- Awarded: 2021
- Award Type: Pilot
- Award #: 875447
Autism spectrum disorder (ASD) results from alterations in the development of neural circuits in the brain and leads to a variety of clinical conditions, including insistence on sameness and resistance to change. An emerging hypothesis is that such diverse traits arise fundamentally from defective interpretation of the environment due to unbalanced integration of actual sensory evidence and internally generated prior beliefs on the outside world.
To test this hypothesis, Hiroki Asari and his team at the European Molecular Biology Laboratory (EMBL Rome, Italy) will study an ASD-related imbalance between feedforward and feedback signals in the superior colliculus in the context of visual implicit learning. They will use two distinct ASD mouse models, Scn2a+/- and Chd8+/N2373K, to identify common neurophysiological dysfunctions to better understand the etiology of ASD at the level of neural circuits.
Asari and his colleagues will first characterize ASD-related changes in visual processing in the superior colliculus using in vivo two-photon calcium imaging in an awake head-fixed condition. Next, they will identify differences in cortical feedback signaling in ASD model mice as well as those in retinal signal integration due to defective neuromodulation. For validation, they will recapitulate such atypical phenotypes in control mice using causal experimental tools. Finally, they will rescue ASD-related dysfunctions by dynamically manipulating the neuronal activity in ASD model mice. In addition to neuronal dynamics, they will also monitor behavioral responses, such as pupil size changes as a measure of arousal, to link neuronal to behavioral phenotypes and assess the restoration at the perceptual level.
The outcome of this study will not only provide insights into the neurophysiological mechanisms of ASD to bridge the gap between changes at the genetic and behavioral levels, but also potentially open a new route of therapeutic treatments that will be eventually applicable to individuals with ASD.
- A platform to identify circuit defects in autism mouse models
- Population coding in the sensory cortex in multiple mouse models of autism
- Identifying convergent cortical circuit impairments across multiple mouse models of autism
- Assessing sensory impairments and aberrant cortical circuit activity in Cntnap2 knockout mice