Neuromodulatory control of cerebellar non-motor functions in mouse models of autism

  • Awarded: 2021
  • Award Type: Bridge to Independence
  • Award #: 550991

Autism spectrum disorder (ASD) can arise from a multitude of genetic and environmental factors and span a wide range of features, including difficulties in social interactions, restricted interests, repetitive behaviors, cognitive and motor challenges. These complex traits are thought to reflect differences in the way people with autism respond to sensory signals.

In the nervous system, alterations in sensory processing can originate at multiple stages, ranging from detecting, transforming and integrating to interpreting sensory information. Individuals with ASD often show differences in the activity of brain areas that integrate multisensory information in order to control diverse motor and cognitive-affective functions. One such structure is the cerebellum. To identify and selectively manipulate the brain circuits that allow the cerebellum to regulate such diverse functions, animal models of the condition are required.

Several findings have challenged the tenet that the cerebellum consists of repetitive stereotypically organized microcircuits. Rather, the cerebellum displays remarkable region-specific heterogeneity in cellular composition, local connectivity and neuromodulatory input. However, it remains unclear how this heterogeneity translates into regional differences in sensory integration, cerebellar output to other brain areas and sensitivity to context-specific neuromodulators on cerebellar function.

The cerebellum receives surprisingly rich neuromodulatory input involved in arousal, autonomic functions, metabolic state and social behaviors. Many of these functions are affected in individuals with ASD, especially those with cerebellar changes.

The overall goal of Stephanie Rudolph’s lab is to use a combination of mouse genetics, electrophysiology, viral tracing and behavioral testing to investigate the role of neuromodulators on cerebellar function and behavior. The focus of their research is on the role of two highly conserved neuromodulators: vasopressin and oxytocin. These neuromodulators regulate inhibitory tone and sensory processing in the cerebellum. They also coordinate behaviors such as aggression, social interaction and fine motor coordination, which are often atypical in neurodevelopmental conditions.

In the current project, Rudolph’s team aims to manipulate neuromodulatory input in genetic mouse models of ASD that have known deficits in cerebellar function (including Ube3, Fmr1 and Shank2 mutants) with the goal of rescuing behavioral changes. Such findings will help to identity potential new therapeutic avenues to regulate social and emotional behaviors and improve cognitive function in ASD.

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