Project Summary: Autism spectrum disorders (ASDs) are prevalent developmental disorders, defined by
impairments in social interactions and communication as well as restricted, repetitive behaviors. The majority of
individuals with ASD exhibit a range of co-morbid symptoms, including gastrointestinal (GI) dysfunction. Up to
91% of people with ASD have chronic GI problems, and GI issues are emphasized as major concerns by patients
and clinicians. GI dysfunction is thought to contribute to core ASD symptoms, as patients with chronic GI pain
exhibit increased social withdrawal, irritability, and stereotyped behaviors. Despite the prevalence and impact of
GI issues in ASD, little is known regarding the extrinsic neural circuits that modulate GI function, the etiology of
GI abnormalities in ASD, and whether GI deficits are mechanistically linked to core ASD symptoms.
Sensory information from the gut is conveyed to the central nervous system (CNS) by two extrinsic
pathways of vagal and spinal sensory afferents whose cell bodies are within the nodose and dorsal root ganglia
(DRG), respectively. GI-innervating DRG neurons are critical for normal GI function, yet little is known about the
development and function of these neurons. Further, we have little understanding of how GI signals are encoded,
processed, and represented in the spinal cord.
In our prior studies, we found that DRG neurons are key sites at which ASD-associated gene mutations
have a critical impact. We showed how aberrant function of DRG neurons that innervate the skin cause over-
reactivity to light touch, and can link multiple ASD phenotypes, including social deficits and anxiety-like
behaviors. We hypothesize that similar over-reactivity to ‘viscerosensory’ signals from the GI system contributes
to ASD symptoms. We further hypothesize that these DRG neurons that connect the GI tract and CNS are critical
sites of dysfunction in ASD. While significant progress has been made to understand brain-specific mechanisms
and circuits underlying ASD pathology, there is a substantial need to understand the contributions of peripheral
neuron and spinal cord circuit disruptions to ASD phenotypes.
This proposal aims to investigate the development and function of GI-innervating DRG neurons and
determine the mechanisms through which a key sensory modality, viscerosensation of the GI tract, may be
altered in mouse models for ASD. Our first goal is to characterize the development and function of colon-
innervating DRG neurons, and determine whether ASD-associated gene mutations cause anatomical and
functional disruptions to colon-innervating DRG neurons. Our second goal is to investigate whether DRG neuron
dysfunction triggers abnormal GI function, aberrant encoding of GI signals in the spinal cord, and increased GI
pain in mouse models for ASD. Lastly, we will test whether test whether a combination of environmental factors
(gut dysbiosis) and genetic factors (ASD-associated gene mutations) results in GI-innervating DRG neuron
dysfunction and GI pain, and ultimately, contributes to anxiety-like behaviors and social impairments in ASD.
