Date

October 2008

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

In mammals, light input through the retina is responsible for entraining the circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. This occurs via retinal projections from a subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) which express the photopigment, melanopsin. Although studies have shown that the rod and cone photoreceptors that mediate image-forming vision are not required for photoentrainment, data suggest that these cells play a role in this process. The goal of this project was to test the hypothesis that during development, maturation of the outer retina regulates the proper development of the ipRGCs. In this way, the rod and cone photoreceptors may influence the function of the circadian system in the adult. I used a strain of retinally degenerate mice (CBA/J) to look at the effects of early retinal degeneration on the circadian system. Wheel running experiments were done to examine photoentrainment in CBA/J mice. These mice show attenuated phase shifting behaviors and entrain to a narrower range of T cycles (non-24 hour cycles) compared to control (CBA/N) mice. Using immunohistochemistry I examined the effects of retinal degeneration on the development of ipRGCs by looking at their numbers, distribution and dendritic stratification. These studies show that dendritic stratification and cell distribution of ipRGCs are unaffected by photoreceptor loss. However, the CBA/J mice have greater numbers of ipRGCs suggesting that rods and cones may control the normal developmental death of ipRGCs. Using the pupillary light reflex (PLR) as a functional assay, I show that the melanopsin pathway is functioning properly at the level of the retina, and therefore, functional changes in the retina are not sufficient to explain the differences in behavior. To examine whether changes in central processing could explain the differences seen in the behaviors of the CBA/J mice, I used immunohistochemistry to examine the structural anatomy of the SCN and found that there are greater numbers of vasoactive intestinal peptide (VIP) -expressing cells, which receive direct retinal input. In addition, there are greater numbers of vasopressin (VP) -positive cells, which are responsible for SCN output. Using tracer studies I labeled the retinal projections to the SCN and found that there is no difference in the degree of anatomical innervation in the SCN of CBA/J mice. To test whether there were differences in functional innervation between the two strains, I conducted light-induced c-fos expression experiments. These studies show that CBA/J mice display a greater degree of c-fos induction compared to the controls. Further work is needed to understand how the differences seen in the CBA/J mice influence behavior. Together the findings in this work implicate a role of visual system maturation in influencing the function of the circadian system.

Identifier

doi:10.6083/M4FX77D3

Division

Neuroscience Graduate Program

School

School of Medicine

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