| Abstract: | The resting brain consumes enormous energy and shows highly organized spontaneous activity. To investigate how this activity is manifest among single neurons, we analyzed spiking discharges of ∼10,000 isolated cells recorded from multiple cortical and subcortical regions of the mouse brain during immobile rest. We found that firing of a significant proportion (∼70%) of neurons conformed to a ubiquitous, temporally sequenced cascade of spiking that was synchronized with global events and elapsed over timescales of 5 to 10 s. Across the brain, two intermixed populations of neurons supported orthogonal cascades. The relative phases of these cascades determined, at each moment, the response magnitude evoked by an external visual stimulus. Furthermore, the spiking of individual neurons embedded in these cascades was time locked to physiological indicators of arousal, including local field potential power, pupil diameter, and hippocampal ripples. These findings demonstrate that the large-scale coordination of low-frequency spontaneous activity, which is commonly observed in brain imaging and linked to arousal, sensory processing, and memory, is underpinned by sequential, large-scale temporal cascades of neuronal spiking across the brain.The brain at rest exhibits slow (<0.1 Hz) but highly organized spontaneous activity as measured by functional MRI (fMRI) (1, 2). Much research in this area has utilized the temporal coordination of these signals to assess the functional organization a large number of brain networks. In recent years, however, new attention has been directed to a less-studied aspect of this signal, namely the conspicuous and discrete spontaneous events that occur simultaneously across the brain (3–5). These global resting-state fMRI events appear to reflect transient arousal modulations at a timescale of ∼10 s (4, 6) and also to be closely related to activity among clusters of cholinergic projection neurons in the basal forebrain (4, 5).The nature of global brain events is of great interest, as is their spatiotemporal dynamics. Some evidence suggests they take the form of traveling waves, propagating coherently according to the principles of the cortical hierarchy (7, 8), and shaping functional connectivity measures important for assessing the healthy and diseased brain (7, 9, 10). Other work has linked such global activity to phenomena as varied as modulation of the autonomic nervous system (11–14), cleansing circulation of cerebrospinal fluid in the glymphatic system (15–19), and memory consolidation mediated by hippocampal sharp-wave ripples (20, 21). In general, the global activity measured through brain imaging appears coordinated over timescales of seconds with a range of other neural and physiological events (11, 12, 14, 21–23). In a few cases, the relationship between local and global neural events has been studied using simultaneous measurements. For example, brain-wide fMRI fluctuations and local field potential (LFP) power changes are locked to the issuance of hippocampal ripples (21, 24). However, very little is understood about the extent to which single neurons participate in the expression and coordination of global spontaneous events of the seconds timescale. To approach this topic, recent technological advances have made it possible to track and compare the spiking activity of a large number of isolated neurons recorded simultaneously across multiple brain areas.A few recent studies utilizing high-density neuronal recording (25) have accumulated initial evidence suggesting a close relationship between the brain state and neuronal population dynamics (26–28). A large proportion of neurons, regardless of their location, showed strong modulations in their discharging rate that were coordinated in time with physiological arousal measures (28), across thirsty and sated states (26), and during exploratory and nonexploratory behaviors (27). Nevertheless, these studies leave open the question of how neuronal population dynamics are organized at a finer timescale of seconds surrounding spontaneous global events during immobile rest, and whether and how such dynamics are coincident with arousal modulations, hippocampal ripples, and sensory excitability. To investigate this topic, we examine the spiking activity recorded from large neuronal populations of neurons in immobilized mice, focusing on their seconds-scale coordination with global events and with one another. We further studied the impact of this spontaneous spiking on the magnitude of visually evoked responses and its time locking with other physiological signals related to arousal, such as LFP changes, hippocampal ripples, and changes in pupil diameter. |
