Theory of distributed persistent activity in large-scale brain circuits

Working memory, the ability to temporarily hold and manipulate pieces of information in our minds, is crucial for thinking and flexible behavior. Scientists often study working memory in the lab by training subjects to make a response based on information from a few seconds in the past. These ‘delayed response tasks’ suggest that working memory, at the level of brain cells, is the result of self-sustaining patterns of neural activity — a group of neurons starts firing when the initial information is presented and maintains that firing internally when the stimulus is no longer present until the animal acts on that information. Researchers made this conclusion based on years of work painstakingly recording the activity of one neuron or a few neurons in a single local area of the brain at a time. However, neural activity patterns associated with working memory are distributed across many brain regions. Now, recent advances allow scientists to record from many hundreds of neurons at once from several parts of the brain of behaving animals. In addition, brain ‘connectomics’ provides quantitative information about how different brain regions are connected. We will form a collaborative team with four laboratories to take advantage of these new tools and rich data to create anatomically realistic computational models of large brain networks that underlie working memory. We will develop these models based on experimental data collected in mice and monkeys performing delayed response tasks. In one task, for example, a mouse will be exposed to two different somatosensory stimuli, then learn a rule that tells them which of two spouts to lick based on each stimulus. We can study how the brain maintains that information in working memory by analyzing brain activity during the delay between the stimulus and the resulting action. Brain recording technology such as the new Neuropixels probe will allow us to make an unprecedented ‘neural activity map’ highlighting how different brain regions behave during the task. We can then develop computer and mathematical models based on this map, revealing how multiple regions of the brain work together to sustain working memory. Progress in this research project has the potential to provide insights into large-scale circuit mechanisms of cognitive deficits associated with schizophrenia and other mental disorders.