Physical features of sensory stimuli are fixed, but sensory perception is context-dependent. The precise mechanisms that govern contextual modulation remain unknown. Here, we trained mice to switch between two contexts: passively listening to pure tones vs. performing a recognition task for the same stimuli. Two-photon imaging showed that many excitatory neurons in auditory cortex were suppressed, while some cells became more active during behavior. Whole-cell recordings showed that excitatory inputs were only modestly affected by context, but inhibition was more sensitive, with PV, SOM+, and VIP+ interneurons balancing inhibition/disinhibition within the network. Cholinergic modulation was involved in context-switching, with cholinergic axons increasing activity during behavior and directly depolarizing inhibitory cells. Network modeling captured these findings, but only when modulation coincidently drove all three interneuron subtypes, ruling out either inhibition or disinhibition alone as sole mechanism for active engagement. Parallel processing of cholinergic modulation by cortical interneurons therefore enables context-dependent behavior.

Sensory systems transform the external world into time-varying spike trains. What features of spiking activity are used to guide behavior? In the mouse olfactory bulb, inhalation of different odors leads to changes in the set of neurons activated, as well as when neurons are activated relative to each other (synchrony) and the onset of inhalation (latency). To explore the relevance of each mode of information transmission, we probed the sensitivity of mice to perturbations across each stimulus dimension (i.e., rate, synchrony, and latency) using holographic two-photon optogenetic stimulation of olfactory bulb neurons with cellular and single-action-potential resolution. We found that mice can detect single action potentials evoked synchronously across <20 olfactory bulb neurons. Further, we discovered that detection depends strongly on the synchrony of activation across neurons, but not the latency relative to inhalation. In BriefUsing two-photon holographic optogenetics, Gill, Lerman et al. show that mice can reliably detect single spikes across small sets of targeted olfactory bulb neurons. They find that detection performance depends strongly on neuronal synchrony, but not on latency relative to inhalation.

Establishing causal links between patterns of neuronal activity and perception is crucial for understanding brain function. Electrical and optogenetic stimulation experiments demonstrated that animals can detect activation of a few neurons. However, these methodologies offer very limited control of ensemble activity and yielded highly divergent thresholds. Here, we use holographic two-photon (2P) optogenetic stimulation to probe the detection of evoked neuronal activity at cellular and single action potential resolution, with millisecond precision. We find that mice can detect single action potentials evoked synchronously across <20 olfactory bulb neurons, while ruling out detection of indirect effects using a novel optical sham-photostimulation technique. Our results demonstrate that mice are acutely attuned to sparse, synchronous ensemble activity signals, introducing order-of-magnitude revisions to earlier estimates of perceptual thresholds.