One of the major changes in the human brain during aging is the deterioration of memory. It has been suggested that specific neurotransmitter systems, such as the cholinergic and the noradrenergic (NE), are intimately involved in memory processes, and that changes in these systems may contribute to the age-related impairment of cognitive function. Most studies of age-related alterations in the brain are performed in the intact animal. While these studies can give valuable information, they cannot distinguish between direct effects on a neuronal population, and secondary effects caused by extrinsic factors or indirectly through other neuronal populations. By placing fetal brain tissue transplants in either young or old host animals, it is possible to create """"""""young-old"""""""" chimeras in the rat host. This study is focussed on examining the neuronal plasticity of transplanted NE neurons from the locus coeruleus (LC-NE) during aging. We propose two experiments: First, transplantation of LC-hippocampal double grafts to the anterior eye chamber and, after 22 months, addition of one more hippocampal transplant. Electrophysiology and immunohistochemistry will be performed to examine the NE innervation into young and old hippocampal grafts in the triple grafts, both which are supposedly innervated by the same NE neurons from the LC graft. The second portion of the study deals with reinnervation of young or old LC-NE neurons into young or old iris transplants. Iris transplants initiate collateral sprouting of transplanted LC neurons. This strong stimulatory response will be tested against aging to investigate a possible change in NE fiber plasticity. We believe that the transplantation model described above can answer some questions concerning intrinsic vs. extrinsic factors involved in age-related changes in noradrenergic neuron plasticity. This is the short-term ,goal of these two experiments. The long-term goal is to understand the mechanisms behind cognitive defects during aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29MH049661-03
Application #
2249028
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
1992-08-01
Project End
1997-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Miscellaneous
Type
Schools of Dentistry
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Granholm, A C; Helt, C; Srivastava, N et al. (2001) Effects of age and GDNF on noradrenergic innervation of the hippocampal formation: studies from intraocular grafts. Microsc Res Tech 54:298-308
Henry, S; Pfenninger, K H; Mott, J L et al. (1999) Anatomical distribution of glycoprotein 93 (gp93) on nerve fibers during rat brain development. Cell Tissue Res 297:67-79
Granholm, A C; Albeck, D; Backman, C et al. (1998) A non-invasive system for delivering neural growth factors across the blood-brain barrier: a review. Rev Neurosci 9:31-55
Nagy, J I; Price, M L; Staines, W A et al. (1998) The hyaluronan receptor RHAMM in noradrenergic fibers contributes to axon growth capacity of locus coeruleus neurons in an intraocular transplant model. Neuroscience 86:241-55
Granholm, A C; Henry, S; Herbert, M A et al. (1998) Kidney cografts enhance fiber outgrowth from ventral mesencephalic grafts to the 6-OHDA-lesioned striatum, and improve behavioral recovery. Cell Transplant 7:197-212
Srivastava, N; Backman, C (1998) Effects of ethanol on development of locus coeruleus brain stem transplants in oculo. Exp Neurol 149:139-50
Albeck, D S; Hoffer, B J; Quissell, D et al. (1997) A non-invasive transport system for GDNF across the blood-brain barrier. Neuroreport 8:2293-8
Granholm, A C; Srivastava, N; Mott, J L et al. (1997) Morphological alterations in the peripheral and central nervous systems of mice lacking glial cell line-derived neurotrophic factor (GDNF): immunohistochemical studies. J Neurosci 17:1168-78
Granholm, A C; Mott, J L; Bowenkamp, K et al. (1997) Glial cell line-derived neurotrophic factor improves survival of ventral mesencephalic grafts to the 6-hydroxydopamine lesioned striatum. Exp Brain Res 116:29-38
Srivastava, N; Granholm, A C; Gerhardt, G A (1997) Collateral sprouting of central noradrenergic neurons during aging: histochemical and neurochemical studies in intraocular triple transplants. Exp Neurol 145:524-35

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