Abstract
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.
Keywords
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Article info
Publication history
Published online: November 28, 2016
Accepted:
November 10,
2016
Received in revised form:
October 25,
2016
Received:
July 18,
2016
Identification
Copyright
© Society of Biological Psychiatry, 2016.
