affect learning and memory can be linked to brain structure in a precise manner. It will also be crucial to avoid the syndrome of ''looking for your keys under the street lamp." If one is manipulating gene X to affect behavior Y, one cannot assume that targeted circuits will react in a simple predictable fashion. Analyses of genetically manipulated mice must be comprehensive and quantitative, casting a wide net with respect to affected circuits and behaviors.

The nonhuman primate is also an increasingly important animal model, particularly for studies of cognition (Rapp and Amaral, 1992; Moss et al., 1999) and studies of hormonal effects (Abel et al., 1999). The issues of estrogen, menopause, and the effects of ERT on the hippocampus will be particularly important to analyze in a primate model, given the similarities between nonhuman primate reproductive physiology and that of humans, as well as the advanced cognitive abilities of the nonhuman primate compared with rodent models. In addition, given the extraordinary resource that aged primates represent, these studies should be multidisciplinary whenever possible in order to ensure that interactive datasets are obtained and that the animals are used as fully as possible.

Restoring Circuits

Given that both normal aging and neurodegenerative disorders disrupt selectively vulnerable circuits, it would appear that the most successful interventions will be those that have a sufficient degree of circuit selectivity. Is there any evidence that damaged or degenerating circuits can be restored in the brain, and if so how successful and selective is the restoration? There is a long history of such attempts and a large resultant literature that is beyond the scope of this review; however, it is informative to the present discussion on aging and neurodegenerative disorders to highlight several of the key approaches that have been attempted, such as tissue transplantation, transplanting engineered cells or viral vectors for gene therapy, the promise of stem cells, and the potential for exploiting the natural neurogenesis that occurs in the adult brain.

Transplantation Strategies

Transplantation of embryonic brain tissue into a damaged adult brain was one of the first strategies developed for circuit repair. Generally, select tissue from the donor embryo brain that contains the neurons destined to provide a replacement for the damaged circuit is surgically implanted in the deafferented region. The most successful animal models have involved the initial surgical destruction of the dopaminergic innervation of caudate followed by the transplantation of fetal substantia nigra from a donor brain in



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