Neurogenic and intact or apoptotic non-neurogenic areas of adult brain release diffusible molecules that differentially modulate the development of subventricular zone cell cultures

In the adult mammalian brain, neurogenic activity is maintained in the subventricular zone (SVZ). Damage to non-neurogenic areas can stimulate SVZ cell proliferation and trigger addition of new neurons in the affected areas. We therefore examined the possible control exerted by specific microenvironment cues on SVZ neurogenic activity. To this end, neonatal SVZ neurospheres were maintained in the presence of diffusible signals derived from the adult neurogenic SVZ or from the non-neurogenic cerebral cortex either previously treated (apoptotic cortex) or not (untreated cortex) with staurosporine, a known apoptosis inducer. To restrict interactions to soluble signals, the explants were separated from the SVZ neurospheres by a microporous membrane. The results indicated that molecules released by the SVZ itself promoted the expansion of SVZ cell population through increased proliferation and reduced apoptosis. In contrast, untreated cortex factors reduced the expansion of SVZ cell population by decreasing proliferation. In addition, SVZ or untreated cortex factors, respectively, promoted or inhibited neuronal differentiation. Following apoptotic damage, cortex factors no longer inhibited and instead promoted the expansion of the SVZ cell population by increasing proliferation. These effects on cell numbers were replicated following use of culture media conditioned with the different explants but were no longer present following heat inactivation, which indicates that proteins were involved. These findings indicate that the neurogenic SVZ delivers autocrine/paracrine signals that promote neurogenesis whereas the non-neurogenic cerebral cortex releases signals that inhibit proliferation and neuronal differentiation. Interestingly, this constitutive growth inhibitory effect of the cerebral cortex is inverted following apoptotic lesion.