Circuit Defects Underlying Deficits in Social Touch in Fragile X Syndrome

ABSTRACT Sensory hypersensitivity and the resulting avoidance behaviors represent a major challenge for most individuals with Fragile X syndrome (FXS) and for many autistic people. Differences in sensory processing can also contribute to inattention/distraction, learning disability, repetitive behaviors, and even social avoidance. Indeed,

exaggerated responses to tactile stimuli could also worsen anxiety about social interactions, especially if they involve physical contact (e.g., shaking hands, hugging, kissing) and if the contact is unwanted. For this proposal we will explore this relationship between sensory hypersensitivity and social experience in FXS/autism. Social

touch per se has not been investigated in animal models of autism, including FXS; therefore, it is presently unknown whether they display unique avoidance behaviors or aversive facial expressions to different types of social touch. It is also not known how such maladaptive behaviors to social touch might be represented in neural

dynamics of relevant brain areas. To address these knowledge gaps, we have developed a novel assay for social touch in mice. We previously demonstrated that Fmr1-/- mice, the main model of FXS, show avoidance and defensive behaviors to repetitive whisker stimulation, akin to tactile defensiveness in humans with FXS. In

more recent studies we have shown that Fmr1-/- mice and maternal immune activation (MIA) model mice both show strikingly similar behavioral phenotypes in response to repeated bouts of social touch, including hyperarousal, running avoidance, and sustained eye closure. Here, we will follow a symptom-to-circuit strategy

to better understand social touch deficits in FXS/autism. First, we will characterize behavioral responses to social touch in Fmr1-/- and MIA mice with our novel behavioral assay we have developed. Second, we will `reverse- engineer' such phenotypes by identifying the underlying circuit and neuronal changes using in vivo

electrophysiological recordings with Neuropixels probes. Finally, we will intervene at the level of neuronal activity in the relevant circuits (focusing on somatosensory cortex and amygdala) with pharmacology and chemogenetics, to mitigate deficits in social touch. Our hope is that these preclinical studies will yield significant

insights for the treatment of FXS/autism.