Abstract
Purpose:
To develop a novel system with which to monitor and experimentally modulate intracranial pressure (ICP) in active, awake mice. To use this system to assess the impact of elevated ICP on the optic nerve and retinal ganglion cells (RGCs).
Methods:
We developed a novel experimental system and used it to measure and modulate ICP in CD1 mice. This system involved surgical implantation of an infusion cannula and a radio wave-emitting pressure monitoring probe through the skull and into the subarachnoid space. The infusion cannula was used to increase ICP via the controlled infusion of artificial cerebrospinal fluid with a gravity-based system. The increased ICP was measured and the data transmitted by the nearby probe where it was collected wirelessly by paired receivers and outputted for offline analysis. We chronically increased ICP for one week and assessed changes in optic nerve structure with histology and Toluidine Blue staining and RGC numbers with antibody staining to beta-III-tubulin in retinal flat mounts (n = 6). Control animals underwent parallel surgery without elevation of ICP (n = 6). Paired t-tests were used to evaluate the difference in optic nerve fiber and RGC counts for elevated ICP versus control groups.
Results:
The system provided robust ICP waveforms which allowed for the identification of both typical respiratory and circulatory patterns. The system was stable over time and did not show any drift in ICP level. Animals were active following surgery and ICP could be consistently measured while the animals were awake. Acute ICP elevation did not cause a concomitant rise in intraocular pressure. ICP was elevated to approximately 30mmHg for one week and resulted in marked optic nerve axonal loss (35.7% reduction of nerve fibers, p < 0.001) and disorganization (dysmorphic and swollen axons) compared to controls. ICP elevation also resulted in prominent RGC loss in retinal flat mounts (20.7% reduction of beta-III-tubulin positive cells, p < 0.001) compared to controls.
Conclusions:
We have developed a novel experimental system for the controlled manipulation of ICP in active, awake mice and found that increased ICP results in RGC soma loss and optic nerve axon degeneration. This model can be used to study both the effects of ICP change and alteration of the ICP-IOP gradient in a variety of ophthalmologic and neurologic conditions.