Hierarchical feedforward models have provided a foundation for most theories of visual processing over the past 40 years. However, in the cerebral cortex there is a dense network of feedback (FB) connections sending topdown information from higher to lower processing centers. The anatomy and function of FB circuits is still poorly understood. This is despite the fact that FB has been implicated in many important visual functions such as contextual modulation, attention and learning. The goal of this application is to understand the anatomical and functional organization of FB connections from the secondary (V2) to the primary visual cortex (V1), and the impact of V2 FB on V1 cell responses. We will test the following hypotheses: 1. Anatomically, V2 FB consists of parallel channels, related to the stripe compartments of V2, with each channel targeting specific V1 layers, V1 compartments and the same V1 cells that provide input to the specific V2 stripe (Aim 1). The different channels also show unique specificities with respect to the functional maps of visual stimulus properties in V1 (Aim 2). 2. Functionally, V2 FB contributes to surround modulation (SM) caused by visual stimulation of the surround regions near the V1 cell's receptive field (RF) (Aim 3). SM is the ability of stimuli in the RF surround to modulate the responses of V1 cells to stimuli inside the RF, a property thought to serve efficient coding of natural images and segmentation of object boundaries (Nurminen & Angelucci, 2014) Ref43. Our understanding of FB anatomy and function has been hampered by the technical limitations of previous methods used to label FB axons and manipulate their activity. Conventional tracers are either poorly sensitive or label axons bidirectional, creating a confound in the interpretation of the axon label. As a result, there are conflicting reports regarding the anatomical and functional specificity of FB connections. Inactivation of FB systems has been performed using methods that lack spatiotemporal precision and cell type selectivity, affecting cells in an entire cortical area. These approaches could not rule out that the effects of FB manipulation were mediated by other indirect pathways. To overcome these limitations, we will investigate the anatomical and functional organization of FB connections from V2 to V1, using novel viral-mediated expression of fluorescent proteins to label FB axons and their synaptic terminals unambiguously.
In Aim 1 these labeling methods will be combined with staining of V1 layers and compartment (CO maps), and in Aim 2 with optical imaging of V1 functional maps.
In Aim 3, manipulation of FB neuron activity will be performed using optogenetic activation of opsin-expressing FB axons, while determining the effects of these manipulations on spontaneous and visually-evoked spike activity in V1 cells, recorded using linear arrays. These data will provide an anatomical and mechanistic foundation for modeling and hypothesis-driven studies of FB function and dysfunction, and lead to a better understanding of the computations performed by this canonical cortical circuit, i.e. top down FB.

Public Health Relevance

Normal brain function depends on the orderly development of circuits in the cerebral cortex and on their intact function. Knowledge of the normal circuitry provides a foundation for understanding the causes of impaired brain function and developing corrective measures. Our studies of the normal circuitry between early visual cortical areas will provide greater insight into the causes and effects of central vision defects when these circuits are damaged by stroke or other neurological or developmental cause. In particular, our studies of feedback circuits between different visual cortical areas will help our understanding of how these pathways mediate the influence of stimulus context on neuronal responsivity, spatial integration, and changes in visual sensitivity associated with top-down attention and learning. The optogenetic studies proposed in this application represent the first attempts to understand the mechanisms of function of feedback circuits in the non-human primate brain. Understanding how these circuits operate in normal vision will provide a foundation for understanding the consequences of their dysfunction in disorders of brain function such as autism, schizophrenia, and attention deficits disorders, which have been directly linked to abnormalities in inter-areal connectivity Refs. 86, 87.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY026812-03
Application #
9438537
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Flanders, Martha C
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Utah
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Nurminen, Lauri; Merlin, Sam; Bijanzadeh, Maryam et al. (2018) Top-down feedback controls spatial summation and response amplitude in primate visual cortex. Nat Commun 9:2281
Bijanzadeh, Maryam; Nurminen, Lauri; Merlin, Sam et al. (2018) Distinct Laminar Processing of Local and Global Context in Primate Primary Visual Cortex. Neuron 100:259-274.e4
Usher, Will; Klacansky, Pavol; Federer, Frederick et al. (2018) A Virtual Reality Visualization Tool for Neuron Tracing. IEEE Trans Vis Comput Graph 24:994-1003
Yarch, Jeff; Federer, Frederick; Angelucci, Alessandra (2017) Local Circuits of V1 Layer 4B Neurons Projecting to V2 Thick Stripes Define Distinct Cell Classes and Avoid Cytochrome Oxidase Blobs. J Neurosci 37:422-436
Angelucci, Alessandra; Bijanzadeh, Maryam; Nurminen, Lauri et al. (2017) Circuits and Mechanisms for Surround Modulation in Visual Cortex. Annu Rev Neurosci 40:425-451
Petruzza, Steve; Venkat, Aniketh; Gyulassy, Attila et al. (2017) ISAVS: Interactive Scalable Analysis and Visualization System. SIGGRAPH Asia 2017 Symp Vis (2017) 2017:
Boutte, Ronald W; Merlin, Sam; Yona, Guy et al. (2017) Utah optrode array customization using stereotactic brain atlases and 3-D CAD modeling for optogenetic neocortical interrogation in small rodents and nonhuman primates. Neurophotonics 4:041502
Venkat, A; Christensen, C; Gyulassy, A et al. (2016) A Scalable Cyberinfrastructure for Interactive Visualization of Terascale Microscopy Data. N Y Sci Data Summit NYSDS 2016: