title: Orexin Receptor Activation Generates Gamma Band Input to Cholinergic and Serotonergic Arousal System Neurons and Drives an Intrinsic Ca(2+)-Dependent Resonance in LDT and PPT Cholinergic Neurons.
abstract: A hallmark of the waking state is a shift in EEG power to higher frequencies with epochs of synchronized intracortical gamma activity (30-60 Hz) - a process associated with high-level cognitive functions. The ascending arousal system, including cholinergic laterodorsal (LDT) and pedunculopontine (PPT) tegmental neurons and serotonergic dorsal raphe (DR) neurons, promotes this state. Recently, this system has been proposed as a gamma wave generator, in part, because some neurons produce high-threshold, Ca(2+)-dependent oscillations at gamma frequencies. However, it is not known whether arousal-related inputs to these neurons generate such oscillations, or whether such oscillations are ever transmitted to neuronal targets. Since key arousal input arises from hypothalamic orexin (hypocretin) neurons, we investigated whether the unusually noisy, depolarizing orexin current could provide significant gamma input to cholinergic and serotonergic neurons, and whether such input could drive Ca(2+)-dependent oscillations. Whole-cell recordings in brain slices were obtained from mice expressing Cre-induced fluorescence in cholinergic LDT and PPT, and serotonergic DR neurons. After first quantifying reporter expression accuracy in cholinergic and serotonergic neurons, we found that the orexin current produced significant high frequency, including gamma, input to both cholinergic and serotonergic neurons. Then, by using a dynamic clamp, we found that adding a noisy orexin conductance to cholinergic neurons induced a Ca(2+)-dependent resonance that peaked in the theta and alpha frequency range (4-14 Hz) and extended up to 100 Hz. We propose that this orexin current noise and the Ca(2+) dependent resonance work synergistically to boost the encoding of high-frequency synaptic inputs into action potentials and to help ensure cholinergic neurons fire during EEG activation. This activity could reinforce thalamocortical states supporting arousal, REM sleep, and intracortical gamma.
authors.affiliation: Department of Physiology, New York Medical College , Valhalla, NY , USA.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishibashi
authors.affiliation: Department of Physiology, New York Medical College , Valhalla, NY , USA.
authors.forename: Iryna
authors.initials: I
authors.lastname: Gumenchuk
authors.affiliation: Department of Physiology, New York Medical College , Valhalla, NY , USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Kang
authors.affiliation: Department of Physiology, New York Medical College , Valhalla, NY , USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Steger
authors.affiliation: Department of Physiology, New York Medical College , Valhalla, NY , USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lynn
authors.affiliation: Department of Physiology, New York Medical College , Valhalla, NY , USA.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Molina
authors.affiliation: Department of Physiology, New York Medical College , Valhalla, NY , USA ; Department of Medicine, New York Medical College , Valhalla, NY , USA.
authors.forename: Leonard M
authors.initials: LM
authors.lastname: Eisenberg
authors.affiliation: Department of Physiology, New York Medical College , Valhalla, NY , USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Leonard
keywords: acetylcholine; arousal; brain slice; hypocretin; oscillations; reticular activating system; serotonin