Garrett Neske - US grants

PROJECT SUMMARY During periods of wakefulness, there is substantial variability in the capacity to detect and discriminate among sensory stimuli and form behaviorally relevant motor actions. This variability in perceptual decision making is due in large part to constant fluctuations in the spatiotemporal characteristics of neuronal network activity in the (neo)cortex. These continuous changes in cortical state substantially affect sensory-evoked cortical responses and, ultimately, perceptually guided behavior. Thus, a comprehensive understanding of cortical sensory processing must take cortical state fluctuations into account and explain their underlying mechanistic basis. Furthermore, it is crucial to understand how different brain structures control cortical state in order to understand how these structures might be impaired in neurological and psychiatric diseases associated with dysfunctional sensory processing. There are two significant gaps in our knowledge about the relation between different cortical states and cortical sensory processing: 1.) The nature of the cortical state that enables optimal sensory processing is unclear, and 2.) Details about the roles of neuromodulatory structures in optimal perceptually guided behavior are scarce. The first deficiency in our knowledge is due to the relative coarseness of the quantification of ?state? in the literature ? primarily stillness versus locomotion. The second deficiency is due to the lack of studies monitoring and manipulating the activity of neuromodulatory pathways during perceptual decision making tasks. My proposal will address these issues. I will train freely moving, head-fixed mice on a novel visual stimulus detection task, and determine the optimal cortical state for task performance by using pupillometry to quantify the spectrum of cortical states. Using this task as a paradigm of perceptually guided behavior, I will then study the neural correlates of optimal task performance in primary visual cortex, assess the state-dependent neuronal activity in locus coeruleus (the source of noradrenergic projections to cortex), and dissect the causal role of locus coeruleus activity in mediating optimal task performance. Overall, my research will shed new light on the mechanisms of state-dependent cortical sensory processing, and perhaps provide novel insight into how optimal sensory processing is impaired in certain neurological and psychiatric disorders.

PROJECT SUMMARY 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.