Divergent projections of the prelimbic cortex mediate autism- and anxiety-like behaviors.

Scientists studied mice with autism and anxiety-like behaviors to understand how these conditions are connected in the brain. They found that overactive brain cells in a region called the prelimbic cortex cause both conditions, but through different pathways. One pathway leads to autism-like behaviors, while another leads to anxiety-like behaviors. When researchers reduced the activity of these brain cells, both conditions improved.

This research helps explain why autism and anxiety often occur together.

This preclinical study using Tmem74 knockout mice investigated the neural circuits underlying autism-anxiety comorbidity. Researchers identified that hyperactive pyramidal neurons in the prelimbic cortex drive both conditions through distinct pathways: the prelimbic-dorsal striatum circuit mediates autism-like behaviors, while the prelimbic-basolateral amygdala circuit mediates anxiety-like behaviors. The study demonstrated that chemogenetic inhibition of these neurons reversed both behavioral phenotypes. Optogenetic manipulation confirmed that selective activation of each circuit produced specific behavioral outcomes.

These findings suggest that autism and anxiety may share common cortical origins but diverge through different downstream neural pathways, potentially explaining their frequent co-occurrence.

While promising for understanding autism-anxiety comorbidity mechanisms, this preclinical research requires extensive validation before clinical application. The identification of distinct neural circuits suggests future targeted interventions might address specific symptom domains separately, potentially improving treatment precision for individuals with both conditions.

This is a preclinical mouse model study using genetic knockout mice, which may not fully represent human autism-anxiety comorbidity. Sample sizes are not reported. The generalizability to human populations and clinical translation remain unclear.

The comorbidity of autism spectrum disorder and anxiety is common, but the underlying circuitry is poorly understood. Here, Tmem74mice showed autism- and anxiety-like behaviors along with increased excitability of pyramidal neurons (PNs) in the prelimbic cortex (PL), which were reversed by Tmem74 re-expression and chemogenetic inhibition in PNs of the PL. To determine the underlying circuitry, we performed conditional deletion of Tmem74 in the PNs of PL of mice, and we found that alterations in the PL projections to fast-spiking interneurons (FSIs) in the dorsal striatum (dSTR) (PL-dSTR) mediated the hyperexcitability of FSIs and autism-like behaviors and that alterations in the PL projections to the PNs of the basolateral amygdaloid nucleus (BLA) (PL-BLA) mediated the hyperexcitability of PNs and anxiety-like behaviors. However, the two populations of PNs in the PL had different spatial locations, optogenetic manipulations revealed that alterations in the activity in the PL-dSTR or PL-BLA circuits led to autism- or anxiety-like behaviors, respectively.

Collectively, these findings highlight that the hyperactivity of the two populations of PNs in the PL mediates autism and anxiety comorbidity through the PL-dSTR and PL-BLA circuits, which may lead to the development of new therapeutics for the autism and anxiety comorbidity.