Adult stem cells in various tissues are relatively quiescent. The cell cycle inhibitor p21^cip1/waf1 (p21) has been shown to be important for maintaining hematopoietic stem cell quiescence and self-renewal. We examined the role of p21 in the regulation of adult mammalian forebrain neural stem cells (NSCs). We found that p21^-/- mice between post-natal age 60-240 d have more NSCs than wild-type (+/+) controls due to higher proliferation rates of p21^-/- NSCs. Thereafter, NSCs in p21^-/- mice decline and are reduced in number at 16 mo relative to p21^+/+ mice. Similarly, both p21^-/- and p21^+/+ NSCs display self-renewal in vitro; however, p21^-/- NSCs display limited in vitro self-renewal (surviving a few passages, then exhausting). Thus, p21 contributes to adult NSC relative quiescence, which we propose is necessary for the life-long maintenance of NSC self-renewal because NSCs may be limited to a finite number of divisions.

Neurogenesis has been implicated in antidepressant drug action and animal models of depression, suggesting that proliferating cells play a role in psychiatric disorders. Similar studies using antipsychotic drugs have yielded conflicting results, perhaps because of the lack of focus on specific cell types. We examine the effect of haloperidol on neural stem cells (NSCs), the ultimate precursors for adult cell genesis. We show that haloperidol increases NSC numbers, resulting in more progenitors and more new neurons and glia in the adult rat brain. The increase in NSCs by haloperidol is dependent on central dopamine D₂ receptors, and these receptors are expressed by NSCs. D₂ receptor stimulation in vitro inhibits NSC proliferation, which is reversed by haloperidol. Thus, haloperidol increases adult mammalian brain proliferation by antagonizing dopamine at D₂ receptors on NSCs. These findings demonstrate a direct link between neural activity and NSC proliferation and implicate cell genesis in antipsychotic drug effects.

Knowledge of drug concentrations in the brains of behaving subjects remains constrained on a number of dimensions, including poor temporal resolution and lack of real-time data. Here, however, we demonstrate the ability of electrochemical aptamer-based sensors to support seconds-resolved, real-time measurements of drug concentrations in the brains of freely moving rats. Specifically, using such sensors, we achieve 1.5 hours. These results demonstrate the utility of such sensors in (i) the determination of the site-specific, seconds-resolved neuropharmacokinetics, (ii) enabling the study of individual subject neuropharmacokinetics and concentration-response relations, and (iii) performing high-precision control over intracranial drug levels.