Integrating sensory information is critical for detection of salient stimuli and direction of appropriate responses, a necessary survival behavior. Disruptions in specific aspects of sensory processing and integration are hallmark features of several neurodevelopmental disorders, underscoring the importance of precise sensory circuit formation. Despite this, the mechanisms by which such synaptic specificity is established in integrative centers remains poorly understood, precluding the development of effective therapies. To fill this gap in knowledge, we will investigate the mechanisms by which sensory circuits are established in the superior colliculus (SC), a critical center where multiple modalitis of sensory information are integrated. Specifically, we will focus on the developmental mechanisms of precise visual connections in the SC, which integrates input from retinal ganglion cells (RGCs) and Layer 5 (L5) neurons of the primary visual cortex (V1) during normal development and how these process are disrupted in neurodevelopmental disorders. First, we will use a combination of in vivo electrophysiology, cutting-edge neuronal tracing, and molecular analysis in a unique knock-in mouse model to determine the mechanisms by which distinct subtypes of L5 V1 neurons integrate into the appropriate subcircuit. Second, we will use a combination of in vivo electrophysiology and axon tracing paradigms in conditional knockout mouse models to dissect the mechanisms by which alignment of visual spatial maps is achieved. Finally, we will use a combination of in vivo electrophysiology, axon tracing and molecular analysis in a mouse model of FXS to determine the specific neural sensory processing deficits and which processes are disrupted to give rise to these deficits. Taken together, the proposed experiments will elucidate novel mechanisms by which precise connectivity and function are established in visual centers in development and neurodevelopmental disorders. Our results will provide critical insights necessary for the design of effective therapeutic strategies to treat these disorders.

Public Health Relevance

Deficits in sensory processing and integration are prevalent in neurodevelopmental disorders, such as autism, schizophrenia, and fragile X syndrome. However, the etiology and neural correlates of sensory deficits in these disorders are poorly defined. In this proposal, we will investigate the mechanisms by which precise sensory connections are established during development, and how these processes are disrupted in neurodevelopmental disorders. Using a combination of molecular, anatomical and electrophysiological techniques in powerful genetic mouse models, we will elucidate novel mechanisms of circuit formation and provide critical insight into sensory circuit dysfunction in fragile X syndrome.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY025627-02S1
Application #
9476394
Study Section
Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section (SPC)
Program Officer
Greenwell, Thomas
Project Start
2015-09-30
Project End
2020-08-31
Budget Start
2017-07-01
Budget End
2017-08-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
Tikidji-Hamburyan, Ruben A; El-Ghazawi, Tarek A; Triplett, Jason W (2016) Novel Models of Visual Topographic Map Alignment in the Superior Colliculus. PLoS Comput Biol 12:e1005315