Chronic Social Defeat Stress Increases Brain Permeability to Ghrelin in Male Mice.

Ghrelin is a stomach-derived hormone that increases feeding and is elevated in response to chronic psychosocial stressors. The effects of ghrelin on feeding are mediated by the binding of ghrelin to the growth hormone secretagogue receptor (GHSR), a receptor located in hypothalamic and extrahypothalamic regions important for regulating food intake and metabolic rate. The ability of ghrelin to enter the brain, however, seems to be restricted to circumventricular organs like the median eminence and the brainstem area postrema, whereas ghrelin does not readily enter other GHSR-expressing regions like the ventral tegmental area (VTA). Interestingly, social stressors result in increased blood-brain barrier permeability, and this could therefore facilitate the entry of ghrelin into the brain. To investigate this, we exposed mice to social defeat stress for 21 d and then peripherally injected a Cy5-labelled biologically active ghrelin analog. The results demonstrate that chronically stressed mice exhibit higher Cy5-ghrelin fluorescence in several hypothalamic regions in addition to the ARC, including the hippocampus and midbrain. Furthermore, Cy5-ghrelin injections resulted in increased FOS expression in regions associated with the reward system in chronically stressed mice. Further histologic analyses identified a reduction in the branching of hypothalamic astrocytes in the ARC-median eminence junction, suggesting increased blood-brain barrier permeability. These data support the hypothesis that during metabolically challenging conditions like chronic stress, ghrelin may be more able to cross the blood-brain barrier and diffuse throughout the brain to target GHSR-expressing brain regions away from circumventricular organs.

Growth Hormone Secretagogue Receptor (GHSR) Signaling in the Ventral Tegmental Area (VTA) Mediates Feeding Produced by Chronic Social Defeat Stress in Male Mice.

Ghrelin, a hormone secreted by the stomach, binds to the growth hormone secretagogue receptor (GHSR) in various brain regions to produce a number of behavioral effects that include increased feeding motivation. During social defeat stress, ghrelin levels rise in correlation with increased feeding and potentially play a role in attenuating the anxiogenic effects of social defeat. One region implicated in the feeding effects of ghrelin is the ventral tegmental area (VTA), a region implicated in reward seeking behaviors, and linked to social defeat in mice. Here we examined the role of GHSR signaling in the VTA in feeding behavior in mice exposed to social defeat stress. Male C57BL/J6 mice that were socially defeated once daily for 3 weeks ate more, had higher plasma ghrelin level and increased GHSR expression in the VTA compared to non-stressed mice. Socially defeated GHSR KO mice failed to increase their caloric intake in response to this stressor but rescue of GHSR expression in the VTA restored feeding responses. Finally, we pharmacologically blocked VTA GHSR signalling with JMV2959 infused via an indwelling VTA cannula connected to a minipump. Vehicle-treated mice increased their caloric intake during social defeat, but JMV2959-infusions attenuated feeding responses and increased anxiety-like behaviors. The data suggest that GHSR signalling in the VTA is critical for the increases in appetite observed during chronic social defeat stress. Furthermore, these data support the idea that GHSR signaling in the VTA may also have anxiolytic effects, and blocking GHSR in this region may result in an anxiety-like phenotype.