Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory

Abstract

Background There are many contradictory findings on 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 (ELISA) 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 inter-individual 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 both a 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.

Acyl ghrelin improves cognition, synaptic plasticity deficits and neuroinflammation following amyloid β (Aβ1‐40) administration in mice

“…This is likely a result of the different mechanisms of action of ghrelin/GHSR signalling with respect to controlling different memory domains encoded by different brain circuits. By contrast to the control of hippocampal‐dependent spatial memory, which may involve neuroinflammation and synaptic plasticity based on our data, the ghrelin/GHSR‐mediated control of the consolidation of contextual fear memory instead requires the down‐regulation of GHSR in the amygdala . The effect of endogenous ghrelin on olfactory memory might involve a different mechanism, such as ghrelin‐induced neurogenesis, which is known to affect olfactory discrimination .…”

“…Considering the important role of ghrelin and GHSR signalling in conveying energy deficit, it is likely that ghrelin/GHSR signalling in the hippocampus enhances spatial learning to promote re‐feeding and restoration of energy balance . However, this ghrelin/GHSR signalling may operate differently in different brain regions because contextual fear memory is also dependent on GHSR but is independent of energy balance …”

Is Ghrelin Synthesized in the Central Nervous System?

“…GHSR-1a is expressed in all three components of the dorsal vagal complex, and central administration of ghrelin to rodents recapitulates some of these actions of the hormone [31,32,33]; however, the extent to which these effects of ghrelin depend on its action at central level in humans is currently uncertain. Finally, it is interesting to stress that studies in rodents have shown that ghrelin system also impacts on higher cognitive functions, such as learning and memory, but the implications of these studies in humans are currently unclear [34,35]. …”

The brain-adipocyte-gut network: Linking obesity and depression subtypes

“…Obesity-dependent ghrelin resistance will suppress these antidepressant and neuroprotective effects (Lutter et al, 2008), promoting MDD. Recent animal studies indicate stressrelated ghrelin resistance also contributes to amygdala hyperactivation and overconsolidation of fear memories, independent of appetite responses (Harmatz et al, 2017).…”