Project: Abstract The proposal is truly translational, as it draws from clinical observation and moves towards rigorous quantification of biomarkers of cognitive impairment in both mouse models and patients. Such a study will serve as a model for studies of other neurodevelopmental disorders in our comprehensive Center. These biomarkers can then, in future studies, be directly related to gene expression. First, we will identify a mechanism-based electrophysiological biomarker of cognitive dysfunction and potential responsiveness to treatment in a genetically well-defined syndrome highly associated with ID. Standardized measures of cognition are limited in their ability to quantify subtle individual differences or to capture clinical heterogeneity that may inform prognosis and intervention. Our group has considerable expertise in the integration of EEG biomarkers with behavior to better characterize children with neurodevelopmental disorders. Second, we will perform parallel studies in mouse models, in order to validate and better understand the genetic basis of biomarker identified in humans and to begin to test treatments that may alter both the cell activation patterns and behavior in these mouse models. Specifically we will test how abnormal oscillations disrupt information flow in awake behaving animals, allowing us to directly link electrophysiological changes to cognition. Innovative methods to study electrophysiological markers in both mouse models and patients. The human EEG experiments in the Jeste Lab will make use of new analysis techniques to measure signal complexity and to quantify resting state spectral power from challenging populations. The mouse experiments will make use of custom-made high density electrophysiological recordings from hundreds of neurons with silicon probes targeted to multiple cortical regions. New attention-based multimodal set shifting task designed in the Golshani lab to record the activity of large neuronal populations during flexible decision making and attentional set shifting, a cognitive domain that is affected in the disorder. Finally, we will use a new generation of miniaturized microscopes to record the activity patterns of large populations of hippocampal neurons over days during learning, allowing us for the first time to follow population dynamics in the same group of neurons during learning and extinction. Importantly, these studies are rooted in gaining a new understanding of ID at a systems level with a desire to find convergence in mechanisms and evidence-based treatments for individuals with this heterogeneous group of disorder.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD087101-05
Application #
9836708
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2019-11-01
Budget End
2020-05-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Dickinson, Abigail; DiStefano, Charlotte; Lin, Yin-Ying et al. (2018) Interhemispheric alpha-band hypoconnectivity in children with autism spectrum disorder. Behav Brain Res 348:227-234
Nachun, Daniel; Gao, Fuying; Isaacs, Charles et al. (2018) Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich's ataxia patients. Hum Mol Genet 27:2965-2977
Meyer, Jochen F; Golshani, Peyman; Smirnakis, Stelios M (2018) The Effect of Single Pyramidal Neuron Firing Within Layer 2/3 and Layer 4 in Mouse V1. Front Neural Circuits 12:29
Dickinson, Abigail; DiStefano, Charlotte; Senturk, Damla et al. (2018) Peak alpha frequency is a neural marker of cognitive function across the autism spectrum. Eur J Neurosci 47:643-651
Rao, Jia-Sheng; Zhao, Can; Zhang, Aifeng et al. (2018) NT3-chitosan enables de novo regeneration and functional recovery in monkeys after spinal cord injury. Proc Natl Acad Sci U S A 115:E5595-E5604
Douglas, P K; Gutman, Boris; Anderson, Ariana et al. (2018) Hemispheric brain asymmetry differences in youths with attention-deficit/hyperactivity disorder. Neuroimage Clin 18:744-752
Lee, Frank Y; Wang, Huei-Bin; Hitchcock, Olivia N et al. (2018) Sleep/Wake Disruption in a Mouse Model of BLOC-1 Deficiency. Front Neurosci 12:759
Somerville, Leah H; Bookheimer, Susan Y; Buckner, Randy L et al. (2018) The Lifespan Human Connectome Project in Development: A large-scale study of brain connectivity development in 5-21 year olds. Neuroimage 183:456-468
Green, Shulamite A; Hernandez, Leanna M; Bowman, Hilary C et al. (2018) Sensory over-responsivity and social cognition in ASD: Effects of aversive sensory stimuli and attentional modulation on neural responses to social cues. Dev Cogn Neurosci 29:127-139
Clark, Duncan B; Fisher, Celia B; Bookheimer, Susan et al. (2018) Biomedical ethics and clinical oversight in multisite observational neuroimaging studies with children and adolescents: The ABCD experience. Dev Cogn Neurosci 32:143-154

Showing the most recent 10 out of 40 publications