Defense Date

2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Physiology

First Advisor

Richard Costanzo

Abstract

The olfactory system has the remarkable capacity for neurogenesis following injury. However, the molecular mechanisms important for reinnervation of the olfactory bulb (OB) remain unknown. The matrix metalloproteinases (MMPs) are important components in many central nervous system (CNS) injury paradigms, yet remain unexplored in olfactory injury and recovery. To address the role of MMPs, the temporal expressions of MMP-9 and MMP-2 were examined in 3 olfactory injury models: nerve transection (NTx), methyl bromide gas (MeBr) exposure, and nerve transection with Teflon barrier (NTx-TB). Each injury model represents a different degree of olfactory injury and neuronal recovery. In NTx, sensory axons are lesioned, leading to neuronal degeneration and subsequent reinnervation of the OB. MeBr exposure damages the cell bodies of sensory neurons in the peripheral olfactory epithelium (OE), leading to degeneration and reinnervation of the OB without direct trauma to the OB. In NTx-TB, sensory axons are lesioned and a barrier is inserted following injury that blocks regenerated neurons from reinnervation of the OB. Following NTx, MMP-9 increased immediately in the OB and was localized to neutrophils, an inflammatory leukocyte. The elevated levels of MMP-9 corresponded to neuronal degeneration. To confirm this relationship, MMP-9 expression was measured following MeBr injury. MMP-9 increased during neuronal degeneration in the OB and was localized to neutrophils in the area of sensory axon degradation. These experiments demonstrated that MMP-9 is important for both neuronal degeneration and the acute inflammatory response following olfactory injury. In NTx injury, MMP-2 expression peaked at day 7 and corresponded to the transition between degeneration and reinnervation of the OB. MMP-2 was localized to the granule cell and external plexiform layers in control and day 7 bulbs. Following NTx-TB, MMP-2 remained low and was not expressed by regenerated axons. The absence of a MMP-2 peak in the NTx-TB injury suggests that this peak depends on reinnervation of the OB. This study demonstrates a temporal correlation between MMP-9 and degeneration and MMP-2 and reinnervation following olfactory injury. These findings provide new insight into the molecular mechanisms underlying olfactory nerve injury. Modulation of MMPs could provide novel therapeutic interventions to improve neuronal recovery following injury.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

October 2010

Included in

Physiology Commons

Share

COinS