A ghrelin–growth hormone axis drives stress-induced vulnerability to enhanced fear

Abstract

Hormones in the hypothalamus-pituitary-adrenal (HPA) axis mediate many of the bodily responses to stressors, yet there is not a clear relationship between the levels of these hormones and stress-associated mental illnesses such as post-traumatic stress disorder (PTSD). Therefore, other hormones are likely to be involved in this effect of stress. Here we used a rodent model of PTSD in which rats repeatedly exposed to a stressor display heightened fear learning following auditory Pavlovian fear conditioning. Our results show that stress-related increases in circulating ghrelin, a peptide hormone, are necessary and sufficient for stress-associated vulnerability to exacerbated fear learning and these actions of ghrelin occur in the amygdala. Importantly, these actions are also independent of the classic HPA stress axis. Repeated systemic administration of a ghrelin receptor agonist enhanced fear memory but did not increase either corticotropin releasing factor (CRF) or corticosterone. Repeated intra-amygdala infusion of a ghrelin receptor agonist produced a similar enhancement of fear memory. Ghrelin receptor antagonism during repeated stress abolished stress-related enhancement of fear memory without blunting stress-induced corticosterone release. We also examined links between ghrelin and growth hormone (GH), a major downstream effector of the ghrelin receptor. GH protein was upregulated in the amygdala following chronic stress, and its release from amygdala neurons was increased by ghrelin receptor stimulation. Virus-mediated overexpression of GH in the amygdala was also sufficient to increase fear. Finally, virus-mediated overexpression of a GH receptor antagonist was sufficient to block the fear enhancing effects of repeated ghrelin receptor stimulation. Thus, ghrelin requires GH in the amygdala to exert fear-enhancing effects. These results suggest that ghrelin mediates a novel branch of the stress response and highlight a previously unrecognized role for ghrelin and growth hormone in maladaptive changes following prolonged stress.

Plasma butyrylcholinesterase regulates ghrelin to control aggression

“…Some studies report that ghrelin relieves anxiety according to measures such as time spent in the open arm of an elevated plus maze (11,12,28). Others conclude that ghrelin acts in the amygdala to enhance fear and anxiety in rat models of posttraumatic stress disorder (15). The latter result supports our finding that chronic reduction of ghrelin promotes lower aggression, whereas chronic elevation has opposite effects.…”

“…Among BChE substrates that might drive differential responses to chronic social stress, ghrelin was the only plausible candidate (15). As BChE's catalytic activity with ghrelin had never been tested at physiological peptide concentrations (∼0.5 nM), we ran in vitro assays at that level and at 25 μM.…”

Sampling Blood from the Lateral Tail Vein of the Rat

“…The acute stress response can alter circulating levels of many molecules, including interleukins and other immune-active factors 7 , hormones of the hypothalamic-pituitary-adrenal axis 8 , hormones in the sympathetic nervous system 9 , ghrelin 10 , endogenous opioids 11 , dopamine, and serotonin Stress responses not only alter the composition of the blood, but also represent a technical obstacle for blood sampling because of the constriction of vasculature via increased drive from the sympathetic nervous system. It becomes increasing difficult to obtain steady blood flow from a rat that is mounting an acute stress response.…”

The potential of epigenetics in stress-enhanced fear learning models of PTSD

“…Evidence exists for effects of both a single restraint event and repeated restraints on subsequent fear learning. Several studies have shown increased freezing upon exposure to a context previously paired with shock in rodents that have undergone brief (30 min-2 h) restraint (Cordero et al 2003;Rodriguez Manzanares et al 2005;Tronson et al 2010), whereas other studies utilizing repeated restraint have observed increased freezing upon exposure to a tone previously paired with shock (Meyer et al 2014;Suvrathan et al 2014;Baratta et al 2015). The degree to which restraint stress affects fear learning, generalization, extinction rate, or extinction retention differs, depending on the method and duration of restraint, the varying delays between the stress and fear conditioning and differences in the amount of shock utilized during conditioning (Miracle et al 2006;Andero et al 2011Andero et al , 2013Chauveau et al 2012).…”