Testosterone modulation of angiogenesis and neurogenesis in the adult songbird brain

Throughout life, new neurons arise from the ventricular zone of the adult songbird brain and are recruited to the song control nucleus higher vocal center (HVC), from which they extend projections to its target, nucleus robustus of the arcopallium (RA). This process of ongoing parenchymal neuronal addition and circuit integration is both triggered and modulated by seasonal surges in systemic testosterone. Brain aromatase converts circulating testosterone to estradiol, so that HVC is concurrently exposed to both androgenic and estrogenic stimulation. These two signals cooperate to trigger HVC endothelial cell division and angiogenesis, by inducing the regionally-restricted expression of vascular endothelial growth factor (VEGF), its matrix-releasing protease MMP9, and its endothelial receptor VEGFR2. The expanded HVC microvascular network then secretes the neurotrophic factor BDNF, which in turn supports the recruitment of newly generated neurons. This process is striking for its spatial restriction and hence functional specificity. While androgen receptors are broadly expressed by the nuclei of the vocal control system, estrogen receptor (ERα) expression is largely restricted to HVC and its adjacent mediocaudal neopallium. The geographic overlap of these receptor phenotypes in HVC provides the basis for a regionally-defined set of paracrine interactions between the vascular bed and neuronal progenitor pool that both characterize and distinguish this nucleus. These interactions culminate in the focal attraction of new neurons to the adult HVC, the integration of those neurons into the extant vocal control circuits, and ultimately the acquisition and elaboration of song.

► Testosterone mediates neuronal addition to the avian vocal control nucleus HVC.
► Testosterone and estradiol induce HVC angiogenesis by enabling VEGF signaling.
► VEGF-stimulated vascular expansion triggers BDNF production by HVC endothelium.
► BDNF expression is sufficient to promote neuronal recruitment and song learning.
► The inhibition of angiogenesis blocks both neuronal recruitment and singing.