GPR179 is required for high sensitivity of the mGluR6 signaling cascade in depolarizing bipolar cells.

Parallel visual pathways are initiated at the first retinal synapse by signaling between the rod and cone photoreceptors and two general classes of bipolar cells. For normal function, ON or depolarizing bipolar cells (DBCs) require the G-protein-coupled receptor, mGluR6, an intact G-protein-coupled cascade and the transient receptor potential melastatin 1 (TRPM1) cation channel. In addition, another seven transmembrane protein, GPR179, is required for DBC function and recruits the regulators of G-protein signaling (RGS) proteins, RGS7 and RGS11, to the dendritic tips of the DBCs. Here we use the Gpr179(nob5) mouse, which lacks GPR179 and has a no b-wave electroretinogram (ERG) phenotype, to demonstrate that despite the absence of both GPR179 and RGS7/RGS11, a small dark-adapted ERG b-wave remains and can be enhanced with long duration flashes. Consistent with the ERG, the mGluR6-mediated gating of TRPM1 can be evoked pharmacologically in Gpr179(nob5) and RGS7(-/-)/RGS11(-/-) rod BCs if strong stimulation conditions are used. In contrast, direct gating of TRPM1 by capsaicin in RGS7(-/-)/RGS11(-/-) and WT rod BCs is similar, but severely compromised in Gpr179(nob5) rod BCs. Noise and standing current analyses indicate that the remaining channels in Gpr179(nob5) and RGS7(-/-)/RGS11(-/-) rod BCs have a very low open probability. We propose that GPR179 along with RGS7 and RGS11 controls the ability of the mGluR6 cascade to gate TRPM1. In addition to its role in localizing RGS7 and RGS11 to the dendritic tips, GPR179 via a direct interaction with the TRPM1 channel alters its ability to be gated directly by capsaicin.

The Effects of Sex and Chronic Restraint on Instrumental Learning in Rats.

Chronic stress has been shown to impact learning, but studies have been sparse or nonexistent examining sex or task differences. We examined the effects of sex and chronic stress on instrumental learning in adult rats. Rats were tested in an aversive paradigm with or without prior appetitive experience, and daily body weight data was collected as an index of stress. Relative to control animals, reduced body weight was maintained across the stress period for males (-7%, P ≤ .05) and females (-5%, P ≤ .05). For males, there were within-subject day-by-day differences after asymptotic transition, and all restrained males were delayed in reaching asymptotic performance. In contrast, stressed females were facilitated in appetitive and aversive-only instrumental learning but impaired during acquisition of the aversive transfer task. Males were faster than females in reaching the appetitive shaping criterion, but females were more efficient in reaching the appetitive tone-signaled criterion. Finally, an effect of task showed that while females reached aversive shaping criterion at a faster rate when they had prior appetitive learning, they were impaired in tone-signaled avoidance learning only when they had prior appetitive learning. These tasks reveal important nuances on the effect of stress and sex differences on goal-directed behavior.