The mechanisms linking sensation and action during learning are poorly understood. Layer 2/3 neurons in the motor cortex might participate in sensorimotor integration and learning; they receive input from sensory cortex and excite deep layer neurons, which control movement. Here we imaged activity in the same set of layer 2/3 neurons in the motor cortex over weeks, while mice learned to detect objects with their whiskers and report detection with licking. Spatially intermingled neurons represented sensory (touch) and motor behaviours (whisker movements and licking). With learning, the population-level representation of task-related licking strengthened. In trained mice, population-level representations were redundant and stable, despite dynamism of single-neuron representations. The activity of a subpopulation of neurons was consistent with touch driving licking behaviour. Our results suggest that ensembles of motor cortex neurons couple sensory input to multiple, related motor programs during learning.

Optogenetic Insights: Mapping functional neural circuits for many behaviors has been almost impossible, so Vogelstein et al. (p. 386 , published online 27 March; see the Perspective by O'Leary and Marder ) developed a broadly applicable optogenetic method for neuron-behavior mapping and used it to phenotype larval Drosophila and thus developed a reference atlas. As optogenetic experiments become routine in certain fields of neuroscience research, creating even more specialized tools is imperative (see the Perspective by Hayashi ). By engineering channelrhodopsin, Wietek et al. (p. 409 , published online 27 March) and Berndt et al. (p. 420 ) created two different light-gated anion channels to block action potential generation during synaptic stimulation or depolarizing current injections. These new tools not only improve understanding of channelrhodopsins but also provide a way to silence cells.

Significance: Long-term plasticity, the ability of synapses to change their strength, is considered a possible basis of learning and memory. Extending the study of individual synapses to timescales relevant for behavior has been challenging: although rats can retain specific memories for several weeks, intracellular recordings that monitor the strength of individual synapses are typically limited to 1 h. Here we introduce an all-optical approach to stimulate and monitor synaptic function for 7 d. We show that long-term depression of hippocampal synapses significantly shortens their lifetime. While synapses with a high probability of transmitter release often recovered from depression, unreliable synapses were selectively removed from the circuit. Thus, specific activity patterns not only modulate synaptic weights but alter hippocampal connectivity.

Channelrhodopsins are light-activated ion channels that mediate cation permeation across cell membranes upon light absorption. Red-light-activated channelrhodopsins are of particular interest, because red light penetrates deeper into biological tissues and also enables dual-color experiments in combination with blue-light-activated optogenetic tools. Here we report the crystal structure of the most red-shifted channelrhodopsin from the algae Chlamydomonas noctigama, Chrimson, at 2.6 Å resolution. Chrimson resembles prokaryotic proton pumps in the retinal binding pocket, while sharing similarity with other channelrhodopsins in the ion-conducting pore. Concomitant mutation analysis identified the structural features that are responsible for Chrimson’s red light sensitivity; namely, the protonation of the counterion for the retinal Schiff base, and the polar residue distribution and rigidity of the retinal binding pocket. Based on these mechanistic insights, we engineered ChrimsonSA, a mutant with a maximum activation wavelength red-shifted beyond 605 nm and accelerated closing kinetics.