PTSD in adolescents: Chronic stress increases acyl-ghrelin for years after the initial traumatic stressor exposure


Chronic stress increases a blood-based hormone called acyl-ghrelin for years after the initial traumatic stressor exposure in some adolescents, and those with elevated levels of the hormone are more likely to develop post-traumatic stress disorder (PTSD) and to experience more severe cases of the condition, according to a study conducted by researchers at the Icahn School of Medicine at Mount Sinai and published August 20 in JAMA Network Open.

Acyl-ghrelin, a blood-based hormone that is released mostly by the gut during times of energy depletion, was originally termed a “hunger hormone,” but the Mount Sinai researchers argue that it is more appropriately classified as a stress hormone and that hunger is a form of stress.

Acyl-ghrelin may be a “missing link” by which chronic stress produces lasting changes in the brain that enhance the risk for mental illness, they said.

Specifically, the research team found that the odds of developing PTSD were almost eight times higher in trauma-exposed adolescents with moderately elevated acyl-ghrelin, compared to trauma-exposed adolescents with low levels of the hormone.

Those with the highest levels of acyl-ghrelin all developed PTSD, and symptom severity was directly related to acyl-ghrelin levels, both in adolescents who met the criteria for PTSD and those who might be considered to have “sub-threshold” PTSD.

Though the researchers’ measured cortisol, another hormone often thought to mediate the effects of stress in the brain and body, it was acyl-ghrelin alone, rather than cortisol or the combination of both hormones, that explained most of the variability in PTSD symptom severity, suggesting it as an especially potent biomarker of the disorder.

“Previous work from our lab, using rodent models of PTSD, showed that acyl-ghrelin was increased by chronic stress exposure for months after the exposure, and that this increase was responsible for driving changes in the brain that led to excessively strong fear memories in rodents, similar to those observed in humans with PTSD,” said Ki Goosens, PhD, Associate Professor of Psychiatry and lead author of the study.

“We also previously showed that in adolescent humans, exposure to severe traumatic stressors led to long-term elevation of the hormone, for years after stressor exposure ended.

This study extended these previous studies to ask whether the acyl-ghrelin levels observed years after trauma exposure in adolescent humans are related to PTSD risk and severity.”

To answer this question, researchers conducted a cross-sectional study on 49 adolescents who had experienced severe trauma and 39 healthy, matched control participants. Children in the trauma group had experienced a terror attack and were injured, or lost a parent, relative or close friend as a result of the attack.

Children from the control group had no terror-associated losses or injuries. Acyl-ghrelin and cortisol were measured in blood and saliva samples, respectively, and all participants were administered the PTSD CheckList – Civilian Version, a standardized rating scale for PTSD.

Their observation of an association between acyl-ghrelin and PTSD in adolescents who experienced severe trauma motivates additional research to investigate the mechanisms underlying trauma-induced elevation of the hormone.

The researchers suggest that blood banks collecting samples from PTSD patients should use methods that preserve acyl-ghrelin for analysis, as the hormone can be readily measured in small quantities of blood.

“We hope that lowering acyl-ghrelin levels in traumatized humans will reduce the risk and severity of subsequent PTSD.

We also believe that stress-induced production of the hormone may also impact other brain circuits that predispose individuals to additional illnesses beyond PTSD,” said Dr. Goosens.

“In the meantime, measuring levels of the hormone in stress-exposed individuals may identify some of those who are at risk of developing PTSD so that early therapeutic interventions may be initiated to prevent development of the disorder.”

Researchers from Khyber Medical University in Pakistan contributed to this work.

When a cue or event threatens the well-being of an organism, stress responses are engaged to promote coping and adaptation.1 Despite the utility of these responses, repeated or prolonged activation of the stress response causes detrimental effects, including increased susceptibility to mental illnesses such as depression, anxiety or posttraumatic stress disorder (PTSD).2, 3, 4, 5, 6, 7, 8

It is thought that the stress response is principally coordinated by hormones of the hypothalamic–pituitary–adrenal (HPA) axis; however, strong correlations between stress-induced alterations in these hormones and mental illness are lacking, and not all effects of chronic stress can be simulated with exogenous administration of the HPA hormones.9, 10

Furthermore, although excessive HPA activity has been linked to heightened fear and anxiety in rodents, there has been little success in the clinical application of these findings.11

Both high and low levels of HPA activity have been observed in humans with stress-sensitive mental disorders and, in some cases, patients respond positively to treatment with exogenous glucocorticoids, one of the adrenal stress hormones.12

Thus, there is a crucial need for novel biomarkers and therapeutic targets.

Recently, it has been found that ghrelin, a peptide hormone, is modulated by exposure to stress.13, 14 Ghrelin is produced by the stomach where it is activated by posttranslational acylation before being transported into the blood stream.

It can then cross the blood–brain barrier13 where it binds to the growth hormone secretagogue receptor 1a (GHSR1a, or ghrelin receptor). Interestingly, the ghrelin receptor is found in the basolateral complex of the amygdala (BLA),15 a brain region that regulates negative emotional states such as fear.

Single infusions of exogenous ghrelin into the amygdala can alter behavior in tasks such as the elevated plus maze and inhibitory avoidance,16 but a relationship between emotional learning and endogenous ghrelin has not been explored. Furthermore, growth hormone (GH), which is released by cells in response to ghrelin receptor activation and altered in the brain by stress,17 is present in BLA neurons.18

The stress sensitivity of ghrelin, together with the localization of its receptor and downstream signaling partner (GH) in BLA, make it an attractive candidate mechanism by which emotional memories may be altered following periods of stress.

PTSD and other trauma- and stress-related disorders can arise following a traumatic experience.19 Chronically stressed individuals are especially vulnerable to developing these disorders in response to trauma.3, 8, 20, 21

Humans with PTSD and other anxiety disorders exhibit hyperactivity in the amygdala,22, 23 and amygdala-dependent processes, such as fear learning to novel stimuli in laboratory settings, are enhanced in humans with PTSD.24

The ‘over-acquisition’ of aversive memories is not merely a symptom of trauma-related disorders. It is also thought to contribute to the genesis of such disorders and may perpetuate distress after the trauma: humans with PTSD have extremely strong memories of the PTSD-inducing trauma, and many symptoms of PTSD, such as social avoidance and sleep disturbance, are secondary to these memories.25, 26, 27

Thus, understanding why certain individuals, such as those with a significant lifetime stress burden, have dysregulated encoding of traumatic memories is critical for both preventing and treating PTSD and other trauma-related disorders.

In addition, by understanding how stress alters brain regions responsible for emotional memory such as the amygdala, we may better understand how stress increases susceptibility to the development of other psychiatric disorders.

In this paper, we used a rodent model of PTSD in which rats were repeatedly exposed to stress and then subjected to auditory Pavlovian fear conditioning. Relative to unstressed controls, these animals displayed enhanced fear learning, mimicking the stress-induced vulnerability to excessive learning about aversive experiences that is a key feature in the acquisition and symptomatology of PTSD. Our studies uncover an essential and novel role for ghrelin and growth hormone in stress-induced susceptibility to exacerbated fear.

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Mount Sinai Hospital


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