Abstract
SummaryNeuronal activity in primary motor cortex (M1) correlates with behavioral state, but the cellular mechanisms underpinning behavioral state-dependent modulation of M1 output remain largely unresolved. Here, we performed in vivo patch-clamp recordings from layer 5B (L5B) pyramidal neurons in awake mice during quiet wakefulness and self-paced, voluntary movement. We show that L5B output neurons display bidirectional (i.e., enhanced or suppressed) firing rate changes during movement, mediated via two opposing subthreshold mechanisms: (1) a global decrease in membrane potential variability that reduced L5B firing rates (L5Bsuppressed neurons), and (2) a coincident noradrenaline-mediated increase in excitatory drive to a subpopulation of L5B neurons (L5Benhanced neurons) that elevated firing rates. Blocking noradrenergic receptors in forelimb M1 abolished the bidirectional modulation of M1 output during movement and selectively impaired contralateral forelimb motor coordination. Together, our results provide a mechanism for how noradrenergic neuromodulation and network-driven input changes bidirectionally modulate M1 output during motor behavior.
Highlights
Neuronal activity in layer 5 (L5) of primary motor cortex (M1) correlates with rhythmic voluntary movements (Armstrong and Drew, 1984a, 1984b)
We found that changing behavioral state, from quiet wakefulness to movement, bidirectionally modulated M1 output via two opposing subthreshold mechanisms: (1) a global decrease in network-driven, slow, large-amplitude Vm fluctuations, which reduced Vm variability, spike probability, and firing rates in layer 5B (L5B) pyramidal neurons (L5Bsuppressed neurons); and (2) a coincident increase in excitatory drive to a subpopulation of L5B neurons (L5Benhanced), which depolarized mean Vm and enhanced firing rates
If the average movement-related firing rate was lower than the first percentile of the distribution of firing rate changes during quiet wakefulness, neurons were classified as suppressed (L5Bsupp, n = 17; Figures 1C and 1F; Table S1), while neurons that displayed an average movement-related firing rate above the 99th percentile were classified as enhanced (L5Benh, n = 24; Figures 1E and 1H; Table S1)
Summary
Neuronal activity in layer 5 (L5) of primary motor cortex (M1) correlates with rhythmic voluntary movements (Armstrong and Drew, 1984a, 1984b). Spontaneous locomotor activity can be controlled by central pattern generators (CPGs) in the spinal cord (Forssberg et al, 1980; Grillner, 1981; Grillner and Zangger, 1979), descending motor commands from M1 are integrated with ongoing rhythmic spinal cord signals and sensory input from the periphery to initiate, adjust, and maintain locomotor function (Armstrong and Drew, 1984a; Beloozerova et al, 2003; Orlovsky, 1972; Ueno and Yamashita, 2011) In lower mammals, such as cats, rabbits, and mice, discrete subpopulations of L5 output neurons display enhanced or suppressed (i.e., bidirectional) firing rate changes during locomotion (Armstrong and Drew, 1984a; Beloozerova et al, 2003; Costa et al, 2004). We are beginning to understand how patterns of motor cortex activity relate to changes in behavioral state in rodents (i.e., quiet wakefulness to movement), the cellular mechanisms underpinning bidirectional modulation of M1 output during self-paced movement remain largely unresolved
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