Dissection of the neural circuitry of short-term memory in behaving mice

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Short-term memory, the ability to hold information in mind over short timescales, is a fundamental cognitive process underlying an array of complex abilities. In contrast to long-term memory, which involves modification of synaptic connections, short-term memory is associated with sustained neural activity in cortical and subcortical structures. In particular, recent studies have suggested that the posterior parietal cortex plays a key role in maintaining mnemonic traces. However, it is not understood how the neural activity in these regions supports the maintenance of short-term memory. The goal of this project is to develop a short-term memory task for head-fixed mice and to leverage recent advances in 2-photon calcium imaging and optogenetics to dissect the neural circuits underlying short-term memory. This goal will be undertaken with the following aims: (Aim 1) Develop a short-term memory task for mice, and measure the neural signature of short-term memory in visual and parietal cortices using 2-photon calcium imaging. (Aim 2) Determine the necessity and time course of sustained activity in specific cortical regions using targeted optogenetic inactivation. (Aim 3a) Investigate the role of norepinephrine on sustained cortical activity during the short-term memory task by optogenetic modulation of noradrenergic tone. (Aim 3b) Determine whether the duration and accuracy of short-term memory maintenance can be improved by optogenetic modulation of norepinephine release. Developing a systems-level understanding of short-term memory will yield critical insights into how the brain represents and maintains information, and may have translational implications for treating deficits in short-term memory commonly observed in normal aging and psychiatric disorders.