The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis.

Augmenting hippocampal neurogenesis represents a potential new strategy for treating depression. Here we test this possibility by comparing hippocampal neurogenesis in depression-prone ghrelin receptor (Ghsr)-null mice to that in wild-type littermates and by determining the antidepressant efficacy of the P7C3 class of neuroprotective compounds. Exposure of Ghsr-null mice to chronic social defeat stress (CSDS) elicits more severe depressive-like behavior than in CSDS-exposed wild-type littermates, and exposure of Ghsr-null mice to 60% caloric restriction fails to elicit antidepressant-like behavior. CSDS resulted in more severely reduced cell proliferation and survival in the ventral dentate gyrus (DG) subgranular zone of Ghsr-null mice than in that of wild-type littermates. Also, caloric restriction increased apoptosis of DG subgranular zone cells in Ghsr-null mice, although it had the opposite effect in wild-type littermates. Systemic treatment with P7C3 during CSDS increased survival of proliferating DG cells, which ultimately developed into mature (NeuN+) neurons. Notably, P7C3 exerted a potent antidepressant-like effect in Ghsr-null mice exposed to either CSDS or caloric restriction, while the more highly active analog P7C3-A20 also exerted an antidepressant-like effect in wild-type littermates. Focal ablation of hippocampal stem cells with radiation eliminated this antidepressant effect, further attributing the P7C3 class antidepressant effect to its neuroprotective properties and resultant augmentation of hippocampal neurogenesis. Finally, P7C3-A20 demonstrated greater proneurogenic efficacy than a wide spectrum of currently marketed antidepressant drugs. Taken together, our data confirm the role of aberrant hippocampal neurogenesis in the etiology of depression and suggest that the neuroprotective P7C3-compounds represent a novel strategy for treating patients with this disease.

Research Note: Retinal cryptochrome gene expression is not altered by presence of light in incubators.

Cryptochromes are blue-, or ultraviolet-, light-absorbing proteins involved in the circadian clock, blue/ultraviolet light perception and potentially magnetoreception. At least 4 separate cryptochrome genes have been identified in avian species. The purpose of this study was to first determine if cryptochrome genes are expressed in the developing duck retina, and second to determine if the presence of lights in incubators affects the expression of cryptochrome genes. To accomplish these goals, duck eggs were placed in one of 2 commercial incubators (Buckeye, Single Stage Incubator, Model, SS-112) at Maple Leaf Farms, Inc., one with "poultry" LEDs obtained from a commercial source (Once Innovation, Agrishift) and the other in the absence of light (dark). Eggs in the incubators were placed on a reciprocating tray, tilting to 45° to simulate the rotation of eggs; thus all eggs spent 50% facing the light source and the other 50% of time facing 45° away from light source. Temperature gradients and humidity were maintained at industry standards. Retinal tissue samples from light and dark incubators were collected on days 3, 7, 11, 16, and 21 of incubation (extraction day, ED) known to be anatomical hallmarks of visual system development (n = 9-18 treatment group/ED timepoint). Samples were prepped and assayed for Cry2 and GAPDH gene transcription using qRT-PCR. Data were analyzed by using 2-ddCt method and a 2-way ANOVA was performed. No significant differences in Cry2 gene expression were observed between the lighted or dark incubator (P > 0.10). When combining light and dark treatment groups there is a significant 9 P < 0.05) increase in retinal Cry2 at ED 21, compared to ED 3 and 7. The presence of cryptochrome does not necessitate a migratory drive as evidenced by the fact that the Cry2 expression has been shown in non-migratory birds. However, since blue/ultraviolet wavelengths also activate the Cry2 photoreceptor, its presence could explain reports that suggest duck welfare can be improved if housed under lights that include ultraviolet wavelengths.