Caspase inhibitor infusion protects an avian song control circuit from seasonal-like neurodegeneration - PubMed (original) (raw)

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

Christopher K Thompson et al. J Neurosci. 2008.

Abstract

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.

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Figures

Figure 1.

Figure 1.

The avian song control system and timeline for experimental procedures. A, Schematic sagittal diagram of the song control system showing projections of major nuclei. The green arrows indicate the descending motor pathway. The red arrows indicate the anterior forebrain pathway. The blue arrow indicates auditory input into the song control system, which includes caudal mesopallium, caudal nidopallium, and nucleus interfacialis. B, Schematic timeline of the experimental procedures. Groups of animals that received unilateral infusion of caspase inhibitors were killed on days 1, 3, and 7. Animals that received unilateral infusion of negative control (Neg. Cont.) for caspase inhibitors were killed on day 7. DLM, Medial nucleus of the dorsolateral thalamus; nXIIts, tracheosyringeal portion of the hypoglossal motor nucleus; lMAN, lateral portion of the magnocellular nucleus of the anterior nidopallium; X, Area X; Sac, sacrifice.

Figure 2.

Figure 2.

In vivo infusion of caspase inhibitors preserved ipsilateral HVC after the transition from breeding to nonbreeding conditions. Each animal within each group is represented by a distinct color across all figures. Circles represent measurements taken in ipsilateral HVC, and squares represent measurements taken in contralateral HVC. *p < 0.05, **p < 0.01, ***p < 0.005, significant differences across hemispheres (pairwise t test). A, Caspase inhibitors significantly protected ipsilateral HVC volume 3 and 7 d after transition to nonbreeding conditions. B, Caspase inhibitors significantly preserved ipsilateral HVC soma area 7 d after transition. C, Caspase inhibitors significantly reduced the increase in ipsilateral HVC neuron density 1 and 3 d after transition. D, Caspase inhibitors significantly protected ipsilateral HVC from neuron loss 3 and 7 d after transition. Infusion of a negative control for caspase inhibitors (Neg. Cont.) did not prevent regression of any attribute of HVC 7 d after the transition to nonbreeding conditions.

Figure 3.

Figure 3.

In vivo infusion of caspase inhibitors near HVC significantly preserved soma area of ipsilateral RA neurons 7 d after the transition to nonbreeding conditions. Each animal within each group is represented by a distinct color. Circles represent measurements taken in ipsilateral RA; squares represent measurements taken in contralateral RA.*p ≤ 0.05, significant difference across hemispheres (pairwise t test).

Figure 4.

Figure 4.

In vivo infusion of caspase inhibitors near HVC significantly reduced the activation of capsase-3 in ipsilateral HVC 3 d after the transition from breeding to nonbreeding conditions. A, Examples of immunohistochemistry for activated caspase-3 in one section taken from a 3 d bird. B, Caspase inhibitors significantly reduced the density of activated caspase-3-positive cells in ipsilateral HVC. C, Caspase inhibitors significantly reduced the number of activated caspase-3-positive cells in ipsilateral HVC. Each animal is represented by a distinct color. *p ≤ 0.05, **p ≤ 0.01, significant differences across hemispheres (pairwise t test). Scale bars, 100 μm.

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