Neurobiology of anxiety in autism spectrum disorders

Patients with autism spectrum disorders (ASD) often suffer of severe anxiety symptoms. Because of the significant negative psychological and physical effects that anxiety symptoms have on individuals with ASD, a better understanding of the causative mechanisms of anxiety in ASD is pivotal in developing tailored and more effective therapeutic interventions for these patients. Considerable research efforts have examined the neural correlates of anxiety, whereas only few studies have investigated these correlates in ASD. The current view is that some aspects of anxiety in ASD possess distinct clinical and neurobiological features . One of the most reliable anomalies reported in both ASD and anxiety disorder patients is an aberrant activity in a number of discrete brain structures measured using functional brain imaging technologies. Among the most prominently affected brain areas is the insular cortex, which is known to orchestrate large-scale brain network dynamics. However, the neural underpinnings of altered brain regional activation and functional connectivity in anxiety and ASD remain unknown and in particular the underlying cellular and molecular mechanisms. We hypothesize that an atypical function of specific classes of GABAergic interneurons, primarily in the insular cortex, leads to functional impairments that manifest as anxiety and ASD core symptoms. Of particular interest are the vasoactive intestinal polypeptide (VIP) -expressing interneurons, as their perturbation during early postnatal development causes profound dysregulation of cortical neural activity and sensory processing. Moreover, our preliminary data indicate that VIP-expressing interneurons play a fundamental role in gating salient stimuli to adaptively shape behavior. We will test our hypotheses employing genetically-altered preclinical models built upon high- risk autism genes, i.e. genes in which ASD-causing mutations have been reported in patients. Importantly, these models are characterized by anxiety-like behaviors and/or impairments in the negative valence domain. This FG project, to our knowledge, is the first research venture addressing causality for anxiety in ASD. This is possible because of the unique experience and highly complementary know-how of the participating laboratories. Taking advantage of a multidisciplinary approach and a range of cutting-edge methodologies, this project will elucidate some of the neurobiological correlates and molecular mechanisms of autism- associated anxiety.