Abstract
Appropriate motor control is critical for normal life, and requires hypothalamic hypocretin/orexin neurons (HONs). HONs are slowly regulated by nutrients, but also display rapid (subsecond) activity fluctuations in vivo. The necessity of these activity bursts for sensorimotor control and their roles in specific phases of movement are unknown. Here we show that temporally-restricted optosilencing of spontaneous or sensory-evoked HON bursts disrupts locomotion initiation, but does not affect ongoing locomotion. Conversely, HON optostimulation initiates locomotion with subsecond delays in a frequency-dependent manner. Using 2-photon volumetric imaging of activity of >300 HONs during sensory stimulation and self-initiated locomotion, we identify several locomotion-related HON subtypes, which distinctly predict the probability of imminent locomotion initiation, display distinct sensory responses, and are differentially modulated by food deprivation. By causally linking HON bursts to locomotion initiation, these findings reveal the sensorimotor importance of rapid spontaneous and evoked fluctuations in HON ensemble activity.
Highlights
A core function of the nervous system is to generate movements that enable exploration of the environment and rapidly link sensory input to action
Recent studies show that hypothalamic hypocretin/orexin neurons (HONs) (Tyree et al, 2018) change their activity on a subsecond timescale, including rapid responses to external sensory stimulation and activity associated with movement (González et al, 2016a; Hassani et al, 2016; Inutsuka et al, 2016; Lee et al, 2005; Mileykovskiy et al, 2005; Takahashi et al, 2008)
We recorded the activity of HONs through the fluorescence of the GCaMP6s Ca2+ sensor (Chen et al, 2013) which was delivered in a vector under the orexin promoter, restricting expression to HONs (GCaMP6s was expressed with 97.4 ± 1.0 % specificity and 65.8 ± 3.7 % penetrance in HONs, cell counts in Methods)(González et al, 2016b)
Summary
A core function of the nervous system is to generate movements that enable exploration of the environment and rapidly link sensory input to action. Recent studies show that hypothalamic hypocretin/orexin neurons (HONs) (Tyree et al, 2018) change their activity on a subsecond timescale, including rapid responses to external sensory stimulation and activity associated with movement (González et al, 2016a; Hassani et al, 2016; Inutsuka et al, 2016; Lee et al, 2005; Mileykovskiy et al, 2005; Takahashi et al, 2008) These observations contrast with traditional views of these cells as sensors of slowly-changing variables such as hormones and nutrients that control arousal and locomotion on longer timescales (Adamantidis et al, 2007; Sakurai et al, 1998; Stanojlovic et al, 2019; Yamanaka et al, 2003). If HONs mediate slow/modulatory movement control, why does their activity change on a subsecond timescale? The answer to this question is not clear from above correlative studies, and requires subsecond quantification of movement combined with temporally-controlled targeted disruption of underlying hypothalamic signals, which remains unstudied
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