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.
