Neurogenesis in the Canary

Angiogenic determinants of endogenous adult neurogenesis

The vocal control nucleus HVC of adult songbirds generates new neurons throughout life from nearby ventricular zone progenitor cells. The recruitment and survival of these neurons is modulated by the gonadal steroids testosterone and estradiol. Yet endothelial cell division is the first cellular response noted in the adult HVC after testosterone administration, and precedes androgen-associated gliogenesis and neuronal recruitment by over a week.

We have found that testosterone rapidly induces the production of both vascular endothelial growth factor (VEGF) and its receptor VEGF-R2/KDR in HVC. This leads to endothelial division, which anticipates the regionally-restricted expansion of the HVC microvasculature. The activated endothelial cells then produce the neurotrophin BDNF, which has been shown to support neuronal recruitment from the mammalian as well as the avian ventricular zone, and whose induction is associated with the recruitment of new neurons to HVC. Gonadal steroid-induced endothelial and matrix-released cytokines may thereby contribute importantly to neuronal recruitment in the adult brain.

In this competitive renewal application, we postulate that gonadal steroid-induced angiogenesis may be critical to neuronal addition to the adult HVC, and that angiogenesis may provide necessary permissive conditions for neuronal recruitment into adult brain parenchyma. To better understand the permissive conditions for the integration of new neurons into adult brain, we propose to ask the following: 1) Is the gonadal steroid-associated induction of VEGF and its receptor necessary for testosterone-induced angiogenesis in the adult HVC? 2) Is steroid-induced angiogenesis necessary for testosterone-mediated neuronal recruitment? Does the suppression of angiogenesis abrogate neuronal addition to HVC? 3) Is local angiogenesis sufficient to direct neuronal recruitment from a neurogenic epithelium? Do new neurons migrate selectively to HVC because of its high BDNF levels after gonadal steroid activation? 4) Do steroid-activated matrix metalloproteinases contribute importantly to neuronal addition? Does MMP inhibition suppress recruitment? These experiments ask if neurogenesis in the adult HVC depends upon antecedent local angiogenesis. They seek to define those necessary and sufficient conditions for neuronal recruitment that may be provided by steroid-activated endothelial cells. By so doing, they extend our understanding of the permissive conditions for neurogenesis in the adult brain, and may inform us as to how to induce neuronal recruitment to, and acceptance by, otherwise non-neurogenic regions of the adult brain.

Funded by NIH 5R37NS029813-13