Ghrelin as a Stress Hormone: Implications for Psychiatric Illness.

The stress response is an adaptive means of maintaining physiological homeostasis in the face of changing environmental conditions. However, protracted recruitment of stress systems can precipitate wear and tear on the body and may lead to many forms of disease. The mechanisms underlying the connection between chronic stress and disease are not fully understood and are likely multifactorial. In this review, we evaluate the possibility that the hormone ghrelin may contribute to the pathophysiology that follows chronic stress. Since ghrelin was discovered as a pro-hunger hormone, many additional roles for it have been identified, including in learning, memory, reward, and stress. We describe the beneficial effects that ghrelin exerts in healthy mammals and discuss that prolonged exposure to ghrelin has been linked to maladaptive responses and behaviors in the realm of psychiatric disease. In addition, we consider whether chronic stress-associated altered ghrelin signaling may enhance susceptibility to posttraumatic stress disorder and comorbid conditions such as major depressive disorder and alcohol use disorder. Finally, we explore the possibility that ghrelin-based therapeutics could eventually form the basis of a treatment strategy for illnesses that are linked to chronic stress and potentially also ghrelin dysregulation, and we identify critical avenues for future research in this regard.

Ghrelin is a persistent biomarker for chronic stress exposure in adolescent rats and humans.

Prolonged stressor exposure in adolescence enhances the risk of developing stress-sensitive mental illnesses, including posttraumatic stress disorder (PTSD), for many years following exposure cessation, but the biological underpinnings of this long-term vulnerability are unknown. We show that severe stressor exposure increased circulating levels of the hormone acyl-ghrelin in adolescent rats for at least 130 days and in adolescent humans for at least 4.5 years. Using a rodent model of longitudinal PTSD vulnerability in which rodents with a history of stressor exposure during adolescence display enhanced fear in response to fear conditioning administered weeks after stressor exposure ends, we show that systemic delivery of a ghrelin receptor antagonist for 4 weeks surrounding stressor exposure (2 weeks during and 2 weeks following) prevented stress-enhanced fear memory. These data suggest that protracted exposure to elevated acyl-ghrelin levels mediates a persistent vulnerability to stress-enhanced fear after stressor exposure ends.

Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory.

BACKGROUND: There are many contradictory findings about the role of the hormone ghrelin in aversive processing, with studies suggesting that ghrelin signaling can both inhibit and enhance aversion. Here, we characterize and reconcile the paradoxical role of ghrelin in the acquisition of fearful memories. METHODS: We used enzyme-linked immunosorbent assay to measure endogenous acyl-ghrelin and corticosterone at time points surrounding auditory fear learning. We used pharmacological (systemic and intra-amygdala) manipulations of ghrelin signaling and examined several aversive and appetitive behaviors. We also used biotin-labeled ghrelin to visualize ghrelin binding sites in coronal brain sections of amygdala. All work was performed in rats. RESULTS: In unstressed rodents, endogenous peripheral acyl-ghrelin robustly inhibits fear memory consolidation through actions in the amygdala and accounts for virtually all interindividual variability in long-term fear memory strength. Higher levels of endogenous ghrelin after fear learning were associated with weaker long-term fear memories, and pharmacological agonism of the ghrelin receptor during the memory consolidation period reduced fear memory strength. These fear-inhibitory effects cannot be explained by changes in appetitive behavior. In contrast, we show that chronic stress, which increases both circulating endogenous acyl-ghrelin and fear memory formation, promotes profound loss of ghrelin binding sites in the amygdala and behavioral insensitivity to ghrelin receptor agonism. CONCLUSIONS: These studies provide a new link between stress, a novel type of metabolic resistance, and vulnerability to excessive fear memory formation and reveal that ghrelin can regulate negative emotionality in unstressed animals without altering appetite.