Brain aging is characterized by a gradual loss of some populations of neurons (e.g. forebrain cholinergic, monoaminergic) as well as decreases in excitatory synapses in cortical telencephalon. The proposed research will examine the possibility that disturpances in neurotrophic relationships contribute to these two classes age-associated effects. Results of colocalization studies conducted during the previous funding period suggest that acidic fibroblast growth factor (aFGF) and brain-derived neurotrophic factor (BDNF) are putative autocrine neurotrophic factors for forebrain cholinergic and midbrain dopaminergic neurons, respectively. The first set of experiments will test the hypothesis that age-related losses in the expression of these factors contribute to the reduced viability of cholinergic and dopaminergic neurons with age.
Specific Aim 1 is to use in situ and solution hybridization techniques to determine if losses in aFGF and BDNF mRNA expression precede or accompany age-related losses in cholinergic and dopaminergic neurons, respectively, as expected if the former events contribute to the latter. The second group of studies is motivated by the discovery that insulin-like growth factor-I (IGF-1) expression is correlated with axon sprouting in adult brain and by the working hypothesis that IGF-1 plays a critical role in the regulation of reactive axonal growth and synaptic replacement throughout life.
Specific Aim #2 will test if lesion-induced increases in IGF-1 expression are reliably correlated with the parameters of axonal growth in cortical telencephalon as would be expected if this factor regulates the growth response.
Aims 2 a and 2b are to determine if parameters of IGF-1 mRNA expression are delayed in association with the delayed time course of sprouting previously documented to be present (a) in aged rat and (b) in the C57BL/Ola mouse strain.
Specific Aim 2 c will determine if intraventricular infusion of antibody to IGF-1 interferes with lesion-induced sprouting of surviving septal and commissural/associational afferents to the partially deafferented rat hippocampus.
Specific Aim 3 will examine the hypothesis that disturbances in IGF-1 expression are associated with disturbances in processes of axonal growth and synaptic replacement that are present in aged and Alzheimer's diseased (AD) hippocampus. Specifically, it will be determined if levels and patterns of IGF-1 mRNA expression are altered with increasing age and Alzheimer's disease and, in particular, if expression is increased in regions of pathological axonal growth. The proposed studies will determine if with increasing age and age-related disease there are disturbances in specific trophic relationships indicated to be important for neuronal survival and maintenance of innervation patterns in adult brain. Through the identification of chemistries that subserve neuronal viability and functional plasticity in adult brain, it should ultimately be possible to exploit these trophic mechanisms for the design of therapeutic strategies to optimize neuronal survival and function through aging and to counteract the deleterious effects of specific neurological diseases.
Showing the most recent 10 out of 281 publications
