Nicotine Acts on Cholinergic Signaling Mechanisms to Directly Modulate Choroid Plexus Function

ABSTRACT

Neuronal cholinergic circuits have been implicated in cognitive function and neurological disease, but the role of cholinergic signaling in other cellular populations within the brain has not been as fully defined. Here, we show that cholinergic signaling mechanisms are involved in mediating the function of the choroid plexus, the brain structure responsible for generating cerebrospinal fluid and releasing various factors into the brain. The choroid plexus was found to express markers of endogenous cholinergic signaling, including multiple nicotinic acetylcholine receptor subtypes in a region-specific manner, and application of nicotine was found to induce cellular activation, as evidenced by calcium influx in primary tissue. During intravenous nicotine self-administration in male rats, nicotine increased expression of transthyretin, a protein selectively produced and released by the choroid plexus, and microRNA-204 (mir-204), a transcript found in high levels in the choroid plexus and cerebrospinal fluid. Finally, human choroid plexus tissue from both sexes was found to exhibit similar nAChR, transthyretin and mir-204 expression profiles, supporting the translational relevance of the findings. Together, these studies demonstrate functionally active cholinergic signaling mechanisms in the choroid plexus, the resulting effects on transthyretin and mi-204 expression, and reveal the direct mechanism by which nicotine modulates function of this tissue.

SIGNIFICANCE STATEMENT Tobacco/nicotine dependence is the largest preventable cause of disease and death worldwide. The current investigations establish the presence of cholinergic signaling mechanisms in the choroid plexus and demonstrate nicotine-mediated changes in transthyretin and mir-204 expression. These changes were attributed to nicotine's direct actions on nicotinic acetylcholine receptors in the choroid plexus tissue. Therefore, these studies elucidate a previously unrecognized cholinergic neuroregulatory system, which may have relevant implications for disease states characterized by cholinergic dysfunction, such as Alzheimer's disease, as well as nicotine dependence.