Caspase inhibitor infusion protects an avian song control circuit from seasonal-like neurodegeneration.

Sex steroids such as androgens and estrogens have trophic effects on the brain and can ameliorate neurodegeneration, and the withdrawal of circulating steroids induces neurodegeneration in several hormone-sensitive brain areas. Very little is known about the underlying molecular mechanisms that mediate neuronal regression caused by hormone-withdrawal, however. Here we show that reduction of programmed cell death by local infusion of caspase inhibitors rescues a telencephalic nucleus in the adult avian song control system from neurodegeneration that is induced by hormone withdrawal. This treatment also has trans-synaptic effects that provide some protection of an efferent target region. We found that unilateral infusion of caspase inhibitors in vivo in adult white-crowned sparrows rescued neurons within the hormone-sensitive song nucleus HVC (used as a proper name) from programmed cell death for as long as seven days after withdrawal of testosterone and a shift to short-day photoperiod and that the activation of caspase-3 was reduced by 59% on average in the ipsilateral HVC compared with the unmanipulated contralateral HVC. Caspase inhibitor infusion near HVC was sufficient to preserve neuron size ipsilaterally in a downstream nucleus, the robust nucleus of the arcopallium. This is the first report that sustained local application of caspase inhibitors can protect a telencephalic brain area from neurodegeneration in vivo and that a degenerating neural circuit rescued with caspase inhibitors produces sufficient trophic support to protect attributes of a downstream target that would otherwise degenerate. These results strengthen the case for the possible therapeutic use of caspase inhibitors under certain neurodegenerative conditions.