Surprisingly, under anesthesia or during sleep, individual neurons in primary sensory cortices reliably represent sensory information, even when perception is absent10?13. This suggests that the breakdown of perception is due to an inability of the primary sensory system to effectively integrate its activity with that of other cortical circuits. Consistently, disorders of perception, such as schizophrenia and autism, are associated with distortions in the spatial and temporal integration of sensory-evoked activity4?7,14. Yet, the circuit mechanisms that allow for integration of sensory information with the underlying neural activity remain largely unknown. Spontaneous neural activity can be recorded with electrophysiology and classified into ?brain states? by decomposing the oscillatory patterns15?17. Herein, I deploy a combination of neurophysiology and optogenetics to quantify the salient features of spatiotemporal responses elicited by visual stimuli. Our preliminary experiments in mice implanted with high density electrocorticography (ECoG) show that simple visual stimuli elicit complex, reproducible, and highly coherent traveling gamma waves (TGW) that span nearly an entire hemicortex. I hypothesize that these TGWs, present in the awake and vigilant animal, are associated with specific and tightly controlled pattern of propagation that permit perception to occur. I will determine circuit mechanisms underlying the generation of long-range evoked TGW responses with optogenetics. Here, I will utilize two anesthetic agents, isoflurane and ketamine, and compare visual evoked activity in awake, naturally drowsy, and pharmacologically anesthetized animals. Isoflurane elicits spectral brain states rich in delta activity which mimic slow wave sleep, while ketamine stimulates gamma activity and other features present in schizophrenia18?22.
In Aim 1, I will quantify the brain spectral state dependent effect on visual evoked TGW responses in mouse cortex in vivo using high density surface electrocorticography (ECoG).
In Aim 2, I will quantify the effect of brain state on the laminar spatiotemporal organization of these visual responses, using multiple multichannel depth probes.
In Aim 3, I will use optogenetics to determine whether projections from the visual thalamus are necessary for the generation and maintenance of visual evoked, highly coherent TGW oscillations. Collectively, the results of this work will provide further insights to understanding how sensory processing is affected by the global spectral brain state. Moreover, our findings will inform how sensory evoked activity integrates with ongoing cortical activity to create conditions in which perception is and is not possible. The ensuing insights may also suggest how sensory processing is altered during behavioral states such as inattention or sleep, and may shed light on how perception is altered in diseases such as schizophrenia23. This grant will also provide indispensable support for an aspiring clinician scientist in an outstanding environment at the University of Pennsylvania, Perelman School of Medicine. Her ultimate career goals are to infuse fundamental neuroscience into clinical medicine to better understand healthy and disease states.

Public Health Relevance

Responses to visual inputs create complex spatiotemporal patterns that initially begin in the primary visual cortex, but then extend into association cortices, long outlasting stimulus presentation. These long-range spatiotemporal properties of visual evoked potentials may be important for sensory processing since they are distorted in states with altered perception including normal physiology (sleep)1, pharmacology (anesthesia)2,3, and pathology (schizophrenia and autism)4?9. This proposal to foster the development of an aspiring MD PhD student, will utilize a combination of neurophysiology, neuroanesthesia, and optogenetics to aid in the understanding of the spatiotemporal distribution of sensory driven activity under conditions of wakefulness, drowsiness, and anesthetic-induced states of diminished perception.

National Institute of Health (NIH)
National Eye Institute (NEI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Agarwal, Neeraj
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University of Pennsylvania
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