Normal sensory perception and motor control depend on dynamic functional interactions among different regions of the neocortex. Dysfunction in these interactions can lead to devastating neurological and neuropsychiatric disorders. While interactions among cortical areas are thought to be mediated primarily by direct synaptic connections between cortical neurons (i.e. direct corticocortical connections), the thalamus may also play a crucial role in these interactions. The thalamus is an obligatory relay for most sensory information sent to the cortex, and the cortex sends massive feedback projections to thalamus, modulating sensory throughput. Relay cells in higher-order thalamic nuclei receive especially strong corticothalamic synaptic inputs from projection neurons in cortical layer 5, and these same thalamic relay cells also send strong thalamocortical synaptic inputs to secondary/higher order cortex. Thus, in addition to monosynaptic corticocortical connections, distinct cortical areas might also interact disynaptically via higher-order thalamus (the ?transthalamic corticocortical pathway?). Despite previous anatomical demonstrations, the functional role of the transthalamic corticocortical pathway remains poorly understood. The primary goal of my proposal is to investigate how higher-order visual thalamus (the lateral posterior nucleus, LP) mediates functional interactions between primary (V1) and secondary (V2) visual cortex in awake, behaving mice, and how direct corticocortical inputs are integrated with transthalamic corticocortical inputs in V2. These investigations will significantly enhance our understanding of the thalamic contribution to dynamic cortical interactions and expand my training in experimental and analytical techniques as I prepare for an independent investigator position. My research proposal consists of three specific aims: 1) To study how the transthalamic interactions between V1 and V2 depend on arousal, 2) To determine how activity in the transthalamic pathway between V1 and V2 shapes visual responses in V2 neurons, and 3) To investigate how synaptic inputs from direct corticocortical projections and transthalamic corticocortical projections are integrated by V2 neurons, and what types of information these two projections carry during active visually guided behavior. During the K99 phase, under the guidance of Dr. Jessica Cardin and the support of my advisory committee (Drs. Michael Higley and Michael Crair), I will become proficient in several techniques, including in vivo 2-photon calcium imaging of neuronal populations and axon terminals and in vivo optogenetic manipulations. During the R00 phase and beyond, my goal is to combine an array of techniques (from detailed study of synaptic transmission in vitro to large-scale monitoring of neuronal activity in task-engaged animals) to study the dynamic interactions between various cortical and thalamic pathways of the visual system, how these interactions develop, and how these interactions underlie visual behavior in both normal and pathological states.

Public Health Relevance

Coordinated activity among different regions of the neocortex is essential for normal sensory perception, cognition, and motor control. My research will focus on the mechanisms by which the visual thalamus mediates functional communication between visual cortical areas through the transthalamic corticocortical circuit. This project will provide insight into core mechanisms of functional communication between visual cortical areas, interactions that are impaired by both diseases affecting visual perception (e.g. schizophrenia) and brain injuries affecting visually guided behavior (e.g. visuo-spatial neglect following trauma).

National Institute of Health (NIH)
National Eye Institute (NEI)
Career Transition Award (K99)
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Special Emphasis Panel (ZEY1)
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Agarwal, Neeraj
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Yale University
Schools of Medicine
New Haven
United States
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