Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism.
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2016-05-10
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Abstract
Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4-22 (Δe4-22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4-22(-/-) mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs.
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Wang, Xiaoming, Alexandra L Bey, Brittany M Katz, Alexandra Badea, Namsoo Kim, Lisa K David, Lara J Duffney, Sunil Kumar, et al. (2016). Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism. Nat Commun, 7. p. 11459. 10.1038/ncomms11459 Retrieved from https://hdl.handle.net/10161/13004.
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Scholars@Duke
Alexandra L Bey
Dr. Alexandra Bey holds both an M.D. and a PhD in Neurobiology. She serves as a Child Psychiatrist in the Duke Autism Clinic and is a valued member of the Duke University School of Medicine's Department of Psychiatry and Behavioral Sciences. Within the Division of Child and Family Mental Health and Community Psychiatry, Dr. Bey’s research and clinical career is dedicated to improving the lives of those with neurodevelopmental disorders. Her overarching research goal is to develop objective, relevant biomarkers to allow for more effective development and testing of novel therapies and to conduct translational research across preclinical models and in individuals with neurodevelopmental differences.
Alexandra Badea
I have a joint appointment in Radiology and Neurology and my research focuses on neurological conditions like Alzheimer’s disease. I work on imaging and analysis to provide a comprehensive characterization of the brain. MRI is particularly suitable for brain imaging, and diffusion tensor imaging is an important tool for studying brain microstructure, and the connectivity amongst gray matter regions.
I am interested in image segmentation, morphometry and shape analysis, as well as in integrating information from MRI with genetics, and behavior. Our approaches target: 1) phenotyping the neuroanatomy using imaging; 2) uncovering the link between structural and functional changes, the genetic bases, and environmental factors. I am interested in generating methods and tools for comprehensive phenotyping.
We use high-performance cluster computing to accelerate our image analysis. We use compressed sensing image reconstruction, and process large image arrays using deformable registration, perform segmentation based on multiple image contrasts including diffusion tensor imaging, as well as voxel, and graph analysis for connectomics.
At BIAC my efforts focus on developing multivariate biomarkers and identifying vulnerable networks based on genetic risk for Alzheimer's disease.
My enthusiasm comes from the possibility to extend from single to integrative multivariate and network based analyses to obtain a comprehensive picture of normal development and aging, stages of disease, and the effects of treatments. I am working on multivariate image analysis and predictive modeling approaches to help better understand early biomarkers for human disease indirectly through mouse models, as well as directly in human studies.
I am dedicated to supporting an increase in female presence in STEM fields, and love working with students. The Bass Connections teams involve undergraduate students in research, providing them the opportunity to do independent research studies and get involved with the community. These students have for example takes classes such as:
BME 394: Projects in Biomedical Engineering (GE)
BME 493: Projects in Biomedical Engineering (GE)
ECE 899: Special Readings in Electrical Engineering
NEUROSCI 493: Research Independent Study 1
Stephen D Mague
Fan Wang
My lab studies neural circuit basis of sensory perception.
Specifically we are interested in determining neural circuits underlying (1) active touch sensation including tactile processing stream and motor control of touch sensors on the face; (2) pain sensation including both sensory-discriminative and affective aspects of pain; and (3) general anesthesia including the active pain-suppression process. We use a combination of genetic, viral, electrophysiology, and in vivo imaging (in free-moving animals) techniques to study these questions.
William Christopher Wetsel
RESEARCH INTERESTS
Last Updated: 27 October 2020
My laboratory uses genetically-modified mice to study the roles that certain genes and gene products play in the presentation of abnormal neuroendocrine, neurological, and psychiatric responses. Traditionally, the identification of neuroendocrine dysfunction has involved biochemical analyses of hormonal responses, those for neurological disorders have relied upon behavioral and postmortem analyses, and those for psychiatric conditions have depended upon phenomenology. The use of genetic technologies has allowed specific genes in selected cells and in neural pathways to be related to certain molecular, biochemical, cellular, physiological, and behavioral dysfunctions. As the Director of the Mouse Behavioral and Neuroendocrine Analysis Core Facility at Duke University (http://sites.duke.edu/mousebehavioralcore/), we have phenotyped many different lines of inbred and mutant mice for my own work as well as for investigators at Duke and at other research institutions. As a consequence, we have helped to develop many different mouse genetic models of neuroendocrine and neuropsychiatric illness. We are working also with academic medicinal chemists and/or certain pharmacological/biotechnological companies to identify novel compounds that will ameliorate abnormal responses in various mutant mouse models. Some of these preclinical studies have formed a basis for clinical trials in humans.
Kafui Dzirasa
Henry Yin
I am interested in understanding the neural mechanisms underlying goal-directed actions. For the first time in history, advances in psychology and neurobiology have made it feasible to pursue the detailed neural mechanisms underlying goal-directed and voluntary actions--how they are driven by the needs and desires of the organism and controlled by cognitive processes that provide a rich representation of the self and the world. My approach to this problem is highly integrative, combining behavioral analysis with electrophysiological techniques as well as tools from molecular biology. In the near future three techniques will be emphasized. 1) Dissecting reward-guided behavior using analytical behavioral assays. 2) In vivo recording from cerebral cortex, thalamus, midbrain, and basal ganglia in awake behaving rodents. Up to hundreds of neurons can be recorded from multiple brain areas that form a functional neural network in a single animal. 3) In vitro (and ex vivo) whole-cell patch-clamp recording in brain slices, with the aid of genetic tools for visualization of distinct neuronal populations. Ultimately, I hope to characterize goal-directed actions at multiple levels of analysis--from molecules to neural networks. This knowledge will provide us with insight into various pathological conditions characterized by impaired goal-directed behaviors, such as drug addiction, obsessive-compulsive disorder, Parkinson's disease, and Huntington's disease.
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