The development of neural circuits in sensory systems is programmed in part by genetics but refined by experience, as the activity of neurons sculpts connectivity within circuits. The term critical period has been popularized to describe specific stages in development when, for reasons only partially understood, an individual's experience plays a more pronounced role in shaping brain development. Neurodevelopmental disorders such as autism spectrum disorders occur due to abnormalities in brain development that may result directly from defects in the mechanisms underlying critical periods. The Chen lab utilizes the mouse visual system as a model to investigate the mechanisms underlying neural circuit development. The primary focus of the lab is the development of the retinogeniculate synapse, the connection between retinal ganglion cells in the retina and relay neurons in the visual thalamus (dLGN). This synapse is highly accessible, and undergoes developmental refinement over a prolonged period of time, enabling the study of distinct stages of remodeling. Recent work defined a visual-experience-dependent stage of development at this synapse that overlaps temporally with critical periods in visual cortex. This observation brings into question the traditional model of feed-forward development of sensory systems, wherein subcortical structures develop prior to and independently from cortical structures. Relay neurons in the dLGN receive numerous feedback projections from the deepest layer of visual cortex, which are important for visual processing in the mature animal. These corticothalamic projections finish innervating the dLGN just prior to onset of experience-dependent remodeling of the retinogeniculate synapse. The goals of this project are to characterize in detail the functional development of corticothalamic projections using electrophysiological techniques, assess the importance of vision in guiding this development, and test the hypothesis that feedback from cortex plays a role in guiding feed-forward development of retinothalamic circuits. In vitro electrophysiology recordings optimized with optogenetic techniques will allow for detailed study of both corticothalamic development and retinogeniculate development, while viral delivery of molecular tools for manipulating neural activity will allow for alteration of cortical feedback in vivo during development. The long-term objective of this work is to advance understanding of neural circuit development, and provide insight into a possible common physiological etiology for many neurodevelopmental disorders. An interaction between cortex and thalamus during sensory system development could offer insight into a mechanism by which many different genetic defects could cause local dysfunction during development that would then propagate to afflict circuits more broadly and result in a common behavioral phenotype.

Public Health Relevance

Autism spectrum disorders are an increasingly prevalent set of neurodevelopmental disorders with a common behavioral phenotype and no effective treatments available. Recent lines of evidence suggest that such disorders may result from inappropriate remodeling of neural circuits in response to experience during critical periods of brain development. This project will explore the basic mechanisms of neural circuit formation in the visual system to evaluate a hypothesis regarding developmental interactions of cortex and thalamus, the conclusions from which will offer further insight into the etiology of neurodevelopmental disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS083437-01
Application #
8520876
Study Section
Special Emphasis Panel (ZRG1-F03A-N (20))
Program Officer
Morris, Jill A
Project Start
2013-04-01
Project End
2016-10-01
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$33,894
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115