Administration of synthetic or purified peptides directly into the brain ventricles is a method commonly used by neuroscientists for exploring physiological and behavioral functions of gene products. i.v. administration is controlled by the blood-brain barrier, which limits its effectiveness, and current approaches for acute or chronic intracerebroventricular delivery have significant technical drawbacks resulting from both the chemical properties of the delivered substance and the experimental procedures. Here we describe a genetic approach for the delivery of secreted peptides or proteins into the cerebrospinal fluid (CSF). Using a choroid plexus-specific promoter, we established a lentiviral-based system, which offers inducible and reversible delivery of a gene product into the CSF. The functionality of this system was demonstrated by using the overexpression of the two established neuropeptides, corticotropin-releasing factor and gonadotropin-releasing hormone, modulating anxiety-like behavior and estrus cycle, respectively. We show that this choroid plexusspecific lentiviral-based system is a reliable, effective, and adaptable research tool for intracerebroventricular delivery.blood-brain barrier | choroid plexus | Lentiviruses | secreted peptides | cerebrospinal fluid P harmacological administration of synthetic peptides or secreted recombinant proteins into the brain ventricles is a common method used by neuroscientists for exploring physiological and behavioral functions of novel or known gene products. Cerebroventricular, rather than systemic administration of these proteins is required to bypass the blood-brain barrier (BBB), and allow the nonselective transport of peptides or proteins from the periphery into the central nervous system (CNS) (1-3).Current solutions for delivery of peptides or secreted proteins to the CNS, for short-term acute administration, include a stereotaxic injection into the ventricular space, known as intracerebroventricular (ICV) administration, or for chronic delivery, an ICV microinjection pump. These methods rely heavily on the solubility and half-life of the injected substance; require chemical or in vitro synthesis of the administered ligand, and may require different purification procedures. The ICV administration is difficult to use in studies requiring repeated or prolonged administration of the ligand, because the microinjection pump procedure depends on the ligand stability and capacity of the reservoir; and complex surgical procedures are required for installation and manipulation of the pump. Furthermore, the current procedures require extensive handling of the experimental animals, which may create behavioral or physiological disturbances.The choroid plexus plays a critical role in the barrier mechanism regulating the exchange of molecules between the brain's internal milieu, and the periphery (4-6). This blood-cerebrospinal fluid (CSF) barrier is composed of epithelial cells with apical tightjunctions that restrict intercellular passage of molecules from fenestra...