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The Journal of Neuroscience, July 9, 2008, 28(28):7130-7136; doi:10.1523/JNEUROSCI.0663-08.2008

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Behavioral/Systems/Cognitive
Caspase Inhibitor Infusion Protects an Avian Song Control Circuit from Seasonal-Like Neurodegeneration

Christopher K. Thompson¹ and Eliot A. Brenowitz^1,2

¹Graduate Program in Neurobiology and Behavior and ²Departments of Psychology and Biology, University of Washington, Seattle, Washington 98195-1525

Correspondence should be addressed to Christopher K. Thompson, University of Washington, Box 351525, Seattle, WA 98195-1525. Email: ckthomps{at}u.washington.edu

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.

Key words: apoptosis; birdsong; caspase; neuroendocrine; neuroethology; neuroprotection; plasticity; testosterone

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Received Feb. 13, 2008; revised May 19, 2008; accepted May 28, 2008.

Correspondence should be addressed to Christopher K. Thompson, University of Washington, Box 351525, Seattle, WA 98195-1525. Email: ckthomps{at}u.washington.edu

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