An automated platform for Assessing Working Memory and prefrontal circuit function

Working memory is a process for actively maintaining and updating task-relevant information, despite interference from competing inputs, and is supported in part by sustained activity in prefrontal cortical pyramidal neurons and coordinated interactions with inhibitory interneurons, which may serve to regulate interference. Chronic stress has potent effects on working memory performance, possibly by interfering with these interactions or by disrupting long-range inputs from key upstream brain regions. Still, the mechanisms by which chronic stress disrupts working memory are not well understood, due in part to a need for scalable, easy-to-implement behavioral assays that are compatible with two-photon calcium imaging and other tools for recording from large populations of neurons. Here, we describe the development and validation of a platform that was designed specifically for automated, high-throughput assessments of working memory and simultaneous two-photon imaging in chronic stress studies. This platform is relatively inexpensive and easy to build; fully automated and scalable such that one investigator can test relatively large cohorts of animals concurrently; fully compatible with two-photon imaging, yet also designed to mitigate head-fixation stress; and can be easily adapted for other behavioral paradigms. Our validation data confirm that mice could be trained to perform a delayed response working memory task with relatively high-fidelity over the course of ∼15 days. Two-photon imaging data validate the feasibility of recording from large populations of cells during working memory tasks performance and characterizing their functional properties. Activity patterns in >70% of medial prefrontal cortical neurons were modulated by at least one task feature, and a majority of cells were engaged by multiple task features. We conclude with a brief literature review of the circuit mechanisms supporting working memory and their disruption in chronic stress states—highlighting directions for future research enabled by this platform.