Farran Briggs - US grants

DESCRIPTION (provided by applicant): An understanding of neuronal circuitry within the brain has important implications for diseases of circuits such as Alzheimer's and Parkinson's diseases. The visual system is an ideal model in which to study neural circuitry because it is precisely organized and much is known about its cellular and compartmental components. This proposal examines the function and anatomy of an important, yet elusive, pathway within the visual system: the corticogeniculate feedback pathway. Geniculate-projecting neurons in primary visual cortex which constitute the corticogeniculate pathway in the visual system will be studied using a three-tiered experimental approach. The first experiment involves recording from individual geniculate-projecting neurons within primary visual cortex in the conscious animal in order to elucidate their function in vivo. In the second experiment, individual geniculate-projecting neurons are identified by their physiology and labeled such that their sub-laminar location can be determined. The third experiment involves identifying the locations and morphological identities of geniculate-projecting neurons targeting specific regions of the lateral geniculate nucleus.

DESCRIPTION (provided by applicant): The research proposed for this award will examine how spatial attention modulates cortical circuit activity in the early visual system. The proposed studies link the candidate's scientific background and future career objectives by examining intentional modulation of neuronal activity at multiple processing levels. Intentional effects will be observed at the individual cellular level (Aim 1), the local circuit level (Aim 2), and the cortical population level (Aims 1 and 3). By employing this novel approach toward understanding attention within the context of cellular and circuit processing, the candidate will draw upon experience across all phases of her research career. During the mentored phase of the proposed award, the candidate will simultaneously examine 1) how spatial attention modulates synaptic efficacy in cortical neurons receiving afferent thalamic input, and 2) how changes in cortical ensemble activity relate to the arrival of afferent information in attentive and non-attentive states. Through the instruction of two co-sponsors, one an expert in spatial attention task design/implementation/analysis and the other an expert in multi-electrode recording techniques/analysis, and with the vast resources already available at the University of California, Davis, the training received during the mentored phase will be invaluable to the longer-term objectives outlined in the independent phase of the proposal. As an independent investigator, the candidate will continue to address questions of functional dynamics in early visual cortical circuits using spatial attention tasks and multi-electrode recording. These experiments will further explore 1) whether and how the effects of spatial attention differ across neuronal cell types and local circuit levels, and 2) whether and how ongoing cortical network activity influences these intentional effects. All experiments proposed will be undertaken in the early visual system of awake-behaving monkeys, an ideal model for a number of reasons. First, while spatial attention influences early visual system activity, little is known about the mechanisms involved. Second, there is a wealth of knowledge available about the primate visual system. Third, the awake-behaving animal paradigm allows for the assessment of functionality in the fully cognizant state. Fourth, and most importantly, the primate visual system is similar to that of humans and therefore provides an ideal model for human cognition.

Abstract Corticothalamic circuits linking primary sensory cortex with primary sensory thalamus in the feedback direction are ubiquitous across sensory modalities and mammalian species and are ideally positioned to regulate the flow of sensory signals from periphery to cortex. However, the functional role of these circuits in sensory perception remains a fundamental mystery in neuroscience. In the visual system, corticogeniculate neurons provide the majority of inputs onto neurons in the lateral geniculate nucleus (LGN), however receptive fields of LGN neurons closely resemble their retinal inputs and not their corticogeniculate inputs. Partly because corticogeniculate influence over LGN activity appears to be modulatory rather than driving, the functional role of corticogeniculate feedback in vision has been difficult to characterize. The goal of this proposal is to employ optogenetics ? an emerging technology that allows for selective and reversible manipulation of neurons in intact animals ? to examine the structural organization of corticogeniculate circuits and to elucidate their functional contributions toward vision. The three Specific Aims of this proposal address three critical features of corticogeniculate circuits: 1) the structure-function relationships among corticogeniculate circuits; 2) the types of information conveyed by corticogeniculate neurons to LGN neurons; and 3) how corticogeniculate signals impact LGN neuronal activity. A series of nine experiments, three in each Aim, examining corticogeniculate morphology, physiology, functional connectivity, receptive field transformations and impact on LGN activity, will systematically test two alternative hypotheses that corticogeniculate feedback is functionally homogenous versus functionally stream-specific. To accomplish the experiments under each of the three Specific Aims, corticogeniculate neurons in ferrets are selectively infected with virus encoding channelrhodopsin2 and mCherry and optogenetically activated during simultaneous multi-electrode array recordings of LGN and visual cortical neuronal responses to drifting gratings and white noise stimuli. Preliminary results suggest that optogenetic activation of corticogeniculate neurons is sufficient to drive changes in LGN responses to visual stimuli. In revealing the structural and functional organization of corticogeniculate circuits, the information they convey to the LGN and their impact on LGN activity, results of the proposed experiments will reveal whether corticogeniculate circuits serve as global gain modulators that synchronize activity across LGN cell types or selectively prioritize information about specific visual features through stream-specific modulations. Furthermore, insights gained about corticogeniculate circuit function could generalize across corticothalamic pathways throughout the sensory system and inform understanding of sensory circuit disruptions associated with sensory-processing deficits observed in many neurological disorders.

