Wider research context
Severe anxiety symptoms frequently co-occur with autism spectrum disorders (ASD) that might also exacerbate their presentation. Given the clinical impact, a better understanding of the neurobiological underpinnings of anxiety in ASD is required to develop more tailored and effective treatments.
Research questions
One of the most reliable anomalies reported in both ASD and anxiety disorder patients is an aberrant functional connectivity between the salience network (SN) and the default mode network. Hubs of the SN, such as the insular cortex (IC), could thus play a domain-general function that when disrupted produces diverse clinical manifestations, depending on distinct key regulatory micro-anatomical targets, such as neuronal subpopulations or circuit motifs. Our preliminary data indicate that IC vasoactive intestinal polypeptide (VIP)-expressing interneurons play a fundamental role in salience detection and in gating sensory stimuli to adaptively shape behavior. We hypothesize, therefore, that atypical IC function would lead to functional impairments that manifest as anxiety and ASD core symptoms.
Approach
We will test this hypothesis in a selection of ASD mouse models with impaired behavioral constructs in the negative valence domain. In parallel, using an unbiased approach, we will explore behavioral traits and functional connectivity alterations shared by these models. Using a range of tests and tasks probing negative valence (manifest as anxiety symptoms), in the frame of the Research Domain Criteria, we intend to identify behavioral repertoires that distinguish ASD from neurotypical mice. By profiling task-induced global immediate early gene expression and the use of interregional cross-correlation matrices and network analysis, we will identify changes in brain functional connectivity between ASD and neurotypic control mice at cellular resolution. These candidate correlates will be further studied using transcriptome-wide measurements to reveal abnormal molecular responses in neurons of ASD mouse models and to identify ASD-related genes whose transcripts are regulated by negative valence tasks.
The project aims to address the following key open questions:
- Are there common and ASD-specific deficits in Negative Valence constructs?
- Is the cytoarchitectonic and connectivity of the IC altered in mouse models with construct and face validity for ASD and its function impaired during tests of Negative Valence constructs (with a specific focus onto VIP interneurons)?
- Does modelling of ASD in mice result in modifications of the molecular fingerprint of distinct IC neurons indicative of specific neuronal functions?
- Besides proving or disproving our working hypothesis of an atypical insula structure/activity in experimental animal models of ASD, are there alterations in brain circuit organization and function that characterize deficits in Negative Valence constructs in these models?
- Are aberrant neurobiological findings (e.g., anomalous brain connectivity) amenable to specific manipulation/treatment?
This project is funded by the FWF.
