Targeted photostimulation uncovers circuit motifs supporting short-term memory

Short-term memory is associated with persistent neural activity without sustained input, arising from the interactions between neurons with short time constants 1,2 . A variety of neural circuit motifs could account for measured neural activity 3–7 . A mechanistic understanding of the neural circuits supporting short-term memory requires probing network connectivity between functionally characterized neurons 8 . We performed targeted photostimulation of small (< 10) groups of neurons, while imaging the response of hundreds of other neurons 9,10 , in anterior-lateral motor cortex (ALM) of mice performing a delayed response task 11 . Mice were instructed with brief auditory stimuli to make directional movements (lick left or lick right), but only after a three second delay epoch. ALM contains neurons with delay epoch activity that is selective for left or right choices. Targeted photostimulation of groups of neurons during the delay epoch allowed us to observe the functional organization of population activity and recurrent interactions underlying short-term memory. These experiments revealed strong coupling between neurons sharing similar selectivity. Brief photostimulation of functionally related neurons produced changes in activity in sparse subpopulations of nearby neurons that persisted for several seconds following stimulus offset, far outlasting the duration of the perturbation. Photostimulation produced behavioral biases that were predictable based on the selectivity of the perturbed neuronal population. These results suggest that ALM contains multiple intercalated modules, consisting of recurrently coupled neurons, that can independently maintain persistent activity.