Systems Biology of Autism: Understanding the Circuitry Linking Sounds to Behavior in Autism Spectrum Disorders

Autism spectrum disorder (ASD) is a complex neurological disorder characterized by deficits in communication and social interaction and abnormal patterns of behavior. Recent studies have highlighted another pervasive sign of ASD that often goes unnoticed – unusual reactions to sensory stimuli. Many children with ASD are either over- or under-sensitive to what they feel, see, or hear. For example, children with ASD often exhibit atypical behavioral outbursts triggered by unexpected sounds or touch, excessive smelling or touching of objects, and difficulties processing visual and sound stimuli. These sensory abnormalities may be some of the earliest signals of autism, providing both early markers of the disorder and targets for early therapeutic intervention. However, surprisingly little is known about the brain circuits that underlie these sensory disorders in ASD. Advanced genetic and optical technologies are now providing unprecedented opportunities to selectively manipulate specific neurons and monitor evolving activity patterns across populations of neurons during behavior. Drs. Sabatini, Takesian, and Polley aim to exploit these technologies to unravel the neural circuit pathologies in the autistic brain that underlie sensory deficits, providing a window into the neurobiological bases of ASD. Furthermore, they will explore novel ways of targeting these circuits to identify new therapeutic strategies.

Deficits in sound processing in ASD are particularly alarming, as they may distort the sensory building blocks that provide a basis for language and social communication. The primary auditory cortex (A1) is an essential hub in an elaborate brain-wide network that processes sounds and triggers sound-driven behaviors. A subset of neurons within the deep layers of A1 send far-ranging projections to the basal ganglia, a brain region that controls motor actions and learning. How these neural pathways that link A1 to the basal ganglia may be altered in the autistic brain is unknown. This study is motivated by the hypothesis that the over-amplification of these pathways causes sound hyper-sensitivity, disrupts sound processing and contributes to motor perturbations, including the repetitive behaviors that characterize ASD. These experiments will interrogate the complex circuits that underlie sound-driven behaviors, illuminate deficits within these circuits associated with ASD, and identify novel ways to induce plasticity within these circuits to reverse these deficits.

To reveal dysregulation of the connections between A1 and the basal ganglia the researchers will use advanced optical and electrophysiological methods in an ASD mouse model with deletion of the Shank3 gene, one of the most commonly identified perturbed genes in individuals with ASD. They will rely on sophisticated behavioral tasks and motor sequencing methods to probe behavioral abnormalities associated with dysregulated connections between A1 and basal ganglia. To determine whether hyper-activity within these circuits is linked to perceptual over-sensitivity and perturbations of sound-driven motor actions, the researchers will monitor the activity of A1 projection neurons during behavioral sequencing. Furthermore, they will test the hypothesis that manipulation of A1 to basal ganglia projection neurons can induce long-lasting changes in the activity of these neurons, restoring normal auditory processing and sound-driven behaviors in ASD mouse models. These experiments will determine whether hyper-active projections from A1 to the basal ganglia contribute to ASD pathology.

Drs. Sabatini, Takesian, and Polley will further aim to identify novel therapeutic approaches to adjust the knob on pathologically over-amplified sensory brain circuits. To this end, they will exploit the remarkable degree of plasticity that exists in the adult brain. They have identified neurons within the auditory cortex that serve as “master controllers” of neural plasticity, and will examine the long-range and local natural activators of these neurons. They will determine whether these activators can be harnessed to reinvigorate plasticity in the adult brain to reverse pathophysiological and behavioral markers in mouse ASD models. By elucidating specific targets within sensory brain circuits, the investigators aim to overcome the challenges of treating complex neurological disorders, such as ASD, with therapies that act indiscriminately across brain regions and cell types. Together, they hope that their collaborative study will provide new insight into the sensory circuit mechanisms of ASD and pave the way for transformative therapies to treat this pervasive and debilitating disorder.