Jordan M Ross - US grants

Project Summary/Abstract Associative fear learning, the underlying cause of disorders such as Post-Traumatic Stress Disorder (PTSD), involves the pairing of a stimulus with an aversive outcome. This pairing produces robust fear responses to the conditioned stimulus. Odor memories, such as those formed during olfactory fear learning are acquired quickly, are long lasting, and are apparent as early as the olfactory bulb (OB) glomeruli, which constitutes the first site of central nervous system olfactory sensory processing. This makes the OB an ideal place to investigate mechanisms underlying sensory processing and plasticity as they relate to fear learning. Herein, we present pilot data establishing that pairing odor presentations with foot shock induces behavioral fear and enhances glomerular responses to the conditioned stimulus (CS) in awake, behaving transgenic mice expressing a fluorescent calcium indicator. Similarly, odor-foot shock experience induces fear and enhances glomerular responses to neutral, unconditioned odor stimuli, a process known as stimulus generalization in which fear is transferred from the CS to neutral, unconditioned stimuli. Furthermore, sensory representations of the CS and neutral odors undergo transformations increasing the representational similarities, possibly leading to behavioral generalization. However, the time course of learning-induced transformations in sensory processing and the neural networks underlying generalized behavior and glomerular alterations is still unknown. By combining behavioral methods with awake, behaving wide-field calcium imaging, we will elucidate when associative olfactory fear learning modulates the processing of sensory information at the glomerular layer of the olfactory bulb and the role of the neural networks responsible for encoding the stimulus-fear association in these transformations, as well as how this relates to generalization of olfactory fear at the behavioral level. We will test the hypothesis that glomerular enhancement to the CS begins during acquisition, while generalized enhancements to odors not paired with shock occur during consolidation, and that activity in the basolateral amygdala (BLA), the putative center of fear learning, is responsible for generalization. To characterize the time course of sensory transformations following learning, mice will be subjected to imaging trials during olfactory fear conditioning and comparisons of the CS and neutral odor-evoked glomerular responses will be made before and at different time points after training. Then a separate cohort of mice will undergo fear conditioning while the BLA is inactivated and both behavioral expressions of fear and training-induced glomerular response alterations will be quantified to assess the impact of BLA activity on behavioral and physiological generalization. Together, these experiments will characterize the biobehavioral adaptations of the OB throughout acquisition and consolidation of associative fear learning. Furthermore, these experiments will provide insights into underlying mechanism of behavioral fear generalization with potential clinical implications in PTSD as well as other sensory processing mechanisms.

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.