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, Ca2+-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 Ca2+-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 Ca2+-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 Ca2+ 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.
Highlights
Gamma band oscillations (30–60 Hz) occur in many cortical and subcortical regions, and are observed in both waking and sleep states
Our findings indicate that the noisy orexin current generates significant high frequency, including gamma band, input to both cholinergic and serotonergic neurons, and that cholinergic LDT and PPT neurons have a broad Ca2+-dependent resonance that peaked in the theta to alpha frequency range (4–14 Hz) and extended up to 100 Hz
Inspection of the counting regions revealed that it was the neurons most weakly labeled for ChAT that appeared negative for EYFP immunoreactivity (Figure 1C, white dots)
Summary
Gamma band oscillations (30–60 Hz) occur in many cortical and subcortical regions, and are observed in both waking and sleep states. Their mechanisms and functions have garnered significant interest, as they are thought to play important roles in several high-level cognitive functions including perceptual binding, visual attention, memory, and decision-making [for review, see Ref. Features of schizophrenia have been linked to altered prefrontal gamma activity and decreased inhibitory function of prefrontal parvalbumin interneurons [for review, see Ref. Altered gamma activity may be involved in other neuropsychiatric disorders [4]. The intracortical mechanisms generating synchronized gamma activity involve synaptic interaction between excitatory cortical pyramidal neurons and fast, synchronized inhibitory input from parvalbumin-containing fast-spiking interneurons [for review, see Ref. Selective activation of parvalbumin interneurons is sufficient to drive local gamma oscillations [5, 6], while their selective inhibition dampens spontaneous gamma activity [6]
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