Distinct Roles for Neuropilin1 and Neuropilin2 during Mouse Corneal Innervation

Trigeminal sensory innervation of the cornea is critical for protection and synthesis of neuropeptides required for normal vision. Little is known about axon guidance during mammalian corneal innervation. In contrast to the chick where a pericorneal nerve ring forms via Npn/Sema signaling, mouse corneal axons project directly into the presumptive cornea without initial formation of an analogous nerve ring. Here we show that during development of the mouse cornea, Npn1 is strongly expressed by the trigeminal ganglion whereas Npn2 is expressed at low levels. At the same time Sema3A and Sema3F are expressed in distinct patterns in the ocular tissues. Npn1sema−/− mutant corneas become precociously and aberrantly innervated by nerve bundles that project further into the corneal stroma. In contrast, stromal innervation was not affected in Npn2−/− mutants. The corneal epithelium was prematurely innervated in both Npn1sema−/− and Npn2−/− mutants. These defects were exacerbated in Npn1sema−/−;Npn2−/− double mutants, which in addition showed ectopic innervation of the region between the optic cup and lens vesicle. Collectively, our data show that Sema3A/Npn1 and Sema3F/Npn2 signaling play distinct roles and both are required for proper innervation of the mouse cornea

Biophysical and functional consequences of receptor-mediated nerve fiber transformation.

Stimulation of the nervous system by substance P, a G protein-coupled receptor, and subsequent receptor internalization causes dendrites to change their shape from homogeneous cylinders to a heterogeneous string of swollen varicosities (beads) connected by thin segments. In this paper we have analyzed this phenomenon and propose quantitative mechanisms to explain this type of physical shape transformation. We developed a mathematical solution to describe the relationship between the initial radius of a cylindrical nerve fiber and the average radii of the subsequently created varicosities and connecting segments, as well as the periodicity of the varicosities along the nerve fiber. Theoretical predictions are in good agreement with our own and published experimental data from dorsal root ganglion neurons, spinal cord, and brain. Modeling the electrical properties of these beaded fibers has led to an understanding of the functional biophysical consequences of nerve fiber transformation. Several hypotheses for how this shape transformation can be used to process information within the nervous system have been put forth

Intranasal Neuropeptide Y as a Potential Therapeutic for Stress-Triggered Disorders in Females

Objective: Examine whether intranasal neuropeptide Y (NPY) is able to alter development of several stress-triggered behavioral impairments in females. Background: Sex is involved in susceptibility to many stress-elicited, neuropsychiatric disorders. However, most of the studies in animal models examining putative therapeutics excludes females. Previous studies in males demonstrated intranasal NPY provided therapeutic relief of stress-elicited behaviors, but not at the same dose in females. Interestingly, the overwhelming majority of studies found that NPY expression is lower in females than in male rodents in many brain areas. Design/Methods: Sprague Dawley female rats were exposed to the Single Prolonged Stress (SPS) animal model and then were immediately infused intranasally with one of several NPY doses starting with 600 μg/rat, which is double the dose effective in males. In a separate cohort of animals, females were infused intranasally with 600μg NPY, a dipeptidyl peptidase IV (DPP4; NPY protease) inhibitor, or both immediately after the SPS stressors. After 14 days they were tested on several behavioral tests. Results: Intranasal NPY at 600μg prevented the SPS-elicited impairment of social interaction. On the forced swim test (FST), there was a dose-response effect of intranasal NPY, with the 1200μg, but not the 600μg, effectively preventing development of the SPS-elicited increased immobility (depressive-like behavior). However, the DPP4 inhibitor and 600μg NPY combined treatment was sufficient at preventing depressive-like behavior on the FST. Conclusions: The results indicate that in females SPS elicits behavioral manifestations of stress-related disorders, such as depressive-like behavior and social impairment. This was prevented with early intervention with high doses of NPY, indicating its therapeutic potential also for females, although a higher dose will likely be required. Furthermore, NPY degradation may play a role in the higher dose requirement for females