Vision is a process by which the image falling on the eyes is processed by specialized neurons within visual brain areas. Neurons in the early stages of visual processing convey information about small bits of the visual scene, like pixel-detectors in a camera. For example, a neuron in visual cortex might respond best to a small white bar at a particular location in visual space. Should this example neuron respond differently when the white bar is part of an object that we have seen before, or one that we are moving towards? Psychology might suggest so, but for almost 60 years, most scientists studying the neural basis of visual perception have implicitly assumed that responses of neurons in visual cortex depend only on the visual image falling on the eyes. It is increasingly clear that neurons in the visual cortex do indeed care about behavioral context – as well as the state of the brain itself. These external, internal, and contextual factors influence how neurons process the visual scene. Exactly how much these “non-visual” factors influence visual cortical neurons remains a significant open question that this project aims to address.

The experiments will record from neurons in the visual cortex of ferrets as they freely explore a naturalistic environment. Using position and eye-tracking cameras, the project will both recreate a movie of what the ferret saw within the environment, and track other observable variables related to behavior. The movie will then be replayed to the ferret while it is anesthetized, thus directly measuring any differences in neuronal responses to the same visual stimulation in these two very different contexts. Analysis will compare the physiological quality and statistical properties of neuronal responses across naturalistic and anesthetized conditions to quantify the contribution of natural context to neuronal responses. Results will relate the differences in the freely moving context to specific sources, like motor actions such as eye and head movements, familiarity with specific visual features, and their behavioral relevance. Experiments will inform models for how these sources influence neuronal activity, setting the stage for understanding the function of non-retinal inputs for sensory perception. The project will provide a foundation for long-term studies of natural vision.
This project is funded by Integrative Strategies for Understanding Neural and Cognitive Systems (NCS), a multidisciplinary program jointly supported by the Directorates for Biology (BIO), Computer and Information Science and Engineering (CISE), Education and Human Resources (EHR), Engineering (ENG), and Social, Behavioral, and Economic Sciences (SBE).

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Because humans rely heavily on vision to experience the world, diseases of the eye are particularly debilitating in that they have significant adverse effects on patient health and quality of life. Much is known about the mechanisms underlying retinal cell loss in eye diseases like glaucoma. However, significantly less is known about how retinal cell loss impacts visual brain areas downstream of the retina. Visual brain areas immediately downstream of the retina, especially the lateral geniculate nucleus (LGN) of the thalamus and its main cortical target, primary visual cortex (V1), are likely to undergo substantial structural and functional reorganization following the removal of their major source of input from the retina. Accordingly, full restoration of visual perception in patients with eye disease will require ?brain-level? vision restoration in addition to repair of the damaged retina. The goal of this new research program is to fill a glaring knowledge gap by examining the effects of retinal cell loss on the structure and function of neurons in the LGN. We have developed a model of retinal ganglion cell (RGC) loss in the ferret through intravitreal injection of kainic acid (KA). Ferrets have a number of visual specializations homologous to primates, including humans, that make them an excellent model in which to study the downstream effects of RGC loss. Importantly, the early visual pathways in ferrets are organized into parallel processing streams enabling examination of differential effects of RGC loss across functionally distinct neuronal classes in the LGN. As a part of Specific Aim 1, we will characterize the extent, pattern, and possible RGC-type specificity of cell loss in our ferret model and compare patterns of RGC loss in the ferret with those observed in human eye disease for phenotypic similarities. Also in Specific Aim 1, we will characterize the impact of RGC loss on the structure and physiology of LGN neurons. In Specific Aim 2, we will describe the rate of changes in LGN neuronal structure and physiology after different survival times following KA-induced RGC loss. We will employ innovative methods such as high-resolution optical coherence tomography imaging, full-field electroretinogram recording, and retinal histology to quantify RGC loss and to guide multi-electrode array recordings in the LGN to scotoma locations. We will record simultaneously from multiple individual neurons in bilateral LGNs downstream of intact and injected eyes in order to quantify physiological response properties and functional connectivity. Finally, we will utilize brain tissue histological analyses to characterize axonal degeneration and neuronal morphology in the LGN in order to quantify downstream structural changes. Quantified structural and physiological data will be correlated per animal to control for variability due to injection size. Patterns of structural and physiological changes will then be examined across cohorts of animals with different survival times post-injection to assess rates of change. The long-term goal of this project is to establish a mechanistic understanding of the impact of RGC loss on the neurons and circuits downstream of the retina in order to inform potential therapeutic treatments and enact a brain-level approach toward vision restoration.