Working memory, the ability to temporarily hold multiple pieces of information for mental manipulation, is central to virtually all cognitive abiliies. Working memory has been closely associated with multiple kinds of neural activity dynamics, such as persistent neural activity, activity ramps, and activity sequences. The neural circuit mechanisms of these dynamics remain unclear. This proposal will apply advanced technologies such as virtual reality, automated monitoring of behavior, in vivo microscopy, ontogenetic, and neural circuit reconstruction to solve fundamental problems in the understanding of working memory. The accumulation of evidence over time scales of seconds, a type of working memory critical for decision-making, will be used as a test bed for studying working memory. The proposal will build upon a rodent evidence-accumulation paradigm that allows quantitative, temporally precise parameterization of working memory and decision-making. The paradigm will be implemented with head-fixed rodents behaving in a virtual reality system (Aim 1), providing mechanical stability that enables the use of two-photon calcium imaging to observe neural activity related to working memory in the neocortex, basal ganglia, and cerebellum (Aim 3). Brain activity will also be perturbed using ontogenetic to probe the roles of brain regions and specific cell types in the formation and stabilization of memory (Aim 2). Finally, we will develop methods for probing the roles of cell types and connectivity in working memory through correlative serial electron microscopy and light microscopy as well as imaging of population responses to ontogenetic stimulation of single cells or groups of cells (Aim 4). This three-year project will produce a catalog of the types of neural circuit dynamics that are related to working memory across many brain regions. In subsequent years, this catalog will be mechanistically investigated by the anatomical and physiological methods developed in Aim 4. The long-term goal of this project is to arrive at a complete, brain-wide understanding of the cellular and circut mechanisms of activity dynamics related to working memory. The understanding is expected to take the form of a new generation of models containing cognitive variables distributed across brain regions, as well as models that explicitly represent neural circuit dynamics. This achievement will be a crucial step towards a mechanistic understanding of the neural basis of cognition.

Public Health Relevance

Working memory, the ability to temporarily hold multiple pieces of information for mental manipulation, is central to virtually all cognitive abilities and s disrupted in diseases such as schizophrenia. The long-term goals of this project are to characterize neural activity dynamics related to working memory in diverse brain regions, and to account for those dynamics in an integrated, brain-wide fashion in terms of cellular and circuit mechanisms. These goals will be achieved by observing, mapping, and perturbing brain circuits using advanced technologies which will be disseminated to the entire neuroscience community to accelerate progress towards understanding brain function and dysfunction.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1-SRB-S (61))
Program Officer
Gnadt, James W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Princeton University
Schools of Arts and Sciences
United States
Zip Code
Scott, Benjamin B; Thiberge, Stephan Y; Guo, Caiying et al. (2018) Imaging Cortical Dynamics in GCaMP Transgenic Rats with a Head-Mounted Widefield Macroscope. Neuron 100:1045-1058.e5
Pinto, Lucas; Koay, Sue A; Engelhard, Ben et al. (2018) An Accumulation-of-Evidence Task Using Visual Pulses for Mice Navigating in Virtual Reality. Front Behav Neurosci 12:36
Deverett, Ben; Koay, Sue Ann; Oostland, Marlies et al. (2018) Cerebellar involvement in an evidence-accumulation decision-making task. Elife 7:
Bradde, Serena; Bialek, William (2017) PCA meets RG. J Stat Phys 167:462-475
Scott, Benjamin B; Constantinople, Christine M; Akrami, Athena et al. (2017) Fronto-parietal Cortical Circuits Encode Accumulated Evidence with a Diversity of Timescales. Neuron 95:385-398.e5
Song, Alexander; Charles, Adam S; Koay, Sue Ann et al. (2017) Volumetric two-photon imaging of neurons using stereoscopy (vTwINS). Nat Methods 14:420-426
Rajan, Kanaka; Harvey, Christopher D; Tank, David W (2016) Recurrent Network Models of Sequence Generation and Memory. Neuron 90:128-42
Scott, Benjamin B; Constantinople, Christine M; Erlich, Jeffrey C et al. (2015) Sources of noise during accumulation of evidence in unrestrained and voluntarily head-restrained rats. Elife 4:e11308
Rickgauer, John Peter; Deisseroth, Karl; Tank, David W (2014) Simultaneous cellular-resolution optical perturbation and imaging of place cell firing fields. Nat Neurosci 17:1816-24