Ghrelin/GHSR signaling protects against depression-like behaviors and preserves hippocampal neurogenesis in stressed mice via the PI3K pathway.
Background
Ghrelin, widely known as an orexigenic (appetite-stimulating) hormone, also plays a critical but less understood role in mood regulation and depression. Previous work has shown ghrelin administration can alleviate depression-like behaviors in rodents subjected to chronic unpredictable mild stress (CUMS), a common animal model for depression. However, the precise molecular mechanisms behind this neuroprotective effect, particularly regarding the integrity of the hippocampus—a brain region vital for mood and memory—have remained unclear. This study investigates the role of the ghrelin/growth hormone secretagogue receptor (GHSR) signaling pathway in preserving hippocampal neurogenesis and synaptic plasticity under chronic stress conditions, aiming to clarify how this system confers resilience.
Study Design
The study used a chronic unpredictable mild stress (CUMS) mouse model. One group of CUMS mice received Ghrelin (5 nmol/kg/day) via intraperitoneal (i.p.) injection for 2 weeks. To assess the role of its receptor, Ghsr-null (knockout) and wild-type mice were evaluated with and without CUMS exposure. Neurogenesis and spine density were measured using Ki67, BrdU, and DCX labeling, alongside Golgi-cox staining. In vitro, primary cultured hippocampal neural stem cells (NSCs) were treated with ghrelin, the GHSR antagonist D-Lys3-GHRP-6 (DLS, 100 μM), and the PI3K inhibitor LY294002 (20 μM), with cell proliferation assessed via CCK8 and EdU assays. Finally, the PI3K inhibitor LY294002 (50 nmol) was administered intracerebroventricularly (i.c.v.) in vivo to confirm the pathway's involvement.
Results
Ghrelin administration successfully decreased depression-like behaviors induced by CUMS and reversed the stress-induced decline in hippocampal neurogenesis and spine density. Ghsr-null mice displayed inherent depression-like behaviors even without stress and, like wild-type mice, showed further deleterious effects on neurogenesis and spine density in the dentate gyrus after CUMS exposure. In vitro, ghrelin demonstrated a direct proliferative effect on hippocampal NSCs. > This pro-neurogenic effect was completely blocked by pre-treatment with the GHSR antagonist D-Lys3-GHRP-6 (DLS, 100 μM). The mechanism was linked to the PI3K pathway, as the ghrelin-induced proliferation was associated with inhibition of G1 cell cycle arrest, an effect that was blocked by the PI3K inhibitor LY294002. Crucially, in vivo administration of LY294002 also significantly blocked the antidepressant-like actions of exogenous ghrelin, confirming the PI3K pathway's essential role in mediating ghrelin's neuroprotective effects.
Key Findings
- Ghrelin (5 nmol/kg/day for 2 weeks, i.p.) decreased depression-like behaviors and increased hippocampal neurogenesis in CUMS mice.
- Ghsr-null mice exhibited baseline depression-like behaviors, indicating an inherent role for GHSR in mood regulation.
- The proliferative effect of ghrelin on hippocampal NSCs was blocked by the GHSR antagonist D-Lys3-GHRP-6 (100 μM).
- Ghrelin's pro-proliferative effect on NSCs was blocked by the PI3K inhibitor LY294002 (20 μM).
- In vivo, the antidepressant-like action of ghrelin was significantly blocked by intracerebroventricular injection of LY294002 (50 nmol).
Why It Matters
This research reinforces the ghrelin system's role beyond metabolism, highlighting its inherent neuroprotective and antidepressant functions. For biohackers and researchers, this suggests that modulating the GHSR pathway may be a viable strategy for enhancing cognitive resilience and combating stress-induced mood disorders. The findings implicate the GHSR/PI3K signaling axis as a key target for therapeutic development against depression. However, this is preclinical animal data; translating these findings into a human protocol is distant. The study underscores a direct link between a gut-derived hormone and brain health, suggesting that interventions targeting ghrelin levels or GHSR activity could potentially support hippocampal integrity. This could influence protocols aimed at cognitive enhancement or mood stabilization, especially in the context of chronic stress.
