Determining the roles of brain-derived neurotrophic factor (BDNF) and neuronal synchrony in the memory-enhancing effects of testosterone in the aging male brain.

PROJECT SUMMARY / ABSTRACT Cognitive decline is a common component of aging, and spatial memory is especially affected by old age. Testosterone levels among men decline steadily with aging, paralleling the age-related decline in cognitive ability, which suggests that there may be a causal link between these two processes. Past

studies have produced mixed results regarding the cognitive benefits of androgen therapies for hypogonadal aged men, highlighting the need for an animal model to experimentally test the therapeutic value of testosterone treatment. With increasing age, there is also a transition from the use of a striatum-dependent response strategy to the use of a hippocampus-dependent place strategy for

solving navigational tasks, and declining testosterone levels may be the cause of this shift. The proposed experiments will assess the physiological mechanisms underlying testosterone-induced changes in spatial memory and strategies, using castrated, aged male rats as a model for hypogonadal aged men. The specific aims of the proposed experiments are to determine: 1) the relative effects of

testosterone and aging on place and response learning in males, 2) the role of brain-derived neurotrophic factor (BDNF) in regulating testosterone-induced changes in spatial memory, and 3) the role of neural synchrony in regulating testosterone-induced changes in spatial memory. Each experiment will involve testosterone injections given to castrated male rats from young, middle-aged,

and old groups. In Experiment 1, rats will be injected with three different physiological doses of testosterone and tested on plus-maze tasks that require the use of either a place or response strategy. This will test whether testosterone can shift older rats to increase their use of a place strategy, more

typical of younger males. Such behavioral results would suggest improved hippocampal function. To test this further, BDNF and related markers of neuroplasticity (TrkB, PSD-95) will be assayed from hippocampal and striatal tissue collected from all subjects. Experiment 2 will test whether BDNF is necessary for the memory-enhancing effects of testosterone by injecting some subjects intra-cranially

(hippocampus or striatum) with a TrkB antagonist (ANA-12) in combination with testosterone dosing. Experiment 3 will explore the effects of testosterone on neural connectivity of the hippocampus and striatum using electrophysiological recordings on active rats. Past work suggests that reduced in-phase

theta waves between the hippocampus and striatum facilitate place learning. Testosterone treatment is, therefore, expected to reduce in-phase activity, possibly restoring neural synchrony in older rats to that which is typical of a younger brain. In combination, these experiments will provide a critical step in

determining the therapeutic value of testosterone for treating age-related memory impairment.