The process by which organisms use incoming sensory information to adjust their motor output in meaningful ways is fundamental to a successful interaction with their environment. Correct wiring during early develop- ment of neural circuits mediating this sensorimotor integration is essential for organismal survival. In develop- ing neural circuits both circuit architecture and the signaling properties of individual neurons within the circuit undergo profound changes. However, organisms can begin to interact meaningfully with their environment even before these circuits are fully mature. This suggests that neural circuits underlying sensory processing and behavior can employ different strategies to carry out their function, based on the circuit's developmental state. The process by which this occurs remains obscure. Since several human neurodevelopmental disorders are believed to result from inappropriate neural circuit formation during early development, it is important to understand the basic mechanisms by which these circuits develop. Our proposal focuses on the developing optic tectum of the Xenopus laevis tadpole as a model system to address these issues. The tectum, and its mammalian homologue the superior colliculus, receives direct input from the retina as well as from other sensory modalities. It functions to integrate visual and other sensory in- formation, and transform this into orienting behavior. Tadpoles are known to rapidly swim away from approach- ing objects, and this avoidance behavior requires processing by local circuits within the tectum. It is not known how these local circuits develop, nor how developmental changes in the organization and response properties of this circuit relate to visually guided motor behavior. We propose to use a combination of behavioral analy- ses, in vivo and in vitro electrophysiology and in vivo Ca++ imaging of neuronal populations, to address how the tectum integrates visual information and transforms it into visual avoidance behavior. In the first aim we characterize the types of stimuli which trigger visual avoidance and address specific hypotheses about how these stimuli are encoded in the tectum. In the second aim, we address the mechanisms by which neurons in the tectum encode behaviorally relevant stimuli, by focusing specifically on the role of tectal neuron intrinsic excitability, the properties of retinotectal synapses, and the role of local inhibition. These experiments will elucidate how multiple developmental processes known to occur at the single cell and network levels in the tectum, can work together to optimize its ability to transform visual input into motor behavior. Understanding the basic mechanisms by which neural circuits adjust multiple properties to achieve stable function will provide important insight into the ability of the CNS to compensate for developmental defi- cits, opening several therapeutic avenues for the early treatment of neurodevelopmental and vision disorders.

Public Health Relevance

Many neurological and psychiatric disorders including autism, schizophrenia, epilepsy and amblyopia are not always clearly associated with a well defined neuropathological profile. Rather, they are believed to result from abnormal functioning at the level of microcircuits within different brain regions, and many of these abnormali- ties are thought to arise during development when these circuits are first formed. Understanding the basic mechanisms by which the microcircuitry of the brain becomes established during development, and how and when functional properties of these microcircuits emerge, is therefore a crucial step towards understanding why neural circuits develop abnormally during some neurological disorders, and is important for developing novel therapeutic strategies.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Sensorimotor Integration Study Section (SMI)
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Steinmetz, Michael A
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Brown University
Schools of Medicine
United States
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Pratt, Kara G; Khakhalin, Arseny S (2013) Modeling human neurodevelopmental disorders in the Xenopus tadpole: from mechanisms to therapeutic targets. Dis Model Mech 6:1057-65
Xu, Heng; Khakhalin, Arseny S; Nurmikko, Arto V et al. (2011) Visual experience-dependent maturation of correlated neuronal activity patterns in a developing visual system. J Neurosci 31:8025-36