Recent studies have shown that nerve growth factor (NGF) can improve learning and memory in animals with injury- or age-related neurodegeneration. However, little information exists regarding the effects of another neurotrophin, brain-derived neurotrophic factor (BDNF). Previous pharmacological approaches seemed to show that BDNF was not efficacious at improving cognition in aged, spatial learning- impaired animals. An alternative interpretation of the results os that BDNF does not diffuse well from the ventricles into the surrounding parenchyma. The present study attempts to use a genetic approach to investigate the potential effects of BDNF on learning and memory deficits in aged mice. The hypotheses to be tested are: 1) over- expression of BDNF in the cerebral cortex and hippocampus in aged mice could prevent atrophy of forebrain cholinergic neurons in vivo.2 ). Over-expression of BDNF in the cerebral cortex and hippocampus could improve spatial learning and memory in aged mice. To test the above hypothesis, the following specific aims are proposed: 1) Make tetO- BDNF/Emx1-cre mice. 2). Assess the ability of BDNF to sustain the phenotype of forebrain cholinergic neurons in aged mice brains through immunohistochemistry. 3). Determine whether the over-expression of the BDNF gene in the cerebral cortex and hippocampus would improve learning and memory in aged mice using the Morris water maze task. The research design uses bacterial recombinase Cre-mediated deletion and tetracycline regulated system in mice to over-express BDNF in the cerebral cortex and hippocampus and to study the consequences of the over-expression upon mutant animals' behavior and anatomy in aged brains. The health-relatedness of the project is that the results of the study will allow us to clarify the potential role of BDNF in the clinical therapy of neurodegenerative diseases.