The cerebellum is important for the control of movement, sensory processing, and regulation of cognitive and emotional function. In adulthood, damage to this region in adulthood leads to debilitating problems with everyday life;in infancy, cerebellar damage dramatically increases the risk of autism, a neurodevelopmental disorder. The long-term goal of this laboratory is to understand how early damage to the cerebellum can lead to symptoms of autism. In particular, the proposed experiments will use new technologies to study the function of individual cerebellar neurons that are involved in learning to anticipate predictable events in both awake mice, both normal and in mice with genetic defects that cause autism in humans. The overall objective of this application is to understand the function of the cerebellum in awake, behaving animals and then to use that information to understand how this circuit malfunctions in mouse models of autism spectrum disorder. This contribution is significant because it will produce detailed and integrated knowledge of the function of an important neural circuit under realistic conditions and apply that knowledge to a common neurodevelopmental disorder. This approach is innovative because this laboratory has developed tools that allow the study of cells that previously could not be examined in awake animals. The work proposed in this application will therefore advance knowledge of how the genetic mutations that cause autism influence the function of neural circuits. In the long run, this information could lead to new approaches to diagnosis, treatment, and prevention of autism spectrum disorder.
The proposed research is relevant to public health because our ability to diagnose and treat neuropsychiatric disorders, including autism, is currently limite by a lack of information about the function of brain circuits that control learning and sensory processing under realistic conditions. Because of the evolutionary conservation of brain structure and function, the study of model organisms such as the mouse should yield fundamental concepts that contribute to understanding the human brain. This work is therefore relevant to the NINDS mission to use fundamental knowledge about the brain to reduce the burden of disease.
|Najafi, Farzaneh; Giovannucci, Andrea; Wang, Samuel S-H et al. (2014) Sensory-driven enhancement of calcium signals in individual Purkinje cell dendrites of awake mice. Cell Rep 6:792-8|
|Piochon, Claire; Kloth, Alexander D; Grasselli, Giorgio et al. (2014) Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism. Nat Commun 5:5586|
|Shi, Diana D; Trigo, Federico F; Semmelhack, Martin F et al. (2014) Synthesis and biological evaluation of bis-CNB-GABA, a photoactivatable neurotransmitter with low receptor interference and chemical two-photon uncaging properties. J Am Chem Soc 136:1976-81|
|Najafi, Farzaneh; Giovannucci, Andrea; Wang, Samuel S-H et al. (2014) Coding of stimulus strength via analog calcium signals in Purkinje cell dendrites of awake mice. Elife 3:e03663|
|Wang, Samuel S-H; Kloth, Alexander D; Badura, Aleksandra (2014) The cerebellum, sensitive periods, and autism. Neuron 83:518-32|
|Sun, Xiaonan R; Badura, Aleksandra; Pacheco, Diego A et al. (2013) Fast GCaMPs for improved tracking of neuronal activity. Nat Commun 4:2170|
|Schneider, Eve R; Civillico, Eugene F; Wang, Samuel S-H (2013) Calcium-based dendritic excitability and its regulation in the deep cerebellar nuclei. J Neurophysiol 109:2282-92|
|Kuhn, Bernd; Hoogland, Tycho M; Wang, Samuel S-H (2011) Cerebellar craniotomy for in vivo calcium imaging of astrocytes. Cold Spring Harb Protoc 2011:1224-7|
|Hoogland, Tycho M; Kuhn, Bernd; Wang, Samuel S-H (2011) Preferential loading of bergmann glia with synthetic acetoxymethyl calcium dyes. Cold Spring Harb Protoc 2011:1228-31|
|Kuhn, Bernd; Hoogland, Tycho M; Wang, Samuel S-H (2011) Injection of recombinant adenovirus for delivery of genetically encoded calcium indicators into astrocytes of the cerebellar cortex. Cold Spring Harb Protoc 2011:1217-23|
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