TY - JOUR T1 - Acetylcholine Acts through Nicotinic Receptors to Enhance the Firing Rate of a Subset of Hypocretin Neurons in the Mouse Hypothalamus through Distinct pre- and Postsynaptic Mechanisms JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0052-14.2015 SP - ENEURO.0052-14.2015 AU - Wen-Liang Zhou AU - Xiao-Bing Gao AU - Marina R. Picciotto Y1 - 2015/02/18 UR - http://www.eneuro.org/content/early/2015/02/18/ENEURO.0052-14.2015.abstract N2 - Hypocretin/orexin neurons regulate many behavioral functions, including addiction. Nicotine acts through nicotinic acetylcholine receptors (nAChRs) to alter firing rate of neurons throughout the brain, leading to addiction-related behaviors. While nAChRs are expressed in the hypothalamus and cholinergic fibers project to this structure, it is unclear how acetylcholine modulates the activity of hypocretin neurons. In this study we stimulated hypocretin neurons in mouse brain slices with ACh in the presence of atropine to dissect pre- and postsynaptic modulation of these neurons through nAChRs. Approximately 1/3 of tested hypocretin neurons responded to pressure application of ACh (1 mM) with an increase in firing frequency. Stimulation of postsynaptic nAChRs with ACh or nicotine resulted in a highly variable inward current in approximately 1/3 of hypocretin neurons. In contrast, ACh or nicotine (1 µM) reliably decreased the frequency of miniature EPSCs (mEPSCs). Antagonism of nAChRs with mecamylamine also suppressed mEPSC frequency, suggesting that an endogenous, tonic activation of presynaptic nAChRs might be required for maintaining functional mEPSC frequency. Antagonism of heteromeric (α4β2) or homomeric (α7) nAChRs alone suppressed mEPSCs to a lesser extent. Finally, blocking internal calcium release reduced the frequency of mEPSCs, occluding the suppressive effect of presynaptic ACh. Taken together, these data provide a mechanism by which phasic ACh release enhances the firing of a subset of hypocretin neurons through postsynaptic nAChRs, but disrupts tonic, presynaptic nAChR-mediated glutamatergic inputs to the overall population of hypocretin neurons, potentially enhancing the signal-to-noise ratio during the response of the nAChR-positive subset of neurons. Significance Statement: Neurons expressing the neuropeptide hypocretin regulate many behavioral functions, including sleep, motivation and behaviors related to addiction. The ability of nicotine to stimulate nicotinic acetylcholine receptors (nAChRs) is essential for its addictive properties, but little is known about whether, and how, nicotine and the endogenous neurotransmitter acetylcholine affect hypocretin neurons. This study suggests that phasic acetylcholine release can enhance the firing of a subset of hypocretin neurons through postsynaptic nAChRs, while disrupting tonic activation of presynaptic nAChRs necessary for maintaining functional glutamatergic inputs to hypocretin neurons. We propose that this mechanism could enhance the signal-to-noise ratio of the electrical response to nicotine or acetylcholine in the nAChR-positive subset of neurons. ER -