A new study by University of Wisconsin-Madison neuroscientists shows how stress chemicals reshape the brains of rodents, research that could lead to better treatments for people with post-traumatic stress disorder (PTSD).
Long after traumatic events such as war, abuse and car accidents, the brains of people with PTSD overreact to loud noises and other stimuli with an exaggerated startle response. Other hallmarks of the disorder include nightmares, insomnia, flashbacks and heightened anxiety, which make it difficult for people to have a normal life. Lacking good treatments, people with PTSD often self-medicate with alcohol and other drugs.
“We have created a rodent model that systematically delineates the chemical steps that occur in the brain in response to trauma, and how these steps ultimately lead to the hallmark features of PTSD: exaggerated startle responses to mild stimuli, long after the stressful experience,” says Vaishali Bakshi, associate professor of psychiatry in the UW School of Medicine and Public Health.
“This is exciting because rodent brains and human brains are wired the same way; new medications for PTSD can be identified by understanding which brain chemicals are mediating trauma effects.”
The study was published recently in the Journal of Neuroscience.
Bakshi says her lab’s “predator stress” model involves exposing a rat for five minutes to a ferret that is just outside its wire cage. There is no physical contact but the rat can see, hear and smell the ferret, a natural predator. Rats that were psychologically traumatized by the ferret still showed exaggerated startle responses to low-level or innocuous challenges a month after the last exposure. This is the equivalent of two to three years in humans, and closely mimics the time course for the exaggerated reactivity that characterizes PTSD.
She says this model more closely captures the essential element of the type of psychological trauma that causes PTSD, because it matches how people with the disorder describe their own traumatizing events. “We know that people commonly say they thought they were going to die, and that’s how the rats react to the ferret,” she says.
This fear response to the repeated psychological trauma created permanent changes in the brain. The repeated exposure to the predator-stress model caused long-lasting hypersensitivity of a certain protein, the alpha1 noradrenergic receptor, in a specific part of the brain known to regulate fear responses: the basolateral amygdala. This receptor hypersensitivity in turn led to exaggerated startle in the traumatized rats, similar to what is seen in PTSD patients. Control rats that never underwent the predator stress had completely normal startle responses.
Moreover, Bakshi’s group identified the chemical in the basolateral amygdala that created the hypersensitivity of the alpha1 receptor. This chemical, a protein called corticotropin-releasing factor (CRF), is released into the basolateral amygdala with each trauma exposure; this repeated CRF release causes the hypersensitivity of the alpha-1 receptor that leads to abnormally exaggerated startle.
Brian Baldo, an assistant professor of psychiatry and collaborator on the project, showed that the proteins (receptors) that mediate the effects of CRF are located on the same amygdala cells as the alpha1 receptors, providing an anatomical framework for understanding the interactions between these two neurochemical systems. Blocking CRF specifically within the basolateral amygdala prevents the PTSD-like profile from developing after trauma exposure.
Additionally, the study found that cells in the basolateral amygdala that are getting sensitized by trauma exposure project to several other parts of the brain that are important for fear, anxiety and drug abuse.
“We believe the mechanism we discovered for trauma-induced ‘re-wiring’ of the amygdala could also be important for stress-induced drug abuse, which is a common problem in people with PTSD,” says Baldo, an expert on reward and addiction.
By discovering the specific chemicals in discrete parts of the brain that control the responses to trauma exposure, Bakshi says her lab can identify possible new medication targets for treating PTSD.
“For example, any chemical that prevents the trauma-induced hypersensitivity of these basolateral amygdala cells from taking place could be a potential new drug target for PTSD prophylaxis,” Bakshi notes. “Imagine how powerful it would be to have a medication that could be taken soon after the trauma occurs so that the sensitized PTSD response never develops. Our model has the ability to identify such chemicals.”
About this PTSD research
The lead author of the paper is Abha Rajbhandari, who carried out the studies as a graduate student in the Neuroscience Training Program.
Funding:The study was supported by grants from the National Institute of Mental Health and NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation.
Source: Susan Lampert Smith – University of Wisconsin Madison Image Credit: The image is credited to the researchers Original Research:Abstract for “Predator Stress-Induced CRF Release Causes Enduring Sensitization of Basolateral Amygdala Norepinephrine Systems that Promote PTSD-Like Startle Abnormalities” by Abha K. Rajbhandari, Brian A. Baldo, and Vaishali P. Bakshi in Journal of Neuroscience. Published online October 20 2015 doi:10.1523/JNEUROSCI.5080-14.2015
Predator Stress-Induced CRF Release Causes Enduring Sensitization of Basolateral Amygdala Norepinephrine Systems that Promote PTSD-Like Startle Abnormalities
The neurobiology of post-traumatic stress disorder (PTSD) remains unclear. Intense stress promotes PTSD, which has been associated with exaggerated startle and deficient sensorimotor gating. Here, we examined the long-term sequelae of a rodent model of traumatic stress (repeated predator exposure) on amygdala systems that modulate startle and prepulse inhibition (PPI), an operational measure of sensorimotor gating. We show in rodents that repeated psychogenic stress (predator) induces long-lasting sensitization of basolateral amygdala (BLA) noradrenergic (NE) receptors (α1) via a corticotropin-releasing factor receptor 1 (CRF-R1)-dependent mechanism, and that these CRF1 and NE α1 receptors are highly colocalized on presumptive excitatory output projection neurons of the BLA. A profile identical to that seen with predator exposure was produced in nonstressed rats by intra-BLA infusions of CRF (200 ng/0.5 μl), but not by repeated NE infusions (20 μg/0.5 μl). Infusions into the adjacent central nucleus of amygdala had no effect. Importantly, the predator stress- or CRF-induced sensitization of BLA manifested as heightened startle and PPI deficits in response to subsequent subthreshold NE system challenges (with intra-BLA infusions of 0.3 μg/0.5 μl NE), up to 1 month after stress. This profile of effects closely resembles aspects of PTSD. Hence, we reveal a discrete neural pathway mediating the enhancement of NE system function seen in PTSD, and we offer a model for characterizing potential new treatments that may work by modulating this BLA circuitry.
SIGNIFICANCE STATEMENT The present findings reveal a novel and discrete neural substrate that could underlie certain core deficits (startle and prepulse inhibition) that are observed in post-traumatic stress disorder (PTSD). It is shown here that repeated exposure to a rodent model of traumatic stress (predator exposure) produces a long-lasting sensitization of basolateral amygdala noradrenergic substrates [via a corticotropin-releasing factor (CRF)-dependent mechanism] that regulate startle, which is exaggerated in PTSD. Moreover, it is demonstrated that the sensitized noradrenergic receptors colocalize with CRF1 receptors on output projection neurons of the basolateral amygdala. Hence, this stress-induced sensitization of noradrenergic receptors on basolateral nucleus efferents has wide-ranging implications for the numerous deleterious sequelae of trauma exposure that are seen in multiple psychiatric illnesses, including PTSD.
“Predator Stress-Induced CRF Release Causes Enduring Sensitization of Basolateral Amygdala Norepinephrine Systems that Promote PTSD-Like Startle Abnormalities” by Abha K. Rajbhandari, Brian A. Baldo, and Vaishali P. Bakshi in Journal of Neuroscience. Published online October 20 2015 doi:10.1523/JNEUROSCI.5080-14.2015