in the brain is translated into changes in the functional interactions between certain brain regions, resulting in pathologically expressed fear, and thus often leading to psychiatric disorders.
“The hope here is that we could eventually come up with strategies for the treatment of generalized anxiety and PTSD, targeting specific parts of the brain circuitry controlling the development of pathological anxiety,” Bolshakov said.
Both researchers look at the expression of PACAP and CRF before and after traumas to see whether that makes an animal more predisposed to developing PTSD.
That is done by measuring how much PACAP is in the brain during trauma and investigating the circuits that revolve around this PACAP/CRF release to, in effect, consolidate or enhance the memory of the trauma.
“Learning implicates memory consolidation,” Meloni said. “That is the hallmark of what is going on in PTSD patients, and we believe that memory consolidation of traumatic events is influenced by these peptides. Therefore, if we could control their actions, we possibly could come up with efficient treatments for PTSD.”
The work is also guided by the knowledge that there is an underlying predisposition to PTSD.
“We know many individuals that develop PTSD have early childhood exposures to abuse and to adverse kinds of living conditions that make them more predisposed to develop PTSD,” Meloni said. “So, it may be because these stress-peptide systems are already dysregulated that there is an enhanced susceptibility to developing PTSD in the wake of a traumatic experience later in life.”
Clinicians know that the trauma—the car crash, explosion, or shooting—can lead to the formation of stronger memories. And Meloni said that when those consolidated memories are triggered by sounds or smell, it can result in a panic attack.
“It’s the memory hyper-consolidation of the cues surrounding the traumatic events that we think PACAP may be involved in,” he said.
Meloni was hopeful that his and Bolshakov’s work in animals could eventually apply to humans.
“We don’t yet know who is going to develop PTSD after exposure to a traumatic event, and only a small percentage of people will. But if you had a treatment that could be given immediately following a trauma—such as a drug that might block PACAP’s or CRF’s effects—you might protect those people who are most susceptible to developing PTSD.”
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