Our lab produced Activity-Regulated Cytoskeleton-Associated (ARC) knockout mice to be used in a collaborative project studying how the loss of the ARC protein may alter the effects of sensory experience or deprivation in the visual cortex (V1), McCurry et al (Nature Neuroscience 2010). The data indicate that the loss of ARC protein leads to an absence of ocular dominance plasticity in response to brief and extended monocular deprivation as well as open-eye potentiation, suggesting that ARC is necessary for deprived-eye depression that normally takes place after monocular deprivation, as seen in the normal mice. The observed deficits occurred in the absence of major changes in visual response properties, since ARC -/- mice exhibited normal visual acuity and retinotopic organization. ARC may play a role in the refinement of response properties such as the reduction or removal of weaker inputs and the potentiation of stronger inputs giving rise to sharpened receptive field properties. This study discovered that when the visual cortex is missing the ARC gene, sensory experience or deprivation cannot alter visual cortical functions. Our lab continues to investigate the mechanisms by which experience-induced molecular changes impact on cortical processing of information, with a particular focus on prefrontal cortical circuits. Normal executive function in goal-directed behavior depends on the prefrontal cortex, and functional brain imaging studies have revealed altered prefrontal activity in response to cognitive challenges in schizophrenia patients. However, the mechanisms by which specific genetic risk factors and behavioral experiences may influence the functional cellular architecture and the developmental trajectory of prefrontal cortical circuits remain largely unknown. We have developed techniques to identify specific neurons with experience-dependent gene expression changes in prefrontal circuits, and combined those techniques with electrophysiological and calcium imaging methods to determine the functional contributions of those neurons to prefrontal circuit outputs. In addition, we have developed chronicle in vivo imaging techniques to track experience-dependent molecular changes in live animals while the animals learn new tasks, which may help to elucidate the processes by which neuronal ensembles in the prefrontal cortes adapt to different environments and situations. Our group continues to investigate the coupling mechanisms between neuronal activity and plasticity-related gene expression in cortical circuits, using both molecular genetic and optical imaging tools. Particularly, we are examining whether the induction of activity-dependent gene expression is modified under the direct influence of specific neuromodulators that are associated with the motivational or emotional relevance of a given behavioral experience. Finally, we continue to apply in vivo imaging and optogenetic techniques to study the functional plasticity of prefrontal circuits in normal adolescent and adult animals, and prefrontal dysfunctions in the mouse models of psychiatric disorders as developed by the other research groups in the Genes, Cognition and Psychosis Program. Those studies may help to monitor the development of abnormal cortical circuits in real time, and elucidate the interactions of genetic risk factors with environmental and social stressors.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2011
Total Cost
$1,042,576
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
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Zip Code
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