Project Summary/Abstract In a world filled with sensory information, the ability to filter out repetitive or redundant stimuli while still maintaining the ability to detect change in the environment is critical to biological success. Studies have characterized reduced cortical responses to repetitive stimuli (adaptation) and augmented cortical responses to stimuli that differ from these expected regularities (novelty detection); however, the cortical circuits that enable flexibly encoding stimuli based on the context in which they are experienced remain unknown. Disinhibitory microcircuits, especially those mediated by vasoactive intestinal polypeptide-expressing inhibitory interneurons (VIPs), may play a role in this flexible coding by altering the inhibition supplied to principal excitatory neurons (PYRs) in neocortex. Despite this, the relationship between neural activity of VIPs and PYRs during adaptation and novelty detection remain poorly understood. In this proposal, I seek to use fast dual-color, three-dimensional, two-photon calcium imaging to simultaneously monitor neural activity of both VIPs and PYRs in primary visual cortex during a classic visual “oddball” paradigm (Aim 1). This paradigm presents the same stimulus in control, repetitive, and rare/deviant contexts, which enables directly recording neural responses to the same stimulus when it is an established regularity and when it is novel and thus deviates from established regularity. I will then use data and theory analysis tools to computationally model neocortical adaptation and novelty detection (Aim 2) by incorporating anatomical and neural recording data from PYRs and interneuron populations (including VIPs), which are often excluded from network models. The creation of this holistic model is likely to reveal fundamental circuitry that gives rise to flexible neural encoding of sensory stimuli. Finally, I will integrate optogenetic interventional tools for circuit manipulation with two-photon imaging to directly test the relationship between VIP neural activity and adaptation and novelty detection in PYRs. Altogether, these aims directly address several of the BRAIN Initiative 2025 high priority goals: monitor neural activity, interventional tools, data and theory analysis, and integrated approaches. Furthermore, the experiments proposed under these aims will result in significant technical and theoretical training for the applicant and will advance essential understanding of how excitatory, inhibitory, and disinhibitory circuits across cortical layers diverge in their dynamic neural activity and differentially contribute to sensory processing.

Project Narrative (3 sentences) The ability to filter repetitive sensory stimulation from conscious perception while remaining able to respond to changes in the environment is quintessential to successfully relating to the world in which one lives; however, the basic neural circuitry that enables this flexible encoding of sensory stimuli is poorly understood. Here we integrate state-of-the-art neurotechnologies to complete large-scale monitoring of neural activity with interventional tools to directly test relationships between genetically defined populations of cortical neurons and then incorporate them into a working computational neural network model. The model developed in this proposal will be distributed to the wider neuroscientific community and the results of the proposed aims will provide significant insight into context-dependent modulation of neural activity that is integral to normal nervous system function and is often disrupted in neuropsychiatric disease.