SAT-052 Ghrelin Signalling Mediates the Impact of Meal Feeding on Hippocampal Neurogenesis and Resultant Behaviour in Male Mice

Abstract Disclosure: A.K. Hornsby: None. F. Hansen: None. M.A. Good: None. J.S. Davies: None. T. Wells: None. Temporal feeding schedules regulate the pattern and activity of hormone secretion, but the broader impact of these feeding rhythms remains poorly understood. We have used a CLAMS-based feeding station to demonstrate that, unlike grazing (GR), meal feeding (MF) elevates GH pulsatility to promote skeletal growth in mice via the action of ghrelin. Here we expand our analysis to investigate the impact of these feeding patterns on additional actions of ghrelin. Cumulative food intake (cF/I) in nocturnal MF wild-type (WT) male mice was 88% of that in ad libitum-fed (AL) mice (P=0.077) without affecting body weight or abdominal adiposity. This was exaggerated in GH secretagogue receptor (GHSR)-null mice (cF/I reduced by 15%; P=0.004) without influencing weight gain. While GR had no effect on cF/I or weight gain, abdominal adiposity was elevated by 32% (P=0.034), this being abolished in the absence of GHSR. MF doubled new neuron (BrdU+/NeuN+) survival in the granule cell layer (GCL) of the rostral dentate gyrus (rDG) (P=0.034), but reduced new non-neuronal (BrdU+/NeuN-) cell survival in the upper blade of the rDG by 71% (P=0.033); these effects being diminished in GHSR-null mice. In contrast, MF and GR doubled new neuron survival in the upper blade of the caudal DG (cDG), but only in the absence of GHSR (P=0.029 and 0.040). While GR had no impact on new neuron survival in the presence of GHSR, GR quadrupled new non-neuronal cell survival in the GCL of the cDG (vs AL-fed mice; (P=0.051). Absence of GHSR reduced new neuron survival by 54% in the upper blade of the cDG in AL mice (P=0.036). In the novel object-in-place (OiP) memory task that relies upon the hippocampus, AL WT mice discriminated significantly between moved and stationary objects (P=0.002). While this was not significant in GR mice (P=0.088) it was fully maintained in MF mice (P=0.0003). In contrast, OiP was maintained in both GR and MF mice in the absence of GHSR (P=0.030 & 0.018). In an open field test, MF GHSR-null mice showed a significant increase in anxiety-like behaviour (44% reduction in inner zone time vs MF WT littermates ; P=0.007), whereas the MF-induced elevation in outer zone velocity in WT mice, (P=0.006) was abolished in the absence of GHSR (P=0.006). GR did not affect time spent in the inner zone (vs AL WT and GR GHSR-null littermates; P=0.723 & 0.609), but overall and inner zone velocity increased in the absence of GHSR signalling (AL GHSR-null vs GR GHSR-null; P=0.027 & 0.019). In conclusion, MF promotes skeletal growth and modifies the spatial dynamics of new adult-born cell survival in the hippocampus to maintain spatial memory, with ghrelin acting to reduce anxiety and maintain exploration. In contrast, GR promotes fat deposition and impairs spatial memory. Our data imply that the impact of the contemporary shift from regular meals to less structured feeding on the ghrelin system may have a range of detrimental health outcomes. Presentation: Saturday, July 12, 2025