Neural activity and behavior are both notoriously variable, with responses differing widely between repeated presentation of identical stimuli or trials. Recent results in humans and animals reveal that these variations are not random in their nature, but may in fact be due in large part to rapid shifts in neural, cognitive, and behavioral states. Here we review recent advances in the understanding of rapid variations in the waking state, how variations are generated, and how they modulate neural and behavioral responses in both mice and humans. We propose that the brain has an identifiable set of states through which it wanders continuously in a nonrandom fashion, owing to the activity of both ascending modulatory and fast-acting corticocortical and subcortical-cortical neural pathways. These state variations provide the backdrop upon which the brain operates, and understanding them is critical to making progress in revealing the neural mechanisms underlying cognition and behavior.

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Variability in cortical neuronal responses to sensory stimuli and in perceptual decision making performance is substantial. Moment-tomoment fluctuations in waking state or arousal can account for much of this variability. Yet, this variability is rarely characterized across the full spectrum of waking states, leaving the characteristics of the optimal state for sensory processing unresolved. Using pupillometry in concert with extracellular multiunit and intracellular whole-cell recordings, we found that the magnitude and reliability of visually evoked responses in primary visual cortex (V1) of awake, passively behaving male mice increase as a function of arousal and are largest during sustained locomotion periods. During these high-arousal, sustained locomotion periods, cortical neuronal membrane potential was at its most depolarized and least variable. Contrastingly, behavioral performance of mice on two distinct visual detection tasks was generally best at a range of intermediate arousal levels, but worst during high arousal with locomotion. These results suggest that large, reliable responses to visual stimuli in V1 occur at a distinct arousal level from that associated with optimal visual detection performance. Our results clarify the relation between neuronal responsiveness and the continuum of waking states, and suggest new complexities in the relation between primary sensory cortical activity and behavior.

Munc13 proteins are key regulators of neurotransmitter release at presynaptic active zones. Kawabe et al. describe a molecular mechanism by which the active zone protein ELKS1 recruits a functionally unique Munc13 isoform, bMunc13-2, to a defined subset of synapses.

The brain exhibits distinct patterns of recurrent activity closely related to behavioral. The neural mechanisms that underlie state-dependent activity in the awake animal are incompletely understood. Here, we demonstrate that two types of state-dependent activity - rapid arousal/movement related signals and a 3-5 Hz alpha-like rhythm - in the primary visual cortex (V1) of mice strongly correlate with activity in the visual thalamus. Inactivation of V1 does not interrupt arousal/movement related signals in most visual thalamic neurons, but it abolishes the 3-5 Hz oscillation. Silencing of the visual thalamus similarly eradicates the alpha-like rhythm and perturbs arousal/movement-related activation in V1. Finally, we observed that whisker movement or locomotion is not required for rapid increases in cortical activation. Our results indicate that thalamocortical interactions together with cell-intrinsic properties of thalamocortical cells play a crucial role in shaping state-dependent activity in V1 of the awake animal.